Conditions: C-Section Pain Management
Keywords: bupivacaine exparel analgesic TAP Block
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 186
Healthy volunteers: yes

Brief summary:
Primary objective: The primary objective of this study is to compare total opioid consumption through 72 hours following EXPAREL+bupivacaine HCl infiltration into the transversus abdominis plane (TAP) after spinal anesthesia to active bupivacaine HCl TAP infiltration after spinal anesthesia in subjects undergoing an elective cesarean section (C-section).

Secondary objective: The secondary objectives are to assess efficacy and safety parameters and patient satisfaction.

Detailed description:
This is a Phase-4, multicenter, randomized, double-blind, active-controlled study planned in approximately 152 adult subjects undergoing elective C-section. All subjects will remain in the hospital for up to 72 hours postsurgery.

Screening:

Subjects will be screened within 30 days prior to surgery; screening on the day of surgery will be allowed but is discouraged. During the screening visit, subjects will be assessed for any past or present 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, alcohol breath test and urine drug screen, and clinical laboratory tests (hematology and chemistry) will be performed.

Day of Surgery:

Pre-operative medications: Use of pre-operative analgesics (eg, opioid medications, acetaminophen, nonsteroidal anti-inflammatory drugs \[NSAIDs\]) is prohibited.

Eligible subjects will be randomized in a blinded 1:1 ratio to either:

* Group 1: EXPAREL+bupivacaine TAP infiltration following spinal anesthesia
* Group 2: Active bupivacaine HCl TAP infiltration following spinal anesthesia On Day 1, prior to the C-section, all subjects will receive a intrathecal injection of 150 mcg preservative-free morphine for spinal injection (eg, Duramorph®) in conjunction with single-shot spinal anesthesia using 1.4-1.6 mL bupivacaine HCl 0.75% and 15 mcg fentanyl. If preservative-free morphine for spinal injection (eg, Duramorph) is unavailable because of a drug shortage, subjects may instead receive an intrathecal injection of 75 mcg preservative-free hydromorphone in conjunction with single-shot spinal anesthesia using 1.4-1.6 mL bupivacaine HCl 0.75% and 15 mcg fentanyl. A combined spinal epidural (CSE) anesthesia technique may also be used provided the epidural component is not used. Subjects who receive the epidural component of the CSE anesthesia must be immediately withdrawn from the study.

Intraoperative medications: The intraoperative use of the following medications is discouraged, but may be permitted if clinically indicated based on the investigator's discretion (all medications must be appropriately recorded \[ie, drug, dose, and route of administration\]): ketamine and midazolam (Versed®). Prophylactic use of dexamethasone for prevention of nausea and vomiting is prohibited.

After delivery of the baby and prior to the TAP infiltration, a small amount of lidocaine (\<2 mL) may be administered subcutaneously to form a skin wheal over the area of the needle insertion site. A 2-point classic TAP block will be performed under ultrasound guidance within 1 hour (± 30 minutes) following skin incision closure of the C-section. A confirmatory ultrasound picture or video will be taken of each side of the abdomen after the TAP needle position has been established and following infiltration of study drug.

TAP infiltration: Subjects randomized to the EXPAREL+bupivacaine group (Group 1) will receive a single 20-mL dose of EXPAREL 266 mg expanded in volume with 20 mL normal saline plus 20 mL 0.25% bupivacaine for a total volume of 60 mL, administered as 30 mL (10 mL EXPAREL, 10 mL 0.25% bupivacaine HCl, and 10 mL saline) on each side of the abdomen. Subjects randomized to the active bupivacaine group (Group 2) will receive 20 mL 0.25% bupivacaine expanded in volume with 40 mL normal saline for a total volume of 60 mL, administered as 30 mL (10 mL 0.25% bupivacaine HCl and 20 mL saline) on each side of the abdomen.

Postsurgical Analgesia: Patient-controlled analgesia is not permitted. The following multimodal pain regimen will be initiated immediately following the delivery of the baby:

* IV ketorolac 15 mg once at the time of skin incision closure and prior to the TAP infiltration
* Intravenous (IV) acetaminophen 1000 mg at the time of skin incision closure
* Scheduled oral (PO) acetaminophen 650 mg beginning 6 hours from the administration of the single dose of IV acetaminophen at the end of surgery and then every 6 hours (q6h) for up to 72 hours or hospital discharge
* Scheduled PO ibuprofen 600 mg beginning 6 hours from the administration of the single dose of IV ketorolac at the end of surgery and then q6h for up to 72 hours or hospital discharge

The date, time, and dose of all standardized multimodal pain medications administered must be recorded. Note: The scheduled PO medication will be administered on a q6h schedule only through hospital discharge.

Rescue Medication: Subjects should only receive opioid rescue pain medication upon request for breakthrough pain. Postsurgical rescue medication will comprise PO immediate-release oxycodone (initiated at 5-10 mg every 4 hours \[q4h\] or as needed \[PRN\]). If a subject is unable to tolerate PO medication or fails the PO oxycodone rescue, IV morphine (initiated at 1-2 mg) or hydromorphone (initiated at 0.3-0.5 mg) may be administered q4h or PRN. All surgical and postsurgical opioid and other analgesics (pain medications) administered must be documented through Day 14 postsurgery. Additionally, an unscheduled pain intensity score using a 10-cm visual analog scale (VAS) must be completed immediately prior to any rescue medication while in the hospital.

Permitted medications for the prevention and treatment of possible medication side effects include the following and may be used at the discretion of the study site principal investigator:

* Ondansetron 4 mg IV immediately after delivery of the baby.
* Ondansetron 4 mg IV (should not exceed a maximum of 12 mg in a 24-hour period) for intraoperative and postoperative nausea and vomiting
* Metoclopramide 10 mg PO PRN for nausea and vomiting
* Nalbuphine IV 2.5 mg PRN for pruritus
* Naloxone IV 50-100 mcg PRN for pruritus.

Postsurgical Assessments:

Subjects will remain in the hospital for up to 72 hours postsurgery. Postsurgical assessments will include:

* Opioid use
* Time of first unassisted ambulation
* Pain intensity scores using a 10-cm VAS at rest
* Discharge readiness
* Subject's satisfaction with postsurgical pain control
* Overall benefit of anesthesia score (OBAS) questionnaire
* Quality of recovery 15-item questionnaire (QoR-15)

While in the hospital, subjects will be provided with a Patient Diary and will use the diary to record all scheduled and unscheduled VAS scores. For all scheduled assessments and unscheduled assessments in the hospital, subjects will assess, "How much pain are you experiencing right now" and a vertical mark will be placed on the VAS line to indicate the level of pain experienced at the time of assessment. If a subject is discharged prior to a scheduled VAS assessment, a member of the study site staff will contact the subject to remind her to complete the scheduled VAS assessment at the scheduled time and to record the assessment in the Patient Diary.

At hospital discharge, the subject will be instructed to record in the Patient Diary VAS pain intensity score daily and all pain medications taken following hospital discharge through Day 14.

At home, the subject will assess pain intensity at rest each day at noon (± 4 hours). This assessment should capture her average pain at rest in the prior 24 hours by assessing "What has been your average pain since your last pain assessment?" (ie, from noon on the previous day to the current assessment). At the same time, the subject should record any pain medication (medication name, date, time, and dose) taken in the prior 24 hours.

A phone call will be made to each subject on Day 14 for safety purposes and to inquire as to whether the subject has made any unscheduled phone calls or office visits related to pain; experienced any hospital readmission; or experienced an emergency room visit since hospital discharge. Adverse events (AEs) and serious adverse events (SAEs) will be recorded from the time the ICF is signed through Day 14.

Arms:
arm 1: Receive a single 20-mL dose of EXPAREL 266 mg expanded in volume with 20 mL normal saline plus 20 mL 0.25% bupivacaine for a total volume of 60 mL. arm 2: Receive 20 mL 0.25% bupivacaine expanded in volume with 40 mL normal saline for a total volume of 60 mL

Interventions: intervention 1: Exparel + Bupivacaine intervention 2: Bupivacaine
Intervention descriptions: intervention 1: EXPAREL is a local analgesic that utilizes bupivacaine in combination with the proven product delivery platform, DepoFoam®. intervention 2: Bupivacaine Hydrochloride is indicated for the production of local or regional anesthesia or analgesia for surgery, dental and oral surgery procedures, diagnostic and therapeutic procedures, and for obstetrical procedures.

Protocol document:
Prot_000.pdf: 
 
 
 
 
 
Clinical Study Protocol 
Amendment 3 
A Multicenter, Randomized, Double-blind, Active-controlled Study to 
Evaluate the Safety and Efficacy of EXPAREL When Administered via 
Infiltration into the Transversus Abdominis Plane (TAP) Versus Bupivacaine 
Alone in Subjects Undergoing Elective Cesarean Section 
 
 
 
Protocol No.: 
EudraCT No.: 
IND No.: 
Study Phase: 
Study Drug: 
Date: 
Study Sites: 
Sponsor: 
 
402-C-411 
Not applicable 
069,198 
4 
EXPAREL® (bupivacaine liposome injectable suspension) 
07-May-2018 
Multicenter study in North America 
Pacira Pharmaceuticals, Inc. 
5 Sylvan Way 
Parsippany, NJ 07054 
Tel: (973) 254-3560 
 
 
 
 
 
Confidentiality Statement 
The information contained in this document is confidential and the property of Pacira Pharmaceuticals, Inc. 
It should not be reproduced, revealed, or sent to third parties other than Institutional Review Boards/Independent 
Ethics Committees and the investigator’s research support staff participating in the conduct of the study without 
the prior written authorization of Pacira Pharmaceuticals, Inc. 


Pacira Pharmaceuticals, Inc. 
EXPAREL® 
402-C-411 (C-Section TAP) 
Clinical Study Protocol Amendment 3 
CONFIDENTIAL 
2 of 68 
07-May-2018 
 
 
 
SIGNATURE PAGE 
 
 
 
 
Digitally signed by Richard Scranton 
DN: cn=Richard Scranton, o=Pacira Pharmaceuticals 
Inc., ou=Chief Scientific Officer, 
May 7, 2018 
email=Richard.Scranton@pacira.com,  c=US 
Date: 2018.05.07 09:14:46 -04'00' 
 
Richard Scranton, MD, MPH 
Chief Scientific Officer 
 
 
 
Date 
 
 
Michael 
Rozycki 
Michael Rozycki, PhD 
Digitally signed by Michael Rozycki 
DN: cn=Michael Rozycki, o=Regulatory 
Affairs, ou=Clinical Regulatory, 
email=michael.rozycki@pacira.com, 
c=US 
Date: 2018.05.07 10:21:19 -04'00' 
 
 
 
 
 
 
Date 
Vice President, Regulatory Affairs 
 
 
 
 
 
Hassan Danesi, MD 
Sr Medical Director 
Date 
 
 
Digitally signed by Vincent Yu 
DN: cn=Vincent Yu, o=Pacira, 
ou=Biometrics, 
email=vincent.yu@pacira.com, c=US 
Date: 2018.05.07 10:25:19 -04'00' 
Vincent Yu, PhD 
Sr Director, Biometrics 
 
 
 
 
 
 
Date 
Hassan Danesi 
Digitally signed by Hassan Danesi 
DN: cn=Hassan Danesi, o=Pacira 
Pharmaceuticals, ou=Medical, 
email=hassan.danesi@pacira.com, c=US 
Date: 2018.05.07 08:56:39 -04'00' 
Richard Scranton 
Vincent Yu 


Pacira Pharmaceuticals, Inc. 
EXPAREL® 
402-C-411 (C-Section TAP) 
Clinical Study Protocol Amendment 3 
CONFIDENTIAL 
3 of 68 
07-May-2018 
 
 
 
2. 
SYNOPSIS 
 
Name of Sponsor/Company: 
Pacira Pharmaceuticals, Inc. 
5 Sylvan Way 
Parsippany, NJ 07054 
(973) 254-3560 
Individual Study Table 
Referring to Part of the Dossier 
Volume: 
Page: 
(For National Authority 
Use Only) 
Name of Finished Products: 
EXPAREL® (bupivacaine liposome injectable 
suspension) 
Name of Active Ingredients: 
Bupivacaine, 1.3%, 13.3 mg/mL 
Title of Study: A Multicenter, Randomized, Double-blind, Active-controlled Study to Evaluate the Safety and 
Efficacy of EXPAREL Plus Bupivacaine When Administered via Infiltration into the Transversus Abdominis Plane 
(TAP) Versus Bupivacaine Alone in Subjects Undergoing Elective Cesarean Section 
Principal investigator: To be determined 
Study Center(s): Multicenter study in North America 
Publications (Reference): None 
Objectives: 
Primary objective: The primary objective of this study is to compare total opioid consumption through 72 hours 
following EXPAREL+bupivacaine HCl infiltration into the transversus abdominis plane (TAP) after spinal anesthesia 
to active bupivacaine HCl TAP infiltration after spinal anesthesia in subjects undergoing an elective cesarean section 
(C-section). 
Secondary objective: The secondary objectives are to assess efficacy and safety parameters and patient satisfaction. 
Methodology: 
This is a Phase-4, multicenter, randomized, double-blind, active-controlled study in approximately 152 adult subjects 
undergoing elective C-section. All subjects will remain in the hospital for up to 72 hours postsurgery. 
Obtaining Informed Consent 
Potential participants may provide informed consent up to 30 days before their scheduled surgery. If a subject can only 
be screened on the day of surgery, the consent process must be started at least 24 hours prior to the day of surgery in 
order to ensure ample time for the subject to review the ICF and have all her questions answered by the 
investigator/study staff prior to providing informed consent. Screening procedures that are standard of care (SOC) at 
the institution may be completed prior to written informed consent. Any screening procedures that are not SOC, must 
be completed after written informed consent is provided and prior to surgery. 
Screening 
Subjects will be screened within 30 days prior to surgery; screening on the day of surgery will be allowed but is 
discouraged. If a subject can only be screened on the day of surgery, the informed consent process must still be  
started at least 24 hours prior to the conduct of any screening procedures that are not considered SOC at the institution 
and such procedures may not be performed until written informed consent is provided  All screening procedures that 
are not SOC must be performed and documented within the 30-day time window (inclusive of the day of surgery for 
those subjects who can only be screened on the day of surgery) as described here. During the screening visit, subjects 
will be assessed for any past or present 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, alcohol breath test and urine drug screen, and clinical laboratory 
tests (hematology and chemistry) will be performed. 


Pacira Pharmaceuticals, Inc. 
EXPAREL® 
402-C-411 (C-Section TAP) 
Clinical Study Protocol Amendment 3 
CONFIDENTIAL 
4 of 68 
07-May-2018 
 
 
 
Name of Sponsor/Company: 
Pacira Pharmaceuticals, Inc. 
5 Sylvan Way 
Parsippany, NJ 07054 
(973) 254-3560 
Individual Study Table 
Referring to Part of the Dossier 
Volume: 
Page: 
(For National Authority 
Use Only) 
Name of Finished Products: 
EXPAREL® (bupivacaine liposome injectable 
suspension) 
Name of Active Ingredients: 
Bupivacaine, 1.3%, 13.3 mg/mL 
Day of Surgery 
Pre-operative medications: Use of pre-operative analgesics (eg, opioid medications, acetaminophen, nonsteroidal 
anti-inflammatory drugs [NSAIDs]) is prohibited. 
Eligible subjects will be randomized in a blinded 1:1 ratio to either: 
• 
Group 1: EXPAREL+bupivacaine TAP infiltration following spinal anesthesia 
• 
Group 2: Active bupivacaine HCl TAP infiltration following spinal anesthesia 
On Day 1, prior to the C-section, all subjects will receive a intrathecal injection of 150 mcg preservative-free 
morphine for spinal injection (eg, Duramorph®) in conjunction with single-shot spinal anesthesia using 1.4-1.6 mL 
bupivacaine HCl 0.75% and 15 mcg fentanyl.  If preservative-free morphine for spinal injection (eg, Duramorph) is 
unavailable because of a drug shortage, subjects may instead receive an intrathecal injection of 75 mcg preservative- 
free hydromorphone in conjunction with single-shot spinal anesthesia using 1.4-1.6 mL bupivacaine HCl 0.75% and 
15 mcg fentanyl. A combined spinal epidural (CSE) anesthesia technique may also be used provided the epidural 
component is not used. Subjects who receive the epidural component of the CSE anesthesia must be immediately 
withdrawn from the study. 
Intraoperative medications: The intraoperative use of the following medications is discouraged, but may be permitted 
if clinically indicated based on the investigator’s discretion (all medications must be appropriately recorded [ie, drug, 
dose, and route of administration]): ketamine and midazolam (Versed®). Prophylactic use of dexamethasone for 
prevention of nausea and vomiting is prohibited. 
After delivery of the baby and prior to the TAP infiltration, a small amount of lidocaine (<2 mL) may be administered 
subcutaneously to form a skin wheal over the area of the needle insertion site. A 2-point classic TAP block, in 2 steps 
(see below), must be performed under ultrasound guidance and must be performed no more than 90 minutes after skin 
incision closure of the C-section. A confirmatory ultrasound picture or video will be taken of each side of the 
abdomen after the TAP needle position has been established and following infiltration of study drug. 
TAP infiltration: The TAP infiltration includes two steps: (1) TAP needle placement and saline hydrodissection and 
(2) study drug mixture infiltration into the TAP. Each step is briefly described below for one side of the abdomen and 
must be repeated on the contralateral side to complete the bilateral, 2-point TAP required for the study. For complete, 
step-by-step instructions on performing the TAP infiltration under ultrasound guidance, please refer to the Pharmacy 
Binder. 
(1) TAP needle placement and saline hydrodissection: For subjects in both study groups, use ultrasound guidance to 
place the TAP needle into the desired location and use a 10-mL syringe pre-filled with normal saline to perform 
hydrodissection of the TAP. (Note: it is not necessary to use the full 10 mL of normal saline for hydodissection.)  
An ultrasound image of the TAP needle must be captured after saline hydrodissection. 
(2) Study drug mixture infiltration into the TAP: Subjects randomized to the EXPAREL+bupivacaine group (Group 
1) will receive 30 mL of a study drug mixture containing 10 mL EXPAREL (133 mg) combined with 10 mL 
bupivacaine HCl 0.25% (25 mg) and 10 mL normal saline (total mixture 30 mL) infiltrated into the TAP. An 
ultrasound image of the TAP needle placement must be captured after study drug infiltration. 
Subjects randomized to the active bupivacaine group (Group 2) will receive 30 mL of a study drug mixture 
containing 10 mL bupivacaine HCl 0.25% (25 mg) combined with 20 mL normal saline (total mixture 30 mL) 
infiltrated into the TAP. An ultrasound image of the TAP needle placement must be captured after study drug 
mixture infiltration. 
Repeat the above steps on the contralateral side to complete the bilateral, 2-point TAP required for the study. 


Pacira Pharmaceuticals, Inc. 
EXPAREL® 
402-C-411 (C-Section TAP) 
Clinical Study Protocol Amendment 3 
CONFIDENTIAL 
5 of 68 
07-May-2018 
 
 
 
Name of Sponsor/Company: 
Pacira Pharmaceuticals, Inc. 
5 Sylvan Way 
Parsippany, NJ 07054 
(973) 254-3560 
Individual Study Table 
Referring to Part of the Dossier 
Volume: 
Page: 
(For National Authority 
Use Only) 
Name of Finished Products: 
EXPAREL® (bupivacaine liposome injectable 
suspension) 
Name of Active Ingredients: 
Bupivacaine, 1.3%, 13.3 mg/mL 
Postsurgical Analgesia: Patient-controlled analgesia is not permitted. 
The following multimodal pain regimen will be used: 
At the time of skin incision closure (Note: it is very important that these be administered at the time of wound closure 
and not prior to or before the end of surgery) 
• 
Intravenous (IV) ketorolac 15 mg (1 dose) 
• 
IV acetaminophen 1000 mg (1 dose) 
Beginning 6 hours after skin incision closure 
• 
Scheduled oral (PO) acetaminophen 650 mg beginning 6 hours from the administration of the single dose of IV 
acetaminophen at the end of surgery and then every 6 hours (q6h) for up to 72 hours or hospital discharge 
• 
Scheduled PO ibuprofen 600 mg beginning 6 hours from the administration of the single dose of IV ketorolac at 
the end of surgery and then q6h for up to 72 hours or hospital discharge 
This multi-modal pain regimen is a requirement for all subjects in the study and is not subject to investigator 
discretion. The date, time, and dose of all standardized multimodal pain medications administered must be recorded. 
Note: The scheduled PO medication will be administered on a q6h schedule only through hospital discharge. 
Rescue Medication: Subjects should only receive opioid rescue pain medication upon request for breakthrough pain. 
Postsurgical rescue medication will comprise PO immediate-release oxycodone (initiated at 5-10 mg every 4 hours 
[q4h] or as needed [PRN]). If a subject is unable to tolerate PO medication or fails the PO oxycodone rescue, IV 
morphine (initiated at 1-2 mg) or hydromorphone (initiated at 0.3-0.5 mg) may be administered q4h or PRN. All 
surgical and postsurgical opioid and other analgesics (pain medications) administered must be documented through 
Day 14 postsurgery. Additionally, an unscheduled pain intensity score using a 10-cm visual analog scale (VAS; see 
Appendix 1) must be completed immediately prior to any rescue medication while in the hospital. 
Permitted medications for the prevention and treatment of possible medication side effects include the following and 
may be used at the discretion of the study site principal investigator: 
• 
Ondansetron 4 mg IV immediately after delivery of the baby. 
• 
Ondansetron 4 mg IV (should not exceed a maximum of 12 mg in a 24-hour period) for intraoperative and 
postoperative nausea and vomiting 
• 
Metoclopramide 10 mg PO PRN for nausea and vomiting 
• 
Nalbuphine IV 2.5 mg PRN for pruritus 
• 
Naloxone IV 50-100 mcg PRN for pruritus. 
Postsurgical Assessments 
Subjects will remain in the hospital for up to 72 hours postsurgery. Postsurgical assessments will include: 
• 
Opioid use 
• 
Subject's satisfaction with postsurgical pain control (see 
• 
Time of first unassisted ambulation 
Appendix 3) 
• 
Pain intensity scores using a 10-cm VAS 
• 
Overall benefit of anesthesia score (OBAS) questionnaire 
(see Appendix 1) at rest 
 
(see Appendix 4) 
• 
Discharge readiness (see Appendix 2) 
• 
Quality of recovery 15-item questionnaire (QoR-15; see 
Appendix 5) 


Pacira Pharmaceuticals, Inc. 
EXPAREL® 
402-C-411 (C-Section TAP) 
Clinical Study Protocol Amendment 3 
CONFIDENTIAL 
6 of 68 
07-May-2018 
 
 
 
Name of Sponsor/Company: 
Pacira Pharmaceuticals, Inc. 
5 Sylvan Way 
Parsippany, NJ 07054 
(973) 254-3560 
Individual Study Table 
Referring to Part of the Dossier 
Volume: 
Page: 
(For National Authority 
Use Only) 
Name of Finished Products: 
EXPAREL® (bupivacaine liposome injectable 
suspension) 
Name of Active Ingredients: 
Bupivacaine, 1.3%, 13.3 mg/mL 
While in the hospital, subjects will be provided with a Patient Binder and will use the binder to record all scheduled 
and unscheduled VAS scores.  For all scheduled assessments and unscheduled assessments in the hospital, subjects 
will assess, “How much pain are you experiencing right now” and a vertical mark will be placed on the VAS line to 
indicate the level of pain experienced at the time of assessment. If a subject is discharged prior to a scheduled VAS 
assessment, a member of the study site staff will contact the subject to remind her to complete the scheduled VAS 
assessment at the scheduled time and to record the assessment in the Participant Diary, which will be provided to the 
subject at the time of hospital discharge. 
At hospital discharge, the subject will be instructed to record in the Participant Diary VAS pain intensity score daily 
and all pain medications taken following hospital discharge through Day 14. 
At home, the subject will assess pain intensity at rest each day at noon (± 4 hours). This assessment should capture 
her average pain at rest in the prior 24 hours by assessing “What has been your average pain since your last pain 
assessment?” (ie, from noon on the previous day to the current assessment). At the same time, the subject should 
record any pain medication (medication name, date, time, and dose) taken in the prior 24 hours. 
A phone call will be made to each subject on Day 14 for safety purposes and to inquire as to whether the subject has 
made any unscheduled phone calls or office visits related to pain; experienced any hospital readmission; or 
experienced an emergency room visit since hospital discharge. Adverse events (AEs) and serious adverse events 
(SAEs) will be recorded from the time the ICF is signed through Day 14. 
Number of Subjects (Planned): Approximately 152 subjects are planned for enrollment into the study. Subjects who 
are withdrawn or discontinued prior to completing the study may be replaced. 
Eligibility Criteria: 
Note: Based on the World Health Organization’s Guidance: Breastfeeding and Maternal Medication, 
Recommendations for Drugs in the Eleventh WHO Model List of Essential Drugs, bupivacaine is compatible with 
breastfeeding and, therefore, there are no restrictions in this study regarding the participation of women who wish to 
breastfeed following treatment with study drug. 
Inclusion Criteria: 
1. Females 18 years of age and older at screening. 
2. Term pregnancies of 37 to 42 weeks gestation, scheduled to undergo elective C-section. 
3. American Society of Anesthesiology (ASA) physical status 1, 2, or 3. 
4. Able to provide informed consent, adhere to the study visit schedule, and complete all study assessments. 
Exclusion Criteria: 
1. Subjects who, in the opinion of the study site principal investigator, have a high-risk pregnancy (eg, multiple 
gestations, pregnancy resulting from in vitro fertilization, gestational diabetes, end-term prolonged bed rest 
required for medical reasons). 
2. Subjects with a pregnancy-induced medical condition or complication (eg, hypertension, pre-eclampsia, 
chorioamnionitis). 
3. Subjects with 3 or more prior C-sections. 
4. Pre-pregnancy body mass index >50 kg/m2 or otherwise not anatomically appropriate to undergo a TAP block. 
5. Allergy, hypersensitivity, intolerance, or contraindication to any of the study medications for which an alternative 
is not named in the protocol (eg, amide-type local anesthetics, opioids, bupivacaine, NSAIDs, spinal anesthesia). 
6. Planned concurrent surgical procedure with the exception of salpingo-oophorectomy or tubal ligation. 


Pacira Pharmaceuticals, Inc. 
EXPAREL® 
402-C-411 (C-Section TAP) 
Clinical Study Protocol Amendment 3 
CONFIDENTIAL 
7 of 68 
07-May-2018 
 
 
 
Name of Sponsor/Company: 
Pacira Pharmaceuticals, Inc. 
5 Sylvan Way 
Parsippany, NJ 07054 
(973) 254-3560 
Individual Study Table 
Referring to Part of the Dossier 
Volume: 
Page: 
(For National Authority 
Use Only) 
Name of Finished Products: 
EXPAREL® (bupivacaine liposome injectable 
suspension) 
Name of Active Ingredients: 
Bupivacaine, 1.3%, 13.3 mg/mL 
7. Severely impaired renal or hepatic function (eg, 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.) 
8. Subjects at an increased risk for bleeding or a coagulation disorder (defined as platelet count less than 
80,000 × 103/mm3 or international normalized ratio greater than 1.5) 
9. Concurrent painful physical condition that may require analgesic treatment (such as long-term, consistent use of 
opioids) in the postsurgical period for pain that is not strictly related to the surgery and which may confound the 
postsurgical assessments. 
10. Clinically significant medical disease in either the mother or baby that, in the opinion of the investigator, would 
make participation in a clinical study inappropriate. This includes any psychiatric or other disease in the mother 
that would constitute a contraindication to participation in the study or cause the mother to be unable to comply 
with the study requirements. 
11. History of, suspected, or known addiction to or abuse of illicit drug(s), prescription medicine(s), or alcohol within 
the past 2 years. 
12. 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 
13. Previous participation in an EXPAREL study. 
In addition, the subject will be ineligible to receive study drug and will be withdrawn from the study if she meets the 
following criteria during surgery: 
14. Any clinically significant event or condition uncovered during the surgery (eg, excessive bleeding, acute sepsis) 
that might render the subject medically unstable or complicate the subject’s postsurgical course. 
15. Receives the epidural component of CSE anesthesia during participation in the study. 
Test Product, Dose, Mode of Administration, and Lot Numbers: 
Name: EXPAREL (bupivacaine liposome injectable suspension) and bupivacaine HCl 0.25% (Group 1) 
Active Ingredient: Bupivacaine, 1.3%, 13.3 mg/mL 
Dosage: Single infiltration of EXPAREL 266 mg in 20 mL admixed with bupivacaine HCl 0.25% in 20 mL and 
normal saline 20 mL (total volume 60 mL) 
Lot Number: To be determined 
Mode of Administration: Infiltration into the TAP under ultrasound guidance 
Reference Product, Dose, Mode of Administration, and Lot Numbers: 
Name: Bupivacaine HCl 0.25% (Group 2) 
Active Ingredient: Bupivacaine 
Dosage: Single infiltration of bupivacaine HCl 0.25% in 20 mL and normal saline 40 mL (total volume 60 mL) 
Lot Number: To be determined 
Mode of Administration: Infiltration into the TAP under ultrasound guidance 


Pacira Pharmaceuticals, Inc. 
EXPAREL® 
402-C-411 (C-Section TAP) 
Clinical Study Protocol Amendment 3 
CONFIDENTIAL 
8 of 68 
07-May-2018 
 
 
 
Name of Sponsor/Company: 
Pacira Pharmaceuticals, Inc. 
5 Sylvan Way 
Parsippany, NJ 07054 
(973) 254-3560 
Individual Study Table 
Referring to Part of the Dossier 
Volume: 
Page: 
(For National Authority 
Use Only) 
Name of Finished Products: 
EXPAREL® (bupivacaine liposome injectable 
suspension) 
Name of Active Ingredients: 
Bupivacaine, 1.3%, 13.3 mg/mL 
Duration of Subject Participation in Study: 
Participation will begin upon signing of the ICF. No more than 7 30 days should pass between signing the ICF and 
surgery. A follow-up telephone call will occur on Day 14 (± 3 days). Therefore, each subject may participate in the 
study for a maximum of 44 47 days. 
Efficacy Assessments: 
The following efficacy measurements will be conducted at the times specified after completion of the last C-section 
wound incision stitch (ie, time of closure of the C-section wound): 
• 
Date, time of administration, and amount of all postsurgical opioid rescue medication taken through Day 14 
• 
Pain intensity scores at rest using a 10-cm VAS at 6, 12, 18, 24, 30, 36, 42, 48, and 72 hours (see Appendix 1) 
and once daily (at noon ± 4 hours) through Day 14. † For pain intensity scores at 18, 24, 30, 36, or 42 hours, if 
the subject is sleeping, do not wake her to assess pain. If she awakens within the assessment window (ie, 1 hour 
for the 18- and 24-hour assessments and 2 hours for the 30-, 36-, and 42-hour assessments), a pain score may be 
collected then. 
Please note that an unscheduled VAS score is also required immediately prior to administration of any rescue 
medication while in the hospital. 
• 
Date and time of first unassisted ambulation 
• 
OBAS questionnaire at 24, 48, and 72 hours (see Appendix 4). † 
• 
Subject satisfaction with postsurgical pain control (using a 5-point Likert scale) at 72 hours or hospital 
discharge (see Appendix 3) 
• 
Discharge readiness at 24, 48, and 72 hours or until the subject attains a score of 9, whichever occurs first (see 
Appendix 2) 
• 
QoR-15 questionnaire at 72 hours or hospital discharge (Appendix 5) 
• 
Unscheduled phone calls or office visits related to pain after discharge through Day 14 
†If a subject is discharged prior to any of the scheduled VAS assessments collected at 6 to 72 hours postsurgery or a 
scheduled OBAS assessment collected at 24 to 72 hours postsurgery, a member of the study site staff will contact the 
subject at the appropriate scheduled times (ie, the time of each assessment scheduled to be collected that occurs after 
hospital discharge) to remind her to complete the VAS and OBAS assessments and to record the scheduled 
assessments in the Participant Diary. This will ensure that for any subject discharged prior to 72 hours, all VAS and 
OBAS assessments required for calculation of the study endpoints are captured. These phone calls will only occur if a 
subject is discharged prior to 72 hours. 
Efficacy Endpoints: 
The primary efficacy endpoint is the total postsurgical opioid consumption in morphine equivalents through 72 hours. 
The secondary efficacy endpoints include: 
• 
Time to first postsurgical opioid rescue medication 
• 
The VAS pain intensity scores (at rest) from 0 6 to 72 hours 
• 
Percentage of opioid-free subjects through 72 hours 


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Name of Sponsor/Company: 
Pacira Pharmaceuticals, Inc. 
5 Sylvan Way 
Parsippany, NJ 07054 
(973) 254-3560 
Individual Study Table 
Referring to Part of the Dossier 
Volume: 
Page: 
(For National Authority 
Use Only) 
Name of Finished Products: 
EXPAREL® (bupivacaine liposome injectable 
suspension) 
Name of Active Ingredients: 
Bupivacaine, 1.3%, 13.3 mg/mL 
Tertiary efficacy endpoints may include (but may not be limited to): 
• 
Percentage of opioid-free subjects through 24 and 48 hours. 
• 
The VAS pain intensity scores (at rest) from 6 to 12 hours, 6 to 24 hours, 6 to 48 hours, 24 to 48 hours, and 48 
to 72 hours. 
• 
Integrated rank assessment using the VAS pain intensity score (at rest) at 24, 48, and 72 hours and the total 
amount of postsurgical opioids consumed through 24, 48, and 72 hours. 
• 
OBAS at each assessed timepoint. 
• 
Time spent in the post-anesthesia care unit (PACU). 
• 
Time to first unassisted ambulation. 
• 
Proportion of subjects meeting Modified Postanesthesia Discharge Scoring System criteria for discharge 
readiness at each assessed timepoint. 
• 
Overall assessment of the subject’s satisfaction with postsurgical pain control (using a 5-point Likert scale) at 
72 hours after surgery (or at hospital discharge if earlier than 72 hours). 
• 
Responses to the QoR-15 questionnaire at 72 hours after surgery (or at hospital discharge if earlier than 
72 hours). 
• 
Number of unscheduled phone calls or office visits related to pain from discharge through Day 14. 
Safety Assessments: 
Adverse events (AEs/SAEs) will be recorded from the time the ICF is signed through Day 14. 
Safety Endpoints: 
Incidence of AEs/SAEs that start after the start of anesthesia through Day 14. 
Statistical Methods: 
A comprehensive statistical analysis plan (SAP) will be developed for this study. Demographic and baseline 
characteristics will be summarized descriptively by treatment group for all subjects who receive study drug. 
Efficacy endpoint analyses will be described in the SAP. 
Safety endpoints will be summarized descriptively by treatment group. 
Sample size for this study was based on Quale et al (2016). The coefficient of variation (CV) from this poster was 
approximately 60%. Assuming a log-normal distribution for total opioid consumption with a 60% CV, 5% alpha, a 
1:1 randomization ratio, and 80% power, a total of 72 subjects per treatment group will be sufficient to detect a 30% 
difference between treatments. Assuming 5% of the subjects are not evaluable, a total sample size of approximately 
152 subjects is needed to ensure 144 evaluable subjects. 
Interim Analysis 
An unblinded interim analysis will be conducted by an independent statistician when approximately 80 treated  
subjects under protocol amendment 2 have completed the 72-hour follow-up for the primary efficacy assessments. The 
objective of this interim analysis is three-fold: (1) to stop the trial for futility if it is improbable to show a significant 
reduction in the primary efficacy endpoints; (2) to stop the trial for early success if a clear benefit is demonstrated; and 
(3) to allow for the possibility of increasing the study sample size if the original sample size assumptions are 
determined to be not viable. Full details and all thresholds for stopping or trial expansion will be covered in a 
prospective interim analysis plan that will become part of the study SAP. 


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Table 1. 
Time and Events Schedule of Study Procedures – Through 72 Hours After Surgery 
 
Study Procedure 
Within 30 
days of 
scheduled 
surgery 
Screening 
(within 7d 
of surgery) 
Day 1 
Hours After Surgery 
OR 
PACU 
6 hr 
(± 30m) 
12 hr 
(± 1hr) 
18 hr 
(± 1hr) 24 hr 
(± 1hr) 
30 hr 
(± 2hr) 36 hr 
(± 2hr) 
42 hr 
(± 2hr) 48 hr 
(± 2hr) 
72 hr 
(± 4hr) 
Explain study purpose and 
procedures; obtain signed 
ICF 
X13 
X13 
Assess/confirm eligibility 
X 
X 
Record/confirm medical 
and surgical history 
X 
X 
Record prior and 
concomitant medications 
X 
X 
Record demographics and 
baseline characteristics 
X 
Measure vital signs (blood 
pressure and heart rate) 
X12 
X 
X 
X3 
Physical exam (according 
to the investigational site’s 
standard of care) 
X 
X 
Drug screen/Alcohol test 
X 
Clinical laboratory tests 
(hematology and 
chemistry; Appendix 6)4 
X5 
Perform 12-lead ECG 
X 
Explain Patient Binder and 
Participant Diary and 
expectations of the subject 
regarding the binder and 
diary 
X 
Randomize subject and 
prepare study drug 
X 


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Table 1. 
Time and Events Schedule of Study Procedures – Through 72 Hours After Surgery 
 
Study Procedure 
Within 30 
days of 
scheduled 
surgery 
Screening 
(within 7d 
of surgery) 
Day 1 
Hours After Surgery 
OR 
PACU 
6 hr 
(± 30m) 
12 hr 
(± 1hr) 
18 hr 
(± 1hr) 24 hr 
(± 1hr) 
30 hr 
(± 2hr) 36 hr 
(± 2hr) 
42 hr 
(± 2hr) 48 hr 
(± 2hr) 
72 hr 
(± 4hr) 
Administer intrathecal 
preservative-free 
morphine/preservative-free 
hydromorphone injection 
in conjunction with single- 
shot spinal anesthesia 
(Section 13.3)11 
X 
Record surgery start and 
stop times 
X 
Perform TAP needle 
placement and saline 
hydrodissection under 
ultrasound guidance using 
up to 10-mL normal saline 
X 
Capture ultrasound image 
of the TAP needle 
placement after saline 
hydrodissection 
X 
Perform 2-point classic 
TAP infiltration no more 
than 90 minutes after skin 
incision closure of the C- 
section 
X 
Take ultrasound picture of 
the 2-point classic TAP 
needle placement after 
study drug infiltration 
X 
Record start and stop times 
of study drug infiltration 
X 
Record intraoperative 
opioids administered and 
doses 
X 


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Table 1. 
Time and Events Schedule of Study Procedures – Through 72 Hours After Surgery 
 
Study Procedure 
Within 30 
days of 
scheduled 
surgery 
Screening 
(within 7d 
of surgery) 
Day 1 
Hours After Surgery 
OR 
PACU 
6 hr 
(± 30m) 
12 hr 
(± 1hr) 
18 hr 
(± 1hr) 24 hr 
(± 1hr) 
30 hr 
(± 2hr) 36 hr 
(± 2hr) 
42 hr 
(± 2hr) 48 hr 
(± 2hr) 
72 hr 
(± 4hr) 
Record date, time in and 
out of the PACU 
X 
Record scheduled 10-cm 
VAS pain intensity score 
(Appendix 1) at rest8,9 
X 
X 
X10 
X 
X 
X 
X10 
X 
X 
Record 10-cm VAS pain 
intensity immediately 
prior to any postsurgical 
opioid medication 
administered while in the 
hospital (Appendix 1) 
Record date, time, and 
dose of all postsurgical 
pain medication1 
Record date, time, and 
dose of all standardized 
multimodal pain 
medications administered 
Record date and time of 
first unassisted ambulation 
Record overall rating of 
subject’s satisfaction with 
postsurgical pain control 
(Appendix 3) 
X3 
Record OBAS 
(Appendix 4)9 
X 
X 
X 
Administer QoR-15 
questionnaire 
(Appendix 5) 
X3 
Assess discharge 
readiness7 (Appendix 2) 
X 
X 


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Table 1. 
Time and Events Schedule of Study Procedures – Through 72 Hours After Surgery 
 
Study Procedure 
Within 30 
days of 
scheduled 
surgery 
Screening 
(within 7d 
of surgery) 
Day 1 
Hours After Surgery 
OR 
PACU 
6 hr 
(± 30m) 
12 hr 
(± 1hr) 
18 hr 
(± 1hr) 24 hr 
(± 1hr) 
30 hr 
(± 2hr) 36 hr 
(± 2hr) 
42 hr 
(± 2hr) 48 hr 
(± 2hr) 
72 hr 
(± 4hr) 
Provide the Participant 
Diary, addressed and 
stamped envelope, and 
instructions for use 
Record date and time of 
hospital discharge 
Document whether the 
subject has made any 
unscheduled phone calls or 
office visits related to pain; 
experienced any hospital 
readmission; or 
experienced an emergency 
room visit since hospital 
discharge. 
Remind subject to return 
the Participant Diary in the 
provided addressed and 
stamped envelope 
Record concomitant 
medications for treatment 
of AEs 
Record AEs/SAEs 
(starting at signing of ICF) 
AE = Adverse event; d=Day (s); ECG = Electrocardiogram; hr=Hour(s); ICF = Informed consent form; m=Minute(s); OBAS = Overall benefit of analgesia score; OR = 
Operating room; PACU = Post-anesthesia care unit; QoR-15 = Quality of Recovery 15-item Questionnaire; SAE = Serious adverse event; VAS=Visual analog scale 
Note: No more than 7 30 days should pass between signing of the ICF and performance of the surgery. Screening on the day of surgery will be permitted but is 
discouraged. 
Note: The end of surgery is defined as the time of closure of the C-section wound. 
1 
Subjects should only receive opioid pain medication (eg, morphine, hydromorphone [Dilaudid], oxycodone) upon request for breakthrough pain. 
2 
Captured after hospital discharge at rest each day at noon (± 4 hours) through Day 14 in the Participant Diary 
3 
At 72 hours postsurgery or prior to hospital discharge, whichever occurs first. 


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4 
Clinical laboratory tests will be conducted in accordance with the investigator’s standard of care including direct bilirubin and either gamma-glutamyl 
transpeptidase (GGT) and lactate dehydrogenase (LDH) OR alanine transaminase (ALT) and aspartate transaminase (AST). Note: if clinical laboratory test results 
are available from with 14 days of surgery, laboratory tests do not have to be repeated at screening 
5 
If clinical laboratory test results are available from within 14 days of surgery, laboratory tests do not have to be repeated at screening 
6 
Following hospital discharge, the subject will record her daily use of pain medication, if any, in the Participant Diary 
7 
Discharge readiness will be assessed at 24, 48, and 72 hours or until the subject attains a score of 9, whichever occurs first 
8 
To assess pain intensity (VAS) at rest, the subject should rest quietly in a supine or seated position that does not exacerbate her postsurgical pain for 3-5 minutes 
before entering the pain score. 
9 
If a subject is discharged prior to any of the scheduled VAS assessments collected at 6 to 72 hours postsurgery or a scheduled OBAS assessment collected at 24 to 
72 hours postsurgery, a member of the study site staff will contact the subject at the appropriate scheduled times (ie, the time of each assessment scheduled to be 
collected that occurs after hospital discharge) to remind her to complete the VAS and OBAS assessments and to record the scheduled assessments in the  
Participant Diary. This will ensure that for any subject discharged prior to 72 hours, all VAS and OBAS assessments required for calculation of the study endpoints 
are captured. These phone calls will only occur if a subject is discharged prior to 72 hours. 
10 For pain intensity scores at 18, 24, 30, 36, or 42 hours, if the subject is sleeping, do not wake her to assess pain. If she awakens within the assessment window (ie, 
1 hour for the 18- and 24-hour assessments and 2 hours for the 30-, 36-, and 42-hour assessments), a pain score may be collected then. 
11 If preservative-free morphine for spinal injection (eg, Duramorph) is unavailable because of a drug shortage, subjects may instead receive an intrathecal injection 
of 75 mcg preservative-free hydromorphone in conjunction with single-shot spinal anesthesia using 1.4-1.6 mL bupivacaine HCl 0.75% and 15 mcg fentanyl. 
12 Vital Signs will include Height and Weight at Screening. 
13 Potential participants may provide informed consent up to 30 days before their scheduled surgery. If a subject can only be screened on the day of surgery, the 
consent process must be started at least 24 hours prior to the day of surgery in order to ensure ample time for the subject to review the ICF and have all her 
questions answered by the investigator/study staff prior to providing informed consent. Screening procedures that are standard of care (SOC) at the institution may 
be completed prior to written informed consent. Any screening procedures that are not SOC, must be completed after written informed consent is provided and 
prior to surgery. 
If a subject can only be screened on the day of surgery, the informed consent process must still be started at least 24 hours prior to the conduct of any screening 
procedures that are not considered SOC at the institution and such procedures may not be performed until written informed consent is provided. 


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Table 2. 
Time and Events Schedule of Study Procedures – Hospital 
Discharge Through Day 14 
 
Study Procedure 
Hospital 
Discharge 
Day 14 
(±3 d) Call 
Explain study purpose and procedures; obtain signed ICF 
Assess/confirm eligibility 
Record/confirm medical and surgical history 
Record prior and concomitant medications 
Record demographics and baseline characteristics 
Measure vital signs (blood pressure and heart rate) 
X3 
Physical exam (according to the investigational site’s 
standard of care) 
Drug screen/Alcohol test 
Clinical laboratory tests (hematology and chemistry; 
Appendix 6)4 
Perform 12-lead ECG 
Explain Patient Binder and Participant Diary and 
expectations of the subject regarding the binder and diary 
X 
Randomize subject and prepare study drug 
Administer intrathecal preservative-free 
morphine/preservative-free hydromorphone injection in 
conjunction with single-shot spinal anesthesia (Section 
13.3)11 
Record surgery start and stop times 
Perform TAP needle placement and saline hydrodissection 
under ultrasound guidance using up to 10-mL normal saline 
Capture ultrasound image of the TAP needle placement after 
saline hydrodissection 
Perform 2-point classic TAP infiltration no more than 90 
minutes after skin incision closure of the C-section 
Take ultrasound picture of the 2-point classic TAP needle 
placement after study drug infiltration 
Record start and stop times of study drug infiltration 
Record intraoperative opioids administered and doses 


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Table 2. 
Time and Events Schedule of Study Procedures – Hospital 
Discharge Through Day 14 
 
 
AE = Adverse event; d=Day (s); ECG = Electrocardiogram; hr=Hour(s); ICF = Informed consent form; m=Minute(s); QoR-15 = Quality of Recovery 15-item 
Questionnaire; SAE = Serious adverse event; VAS=Visual analog scale 
Note: The end of surgery is defined as the time of closure of the C-section wound. 
1 
Subjects should only receive opioid pain medication (eg, morphine, hydromorphone [Dilaudid], oxycodone) upon request for breakthrough pain. 
2 
Captured after hospital discharge at rest each day at noon (± 4 hours) through Day 14 in the Participant Diary 
3 
At 72 hours postsurgery or prior to hospital discharge, whichever occurs first. 
Study Procedure 
Hospital 
Discharge 
Day 14 
(±3 d) Call 
Record date, time in and out of the PACU 
Record scheduled 10-cm VAS pain intensity score 
(Appendix 1) at rest8,9 
2 
Record 10-cm VAS pain intensity immediately prior to 
any postsurgical opioid medication administered while in 
the hospital (Appendix 1) 
Record date, time, and dose of all postsurgical pain 
medication1 
6 
Record date, time, and dose of all standardized multimodal 
pain medications administered 
Record date and time of first unassisted ambulation 
Record overall rating of subject’s satisfaction with 
postsurgical pain control (Appendix 3) 
X3 
Administer QoR-15 questionnaire (Appendix 5) 
X3 
Assess discharge readiness7 (Appendix 2) 
X3 
Provide the Patient Participant Diary, addressed and stamped 
envelope, and instructions for use 
X 
Record date and time of hospital discharge 
X 
Document whether the subject has made any unscheduled 
phone calls or office visits related to pain; experienced any 
hospital readmission; or experienced an emergency room 
visit since hospital discharge. 
X 
Remind subject to return the Patient Participant Diary in the 
provided addressed and stamped envelope 
X 
Record concomitant medications for treatment of AEs 
Record AEs/SAEs (starting at signing of ICF) 


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4 
Clinical laboratory tests will be conducted in accordance with the investigator’s standard of care including direct bilirubin and either gamma-glutamyl 
transpeptidase (GGT) and lactate dehydrogenase (LDH) OR alanine transaminase (ALT) and aspartate transaminase (AST). Note: if clinical laboratory test results 
are available from with 14 days of surgery, laboratory tests do not have to be repeated at screening 
5 
If clinical laboratory test results are available from within 14 days of surgery, laboratory tests do not have to be repeated at screening 
6 
Following hospital discharge, the subject will record her daily use of pain medication, if any, in the Participant Diary 
7 
Discharge readiness will be assessed at 24, 48, and 72 hours or until the subject attains a score of 9, whichever occurs first 
8 
To assess pain intensity (VAS) at rest, the subject should rest quietly in a supine or seated position that does not exacerbate her postsurgical pain for 3-5 minutes 
before entering the pain score. 
9 
For pain intensity scores at 18, 24, 30, 36, or 42 hours, if the subject is sleeping, do not wake her to assess pain. If she awakens within the assessment window (ie, 
1 hour for the 18- and 24-hour assessments and 2 hours for the 30-, 36-, and 42-hour assessments), a pain score may be collected then. 
10 If preservative-free morphine for spinal injection (eg, Duramorph) is unavailable because of a drug shortage, subjects may instead receive an intrathecal injection 
of 75 mcg preservative-free hydromorphone in conjunction with single-shot spinal anesthesia using 1.4-1.6 mL bupivacaine HCl 0.75% and 15 mcg fentanyl. 
11 Vital Signs will include Height and Weight at Screening. 
12 Potential participants may provide informed consent up to 30 days before their scheduled surgery. If a subject can only be screened on the day of surgery, the 
consent process must be started at least 24 hours prior to the day of surgery in order to ensure ample time for the subject to review the ICF and have all her 
questions answered by the investigator/study staff prior to providing informed consent. Screening procedures that are standard of care (SOC) at the institution may 
be completed prior to written informed consent. Any screening procedures that are not SOC, must be completed after written informed consent is provided and 
prior to surgery. 
If a subject can only be screened on the day of surgery, the informed consent process must still be started at least 24 hours prior to the conduct of any screening 
procedures that are not considered SOC at the institution and such procedures may not be performed until written informed consent is provided. 


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3. 
TABLE OF CONTENTS 
SIGNATURE PAGE ........................................................................................................................2 
2. 
SYNOPSIS ...................................................................................................................3 
3. 
TABLE OF CONTENTS ............................................................................................ 18 
4. 
LIST OF ACRONYMS/ABBREVIATIONS ............................................................. 22 
5. 
ethics ...........................................................................................................................24 
5.1. 
Institutional Review Board/Independent Ethics Committee .......................................24 
5.2. 
Ethical Conduct of the Study ...................................................................................... 24 
5.3. 
Subject Information and Consent ................................................................................24 
6. 
INVESTIGATORS AND STUDY ADMINISTRATION STRUCTURE .................24 
7. 
INTRODUCTION ......................................................................................................25 
7.1. 
Indication ....................................................................................................................25 
7.2. 
Current Therapies/Treatments .....................................................................................25 
7.3. 
EXPAREL (bupivacaine liposome injectable suspension) .........................................26 
7.4. 
Summary of Human Experience with EXPAREL ...................................................... 26 
8. 
OBJECTIVES .............................................................................................................27 
8.1. 
Primary Objective .......................................................................................................27 
8.2. 
Secondary Objectives .................................................................................................27 
9. 
OVERALL STUDY DESIGN AND PLAN ...............................................................27 
9.1. 
Study Design ...............................................................................................................27 
9.1.1. 
Duration of the Study and Subject Participation ........................................................31 
9.1.2. 
Study Stopping Rules .................................................................................................31 
9.2. 
Discussion of Study Design ........................................................................................31 
10. 
STUDY POPULATION .............................................................................................32 
10.1. 
Inclusion Criteria ........................................................................................................32 
10.2. 
Exclusion Criteria .......................................................................................................32 
10.3. 
Removal of Subjects from Therapy or Assessment .................................................... 33 
10.3.1. 
Withdrawal Secondary to Adverse Events .................................................................34 
10.3.2. 
Voluntary or Study Investigator Withdrawal ..............................................................34 
11. 
TREATMENTS ..........................................................................................................35 
11.1. 
Treatment to be Administered .....................................................................................35 
11.1.1. 
Infiltration Instructions/Procedure ..............................................................................36 


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11.1.2. 
EXPAREL Administration Considerations ................................................................37 
11.1.3. 
Intrathecal Morphine/Hydromorphone Administration Considerations .....................37 
11.2. 
Identity of the Investigational Products ...................................................................... 37 
11.2.1. 
Description of EXPAREL ..........................................................................................37 
11.2.2. 
Description of Reference Product ...............................................................................38 
11.3. 
Method of Assigning Subjects to Treatment ..............................................................38 
11.3.1. 
Randomization Scheme............................................................................................... 38 
11.3.2. 
Randomization Procedures ......................................................................................... 38 
11.3.3. 
Replacement of Subjects ............................................................................................. 38 
11.4. 
Selection of Doses in the Study ..................................................................................38 
11.5. 
Blinding ......................................................................................................................39 
11.5.1. 
Blinding Procedures ....................................................................................................39 
11.5.2. 
Unblinding Procedures ............................................................................................... 40 
11.6. 
Prior and Concomitant Therapy and Medications ...................................................... 40 
11.6.1. 
Prior Therapy and Medications ..................................................................................40 
11.6.2. 
Restricted Therapy and Medications During Surgery ................................................. 40 
11.6.3. 
Permitted Therapy or Medications after Surgery ........................................................ 41 
11.7. 
Treatment Compliance ................................................................................................42 
11.8. 
Accountability of Study Drug .....................................................................................42 
12. 
STUDY ENDPOINTS AND MEASUREMENTS .....................................................42 
12.1. 
Efficacy Measurements ...............................................................................................42 
12.2. 
Efficacy Endpoints ......................................................................................................43 
12.3. 
Safety Assessments ..................................................................................................... 44 
12.4. 
Safety Endpoints .........................................................................................................44 
12.5. 
Appropriateness of Measures .....................................................................................44 
13. 
STUDY PROCEDURES ............................................................................................44 
13.1. 
Instructions for Conducting Procedures and Measures ...............................................44 
13.1.1. 
Patient Binder and Patient Participant Diary .............................................................. 44 
13.1.2. 
Pain Intensity Assessments .........................................................................................45 
13.1.3. 
Overall Benefit of Analgesia Score Questionnaire ..................................................... 45 
13.1.4. 
Subject Satisfaction with Postsurgical Pain Control ..................................................46 
13.1.5. 
Discharge Readiness .................................................................................................. 46 


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13.1.6. 
Quality of Recovery .................................................................................................... 46 
13.2. 
Obtaining Informed Consent ......................................................................................46 
13.3. 
Screening/Baseline Procedures ...................................................................................46 
13.4. 
Day 1 - Operating Room .............................................................................................47 
13.5. 
Day 1 - Post-anesthesia Care Unit ..............................................................................48 
13.6. 
Day 1 - Prior to PACU Discharge ..............................................................................48 
13.7. 
Days 1-3 (0-72 Hours After Surgery/Hospital Discharge) ......................................... 49 
13.8. 
After Hospital Discharge Through Day 14 .................................................................49 
13.9. 
Day 14 Phone Call ......................................................................................................50 
14. 
ADVERSE EVENT REPORTING ............................................................................. 50 
14.1. 
Adverse Events ...........................................................................................................50 
14.1.1. 
Definitions ..................................................................................................................50 
14.1.2. 
Recording Adverse Events ......................................................................................... 51 
14.1.3. 
Severity of Adverse Events ........................................................................................51 
14.1.4. 
Relationship of Adverse Events to Study Drug ..........................................................52 
14.1.5. 
Outcome of Adverse Events ....................................................................................... 52 
14.1.6. 
Action Taken with Subject Because of an Adverse Event .........................................53 
14.2. 
Serious Adverse Events ..............................................................................................53 
14.2.1. 
Definition of a Serious Adverse Event .......................................................................53 
14.2.2. 
Reporting Serious Adverse Events ............................................................................. 54 
15. 
STATISTICAL METHODS .......................................................................................55 
15.1. 
Study Objective ..........................................................................................................55 
15.2. 
Study Endpoints ..........................................................................................................55 
15.3. 
Determination of Sample Size ....................................................................................55 
15.4. 
Analysis Populations ..................................................................................................55 
15.5. 
Handling Subject Dropouts and Discontinuations ...................................................... 55 
15.6. 
Statistical Analyses ..................................................................................................... 55 
15.6.1. 
Baseline Characteristics ..............................................................................................56 
15.6.2. 
Study Compliance .......................................................................................................56 
15.6.3. 
Efficacy Analyses .......................................................................................................56 
15.6.3.1. 
Primary Efficacy Endpoint ......................................................................................... 56 
15.6.3.2. 
Secondary Efficacy Endpoints ....................................................................................56 


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15.6.3.3. 
Tertiary Efficacy Endpoint(s) .....................................................................................56 
15.6.4. 
Safety Analyses ..........................................................................................................56 
15.7. 
Significance Testing ...................................................................................................57 
15.8. 
Interim Analyses .........................................................................................................57 
16. 
REFERENCES ...........................................................................................................58 
17. 
INVESTIGATOR AGREEMENT ............................................................................. 60 
18. 
APPENDICES ............................................................................................................61 
Appendix 1: Subject’s Reported Pain (Visual Analog Scale) at Rest .........................................62 
Appendix 2: Discharge Readiness ...............................................................................................63 
Appendix 3: Subject Satisfaction with Postsurgical Pain Control (Likert Scale) ......................64 
Appendix 4: Overall Benefit of Analgesia Score Questionnaire ................................................ 65 
Appendix 5: Quality of Recovery 15-item Questionnaire ...........................................................66 
Appendix 6: Clinical Laboratory Tests ....................................................................................... 68 
 
 
LIST OF TABLES 
Table 1. 
Time and Events Schedule of Study Procedures – Through 72 Hours After Surgery   
10 
Table 2. 
Time and Events Schedule of Study Procedures – Hospital Discharge 
Through Day 14 ..........................................................................................................15 


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4. 
LIST OF ACRONYMS/ABBREVIATIONS 
 
 
AE 
Adverse event 
ALT 
Alanine transaminase 
ANOVA 
Analysis of variation 
ASA 
American Society of Anesthesiology 
AST 
Aspartate transaminase 
CSE 
Combined spinal epidural 
C-section 
Cesarean section 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
Cmax 
Maximum plasma concentration 
CRF 
Case Report Form 
CV 
Coefficient of variation 
ECG 
Electrocardiogram 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transpeptidase 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IRT 
Interactive response technology 
IV 
Intravenous 
LDH 
Lactate dehydrogenase 
LS 
Least squares 
MedDRA 
Medical Dictionary for Regulatory Activities 
NRS 
Numeric rating scale 
NSAIDs 
Non-steroidal anti-inflammatory drugs 
OBAS 
Overall benefit of analgesia score 
OR 
Operating room 
PACU 
Post-anesthesia care unit 
PO 
Oral (per os) 
PRN 
As needed (Pro re nata) 
PTAE 
Pretreatment adverse event 
PVC 
Premature ventricular contraction 
q4h 
Every 4 hours 
q6h 
Every 6 hours 
QoR-15 
Quality of recovery 15-item questionnaire 
SAE 
Serious adverse event 


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SAP 
Statistical analysis plan 
SNRIs 
Selective norepinepherine reuptake inhibitors 
SSRIs 
Selective serotonin reuptake inhibitors 
TAP 
Transversus abdominis plane 
TEAE 
Treatment-emergent adverse event 
ULN 
Upper limit of normal 
US 
United States (of America) 
VAS 
Visual analog scale 
wWOCF 
Windowed    Worst-Observation-Carried-Forward 
 
 


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5. 
ETHICS 
 
5.1. 
Institutional Review Board/Independent Ethics Committee 
Prior to enrolling subjects into this study, each study site will obtain the approval of an 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) that complies with the 
International Conference on Harmonisation (ICH) Good Clinical Practices (GCP) and/or the 
United States (US) Food and Drug Administration (FDA) Title 21 Code of Federal Regulations 
(CFR) Part 56. Attention is directed to the basic elements that are required to be incorporated 
into the Informed Consent Form (ICF) under 21 CFR Part 50.25 and ICH GCP. 
 
5.2. 
Ethical Conduct of the Study 
This study will be conducted in accordance with the clinical research guidelines established by 
the FDA Title 21 CFR, Parts 50, 54, 56, and 312, and the ICH GCP. Study documents will be 
maintained in accordance with applicable regulations. 
 
5.3. 
Subject Information and Consent 
Before a subject undergoes any study-specific screening procedures, the investigator or designee 
will thoroughly explain to the subject the purpose of the study, the associated procedures, and 
any expected effects and potential adverse reactions.  A copy of the IRB-approved ICF will be 
provided to the subject, who will be given sufficient time and opportunity to inquire about the 
details of the study and decide whether or not to participate. The subject, and the study staff with 
whom she discusses the ICF, will sign and date the ICF. A photocopy of the signed ICF will be 
given to the subject. 
The investigator will explain to the subject that she is completely free to decline entry into the 
study and may withdraw from the study at any time, for any reason, without risking her medical 
care.  Similarly, the investigator and/or Pacira Pharmaceuticals, Inc. (Pacira) will be free to 
withdraw the subject at any time for safety or administrative reasons. Any other requirements 
necessary for the protection of the human rights of the subject will also be explained, according 
to the current ICH GCP (E6) and the Declaration of Helsinki (1964, and as amended through 
2000 [Edinburgh]). 
6. 
INVESTIGATORS AND STUDY ADMINISTRATION 
STRUCTURE 
Information regarding the investigators, study sites, and other service providers is available upon 
request to the IRB/IECs and regulatory agencies. 


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7. 
INTRODUCTION 
7.1. 
Indication 
EXPAREL® was developed to extend pain relief with a single dose administration without the 
use of indwelling catheters and to decrease the requirement for supplemental opioid medications. 
It is indicated for use as an analgesic injected into the surgical site for postsurgical pain relief. 
Effective postsurgical pain control is a critical element in patient recovery following surgery, 
as the majority of patients may experience significant pain, particularly in the first few days. 
Improved postsurgical pain management contributes to better healing, faster patient mobilization, 
shortened hospital stays, and reduced healthcare costs (American Society of Anesthesiologists 
Task Force on Pain Management 1995). 
7.2. 
Current Therapies/Treatments 
Current modalities of postoperative analgesia include wound infiltration with local anesthetics 
combined with the systemic administration of analgesics (multimodal therapy). Multimodal 
therapy usually includes opioid medications, which have considerable drawbacks including time 
and resources required for monitoring opioid-related side effects. A reduction in the use of 
postoperative opioids is desirable to decrease the incidence and severity of opioid-induced 
adverse effects, such as respiratory depression, nausea, vomiting, constipation, somnolence, 
pruritus, and urinary retention. 
With over 70 million surgeries performed annually in the US, postoperative pain is a ubiquitous 
condition among our population. While it is a predictable component of the postoperative 
process, such pain is often poorly managed, resulting in clinical and physiological changes that 
increase morbidity and mortality (inability to ambulate early, etc), diminish quality of life, 
and extend length of stay, thereby increasing hospital expenditures (Oderda 2007) and reducing 
patient satisfaction. Effective relief of acute pain with minimal opioid complications, on the 
other hand, may improve clinical outcomes, avoid complications (like delay in regaining bowel 
function or an inability to tolerate liquid and solid oral intake, etc.), and conserve healthcare 
resources. As such, the Joint Commission on Accreditation of Healthcare Organizations requires 
that all healthcare facilities practice adequate pain management and monitor opioid-related 
adverse events (AEs) (Apfelbaum 2003). 
Opioid analgesics have long been established to be the most effective agents used for the 
management of moderate to severe postoperative pain, and are currently considered the mainstay 
of treatment.  Opioid-only regimens are common and intravenous (IV) patient-controlled 
analgesia is a widely used delivery system for morphine sulfate. Adverse events related to 
opioid administration (eg, nausea, vomiting, ileus, confusion), however, represent one important 
reason that there is a need to develop opioid-sparing strategies. Indeed, fear of gastrointestinal 
side effects such as nausea and vomiting, as well as respiratory depression, present major 
limitations for the widespread use of opioid analgesics (Chernin 2001 and Viscusi 2009). 


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Furthermore, management of opioid-related events often requires medical attention (eg, opioid 
antagonists, antiemetic agents) and increased pharmacy/nursing time, which may raise healthcare 
expenses (Carroll 1994). 
7.3. 
EXPAREL (bupivacaine liposome injectable suspension) 
Bupivacaine is one of the longer-acting local anesthetics, but even so it has a limited duration 
of action after local administration, usually reported as less than 8 hours. EXPAREL (Pacira 
Pharmaceuticals, Inc., Parsippany, New Jersey) is a bupivacaine liposome injectable suspension. 
It consists of microscopic spherical, multivesicular liposomes (DepoFoam® drug delivery 
system), organized in a honeycomb-like structure comprising numerous non-concentric internal 
aqueous chambers containing a bupivacaine base at a concentration of 13.3 mg/mL.  Each 
chamber is separated from adjacent chambers by lipid membranes. The lipids (phospholipids, 
cholesterol, and triglycerides) are naturally occurring or close analogs of endogenous lipids. 
Bupivacaine is slowly released from the DepoFoam particles by a complex mechanism involving 
reorganization of the barrier lipid membranes and subsequent diffusion of the drug over an 
extended period of time. 
EXPAREL was approved by the US FDA in 2011 for administration into the surgical site to 
produce postsurgical analgesia. The active ingredient (bupivacaine) and inactive ingredient 
(DepoFoam) of EXPAREL are each contained, though separately, in FDA-approved products: 
• 
Bupivacaine HCl solution, a well-characterized anesthetic/analgesic, with more than 
35 years of its use in the US. 
• 
DepoFoam, a liposomal extended-release formulation contained in the marketed product 
DepoCyt® (1999).  The form of DepoFoam used in EXPAREL has a slightly different 
mixture of lipid components than that used in DepoCyt. 
7.4. 
Summary of Human Experience with EXPAREL 
Pacira has conducted more than 36 clinical studies and one observational follow-up study to 
investigate EXPAREL. Across these studies, over 1800 human subjects received EXPAREL at 
doses ranging from 2 mg to 665 mg (equivalent to 2 mg to 750 mg bupivacaine HCl) 
administered by various routes: local infiltration into the surgical site, subcutaneous, perineural 
(or “nerve block”), and epidural.  The product has been generally well tolerated and, in active 
comparator studies, reported AEs occurred at a similar rate as the corresponding bupivacaine 
HCl controls. 
Across the entire clinical development program, in doses up to 665 mg, no adverse safety signal 
attributed to either the central nervous or cardiovascular systems was reported with EXPAREL. 
Adverse events that are occasionally reported with high doses of standard bupivacaine solution 
have not been observed. In two rigorous QTc studies, EXPAREL did not cause significant QTc 
prolongation even at the highest dose evaluated. 


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The robust nature of the efficacy results in both wound infiltration pivotal studies 
(SKY0402-C-316 and SKY0402-C-317) was demonstrated across subgroups of subjects with 
various prognostic features and across demographic subgroups. 
Following the NDA submission of EXPAREL, numerous clinical studies were conducted in 
which EXPAREL was administered via various routes of administration including infiltration 
into the transversus abdominis plane (TAP) (Sterlicht 2014, Feierman 2014) and intraoperative 
wound infiltration or instillation.  Additionally, as of June 2017, more than 3 million patients 
have received EXPAREL in the postmarketing setting. 
Please refer to the Investigator’s Brochure for additional information regarding the completed 
studies. Please see the EXPAREL Full Prescribing Information for complete safety information 
regarding EXPAREL (liposome bupivacaine injectable suspension) in the setting of wound 
infiltration. 
8. 
OBJECTIVES 
8.1. 
Primary Objective 
The primary objective of this study is to compare total opioid consumption through 72 hours 
following EXPAREL+bupivacaine HCl infiltration into the TAP after spinal anesthesia to active 
bupivacaine infiltration in the TAP after spinal anesthesia in subjects undergoing elective 
cesarean section (C-section). 
8.2. 
Secondary Objectives 
The secondary objectives are to assess efficacy and safety parameters and patient satisfaction. 
9. 
OVERALL STUDY DESIGN AND PLAN 
9.1. 
Study Design 
This is a Phase-4, multicenter, randomized, double-blind, active-controlled study in 
approximately 152 adult subjects undergoing elective C-section. 
Obtaining Informed Consent 
Potential participants may provide informed consent up to 30 days before their scheduled 
surgery. If a subject can only be screened on the day of surgery, the consent process must be 
started at least 24 hours prior to the day of surgery in order to ensure ample time for the subject 
to review the ICF and have all her questions answered by the investigator/study staff prior to 
providing informed consent. Screening procedures that are standard of care (SOC) at the 
institution may be completed prior to written informed consent. Any screening procedures that 
are not SOC, must be completed after written informed consent is provided and prior to surgery. 
(see Section 13.3). 


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Screening 
Subjects will be screened within 7 30 days prior to surgery; screening on the day of surgery will 
be allowed but is discouraged. If a subject can only be screened on the day of surgery, the 
informed consent process must still be started at least 24 hours prior to the conduct of any 
screening procedures that are not considered SOC at the institution and such procedures may not 
be performed until written informed consent is provided All screening procedures that are not 
SOC must be performed and documented within the 730-day time window (inclusive of the day 
of surgery for those subjects who can only be screened on the day of surgery) as described here. 
During the screening visit, subjects will be assessed for any past or present medical conditions 
that in the opinion of the investigator would preclude them from study participation. 
After the ICF is signed, a medical history, surgical history, physical examination, 12-lead 
electrocardiogram (ECG), vital sign measurements, clinical laboratory tests (hematology and 
chemistry), alcohol breath test, and urine drug screen will be performed. 
Day of Surgery 
Pre-operative medications: Use of pre-operative analgesics (eg, opioid medications, 
acetaminophen, nonsteroidal anti-inflammatory drugs [NSAIDs]) is prohibited. 
Eligible subjects will be randomized in a blinded 1:1 ratio to either: 
• 
Group 1: EXPAREL+bupivacaine TAP infiltration following spinal anesthesia 
• 
Group 2: Active bupivacaine TAP infiltration following spinal anesthesia 
On Day 1, prior to the C-section, all subjects will receive a intrathecal injection of 150 mcg 
preservative-free morphine for spinal injection (eg, Duramorph®) in conjunction with single-shot 
spinal anesthesia using 1.4-1.6 mL bupivacaine HCl 0.75% and 15 mcg fentanyl. If preservative- 
free morphine for spinal injection (eg, Duramorph) is unavailable because of a drug shortage, 
subjects may instead receive an intrathecal injection of 75 mcg preservative-free hydromorphone 
in conjunction with single-shot spinal anesthesia using 1.4-1.6 mL bupivacaine HCl 0.75% and 
15 mcg fentanyl. A combined spinal epidural (CSE) anesthesia technique may also be used 
provided the epidural component is not used. Subjects who receive the epidural component of 
the CSE anesthesia must be immediately withdrawn from the study. 
Intraoperative medications: The intraoperative use of the following medications is discouraged, 
but may be permitted if clinically indicated based on the investigator’s discretion (all 
medications must be appropriately recorded [ie, drug, dose, and route of administration]): 
ketamine and midazolam (Versed®). Prophylactic use of dexamethasone for prevention of nausea 
and vomiting is prohibited. 
After delivery of the baby and prior to the TAP infiltration, a small amount of lidocaine (<2 mL) 
may be administered subcutaneously to form a skin wheal over the area of the needle insertion 
site.  A 2-point classic TAP block, in 2 steps (see below), must be performed under ultrasound 
guidance and must be performed no more than 90 minutes after skin incision closure of the 


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C- section. A confirmatory ultrasound picture or video will be taken of each side of the abdomen 
after the TAP needle position has been established and after infiltration of study drug. 
TAP infiltration: The TAP infiltration includes two steps: (1) TAP needle placement and saline 
hydrodissection and (2) study drug mixture infiltration into the TAP. Each step is briefly 
described below for one side of the abdomen and must be repeated on the contralateral side to 
complete the bilateral, 2-point TAP required for the study. For complete, step-by-step 
instructions on performing the TAP infiltration under ultrasound guidance, please refer to the 
Pharmacy Binder. 
(1) TAP needle placement and saline hydrodissection: For subjects in both study groups, use 
ultrasound guidance to place the TAP needle into the desired location and use a 10-mL 
syringe pre-filled with normal saline to perform hydrodissection of the TAP.  (Note: it is 
not necessary to use the full 10 mL of normal saline for hydodissection.) An ultrasound 
image of the TAP needle placement must be captured after saline hydrodissection. 
(2) Study drug mixture infiltration into the TAP: Subjects randomized to the 
EXPAREL+bupivacaine group (Group 1) will receive 30 mL of a study drug mixture 
containing 10 mL EXPAREL (133 mg) combined with 10 mL bupivacaine HCl 0.25% (25 
mg) and 10 mL normal saline (total mixture 30 mL) administered into the TAP. An 
ultrasound image of the TAP needle placement must be captured after study drug 
infiltration. 
Subjects randomized to the active bupivacaine group (Group 2) will receive 30 mL of a 
study drug mixture containing 10 mL bupivacaine HCl 0.25% (25 mg) combined with 
20 mL normal saline (total mixture 30 mL) administered into the TAP. An ultrasound 
image of the TAP needle placement must be captured after study drug mixture infiltration. 
Repeat the above steps on the contralateral side to complete the bilateral, 2-point TAP required 
for the study. 
Postsurgical Analgesia: Patient-controlled analgesia is not permitted 
The following multimodal pain regimen will be used: 
At the time of skin incision closure (Note: it is very important that these be administered at the 
time of wound closure and not prior to or before the end of surgery) 
• Intravenous (IV) ketorolac 15 mg (1 dose) 
• IV acetaminophen 1000 mg (1 dose) 
Beginning 6 hours after skin incision closure 
• Scheduled oral (PO) acetaminophen 650 mg beginning 6 hours from the administration of 
the single dose of IV acetaminophen at the end of surgery and then every 6 hours (q6h) for 
up to 72 hours or hospital discharge 


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• Scheduled PO ibuprofen 600 mg beginning 6 hours from the administration of the single 
dose of IV ketorolac at the end of surgery and then q6h for up to 72 hours or hospital 
discharge 
This multi-modal pain regimen is a requirement for all subjects in the study and is not subject 
to investigator discretion. The date, time, and dose of all standardized multimodal pain 
medications administered must be recorded. Note: The scheduled PO medication will be 
administered on a q6h schedule only through hospital discharge. 
Rescue Medication: Subjects should only receive opioid rescue pain medication upon request for 
breakthrough pain. Postsurgical rescue medication will comprise PO immediate-release 
oxycodone (initiated at 5-10 mg every 4 hours [q4h] or as needed [PRN]). If a subject is unable 
to tolerate PO medication or fails the PO oxycodone rescue, IV morphine (initiated at 1-2 mg) or 
hydromorphone (initiated at 0.3-0.5 mg) may be administered q4h or PRN. All surgical and 
postsurgical opioid and other analgesics (pain medications) administered must be documented 
through Day 14 postsurgery. Additionally, an unscheduled pain intensity score using a 10-cm 
visual analog scale (VAS; see Appendix 1) must be completed immediately prior to any rescue 
medication while in the hospital. 
Permitted medications for the prevention and treatment of possible medication side effects 
include the following and may be administered at the discretion of the study site principal 
investigator: 
• Ondansetron 4 mg IV immediately after delivery of the baby. 
• Ondansetron 4 mg IV (should not exceed a maximum of 12 mg in a 24-hour period) for 
intraoperative and postoperative nausea and vomiting 
• Metoclopramide 10 mg PO PRN for nausea and vomiting 
• Nalbuphine IV 2.5 mg PRN for pruritus 
• Naloxone IV 50-100 mcg PRN for pruritus. 
Postsurgical Assessments 
Subjects will remain in the hospital for up to 72 hours after surgery. Postsurgical assessments 
will include: 
• Opioid use 
• Time of first unassisted ambulation 
• Pain intensity scores at rest using a 10-cm VAS (see Appendix 1) 
• Discharge readiness (see Appendix 2) 
• Subject’s satisfaction with postsurgical pain control (see Appendix 3) 
• Overall benefit of anesthesia score (OBAS) questionnaire (see Appendix 4) 
• The Quality of recovery 15-item questionnaire (QoR-15; see Appendix 5) 
A phone call will be made to each subject on Day 14 for safety purposes and to inquire as to 
whether the subject made any unscheduled phone calls or office visits related to pain; 


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experienced any hospital readmission; or experienced an emergency room visit since hospital 
discharge. Adverse events and serious adverse events (SAEs) will be recorded from the time the 
ICF is signed through Day 14.  Any concomitant medications to treat AEs through Day 14 will 
also be recorded. 
9.1.1. 
Duration of the Study and Subject Participation 
Participation will begin at the signing of the ICF.  No more than 7 30 days should pass between 
signing of the ICF and performance of the surgery.  The time from study drug administration 
through the end of participation is 14 ± 3 days.  Therefore, subjects may participate in the study 
for up to 44 47 days. 
9.1.2. 
Study Stopping Rules 
If Pacira, the investigator, or officials from regulatory authorities discover conditions during the 
study that indicate that the study or study site should be terminated, this action may be taken 
after Pacira has consulted with appropriate regulatory authorities and notified the investigator(s). 
The Pacira Medical Monitor and Pharmacovigilance team review all SAEs reported from Pacira 
clinical studies on an ongoing basis and in real time (ie, as the events are reported). The Medical 
Monitor is responsible for temporarily halting the study if the type, frequency, or 
seriousness/severity of such events suggests a potential threat to the safety of the study 
participants. If such action is taken, a thorough review of all available data will be conducted. 
Based on the results of this review and discussions with investigators and/or regulatory 
authorities as warranted, the study may be restarted or permanently terminated. 
In addition, any death will be thoroughly reviewed and appropriate action taken. 
9.2. 
Discussion of Study Design 
EXPAREL is approved for infiltration into a surgical wound. This Phase-4, multicenter, 
double-blind study will evaluate the efficacy and safety of EXPAREL+bupivacaine infiltration 
into the TAP compared to active bupivacaine infiltration into the TAP following bupivacaine 
HCl spinal anesthesia in subjects undergoing elective C-section. The double-blind study design 
is intended to avoid potential bias resulting from subject or investigator knowledge of the 
assigned treatment. 
The physiology of pain involves multiple complex pathways and mechanisms and the successful 
management of pain requires the use of a combination of pain medications in a “balanced” or 
multimodal approach to achieve a state of balanced analgesia (White 2010). 
The practice of multimodal analgesia is being adopted across different patient-care pathways and 
is becoming the standard of care at major surgery centers globally. There is quite a variety of 
options of medications within the multimodal approach either in different combinations or when 
used alone. In all cases, the goal is to reduce postoperative pain associated with surgery and 


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reduce opioid use and opioid-related adverse events. In some cases, such an approach may also 
reduce the average length of hospital stay (Elvir-Lazo 2010). 
EXPAREL (liposomal bupivacaine) is an amide local anesthetic indicated for single-dose 
infiltration into the surgical site to produce postsurgical analgesia. This study is designed to 
assess the effectiveness of EXPAREL administered as a TAP in a multimodal setting to reduce 
total postsurgical opioid consumption. All subjects in the study will be eligible to receive an 
opioid analgesic, if needed, to control breakthrough postsurgical pain as part of the multimodal 
approach to pain management. 
10. 
STUDY POPULATION 
Note: Based on the World Health Organization’s Guidance: Breastfeeding and Maternal 
Medication, Recommendations for Drugs in the Eleventh WHO Model List of Essential Drugs 
(WHO 2002), bupivacaine is compatible with breastfeeding and, therefore, there are no 
restrictions in this study regarding the participation of women who wish to breastfeed following 
treatment with study drug. 
10.1. 
Inclusion Criteria 
Subjects eligible for study entry will meet all of the following criteria: 
1. Females 18 years of age and older at screening. 
2. Term pregnancies of 37 to 42 weeks gestation, scheduled to undergo elective C-section. 
3. ASA physical status 1, 2, or 3. 
4. Able to provide informed consent, adhere to the study visit schedule, and complete all 
study assessments. 
10.2. 
Exclusion Criteria 
A subject will not be eligible for the study if she meets any one of the following criteria: 
1. Subjects who, in the opinion of the investigator, have a high-risk pregnancy (eg, multiple 
gestations, pregnancy resulting from in vitro fertilization, gestational diabetes). 
2. Subjects with a pregnancy-induced medical condition or complication (eg, hypertension, 
pre-eclampsia, chorioamnionitis). 
3. Subjects with 3 or more prior C-sections 
4. Pre-pregnancy body mass index >50 kg/m2 or otherwise not anatomically appropriate to 
undergo a TAP block. 
5. Allergy, hypersensitivity, intolerance, or contraindication to any of the study medications 
for which an alternative is not named in the protocol (eg, amide-type local anesthetics, 
opioids, bupivacaine, NSAIDs, spinal anesthesia). 


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6. Planned concurrent surgical procedure with the exception of salpingo-oophorectomy or 
tubal ligation. 
7. Severely impaired renal or hepatic function (eg, 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.) 
8. Subjects at an increased risk for bleeding or a coagulation disorder (defined as platelet 
count less than 80, 000 × 103/mm3 or international normalized ratio greater than 1.5) 
9. Concurrent painful physical condition that may require analgesic treatment (such as 
long-term, consistent use of opioids) in the postsurgical period for pain that is not strictly 
related to the surgery and which may confound the postsurgical assessments. 
10. Clinically significant medical disease in either the mother or baby that, in the opinion of 
the investigator, would make participation in a clinical study inappropriate. This includes 
any psychiatric or other disease in the mother that would constitute a contraindication to 
participation in the study or cause the mother to be unable to comply with the study 
requirements. 
11. History of, suspected, or known addiction to or abuse of illicit drug(s), prescription 
medicine(s), or alcohol within the past 2 years. 
12. 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 
13. Previous participation in an EXPAREL study. 
In addition, the subject will be ineligible to receive study drug and will be withdrawn from 
the study if she meets the following criteria during surgery: 
14. Any clinically significant event or condition uncovered during the surgery (eg, excessive 
bleeding, acute sepsis) that might render the subject medically unstable or complicate the 
subject’s postsurgical course. 
15. Receives the epidural component of CSE anesthesia during participation in the study. 
10.3. 
Removal of Subjects from Therapy or Assessment 
Every reasonable effort shall be made to maintain subject compliance and participation in the 
study. Reasons for discontinuation of any subject from the study will be recorded. 
If any clinically significant event or condition is uncovered during the surgery (eg, excessive 
bleeding, acute sepsis) the subject should be withdrawn from study and the event or condition 
should be reported as an AE or SAE. 


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Additionally, any subjects who receive the epidural component of the CSE anesthesia must be 
immediately withdrawn from the study. 
If a subject withdraws from the study and has an ongoing AE, every effort must be made to 
follow-up on such events until satisfactory resolution is obtained, or further follow-up is 
otherwise no longer warranted. 
10.3.1. 
Withdrawal Secondary to Adverse Events 
If a subject experiences an AE that renders her incapable of continuing with the remaining 
assessments, she will be discontinued from further participation in the study.  A final evaluation 
should be performed so that the subject’s study participation can be terminated in a safe and 
orderly manner. If such a subject discontinues prior to hospital discharge, all assessments to be 
conducted at 72 hours/hospital discharge should be conducted as part of this final examination. 
If such a subject discontinues following hospital discharge, all information captured in the 
Patient Participant Diary should be collected and a final telephone call for safety should be made. 
Any subject who discontinues because of an AE should be instructed to notify the study 
personnel of any abnormalities and to come to the study site if medical evaluation is needed and 
the urgency of the situation permits. Any subject exhibiting undesirable side effects will receive 
appropriate treatment at the discretion of the investigator until resolution of the effect. 
This study involves a single infiltration of study drug; therefore, subjects should not be 
terminated from the ongoing study assessments as long as they are willing and able to continue 
with the follow-up schedule according to the protocol.  For emergencies and other unscheduled 
visits to a medical facility other than the study site, medical records must be obtained by the 
investigator and appropriate information captured in the subject’s case report form (CRF). 
10.3.2. 
Voluntary or Study Investigator Withdrawal 
Subjects are free to discontinue from the study at any time, without prejudice to future treatment. 
A subject may be discontinued from the study if she refuses EXPAREL infiltration or refuses to 
comply with study procedures. Subjects should be encouraged to complete the study safety 
assessments.  Reasons for discontinuation from the study will be recorded. 
If a subject is discontinued by the investigator or voluntarily withdraws from the study after 
receiving study drug, the subject will be asked to complete a final evaluation so that she can be 
withdrawn in a safe and orderly manner. If such a subject discontinues prior to hospital 
discharge, all assessments to be conducted at 72 hours/hospital discharge should be conducted as 
part of this final examination. If such a subject discontinues following hospital discharge, all 
information captured in the Participant Diary should be collected and a final telephone call for 
safety should be made. 
After termination from the study, the subject may be followed for safety including monitoring of 
AEs through Day 14. 


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11. 
TREATMENTS 
11.1. 
Treatment to be Administered 
There will be two treatment groups; eligible subjects will be randomized in a blinded 1:1 ratio to 
either: 
• 
Group 1: EXPAREL+bupivacaine TAP infiltration following spinal anesthesia 
• 
Group 2: Active bupivacaine TAP infiltration following spinal anesthesia 
On Day 1, prior to the C-section, all subjects will receive a intrathecal injection of 150 mcg 
preservative-free morphine for spinal injection (eg, Duramorph) in conjunction with single-shot 
spinal anesthesia using 1.4-1.6 mL bupivacaine HCl 0.75% and 15 mcg fentanyl. If preservative- 
free morphine for spinal injection (eg, Duramorph) is unavailable because of a drug shortage, 
subjects may instead receive an intrathecal injection of 75 mcg preservative-free hydromorphone 
in conjunction with single-shot spinal anesthesia using 1.4-1.6 mL bupivacaine HCl 0.75% and 
15 mcg fentanyl. A CSE anesthesia technique may also be used provided the epidural component 
is not used. Subjects who receive the epidural component of the CSE anesthesia must be 
immediately withdrawn from the study. 
After delivery of the baby and prior to the TAP infiltration, a small amount of lidocaine (<2 mL) 
may be administered subcutaneously to form a skin wheal over the area of the needle insertion 
site.  A 2-point classic TAP block, in 2 steps (see below), must be performed under ultrasound 
guidance and must be performed no more than 90 minutes after skin incision closure of the C- 
section. A confirmatory ultrasound picture or video will be taken of each side of the abdomen 
after the TAP needle position has been established and after infiltration of study drug. 
TAP infiltration: The TAP infiltration includes two steps: (1) TAP needle placement and saline 
hydrodissection and (2) study drug mixture infiltration into the TAP. Each step is briefly 
described below for one side of the abdomen and must be repeated on the contralateral side to 
complete the bilateral, 2-point TAP required for the study. For complete, step-by-step 
instructions on performing the TAP infiltration under ultrasound guidance, please refer to the 
Pharmacy Binder. 
(1) TAP needle placement and saline hydrodissection: For subjects in both study groups, use 
ultrasound guidance to place the TAP needle into the desired location and use a 10-mL 
syringe pre-filled with normal saline to perform hydrodissection of the TAP.  (Note: it is 
not necessary to use the full 10 mL of normal saline for hydodissection.) An ultrasound 
image of the TAP needle must be captured after saline hydrodissection. 
(2) Study drug mixture infiltration into the TAP: Subjects randomized to the 
EXPAREL+bupivacaine group (Group 1) will receive 30 mL of a study drug mixture 
containing 10 mL EXPAREL (133 mg) combined with 10 mL bupivacaine HCl 0.25% (25 
mg) and 10 mL normal saline (total mixture 30 mL) administered into the TAP. An 


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ultrasound image of the TAP needle placement must be captured after study drug 
infiltration. 
Subjects randomized to the active bupivacaine group (Group 2) will receive 30 mL of a 
study drug mixture containing 10 mL bupivacaine HCl 0.25% (25 mg) combined with 
20 mL normal saline (total mixture 30 mL) administered into the TAP. An ultrasound 
image of the TAP needle placement must be captured after study drug mixture infiltration. 
Repeat the above steps on the contralateral side to complete the bilateral, 2-point TAP required 
for the study. 
11.1.1. 
Infiltration Instructions/Procedure 
On Day 1, prior to the C-section, all subjects will receive an intrathecal injection of 150 mcg 
preservative-free morphine for spinal injection (eg, Duramorph) in conjunction with single-shot 
spinal anesthesia using 1.4-1.6 mL bupivacaine HCl 0.75% and 15 mcg fentanyl. If preservative- 
free morphine for spinal injection (eg, Duramorph) is unavailable due to a drug shortage, 
subjects may instead receive an intrathecal injection of 75 mcg preservative-free hydromorphone 
in conjunction with single-shot spinal anesthesia using 1.4-1.6 mL bupivacaine HCl 0.75% and 
15 mcg fentanyl. A CSE anesthesia technique may also be used provided the epidural component 
is not used. Subjects who receive the epidural component of the CSE anesthesia must be 
immediately withdrawn from the study. 
The TAP infiltration includes two steps: (1) TAP needle placement and saline hydrodissection 
and (2) study drug mixture infiltration into the TAP. Each step is briefly described below for one 
side of the abdomen and must be repeated on the contralateral side to complete the bilateral, 2- 
point TAP required for the study. For complete, step-by-step instructions on performing the TAP 
infiltration under ultrasound guidance, please refer to the Pharmacy Binder. 
(1) TAP needle placement and saline hydrodissection: For subjects in both study groups, use 
ultrasound guidance to place the TAP needle into the desired location and use a 10-mL 
syringe pre-filled with normal saline to perform hydrodissection of the TAP.  (Note: it is 
not necessary to use the full 10 mL of normal saline for hydodissection.) An ultrasound 
image of the TAP needle must be captured after saline hydrodissection. 
(2) Study drug mixture infiltration into the TAP: Subjects randomized to the 
EXPAREL+bupivacaine group (Group 1) will receive 30 mL of a study drug mixture 
containing 10 mL EXPAREL (133 mg) combined with 10 mL bupivacaine HCl 0.25% (25 
mg) and 10 mL normal saline (total mixture 30 mL) administered into the TAP. An 
ultrasound image of the TAP needle placement must be captured after study drug 
infiltration. 
Subjects randomized to the active bupivacaine group (Group 2) will receive 30 mL of a 
study drug mixture containing 10 mL bupivacaine HCl 0.25% (25 mg) combined with 


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20 mL normal saline (total mixture 30 mL) administered into the TAP. An ultrasound 
image of the TAP needle placement must be captured after study drug mixture infiltration. 
Repeat the above steps on the contralateral side to complete the bilateral, 2-point TAP required 
for the study. 
The maximum dosage of EXPAREL should not exceed 266 mg. Product handling and storage 
procedures will be in accordance with the product package insert (see also Section 11.1.2). 
11.1.2. 
EXPAREL Administration Considerations 
Because of the potential risk of severe adverse effects associated with the administration of 
bupivacaine, the study sites must be equipped to manage subjects with any evidence of cardiac, 
neurological, or respiratory toxicity. 
Administration of additional local anesthetics, including lidocaine, is prohibited and no agents 
other than bupivacaine HCl 0.25% in 20 mL are to be admixed with EXPAREL. Lidocaine and 
other local anesthetics are not permitted to be locally administered during the surgery because 
they are known to interact with EXPAREL resulting in the displacement of bupivacaine and 
elevated plasma levels. 
EXPAREL may not be administered to a subject if the vial has been open for more than 4 hours. 
In order to prevent EXPAREL from settling, gently inverting and re-inverting the syringe prior 
to administration is recommended. 
11.1.3. 
Intrathecal Morphine/Hydromorphone Administration 
Considerations 
The most serious adverse experience encountered during administration of intrathecal morphine/ 
hydromorphone, respiratory depression and/or respiratory arrest, may be severe and could 
require intervention.   Naloxone injection and resuscitative equipment should be immediately 
available for administration in case of life-threatening or intolerable side effects and whenever 
intrathecal morphine/ hydromorphone therapy is being initiated. 
Intrathecal morphine/ hydromorphone is contraindicated in patients with medical conditions that 
would preclude the administration of opioids via the IV route, including an allergy to morphine/ 
hydromorphone or other opiates, acute bronchial asthma, or upper airway obstruction. 
Morphine/ hydromorphone, like all opioid analgesics, may cause severe hypotension in 
individuals whose ability to maintain blood pressure is compromised by a depleted blood volume 
or a concurrent administration of drugs, such as phenothiazines or general anesthetics. 
11.2. 
Identity of the Investigational Products 
11.2.1. 
Description of EXPAREL 
EXPAREL (bupivacaine liposome injectable suspension) is formulated as a sterile, 
non-pyrogenic, white to off-white, preservative-free homogenous suspension of bupivacaine 


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encapsulated into multivesicular liposomes (the DepoFoam drug delivery system). Bupivacaine 
is present at a nominal concentration of 13.3 mg/mL. For the purposes of this study, EXPAREL 
will be provided in 20 mL, 1.3% (13.3 mg/mL) single-use, clear glass vials. EXPAREL vials 
should be stored refrigerated between 2°C to 8°C (36°F to 46°F). 
11.2.2. 
Description of Reference Product 
The reference product is 20 mL bupivacaine HCl 0.25% and 40 mL normal saline (total volume 
60 mL) administered as an infiltration into the TAP under ultrasound guidance after spinal 
anesthesia. Bupivacaine HCl is a long-acting local anesthetic, used for surgical anesthesia and 
acute pain management. It is an alternative to NSAIDs and opioids. 
11.3. 
Method of Assigning Subjects to Treatment 
11.3.1. 
Randomization Scheme 
Subjects will be randomized in a 1:1 ratio. The randomization code will be generated by a 
centralized randomization system, which will also be used to communicate subject 
randomizations to study sites. All randomized subjects will have both a unique subject identifier 
and a unique random code identifier. No subject or random code identifiers will be reused once 
assigned. 
11.3.2. 
Randomization Procedures 
Once a subject is identified as being qualified for the study in accordance with the eligibility 
criteria (see Section 10.1 and Section 10.2), and is at the study site for surgery, the unblinded 
research pharmacist or designee will obtain a randomization assignment. The subject will be 
considered randomized into the study once the study treatment assignment is received. 
11.3.3. 
Replacement of Subjects 
Subjects who withdraw from the study before being randomized may be replaced. Once 
assigned, subject numbers will not be reused; subjects enrolled to replace those who withdraw 
will be assigned a unique subject number. 
11.4. 
Selection of Doses in the Study 
During the clinical development of EXPAREL, single doses ranging from 2 mg to 665 mg have 
been safely administered via various routes. Pharmacokinetic studies have shown that because 
EXPAREL releases bupivacaine gradually as the lipid structure breaks down, administration of 
EXPAREL 266 mg results in a maximum plasma concentration (Cmax) equivalent to that seen 
with standard bupivacaine 100 mg.  Clinical studies have shown that for wound infiltration a 
total dose of 266 mg (20 mL) of EXPAREL is safe and efficacious. Based on this experience, 
the FDA-approved marketed dose of 266 mg was deemed appropriate for this study. 
Intrathecal preservative-free morphine for spinal injection (eg, Duramorph) is commonly used 
during C-section, usually at a dose between 0.1 mg and 0.2 mg (Sviggum 2106). The midpoint of 


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0.15 mg (150 mcg) is preferred by some anesthesiologists because it balances duration of 
analgesia (which may be shorter with a lower dose) and incidence of opioid-related adverse 
events such as nausea and vomiting (which may increase with a higher dose). If preservative-free 
morphine for spinal injection (eg, Duramorph) is unavailable because of a drug shortage, 
preservative-free hydromorphone may also be used in C-section, usually at a dose that is 50% 
lower than that for intrathecal morphine. The study dose of 0.15 mg (150 mcg) of intrathecal 
morphine or 0.075 mg (75 mcg) of intrathecal hydromorphone is also supported by a recent 
dose-finding study that sought to determine the effective analgesic dose for 90% of patients 
(ED90) for both intrathecal morphine and hydromorphone in patient undergoing C-section 
(Sviggum 2106). 
11.5. 
Blinding 
11.5.1. 
Blinding Procedures 
To maintain the double-blind study design, only the unblinded study personnel who are NOT 
involved with protocol-specific, postsurgical assessments may prepare and administer the study 
drug. Staff members conducting study-specific, postsurgical assessments and the subjects will 
remain blinded to the assigned treatment throughout the study. If a subject experiences an SAE, 
Pacira will only unblind the subject’s treatment if doing so is necessary to manage the treatment 
of the SAE.  Expedited SAEs will be unblinded by Pacira for regulatory reporting purposes. 
At each site, only the designated unblinded pharmacist will receive the unblinded randomization 
assignments and be responsible for preparing study drug. 
Assignment of blinded and unblinded responsibilities regarding the preparation of study drug 
should take into account that EXPAREL must be administered within 4 hours of opening 
the vial. Syringes containing study drug will need to be gently inverted several times 
to re-suspend any settling of the study drug that may have occurred prior to administration. 
The individuals preparing and administering study drug will not be allowed to perform any of 
the study assessments or reveal the assigned study treatment to any other members of the study 
team at any time. The infiltration of study drug will be recorded using the minimal amount of 
information necessary to avoid unblinding staff who will be participating in blinded procedures 
(see Pharmacy Binder for additional details). 
No crossover will be permitted between the blinded and unblinded study site personnel during 
the study period.  The assignment of site monitors will also be segregated.  Blinded monitors will 
review CRFs, clinic charts, and all other study-related documents that do not disclose the 
allocation of study treatment. Care should be taken in recording and review of operating room 
records to not record information in an unblinded fashion. Pharmacy or any other clinic records 
providing unblinded information (eg, randomization, study drug preparation, study drug 
accountability, study drug infiltration) will be reviewed by specialized unblinded monitors who 
will notify Pacira of treatment noncompliance. 


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11.5.2. 
Unblinding Procedures 
Subject treatment assignments should not be unblinded during the study by blinded study 
personnel. The investigator will have the ability to unblind a subject through the randomization 
system if it is felt that subject safety warrants such unblinding. However, if possible, the 
investigator should discuss the safety issues with the Pacira Medical Monitor before attempting 
such unblinding.  Any unblinding will be documented through immediate notification of the 
Pacira study team and the investigator within the interactive response technology (IRT) system 
used for randomization. The reason for unblinding will be documented. Any accidental 
unblinding events (ie, through mishaps in the operating room or miscommunication among study 
staff) must be reported to Pacira immediately. 
Any unblinding performed through the randomization system will be recorded as a transaction 
and the appropriate study personnel will be notified that such a transaction occurred. 
Any incidence(s) of unblinding will be noted in the clinical study report with a full discussion of 
the events leading to the decision to unblind. 
11.6. 
Prior and Concomitant Therapy and Medications 
11.6.1. 
Prior Therapy and Medications 
Use of any of the following medications within the times specified before surgery is prohibited: 
long-acting opioid medication, NSAIDs, aspirin (except for low-dose aspirin used for 
cardioprotection), or acetaminophen within 3 days, or any opioid medication within 24 hours. 
Initiation of treatment with any of the following medications is prohibited within 1 month of 
study drug administration or if the medication(s) are being given to control pain: SSRIs, SNRIs, 
gabapentin, pregabalin (Lyrica), or duloxetine (Cymbalta). If a subject is taking one of these 
medications for a reason other than pain control, she must be on a stable dose for at least 1 month 
prior to study drug administration. 
11.6.2. 
Restricted Therapy and Medications During Surgery 
As described in the EXPAREL package insert, no agents are to be admixed with EXPAREL 
(eg, epinephrine, dexamethasone, clonidine) other than bupivacaine. Lidocaine and other local 
anesthetics are not permitted to be locally administered during the surgery because they are 
known to interact with EXPAREL resulting in the displacement of bupivacaine and elevated 
plasma levels. When a topical antiseptic is applied to the surgical site, the solutions are not to 
come in contact with each other (eg, the area must be dry before EXPAREL is administered). 
Upon discovering use of any prohibited therapy and/or medication during or after surgery, the 
investigator should document all events that led to the deviation, write a note to file, and notify 
the Pacira Medical Monitor accordingly. 


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11.6.3. 
Permitted Therapy or Medications after Surgery 
Patient-controlled analgesia is not permitted. 
The following multimodal pain regimen will be used: 
At the time of skin incision closure (Note: it is very important that these be administered at the 
time of wound closure and not prior to or before the end of surgery.) 
• Intravenous (IV) ketorolac 15 mg (1 dose) 
• IV acetaminophen 1000 mg (1 dose) 
Beginning 6 hours after skin incision closure 
• Scheduled PO acetaminophen 650 mg beginning 6 hours from the administration of the 
single dose of IV acetaminophen at the end of surgery and then q6h for up to 72 hours or 
hospital discharge 
• Scheduled PO ibuprofen 600 mg beginning 6 hours from the administration of the single 
dose of IV ketorolac at the end of surgery and then q6h for up to 72 hours or hospital 
discharge 
This multi-modal pain regimen is a requirement for all subjects in the study and is not subject 
to investigator discretion. The date, time, and dose of all standardized multimodal pain 
medications administered must be recorded. 
Subjects should only receive opioid rescue pain medication upon request for breakthrough pain. 
Postsurgical rescue medication will comprise PO immediate-release oxycodone (initiated at 
5-10 mg q4h or PRN). If a subject is unable to tolerate PO medication or fails the PO oxycodone 
rescue, IV morphine (initiated at 1-2 mg) or hydromorphone (initiated at 0.3-0.5 mg) may be 
administered q4h or PRN. Patient-controlled analgesia is not permitted. All surgical opioid 
and postsurgical opioid and other analgesics (pain medications) administered must be 
documented through Day 14 postsurgery.  Additionally, an unscheduled pain intensity score 
using the VAS (see Appendix 1) must be completed immediately prior to any rescue medication 
while in the hospital. 
Permitted medications for the prevention and treatment of possible medication side effects 
include the following and may be administered at the discretion of the study site principal 
investigator: 
• Ondansetron 4 mg IV immediately after delivery of the baby. 
• Ondansetron 4 mg IV (should not exceed a maximum of 12 mg in a 24-hour period) for 
intraoperative and postoperative nausea and vomiting 
• Metoclopramide 10 mg PO PRN for nausea and vomiting 
• Nalbuphine IV 2.5 mg as needed PRN for pruritus 
• Naloxone IV 50-100 mcg PRN for pruritus. 


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11.7. 
Treatment Compliance 
Study drug will be administered by the study staff and, thus, treatment compliance is ensured. 
11.8. 
Accountability of Study Drug 
Shipment of EXPAREL for the study will contain an investigational drug transmittal and receipt 
form to assist the investigator or designee (eg, pharmacist) in maintaining current and accurate 
inventory records.  At a minimum, the investigator or designee will maintain accurate records 
demonstrating dates and units of drug received, lot numbers, subjects to whom drug was 
administered, and accounts of any drug destroyed accidentally or deliberately. The investigator 
must retain vials containing used, unused, or expired EXPAREL for return or destruction, as 
instructed by Pacira, following confirmation of drug accountability data by a study monitor. 
A record of drug return or destruction will be maintained and provided to Pacira. Inventory 
records must be readily available for inspection by the study monitor and/or appropriate 
regulatory authorities at any time. A copy of the inventory records, drug accountability 
information, and notice of return or destruction will be returned to Pacira at the end of the study. 
Only authorized personnel identified by the investigator will have the ability to access and 
administer the drug. 
12. 
STUDY ENDPOINTS AND MEASUREMENTS 
12.1. 
Efficacy Measurements 
The following efficacy measurements will be conducted at the times specified after completion 
of the last C-section wound incision stitch (ie, time of closure of the C-section wound): 
• 
Date, time of administration, and amount of all postsurgical opioid rescue medication taken 
through Day 14. 
• 
Pain intensity scores at rest using a 10-cm VAS at 6, 12, 18, 24, 30, 36, 42, 48, and 72 
hours (see Appendix 1) at rest and once daily (at noon ± 4 hours) through Day 14. For pain 
intensity scores at 18, 24, 30, 36, or 42 hours, if the subject is sleeping, do not wake her to 
assess pain. If she awakens within the assessment window (ie, 1 hour for the 18- and 24- 
hour assessments and 2 hours for the 30-, 36-, and 42-hour assessments), a pain score may 
be collected then.† 
• 
Discharge readiness at 24, 48, and 72 hours or until the subject attains a score of 9, 
whichever occurs first. 
• 
Date and time of first unassisted ambulation. 
• 
Subject satisfaction with postsurgical pain control (using a 5-point Likert scale) at 72 hours 
(or prior to hospital discharge). 
• 
Quality of Recovery 15-item questionnaire at 72 hours (or prior to hospital discharge). 
• 
OBAS questionnaire at 24, 48, and 72 hours.† 


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• 
Unscheduled phone calls or office visits related to pain after discharge through Day 14. 
†  If a subject is discharged prior to any of the scheduled VAS assessments collected at 6 to 
72 hours postsurgery or a scheduled OBAS assessment collected at 24 to 72 hours postsurgery, 
a member of the study site staff will contact the subject at the appropriate scheduled times 
(ie, the time of each assessment scheduled to be collected that occurs after hospital discharge) 
to remind her to complete the VAS and OBAS assessments and to record the scheduled 
assessments in the Participant Diary. This will ensure that for any subject discharged prior to 
72 hours, all VAS and OBAS assessments required for calculation of the study endpoints are 
captured. These phone calls will only occur if a subject is discharged prior to 72 hours. 
12.2. 
Efficacy Endpoints 
The primary efficacy endpoint is the total postsurgical opioid consumption in morphine 
equivalents through 72 hours. 
The secondary efficacy endpoints include: 
• 
Time to first postsurgical opioid rescue medication 
• 
The VAS pain intensity scores at rest from 6 to 72 hours 
• 
Percentage of opioid-free subjects through 72 hours 
Tertiary efficacy endpoints may include (but may not be limited to): 
• 
Percentage of opioid-free subjects through 24 and 48 hours. 
• 
The VAS pain intensity scores at rest from 6 to 12 hours, 6 to 24 hours, 6 to 48 hours, 24 to 
48 hours, and 48 to 72 hours. 
• 
Integrated rank assessment using the VAS pain intensity score at rest at 24, 48, and 72 
hours and the total amount of postsurgical opioids consumed through 24, 48, and 72 hours 
(Silverman 1993). 
• 
Overall benefit of analgesia scores at each assessed timepoint. 
• 
Time spent in the post-anesthesia care unit (PACU). 
• 
Time to first unassisted ambulation. 
• 
Proportion of subjects meeting Modified Postanesthesia Discharge Scoring System criteria 
for discharge readiness at each assessed timepoint. 
• 
Overall assessment of the subject’s satisfaction with postsurgical pain control (using a 
5-point Likert scale) at 72 hours after surgery (or at hospital discharge if earlier than 
72 hours). 
• 
Responses to the QoR-15 questionnaire at 72 hours after surgery (or at hospital discharge if 
earlier than 72 hours). 


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• 
Number of unscheduled phone calls or office visits related to pain from discharge through 
Day 14. 
12.3. 
Safety Assessments 
Adverse events will be monitored from the time the ICF is signed through Day 14. 
12.4. 
Safety Endpoints 
Incidence of treatment-emergent AEs (TEAEs) and SAEs will be assessed through Day 14. 
12.5. 
Appropriateness of Measures 
Endpoints selected for this study were based on well-established clinical measurements used in 
peer-reviewed studies. 
13. 
STUDY PROCEDURES 
A time and events schedule for all study procedures is provided in Table 1 and Table 2. 
13.1. 
Instructions for Conducting Procedures and Measures 
All assessments conducted after baseline will be timed from when the last C-section wound 
incision stitch is completed (ie, time of closure of the C-section wound). Day 1 is defined as the 
day on which study drug is administered. The beginning of surgery is defined as the time of the 
first incision. The end of surgery is defined as the time of closure of the C-section wound. 
Postsurgical is defined as after the end of surgery. 
Subjects will be hospitalized for up to 72 hours after surgery. Postsurgical analgesia and 
collection of study data through hospital discharge will take place under the supervision of study 
staff. Following hospital discharge, the subject will record use of pain medication, if any, in the 
Participant Diary. Additionally, the subject will record a daily (at noon ± 4 hours) 10-cm VAS 
pain score at rest in the Participant Diary daily from hospital discharge through Day 14. This 
assessment should capture her average pain at rest in the prior 24 hours by assessing, “What has 
been your average pain since your last pain assessment?” (ie, from noon on the previous day to 
the current assessment). At the same time, the subject should record any pain medication 
(medication name, dose, date, and time) taken in the prior 24 hours. 
Because the Day-14 assessment is a phone call, subjects will be provided with an addressed and 
stamped envelope in which to return the Participant Diary to the investigator. 
13.1.1. 
Patient Binder and Participant Diary 
The Patient Binder will be given to the subject at the first scheduled assessment (ie, 6 hours) 
following surgery.  While in the hospital, the subject will use the binder to record all scheduled 
VAS (ie, at 6, 12, 18, 24, 30, 36, 42, 48, and 72 hours) and OBAS (ie, at 24, 48, and 72 hours) 
assessments.  She will also use the binder while in the hospital to record any unscheduled VAS 
assessments prior to receiving rescue medication. 


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If a subject is discharged prior to any of the scheduled VAS assessments collected at 6 to 
72 hours postsurgery or a scheduled OBAS assessment collected at 24 to 72 hours postsurgery, a 
member of the study site staff will contact the subject at the appropriate scheduled times (ie, the 
time of each assessment scheduled to be collected that occurs after hospital discharge) to remind 
her to complete the VAS and OBAS assessments and to record the scheduled assessments in the 
Participant Diary, which will be provided to the subject at the time of hospital discharge. This 
will ensure that for any subject discharged prior to 72 hours, all VAS and OBAS assessments 
required for calculation of the study endpoints are captured. These phone calls will only occur if 
a subject is discharged prior to 72 hours. 
At hospital discharge, study personnel will use the Participant Diary to record any pain 
medication provided to the subject for home use and any prescription provided for any pain 
medication to be filled following discharge.  This information should include medication name, 
dose, and instructions for use. 
At hospital discharge, the subject will be instructed to record a daily VAS pain intensity score 
and all pain medications taken following hospital discharge through Day 14 in the Participant 
Diary. 
At home, the subject will assess pain intensity at rest each day at noon (± 4 hours). This 
assessment should capture her average pain at rest in the prior 24 hours by assessing, “What has 
been your average pain since your last pain assessment?” (ie, from noon on the previous day to 
the current assessment). At the same time, the subject should record any pain medication (date, 
time, and dose) taken in the prior 24 hours. 
13.1.2. 
Pain Intensity Assessments 
Pain intensity scores at rest using a 10-cm VAS at 6, 12, 18, 24, 30, 36, 42, 48, and 72 hours (see 
Appendix 1) at rest and once daily (at noon ± 4 hours) through Day 14. For pain intensity scores 
at 18, 24, 30, 36, or 42 hours, if the subject is sleeping, do not wake her to assess pain. If she 
awakens within the assessment window (ie, 1 hour for the 18- and 24-hour assessments and 2 
hours for the 30-, 36-, and 42-hour assessments), a pain score may be collected then. See Section 
13.1.1 regarding subjects discharged prior to 72 hours. 
To assess pain intensity (VAS) at rest, the subject should rest quietly in a supine or seated 
position that does not exacerbate her postsurgical pain for 3-5 minutes before entering the pain 
score. 
13.1.3. 
Overall Benefit of Analgesia Score Questionnaire 
The OBAS questionnaire (Lehmann 2010; see Appendix 4) will be completed at 24, 48, and 72 
hours. See Section 13.1.1 regarding subjects discharged prior to 72 hours. 


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13.1.4. 
Subject Satisfaction with Postsurgical Pain Control 
The subject’s satisfaction with postsurgical pain control will be assessed at 72 hours (or hospital 
discharge, whichever occurs first; see Appendix 3). 
13.1.5. 
Discharge Readiness 
The subject’s discharge readiness will be assessed using the Modified Postanesthesia Discharge 
Scoring System criteria (Chung 1995a; Chung 1995b; see Appendix 2). The discharge readiness 
assessment will be used for data collection only and is not intended to interfere with the 
investigational site’s policy for determining when the subject should be discharged from the 
hospital. Discharge readiness will be assessed at 24, 48, and 72 hours or hospital discharge or 
until the subject attains a score of 9, whichever occurs first. 
13.1.6. 
Quality of Recovery 
The subject’s quality of recovery will be assessed using the QoR-15 questionnaire at 72 hours, 
(or hospital discharge, whichever occurs first; see Appendix 5). 
13.2. 
Obtaining Informed Consent 
Potential participants may provide informed consent up to 30 days before their scheduled 
surgery. If a subject can only be screened on the day of surgery, the consent process must be 
started at least 24 hours prior to the day of surgery in order to ensure ample time for the subject 
to review the ICF and have all her questions answered by the investigator/study staff prior to 
providing informed consent. Screening procedures that are standard of care (SOC) at the 
institution may be completed prior to written informed consent. Any screening procedures that 
are not SOC, must be completed after written informed consent is provided and prior to surgery. 
(see Section 13.3). 
13.3. 
Screening/Baseline Procedures 
Subjects will be screened within 30 days prior to surgery; screening on the day of surgery will be 
allowed but is discouraged. If a subject can only be screened on the day of surgery, the informed 
consent process must still be started at least 24 hours prior to the conduct of any screening 
procedures that are not considered SOC at the institution and such procedures may not be 
performed until written informed consent is provided  All screening procedures that are not SOC 
must be performed and documented within the 30-day time window (inclusive of the day of 
surgery for those subjects who can only be screened on the day of surgery) as described here. 
The following screening/baseline procedures should be performed within 30 days prior to 
administration of study drug.  Screening on the day of surgery will be permitted but is 
discouraged. 
• 
Explain study purpose and procedures 
• 
Obtain signed ICF, if not provided earlier 


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• 
Assess eligibility 
• 
Record medical/surgical history 
• 
Record prior and concomitant medications 
• 
Record demographics and baseline characteristics 
• 
Explain to the subject that she will be provided with a Patient Binder while in the hospital 
and that she will be expected to capture specific information in the binder while in the 
hospital. 
• 
Explain to the subject that she will be provided with a Participant Diary upon discharge 
from the hospital and that she will be expected to capture specific information in the 
diary after discharge through Day 14. 
• 
Measure vitals (blood pressure, height, weight, and heart rate) 
• 
Perform physical exam according to the investigational site’s standard of care 
• 
Perform 12-lead ECG 
• 
Conduct urine drug screen and breath alcohol test 
• 
Clinical laboratory tests in accordance with the investigator’s standard of care including 
(Appendix 6): 
1. Direct bilirubin 
2. Gamma-glutamyl transpeptidase (GGT) and lactate dehydrogenase (LDH) 
OR 
ALT and AST. 
Note: if clinical laboratory test results are available from with 14 days of surgery, 
laboratory tests do not have to be repeated at screening 
• 
Record AEs starting when the ICF is signed 
• 
Record concomitant medications for treatment of AEs 
13.4. 
Day 1 - Operating Room 
• 
Assess/confirm eligibility 
• 
Confirm medical/surgical history 
• 
Update prior and concomitant medications 
• 
Measure vital signs (blood pressure and heart rate) 
• 
Perform physical exam according to the investigational site’s standard of care 
• 
Randomize subject and prepare study drug 
• 
Administer an intrathecal injection of 150 mcg preservative-free morphine for spinal 
injection (eg, Duramorph®) in conjunction with single-shot spinal anesthesia using 


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1.4-1.6 mL bupivacaine HCl 0.75% and 15 mcg fentanyl. If preservative-free morphine 
for spinal injection (eg, Duramorph) is unavailable because of a drug shortage, subjects 
may instead receive an intrathecal injection of 75 mcg preservative-free hydromorphone 
in conjunction with single-shot spinal anesthesia using 1.4-1.6 mL bupivacaine HCl 
0.75% and 15 mcg fentanyl. A CSE anesthesia technique may also be used provided the 
epidural component is not used. Subjects who receive the epidural component of the 
CSE anesthesia must be immediately withdrawn from the study. 
• 
Record start and stop time of surgery (Note: end of surgery is defined as the closure of 
the C-section wound) 
• 
Record intraoperative opioids administered and doses 
• 
Record any AEs or SAEs 
• 
Record concomitant medications for treatment of AEs 
13.5. 
Day 1 - Post-anesthesia Care Unit 
• 
Perform TAP needle placement and saline hydrodissection under ultrasound guidance 
• 
Capture ultrasound image of the TAP needle placement after saline hydrodissection 
• 
Perform 2-point classic TAP infiltration no more than 90 minutes after skin incision 
closure of the C-section 
• 
Collect ultrasound image of two-point TAP needle placement after infiltration of study 
drug 
• 
Record start and stop time of study drug infiltration 
13.6. 
Day 1 - Prior to PACU Discharge 
• 
Record date, time in and out of the PACU 
• 
Measure vital signs (blood pressure and heart rate) 
• 
Record an unscheduled VAS pain intensity score before any postsurgical opioid 
medication while in the hospital. 
• 
Record date, time, and dose of all postsurgical opioid and other pain medication. Note: 
Subjects should only receive opioid pain medication (eg, morphine, hydromorphone 
[Dilaudid], oxycodone) upon request for breakthrough pain. 
• 
Record date, time, and dose of all standardized multimodal pain medications 
administered 


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13.7. 
Days 1-3 (0-72 Hours After Surgery/Hospital Discharge) 
• 
At the first scheduled assessment (ie, 6 hours) provide the Patient Binder 
• 
Record scheduled pain intensity scores at rest using a 10-cm VAS (see Appendix 1) at 6, 
12, 18, 24, 30, 36, 42, 48, and 72 hours. For pain intensity scores at 18, 24, 30, 36, or 42 
hours, if the subject is sleeping, do not wake her to assess pain. If she awakens within the 
assessment window (ie, 1 hour for the 18- and 24-hour assessments and 2 hours for the 
30-, 36-, and 42-hour assessments), a pain score may be collected then. See Section 
13.1.1 regarding subjects discharged prior to 72 hours. 
• 
Record date, time, and dose of all standardized multimodal pain medications 
administered 
• 
Record an unscheduled VAS pain intensity score immediately before any postsurgical 
opioid medication while in the hospital. 
• 
Record date, time, and dose of all postsurgical opioid and other pain medications 
administered through 72 hours.  Note: Subjects should only receive opioid pain 
medication (morphine, hydromorphone [Dilaudid], oxycodone) upon request for 
breakthrough pain, PRN. 
• 
Record date and time of subject’s first unassisted ambulation 
• 
Record OBAS (see Appendix 4) at 24, 48, and 72 hours.   See Section 13.1.1 regarding 
subjects discharged prior to 72 hours. 
• 
Record discharge readiness (see Appendix 2) at 24, 48, and 72 hours or hospital 
discharge, or until the subject attains a score of 9, whichever occurs first 
• 
Record overall rating of subject’s satisfaction with postsurgical pain control at 72 hours 
(or hospital discharge, whichever occurs first; see Appendix 3) 
• 
Record QoR-15 data at 72 hours (or hospital discharge, whichever occurs first; see 
Appendix 5) 
• 
Record date and time of hospital discharge 
• 
Record any AEs or SAEs 
• 
Record any concomitant medications for treatment of AEs 
13.8. 
After Hospital Discharge Through Day 14 
• 
Record VAS pain intensity scores at rest (see Appendix 1) in the Participant Diary at 
noon (± 4 hours) each day through Day 14. This assessment should capture the subject’s 
average pain at rest in the prior 24 hours by assessing, “What has been your average pain 
since your last pain assessment?” (ie, from noon on the previous day to the current 
assessment). 


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• 
Record the use of pain medication, if any, in the Participant Diary daily through Day 14 
13.9. 
Day 14 Phone Call 
• 
Document whether the subject has made any unscheduled phone calls or office visits 
related to pain; experienced any hospital readmission; or experienced an emergency room 
visit since hospital discharge. 
• 
Record any AEs or SAEs 
• 
Record any concomitant medications for treatment of AEs 
• 
Remind subject to return the Participant Diary in the provided addressed and stamped 
envelope 
14. 
ADVERSE EVENT REPORTING 
Consistent with the current regulatory guidance provided by the US CFR and the ICH GCP, 
AE and SAE are defined in Section 14.1.1 and Section 14.2.1, respectively. 
The concepts of AE and SAE represent regulatory instruments used to evaluate and monitor the 
safety of clinical study subjects. Therefore, these terms only apply in light of their regulatory 
definition. The term serious, in a regulatory sense, does not necessarily mean severe. The SAE 
concept is primarily used to identify, during the conduct of the study, those SAEs that may 
require expedited reporting to regulatory authorities. 
14.1. 
Adverse Events 
14.1.1. 
Definitions 
Definition of Adverse Event (AE): Any untoward medical occurrence associated with the use of 
a drug in humans, whether or not considered drug related. An AE (also referred to as an adverse 
experience) can be any unfavorable and unintended sign (eg, abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a drug, without any judgment about 
causality. An AE can arise from any use of the drug (eg, off-label use in combination with 
another drug) and from any route of administration, formulation, or dose, including an overdose. 
An AE can be any unfavorable and unintended change in a body structure or body function. 
Adverse events include any clinically significant deterioration of a subject’s medical status. 
The AE may involve any organ or system and can be represented by the new onset or the 
deterioration of a disease, a syndrome, a symptom, a physical sign, as well as by findings and 
results of instrumental examinations and laboratory tests.  Any medically relevant and untoward 
change after the subject signs the ICF, including frequency or pattern changes for a fluctuating 
condition (eg, migraine) is considered an AE. 
An AE that occurs after the ICF has been signed and before the start of the study drug 
administration is identified as a pretreatment AE (PTAE). An AE that occurs after the 
administration of a study treatment is considered a TEAE. 


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Definition of Adverse Reaction: Any AE caused by a drug. Adverse reactions are a subset of all 
suspected adverse reactions for which there is reason to conclude that the drug caused the event. 
Definition of Suspected Adverse Reaction: Any AE for which there is a reasonable possibility 
that the drug caused the AE. For the purposes of investigational new drug (IND) safety 
reporting, ‘reasonable possibility’ means there is evidence to suggest a causal relationship 
between the drug and the AE. A suspected adverse reaction implies a lesser degree of certainty 
about causality than adverse reaction, which means any AE caused by a drug.  Suspected adverse 
reactions are a subset of all AEs for which there is a reasonable possibility that the drug caused 
the event. 
14.1.2. 
Recording Adverse Events 
It is the responsibility of the investigator to document all AEs (ie, PTAEs and TEAEs) with an 
onset after the subject signs the ICF. For the purpose of this study, all AEs that occur through 
Day 14 after surgery must be recorded regardless of whether or not they are considered related to 
study drug. Whenever feasible, AE terms should be documented as medical diagnoses (highest 
possible level of integration); otherwise, the AEs should be reported separately as individual 
signs or symptoms. Only one AE per line should be recorded in the AE CRF; for example, an 
AE of nausea and vomiting should be listed as two separate events: the event of nausea and the 
event of vomiting.  If a diagnosis is established after symptoms are recorded on the AE CRF, 
the diagnosis should be recorded and the symptoms collapsed (removed; ie, lined through and 
initialed). Whenever possible, abnormal laboratory results should be reported as their clinical 
corollary (eg, low potassium should be recorded as hypokalemia). 
A continuous AE with varying grades of severity must be recorded as one AE.  The highest 
grade of severity experienced by that subject during the course of the continuous AE must be 
recorded. 
Any condition noted before the subject signs the ICF will be listed as Medical History and is 
considered a pre-existing condition. If a pre-existing condition changes (ie, becomes more 
severe or more frequent) at any time after the ICF is signed, or after study drug administration, 
it is considered an AE. Note: A change in treatment for a pre-existing condition (eg, new high 
blood pressure medication), does not necessarily indicate an AE. 
Information recorded on the AE CRF will include the AE term, the date and time of onset, 
severity, seriousness, relationship to study drug, action taken with study drug, action taken for 
the AE, and the outcome of the AE, including the date and time of resolution, if applicable. 
14.1.3. 
Severity of Adverse Events 
The severity of an AE must be categorized using the following guidelines: 
Mild: 
An AE that is easily tolerated by the subject, causing minimal 
discomfort and not interfering with everyday activities. 


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Moderate: 
An AE that is discomforting and interferes with normal everyday 
activities. 
Severe: 
An AE that prevents normal everyday activities. 
The term “severe” is often used to describe the intensity (severity) of a specific event (as in mild, 
moderate, or severe myocardial infarction); the event itself, however, may be of relatively minor 
medical significance (such as severe headache). This is not the same as "serious," which is based 
on subject/event outcome or action criteria usually associated with events that pose a threat to a 
subject's life or functioning.  Seriousness (not severity) serves as a guide for defining regulatory 
reporting obligations. 
14.1.4. 
Relationship of Adverse Events to Study Drug 
The investigator must assess the relationship of the AE to study drug after careful medical 
consideration on a case-by-case basis.  General guidelines for determining the AE’s causality to 
the study drug are provided below. 
Unrelated: 
A causal relationship between the study drug and the AE can be 
easily ruled out (eg, based on the temporal sequence, absence of a 
reasonable pathophysiological mechanism, or direct evidence of 
actual cause). 
Unlikely: 
A clinical event with a temporal relationship to study drug 
administration which makes a causal relationship improbable and in 
which other drugs, chemicals, or underlying disease provide a 
plausible explanation; 
Possible: 
A clinical event with a reasonable time sequence to administration 
of the study drug but which could also be explained by a concurrent 
disease or other drugs or chemicals; 
Probable: 
A clinical event with a reasonable time sequence to administration 
of the study drug unlikely to be attributed to a concurrent disease or 
other drugs or chemicals and which follows a clinically reasonable 
response on withdrawal (dechallenge); or 
Definite: 
The pharmacological properties of the study drug(s) or of the 
substance class, and the course of the AE after dechallenge and, if 
applicable, after rechallenge, and/or specific test indicate 
involvement of the study drug(s) in the occurrence/worsening of the 
AE, and no indication of other causes exists. 
14.1.5. 
Outcome of Adverse Events 
The investigator will assess the outcome of the AE after careful medical consideration, on a 
case-by-case basis.  General guidelines are provided below: 


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Recovered/Resolved: 
The event resolved and the subject recovered from the AE. 
 
Recovered/Resolved 
with Sequelae: 
Not Recovered/ 
Not Resolved: 
The initial event resolved, but has a continuing abnormal condition 
as a result of the AE. 
At the time of last assessment, the event was ongoing, with an 
undetermined outcome. Note: ongoing AEs are not to be considered 
resolved as a result of death. 
Recovering/Resolving: 
At the time of last assessment, the event was decreasing in 
frequency, severity, etc, and a resolution was expected. 
Fatal: 
The AE directly caused death. 
Unknown: 
There was an inability to access the subject or the subject’s records 
to determine the outcome (eg, subject withdrew consent or was 
lost to follow-up). 
14.1.6. 
Action Taken with Subject Because of an Adverse Event 
The investigator will provide any actions taken regarding the subject (eg, treatment, diagnostic 
tests, laboratory tests, or therapy) for each reported AE. 
• 
None 
• 
Medication 
• 
Non-pharmaceutical therapy (The specific therapy used must be recorded in the 
CRF.) 
• 
Discontinued from study 
• 
Other (The specific action taken must be recorded in the CRF.) 
14.2. 
Serious Adverse Events 
14.2.1. 
Definition of a Serious Adverse Event 
Definition of an SAE: An AE is considered “serious” if, in the view of either the investigator or 
Sponsor, it results in any of the following outcomes: 
• Death1 
• A life-threatening adverse event2 
• Inpatient hospitalization or prolongation of existing hospitalization3 
• A persistent or significant incapacity4 
• Congenital anomaly/birth defect 
• Medically significant5 


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1Death: Any event resulting in a subject’s death must be reported as an SAE.  However, death, 
in and of itself, is not an AE; it is an outcome. The cause of death is the AE. Therefore, the 
investigator should make every effort to obtain and document the cause of death for all subjects 
who die during the study. If, despite all efforts, the cause of death remains unknown, the AE 
should be documented as an “unspecified fatal event.” 
2Life-threatening: An AE is considered life-threatening if, in the view of either the investigator 
or Sponsor, its occurrence places the subject at immediate risk of death. It does not include an 
AE that had it occurred in a more severe form might have caused death. 
3Hospitalization: It should be noted that hospitalization, in and of itself, does not represent an 
SAE.  It is the AE leading to the subject’s hospitalization that becomes “serious” when it 
requires inpatient care. Consequently, an SAE should not be reported in case of preplanned 
hospitalizations for a pre-existing condition that did not worsen during the study. However, 
any medical condition that delays a subject’s discharge from the hospital (ie, prolonged 
hospitalization) or requires the subject to be readmitted should be reported as an SAE. 
4Persistent or significant incapacity: A substantial disruption of a person’s ability to conduct 
normal life functions. 
5Medically Significant: Important medical events that may not result in death, be life- 
threatening, or require hospitalization, may be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such medically 
significant events include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, 
or the development of drug dependency or drug abuse. 
14.2.2. 
Reporting Serious Adverse Events 
Any SAE or death that occurs at any time after the subject signs the ICF through Day 14, 
whether or not related to EXPAREL, must be reported by the investigator or designee to Pacira 
Drug Safety either email (drugsafety@pacira.com) or fax to 973-201-0649 within 24 hours of 
discovery. In addition, the Investigator or designee is encouraged to contact the Medical 
Monitor to discuss the case, as needed. 
Investigators should not wait to receive additional information to fully document the event 
before notifying Pacira Drug Safety or designee of the SAE. The fax or email report should be 
followed by a full written summary using the SAE Form detailing relevant aspects of the SAE in 
question.  Where applicable, information from relevant hospital records and autopsy reports 
should be obtained and all patient-identifying information redacted prior to forwarding to Pacira. 
In the event of a fatal or life-threatening SAE, any required follow-up must be provided to Pacira 
Drug Safety or designee immediately. The investigator will follow all SAEs until resolved or the 
condition stabilizes and further follow-up is not warranted. 


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If the investigator is made aware of any SAEs after Day 14, these should also be reported to 
Pacira Drug Safety or designee provided the SAE is considered related to EXPAREL. The site 
would then provide a completed SAE form within 1 business day and the event would be 
followed until resolution, or until adequate stabilization is met. 
15. 
STATISTICAL METHODS 
A comprehensive statistical analysis plan (SAP) will be developed for this study. 
15.1. 
Study Objective 
The primary objective of this study is to compare total opioid consumption through 72 hours 
following EXPAREL+bupivacaine HCl infiltration into TAP after spinal anesthesia to active 
bupivacaine HCl infiltration into the TAP after spinal anesthesia in subjects undergoing elective 
C-section. 
15.2. 
Study Endpoints 
The endpoints to be assessed in this study are listed in Section 12.2 (Efficacy Endpoints) and 
Section 12.4 (Safety Endpoints). 
15.3. 
Determination of Sample Size 
Sample size for this study was based Quale et al (2016). The coefficient of variation (CV) from 
this poster was approximately 60%. Assuming a log-normal distribution for total opioid 
consumption with a 60% CV, 5% alpha, a 1:1 randomization ratio, and 80% power 72 subjects 
per treatment arm is sufficient to detect a 30% difference between treatments. Assuming 5% of 
the subjects are not evaluable a total sample size of approximately 152 subjects are needed to 
ensure 144 evaluable subjects. 
15.4. 
Analysis Populations 
The safety analysis set will include all subjects who receive study drug. All analyses based on 
the safety set will be by actual treatment received. 
The efficacy analysis set will include all randomized subjects who undergo C-section. All 
analyses based on the efficacy analysis set will be by randomized treatment regardless of 
treatment actually received. 
The per-protocol efficacy analysis set will include all subjects in the efficacy analysis set who do 
not have any important protocol deviations. All analyses based on the per-protocol analysis set 
will be by randomized treatment regardless of treatment actually received. 
15.5. 
Handling Subject Dropouts and Discontinuations 
Methods for dealing with missing data will be described in the SAP. 
15.6. 
Statistical Analyses 


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15.6.1. 
Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively by treatment group. 
15.6.2. 
Study Compliance 
The percentage of subject in each analysis set and the percentage who fail to complete the study 
(as well as the reasons for discontinuation) will be displayed by treatment group. 
15.6.3. 
Efficacy Analyses 
A comprehensive statistical analysis plan (SAP) will be developed for this study. All efficacy 
endpoint analyses will be conducted for the efficacy analysis set. The primary efficacy endpoint 
will also be analyzed using the per-protocol analysis set as a sensitivity analysis. 
Summary statistics (n, mean, median, standard deviation, minimum, maximum) will be shown 
for each continuous measure of efficacy by treatment group.  Number and percentage of subjects 
in each category will be shown for each categorical measure of efficacy by treatment group. For 
time to event measures of efficacy, medians and Kaplan-Meier estimates will be shown by 
treatment group. 
Baseline is defined as the last non-missing assessment of a given endpoint prior to first dose of 
trial drug unless otherwise specified. 
All assessments will be listed in subject data listings. 
15.6.3.1. 
Primary Efficacy Endpoint 
The analysis of total postsurgical opioid consumption through 72 hours will be described in the 
SAP. 
15.6.3.2. 
Secondary Efficacy Endpoints 
The analyses of the secondary efficacy endpoints will be described in the SAP. 
15.6.3.3. 
Tertiary Efficacy Endpoint(s) 
The analyses of the tertiary efficacy endpoints will be described in the SAP. 
15.6.4. 
Safety Analyses 
Adverse event verbatim terms will be mapped to preferred terms and related system/organ class 
using the Medical Dictionary for Regulatory Activities (MedDRA). All summaries of AEs will 
include AEs that occur after the beginning of anesthesia.  All summaries of AEs will be based on 
the safety analysis set. Events that start prior to anesthesia will be identified in listings only. 
Incidence rates of AEs after the start of anesthesia and the proportion of subjects prematurely 
withdrawn from the study due to an AE will be shown for each treatment group. Incidence rates 
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anesthesia and by severity.  Incidence rates of SAEs will also be shown for each treatment group. 
All incidence rates will be categorized and shown by system/organ class and preferred term. 
15.7. 
Significance Testing 
Significance testing will be described in the SAP. 
15.8. 
Interim Analyses 
An unblinded interim analysis will be conducted by an independent statistician when 
approximately 80 treated subjects under protocol amendment 2 have completed the 72-hour 
follow-up for the primary efficacy assessments.  The objective of this interim analysis is three- 
fold: 
1. To stop the trial for futility if it is improbable to show a significant reduction in the 
primary efficacy endpoints; 
2. To stop the trial for early success if a clear benefit is demonstrated 
3. To allow for the possibility of increasing the study sample size if the original sample size 
assumptions are determined to be not viable. 
If the predictive probability at the current maximum sample size is less than a predetermined 
threshold, then the trial will terminate for futility.  A group sequential stopping boundary will be 
used for the early success stopping analysis. If the trial stops early for neither success nor 
futility, predictive probabilities will be calculated for the current maximum sample size (144 
treated subjects) and larger sample sizes up to 200 subjects. The sample size may be extended to 
a number that achieves higher predictive probability of trial success (Saville 2017). The final 
decision to stop, continue or increase the sample size will be made by Pacira. Full details and all 
thresholds for stopping or trial expansion will be covered in a prospective interim analysis plan 
that will become part of the study SAP. 


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16. 
REFERENCES 
American Society of Anesthesiologists Task Force on Pain Management. Practice guidelines 
for acute pain management in the postoperative setting: A report by the American Society 
for Anesthesiologist Task Force on Pain Management Acute Pain Section. Anesthesiology. 
1995;82:1071-1081. 
Apfelbaum JL, Chen C, Mehta SS, et al. Postoperative pain experience: Results from a national 
survey suggests postoperative pain continues to be undermanaged. Anesth Analg. 
2003;97:535-540. 
Carroll NV, Miederhoff PA, Cox FM, et al. Costs incurred by outpatient surgical centers in 
managing postoperative nausea and vomiting. J Clin Anesth. 1994;6:364-369. 
Chernin T. Painkillers and pill popping. Drug Topics. 2001;15:31. Accessed 04 January 2011. 
Available at: http://drugtopics.modernmedicine.com/drugtopics/PainManagement/ 
ArticleStandard/article/detail/118858. 
Chung F.  Discharge criteria – A new trend.  Can J Anesth. 1995a;42:1056-1058. 
Chung F, Chan VW, Ong D. A post-anesthetic discharge scoring system for home readiness 
after ambulatory surgery. J Clin Anesth. 1995b;7(6):500-506. 
Elvir-Lazo, O.L. The role of multimodal analgesia in pain management after ambulatory surgery. 
Curr Opin Anaesthesiol. 2010 Dec;23(6):697-703. 
EXPAREL Full Prescribing Information, October 2011. 
EXPAREL investigator’s Brochure, Edition 16, 23 October 2013. 
Feierman DE, Kronenfeld M, Gupta PM. Liposomal bupivacaine infiltration into the transversus 
abdominis plane for postsurgical analgesia in open abdominal umbilical hernia repair: Results 
from a cohort of 13 patients. J Pain Res. 2014;7:477-482. 
Lehmann N, Joshi GP, Dirkmann D, et al.  Development and longitudinal validation of the 
overall benefit of analgesia score: A simple multi-dimensional quality assessment instrument. 
Br J Anasth. 2010;105(4):511-518. Epub 2010 Aug 6. 
Oderda GM, Said Q, Evans RS, et al. Opioid-related adverse drug events in surgical 
hospitalizations: Impact on cost and length of stay. Ann Pharmacother. 2007;41(3):400-406. 
Quale M, Cunningham G, Foster C, and Hutchins J.  Addition of transversus abdominis plane 
infiltration with liposomal bupivacaine to intrathecal morphine for postoperative analgesia after 
Caesarean delivery: a retrospective study. Abstract 1497. American Society of Regional 
Anesthesia and Pain Management. 41st Annual Regional Anesthesiology and Acute Pain 
Medicine Meeting. 31-Mar-2016 to 02-Apr-2016. New Orleans, LA, US. 
Saville BR, Conner JT, Ayers GD, Alvarez J. The utility of Bayesian predictive probabilities for 
interim monitoring of clinical trials. Clin Trials. 2014 Aug; 11(4): 485–493. 


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Silverman DG, O'Connor TZ, Brull SJ. Integrated assessment of pain scores and rescue 
morphine use during studies of analgesic efficacy. Anesth Analg. 1993;77:168-170. 
Sternlicht A, Shapiro M, Robelen G, et al. Infiltration of liposome bupivacaine into the 
transversus abdominis plane for postsurgical analgesia in robotic laparoscopic prostatectomy: 
A pilot study. Local Reg Anesth. 2014;7:69-74. 
Sviggum, H.P., et al., Intrathecal Hydromorphone and Morphine for Postcesarean Delivery 
Analgesia: Determination of the ED90 Using a Sequential Allocation Biased-Coin Method. 
Anesth Analg, 2016. 123(3): p. 690-7. 
Viscusi ER. New and emerging treatment options for acute postoperative pain in the inpatient 
setting: Barriers to effective pain management. Medscape Pharmacists. Accessed 04 January 
2011.  Available at: http://www.medscape.org/viewarticle/713472_2. 
White PF, Kehlet H. Improving postoperative pain management: what are the unresolved issues? 
Anesthesiology 2010; 112:220–225. 
World Health Organization (2002). Breastfeeding and maternal medication. Recommendations 
for drugs in the eleventh WHO model list of essential drugs. Accessed at http://www.who.int 
/maternal_child_adolescent/documents/55732/en/ 12-Feb-2017. 


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17. 
INVESTIGATOR AGREEMENT 
Printed Name of investigator: 
Printed Title/Position: 
Printed Institution Address: 
  
 
 
 
 
 
 
 
I have reviewed this protocol (including Appendices) and agree: 
• To assume responsibility for the proper conduct of the study at this site; 
• To conduct the study in compliance with this protocol, with any future amendments, 
and with any other study conduct procedures provided by Pacira Pharmaceuticals, Inc. 
(Pacira) or designee. I also agree to comply with Good Clinical Practice and all 
regulatory requirements; 
• Not to implement any changes to the protocol without agreement from Pacira or designee 
and prior review and written approval from the Independent Ethics Committee, except 
where it is necessary to eliminate an immediate hazard to the subjects or for 
administrative aspects of the study (where permitted by applicable regulatory 
requirements); 
• That I am thoroughly familiar with the appropriate use of the investigational product(s), 
as described in this protocol, and with other relevant information (eg, the investigator’s 
Brochure); 
• To ensure that all persons assisting me with the conduct of this study are adequately 
informed about the investigational product(s) and about their study-related duties and 
functions as described in this protocol; 
• That I am aware that regulatory authorities may require investigators to disclose all 
information about significant ownership interests and/or financial ties related to the 
Sponsor and/or the investigational product(s).  Consequently, I agree to disclose all 
such significant financial information to Pacira and to update this information promptly 
if any relevant changes occur during the course of the study through 1 year following 
completion of the study.  I also agree that any information regarding my significant 
financial interest related to Pacira and/or the investigational product(s) will be disclosed 
to the regulatory authorities by Pacira. 
 
 
 
 
Signature of investigator 
Date 


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18. 
APPENDICES 


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Appendix 1:  Subject’s Reported Pain (Visual Analog Scale) at Rest 
Subjects will be evaluated for pain intensity scores at rest using the 10-cm VAS at rest at 6, 12, 
18, 24, 30, 36, 42, 48, and 72 hours after surgery and then once daily (at noon ± 4 hours) through 
Day 14. For pain intensity scores at 18, 24, 30, 36, or 42 hours, if the subject is sleeping, do not 
wake her to assess pain. If she awakens within the assessment window (ie, 1 hour for the 
18- and 24-hour assessments and 2 hours for the 30-, 36-, and 42-hour assessments), a pain score 
may be collected then. 
If a subject is discharged prior to any of the scheduled VAS assessments collected at 6 to 72 
hours postsurgery, a member of the study site staff will contact the subject at the appropriate 
scheduled times (ie, the time of each assessment scheduled to be collected from 6 to 72 hours 
that occurs after hospital discharge) to remind her to complete the VAS assessment and to record 
the scheduled assessment in the Participant Diary. This will ensure that for any subject 
discharged prior to 72 hours, all VAS assessments required for calculation of the study endpoints 
are captured. These phone calls will only occur if a subject is discharged prior to 72 hours. 
While in the hospital, subjects will also record an unscheduled VAS pain score immediately 
before any requested opioid pain medication. 
To assess pain intensity (VAS) at rest, the subject should rest quietly in a supine or seated 
position that does not exacerbate her postsurgical pain for 3-5 minutes before entering the pain 
score. 
While in the hospital, subjects are to assess, “How much pain are you experiencing right now?” 
and a vertical mark will be placed on the line below to indicate the level of pain experienced at 
the time of assessment. 
At home, the subject will assess pain intensity at rest each day at noon (± 4 hours). This 
assessment should capture her average pain at rest in the prior 24 hours by assessing, “What has 
been your average pain since your last pain assessment?” (ie, from noon on the previous day to 
the current assessment). 
 
 
Visual Analog Scale (VAS) 
 
 
 
No 
Pain 
 
(For reference only; not for clinical use.) 
Pain as Bad 
as it Could 
Possible Be 


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Appendix 2: 
Discharge Readiness 
The subject’s discharge readiness will be assessed using the Modified Postanesthesia Discharge 
Scoring System below (Chung 1995a; Chung 1995b). 
 
The discharge readiness assessment will be used for data collection only and is not intended to 
interfere with the investigational site’s policy for determining when the subject should be 
discharged from the hospital. 
 
Discharge readiness will be assessed at 24, 48, and 72 hours, or hospital discharge, or until the 
subject attains score of 9, whichever comes first. Once a score of 9 is reached, no further 
discharge readiness assessments are required 
 
Modified Postanesthesia Discharge Scoring System 
 
Parameter 
Score 
Vital Signs: measure systolic blood pressure, heart rate, respiratory rate, 
temperature 
• 
All 4 vital signs are within 20% of the preoperative values 
• 
Any of the 4 vital signs are within 20-40% of the preoperative 
values and none exceeds 40% of the preoperative value 
• 
Any of the 4 vital signs are >40% of the preoperative values 
2 
1 
0 
Ambulation 
2 
• 
Steady gait/no dizziness 
• 
With assistance 
1 
• 
None/dizziness 
0 
Nausea and Vomiting 
2 
• 
Minimal: no nausea/vomiting or nausea not requiring treatment 
• 
Moderate: nausea without vomiting and can tolerate liquids 
1 
• 
Severe: nausea/vomiting and unable to tolerate oral liquids 
0 
Pain 
• 
Minimal: requiring one or less pain rescue in the prior 12 hours 
• 
Moderate: requiring more than one pain rescue in the prior 12 
hours 
• 
Severe: requiring supplemental IV analgesia for pain rescue 
2 
1 
0 
Surgical Bleeding 
• 
Minimal: no action required 
• 
Moderate: requires dressing change because it has soaked through 
or a compressive dressing 
• 
Severe: requires a suture or a return to the operating room 
2 
1 
0 


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Appendix 3: 
Subject Satisfaction with Postsurgical Pain Control (Likert Scale) 
The subject's satisfaction with postsurgical pain control will be conducted at 72 hours after 
surgery (or at hospital discharge, whichever occurs first). 
 
 
Please circle the number below that best describes your overall satisfaction with your pain 
control, pain management and treatment after surgery. (Select one number only.) 
 
 
1. Extremely dissatisfied 
2. Dissatisfied 
3. Neither satisfied nor dissatisfied 
4. Satisfied 
5. Extremely satisfied 


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Appendix 4: 
Overall Benefit of Analgesia Score Questionnaire 
The OBAS questionnaire will be completed at 24, 48, and 72 hours after surgery (ie, closure of 
the C-section wound). 
Note: If a subject is discharged prior to any of the scheduled OBAS assessments collected at 24 
to 72 hours postsurgery, a member of the study site staff will contact the subject at the 
appropriate scheduled times (ie, the time of each assessment scheduled to be collected from 24 to 
72 hours that occurs after hospital discharge) to remind her to complete the OBAS questionnaire 
and to record her answers to the questionnaire in the Participant Diary. This will ensure that for 
any subject discharged prior to 72 hours, all OBAS assessments required for calculation of the 
study endpoints are captured. These phone calls will only occur if a subject is discharged prior to 
72 hours. 
 
 
1.   Please rate your current pain at rest on a scale between 
0=minimal pain and 4=maximum imaginable pain 
2.   Please grade any distress and bother from vomiting in the past 24 hours 
(0=not at all to 4=very much) 
3.   Please grade any distress and bother from itching in the past 24 hours 
(0=not at all to 4=very much) 
4.   Please grade any distress and bother from sweating in the past 24 hours 
(0=not at all to 4=very much) 
5.   Please grade any distress and bother from freezing in the past 24 hours 
(0=not at all to 4=very much) 
6.   Please grade any distress and bother from dizziness in the past 24 hours 
(0=not at all to 4=very much) 
7.  How satisfied are you with your pain treatment during the past 24 hours 
(0=not at all to 4=very much) 


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Appendix 5: 
Quality of Recovery 15-item Questionnaire 
The QoR-15 will be conducted at 72 hours after surgery (or at hospital discharge, whichever 
occurs first). 
Part A 
How have you been feeling in the last 24 hours? 
(0 to 10, where: 0 = none of the time [poor] and 10 = all of the time [excellent]) 
 
 
1. 
Able to breathe easily 
None of    
 All of 
the time 0   1   2   3   4   5   6   7   8   9   10  the time 
 
 
 
 
2. 
Been able to enjoy food 
None of    
 
 
All of 
the time 0   1   2   3   4   5   6   7   8   9   10  the time 
 
 
 
 
3. 
Feeling rested 
None of    
 
 
All of 
the time 0   1   2   3   4   5   6   7   8   9   10  the time 
 
 
 
 
4. 
Have had a good sleep 
None of    
 
 
All of 
the time 0   1   2   3   4   5   6   7   8   9   10  the time 
 
 
 
 
5. 
Able to look after personal 
None of    
 
 
All of 
toilet and hygiene unaided 
the time 0   1   2   3   4   5   6   7   8   9   10  the time 
 
 
 
 
6. 
Able to communicate with 
None of    
 
 
All of 
family or friends 
the time 0   1   2   3   4   5   6   7   8   9   10  the time 
 
 
 
 
7. 
Getting support from hospital 
None of    
 
 
All of 
doctors and nurses 
the time 0   1   2   3   4   5   6   7   8   9   10  the time 


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8. 
Able to return to work or 
None of 
All of 
 
usual home activities 
the time 0   1   2   3   4   5   6   7   8   9   10  the time 
 
 
 
 
9. 
Feeling comfortable and in 
None of    
 
 
All of 
control 
the time 0   1   2   3   4   5   6   7   8   9   10  the time 
 
 
 
 
10. 
Having a feeling of general 
None of    
 
 
All of 
well-being 
the time 0   1   2   3   4   5   6   7   8   9   10   the time 
 
 
Part B 
Have you had any of the following in the last 24 hours? 
(10 to 0, where: 10 = none of the time [excellent] and 0 = all of the time [poor]) 
 
 
11. 
Moderate pain 
None of    
 All of 
the time 10 9 8   7   6   5 4   3   2   1 0  the time 
 
 
 
 
12. 
Severe pain 
None of    
 
 
All of 
the time 10 9 8   7   6   5 4   3   2   1 0  the time 
 
 
 
 
13. 
Nausea or vomiting 
None of    
 
 
All of 
the time 10 9 8   7   6   5 4   3   2   1 0  the time 
 
 
 
14. 
Feeling worried or anxious 
None of    
 All of 
the time 10 9 8   7   6   5 4   3   2   1 0  the time 
 
 
 
 
15. 
Feeling sad or depressed 
None of    
 
 
All of 
the time 10 9 8   7   6   5 4   3   2   1 0   the time 
 
 
Total Score 
 
 


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Appendix 6: 
Clinical Laboratory Tests 
Clinical laboratory tests (hematology and chemistry) will be conducted at screening in accordance with 
the investigator’s standard of care including: 
 
1. Direct bilirubin 
2. Gamma-glutamyl transpeptidase (GGT) and lactate dehydrogenase (LDH) 
OR 
Alanine transaminase (ALT) and aspartate transaminase (AST). 

SAP_001.pdf: 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
Protocol Title 
A Multicenter, Randomized, Double-blind, Active-controlled 
Study to Evaluate the Safety and Efficacy of EXPAREL When 
Administered via Infiltration into the Transversus Abdominis Plane 
(TAP) Versus Bupivacaine Alone in Subjects Undergoing Elective 
Cesarean Section. 
Protocol Number 
402-C-411 
Protocol Version 
Amendment 3 
Protocol Date: 
Original: 16 March 2017 
Amendment 1: 12 April 2017 
Amendment 2: 22 September 2017 
Amendment 3: 07May2018 
Study Drug 
EXPAREL (bupivacaine liposome injectable suspension) 
Study Phase 
4 
IND Number 
069,198 
Sponsor 
Pacira Pharmaceuticals, Inc. 
5 Sylvan Way 
Parsippany, NJ 07054 
Tel: 973-254-3560 
SAP Version 
1.0 
Date 
03 January 2019 


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Chao Wang, PhD
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Vincent Yu, PhD 
Senior Director, Biometrics 
Pacira Pharmaceuticals, Inc 
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,JRU*UDFKHY, MD 
Senior Medical Director, Clinical Operations 
Pacira Pharmaceuticals, Inc 
Date 
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-XOLD<DQJ, MD 
VP, Clinical Research  
Pacira Pharmaceuticals, Inc 
Date
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Michael Rozycki, PhD 
Vice President, Regulatory Affairs 
Pacira Pharmaceuticals, Inc
Date 
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Richard Scranton, MD, MPH 
Chief Medical Officer  
Pacira Pharmaceuticals, Inc 
Date 


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Statistical Analysis Plan 
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2. 
TABLE OF CONTENTS 
1. 
SIGNATURE PAGE 
2 
2. 
TABLE OF CONTENTS 
3 
3. 
LIST OF ABBREVIATIONS 
5 
4. 
INTRODUCTION 
7 
5. 
STUDY OBJECTIVES 
8 
5.1. 
Primary Objective 
8 
5.2. 
Secondary Objectives 
8 
6. 
STUDY OVERVIEW 
8 
7. 
DEFINITIONS 
9 
8. 
ANALYSIS SETS 
10 
9. 
STATISTICAL METHODS OF ANALYSIS 
11 
9.1. 
General Principles 
11 
9.1.1. 
Handling Missing Values 
11 
9.1.1.1. 
Total postsurgery opioid consumption 
11 
9.1.1.2. 
VAS Pain Intensity Scores and Area Under the VAS-Time Curve 
12 
9.1.1.3. 
Exposure, Surgery, and Rescue Medication Date or Time 
15 
9.1.1.4. 
Adverse Event or Concomitant Medications Dates or Times 
15 
9.1.1.5. 
Adverse Event Severity or Relationship to Study Drug 
16 
9.1.1.6. 
Time to Event 
16 
9.1.2. 
Handling Erroneous Values 
16 
9.1.3. 
Multiplicity Adjustments 
16 
9.1.4. 
By-Center Analyses 
16 
9.2. 
Subject Disposition 
17 
9.3. 
Description of Demographics and Baseline Characteristics 
17 
9.3.1. 
Demographics 
17 
9.3.2. 
Baseline Characteristics 
18 
9.4. 
Surgery Characteristics 
18 
9.5. 
Intraoperative, Prior and Concomitant Medications 
19 
9.6. 
Measurements of Treatment Compliance 
20 
9.7. 
Efficacy Analysis 
20 
9.7.1. 
Efficacy Endpoints 
20 
9.7.1.1. 
Primary Efficacy 
20 
9.7.1.2. 
Secondary Efficacy 
20 


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9.7.1.3. 
Tertiary Efficacy 
20 
9.7.1.4. 
Area under the Curve 
21 
9.7.1.5. 
Summed Pain Intensity Score 
21 
9.7.1.6. 
Opioid Dose Conversion 
22 
9.7.1.7. 
Overall Benefit of Analgesia Score (OBAS) 
23 
9.7.1.8. 
Safety Endpoints 
23 
9.7.2. 
Methods of Analysis 
23 
9.7.2.1. 
Primary Efficacy Analysis 
23 
9.7.2.2. 
Secondary Efficacy Analyses 
24 
9.7.2.3. 
Tertiary Efficacy Analyses 
26 
9.7.2.4. 
By-Subgroup Analysis 
29 
9.8. 
Safety Analyses 
29 
9.8.1. 
Adverse Events 
30 
9.8.2. 
Vital Signs 
32 
9.8.3. 
Interim Analysis 
33 
10. 
SAMPLE SIZE CALCULATIONS 
34 
11. 
REFERENCES 
35 
12. 
TIME AND EVENTS SCHEDULE OF STUDY PROCEDURES 
36 
13. 
LAYOUT OF TABLES, LISTINGS AND FIGURES 
37 
14. 
LIST OF TABLES 
39 
15. 
LIST OF LISTINGS 
94 
16. 
LIST OF FIGURES 
121 
17. 
APPENDIX 
123 


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Statistical Analysis Plan 
 
 
 
3. 
LIST OF ABBREVIATIONS 
 
 
Abbreviation 
Description 
 
AE 
Adverse event 
ANOVA 
Analysis of variance 
ANCOVA 
Analysis of covariance 
ATC 
Anatomical therapeutic class 
BMI 
Body mass index 
bpm 
Beats per minute 
CI 
Confidence interval 
CMH 
Cochran-Mantel-Haenszel 
CRF 
Case report form 
CSR 
Clinical study report 
d 
Day 
ECG 
Electrocardiogram 
EMA 
European Medicines Agency 
FDA 
Food and Drug Administration 
FNB 
Femoral nerve block 
hr, h 
hour 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
ICU 
Intensive care unit 
IV 
Intravenous 
LOCF 
Last observation carried forward 
LS 
Least square 
MedDRA 
Medical dictionary for regulatory affairs 
MMRM 
Mixed model repeated measures 
MPADSS 
Modified Postanesthesia Discharge Scoring System 
min 
minutes 
OMED 
Oral morphine equivalent dose in mg 
n 
Number of subjects 
OBAS 
Overall benefit of analgesia 
OR 
Operating room 
PACU 
Postanesthesia care unit 
PCA 
Patient-controlled analgesia 
PK 
Pharmacokinetics 
PO 
Oral 
ROW 
Rest of world 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SE 
Standard error 
SPIS 
Sum of pain intensity scores 
TAP 
Transversus abdominis plane 


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Statistical Analysis Plan 
 
 
 
 
Abbreviation 
Description 
 
TEAE 
Treatment-emergent adverse event 
TKA 
Total knee arthroplasty 
TLF 
Table, listings and figures 
TUG 
Timed up-and-go 
TWT 
Timed walk test 
VAS 
Visual analog scale 
WHO 
World Health Organization 
WHO-DD 
World Health Organization – Drug Dictionary 
wWOCF 
Windowed worst observation carried forward 
 


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Statistical Analysis Plan 
 
 
 
4. 
INTRODUCTION 
This Statistical Analysis Plan (SAP) describes the planned statistical analysis and reporting of the 
clinical study 402-C-411 titled “A Multicenter, Randomized, Double-blind,  Active-controlled 
Study to Evaluate the Safety and Efficacy of EXPAREL Plus Bupivacaine When Administered via 
Infiltration into the Transversus Abdominis Plane (TAP) Versus Bupivacaine Alone in Subjects 
Undergoing Elective Cesarean Section.” 
The structure and content of this SAP provide sufficient detail to meet the requirements 
identified by the US Food and Drug Administration (FDA), European Medicines Agency (EMA), 
and International Conference on Harmonization (ICH) of Technical Requirements for 
Registration of Pharmaceuticals for Human Use: Guidance on Statistical Principles in Clinical 
Trials (1998). All work planned and reported for this SAP will follow internationally accepted 
guidelines, published by the American Statistical Association (1999) and the Royal Statistical 
Society (1993), for statistical practice. 
The purposes of this SAP are to: 
• Outline the types of analyses and presentations of data that will form the basis for 
drawing conclusions to the study objectives and hypotheses outlined in the protocol. 
• Explain in detail how the data will be handled and analyzed, adhering to commonly 
accepted standards and practices for Good Statistical Practice. 
The planned analyses identified in this SAP may be included in the clinical study report (CSR), 
regulatory submissions, or manuscripts. Post-hoc exploratory analyses not necessarily 
identified in this SAP may be performed to further examine study data. Any post-hoc, 
unplanned, or exploratory analyses performed will be clearly identified as such in the final CSR. 
The following documents related to clinical study Protocol 402-C-411 were reviewed in 
preparation of this SAP: 
• Protocol Amendment 3, issued 7 May 2018. 
• ICH Guidance on Statistical Principles for Clinical Trials (E9). 
The reader of this SAP is encouraged to also read the clinical protocol and other identified 
documents for details on the planned conduct of this study. Operational aspects related to 
collection and timing of planned clinical assessments are not repeated in this SAP unless 
relevant to the planned analyses. 


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Statistical Analysis Plan 
 
 
 
5. 
STUDY OBJECTIVES 
 
5.1. 
Primary Objective 
The primary objective of this study is to compare total opioid consumption through 72 hours 
following EXPAREL+Bupivacaine HCl infiltration into the transversus abdominis plane (TAP) after 
spinal anesthesia to active bupivacaine HCl TAP infiltration after spinal anesthesia in subjects 
undergoing an elective cesarean section (C-section). 
 
5.2. 
Secondary Objectives 
The secondary objectives are to assess efficacy and safety parameters and patient satisfaction. 
 
 
6. 
STUDY OVERVIEW 
This is a Phase-4, multicenter, randomized, double-blind, active-controlled study in 
approximately 186 adult subjects undergoing elective C-section. All subjects will remain in the 
hospital for up to 72 hours postsurgery. 
Subjects will be randomized in a 1:1 allocation ratio to receive either: 
• EXPAREL+bupivacaine TAP infiltration following spinal anesthesia hereafter referred to 
as EXPAREL+Bupivacaine. 
• Active bupivacaine TAP infiltration following spinal anesthesia hereafter referred to as 
Bupivacaine. 
Hereafter, treatment group “EXPAREL+bupivacaine” will sometimes be labeled as “EXPAREL 
266 mg” and “Active bupivacaine” will be labeled as “IR Buipivacaine”. Subjects will be allowed 
rescue medication upon request to control their pain. Rescue medication will be oral (PO) 
immediate release oxycodone. If subject cannot  tolerate PO medication, intravenous (IV) 
morphine or hydromorphone may be used as rescue medication. 
Pain will be assessed using a 10 cm visual analog scale (VAS). Pain will be assessed at multiple 
prescheduled time points during the study and prior to taking any rescue medication. Subjects 
will remain in the hospital for up to 72 hours postsurgery. 
Other postsurgical assessments include: 
• Opioid use 
• Time of first unassisted ambulation 
• Pain intensity scores using a 10-cm VAS at rest 
• Discharge readiness 
• Subject's satisfaction with postsurgical pain control 


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• Overall benefit of anesthesia score (OBAS) questionnaire 
• Quality of recovery 15-item questionnaire (QoR-15) 
 
 
7. 
DEFINITIONS 
Study Day 
If event occurs earlier than the start of study drug, Study Day is calculated as the date of event 
minus the date of the start of study drug administration. Otherwise Study Day is calculated as 
the date of event minus the date of the start of study drug administration plus one (+1). Study 
Day is based on the calendar dates, thus days before the date of surgery have negative values 
while those on or after the date of surgery are positive. 
Treatment-emergent Adverse Events 
Treatment-emergent adverse events (TEAEs) are the adverse events started on/after the study 
drug administration. 
Time 0 (zero) 
Time 0 is defined as the date and time of the end of surgery. 
Time Periods 
All scheduled times have a window associated with them (see Time and Events Schedule for 
individual time point windows). Various time frames are used in the data analyses which are 
dependent on these windows. 
Table 1: Time Window for VAS Assessment 
 
Defined time VAS Time Point (hrs) 
Acceptable Window (hrs) 
6 
± 0.5 
12, 18, 24 
± 1 
30, 36, 42, 48 
± 2 
72 
± 4 
 
If there are two or more VAS data points that fit into the same time window, the data point 
close to the center of the window will be used. If two data points are of equal distance to the 
center, the one with higher VAS score will be used for analysis. For programming purpose, the 
VAS time point for analysis (ANL01FL=Y) will be numbered by their schedule, eg, ATPTN = 6, 12, 
18, …, 72. Other VAS time points will be numbered by the VAS time relative to the surgical end 
time in hours (with 1 decimal point), eg, 47.5. 
If after applying the time window, the VAS data point for the scheduled window becomes 
missing, it will be imputed as per Section 9.1.1.2. 


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Baseline 
Baseline is defined as the last available measurement or assessment prior to the start of study 
treatment. 
Ready for Discharge 
Ready for discharge is defined as a total score of 9 or more on the Modified Postanesthesia 
Discharge Scoring System (MPADSS). The total score is the sum of all scores. If there are 
missing data, then the total score will not be calculated. 
Discharge Time 
Discharge time is defined as Discharge day - admission day + 1. 
Summed Pain Intensity Score (SPIS) 
Sum of pain intensity scores (SPIS) are calculated by summing the observed or imputed VAS 
scores for the time-frames of interest. Only the scheduled VAS assessments will be used to 
derive SPIS. 
Time to Event 
Time to event will be calculated as the time from end of surgery to time of event in hours. 
Opioid-free 
Opioid-free is defined as not received opioid rescue medication during the time interval. 
Opioid-sparing 
Subjects meet the opioid sparing criteria if the following conditions are satisfied: 
• For  0-72  hours  opioid  consumption,  all  doses  add  up  to  ≤15mg  (oral  morphine 
equivalent dose [OMED]) AND the OBAS score = 0 for all of the following questions, 
o Questions 2, 3, 4, 5, and 6. 
o If any of the above OBAS score is missing, then opioid-sparing is set to missing. 
Opioid Window 
Opioid window is a time interval starting when the opioid medication is administered through 
the time when the medication’s analgesic effect is worn out. 
 
 
8.       ANALYSIS SETS 
The safety analysis set includes all subjects who receive study drug.  All analyses based on the 
safety set will be by actual treatment received. 


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The modified intent-to-treat principal (MITT) analysis set will be used for efficacy analysis. It 
includes all randomized subjects in the safety analysis set who undergo C-section, receive study 
drug on/after 17 February 2018, and whose ultrasound images show correct TAP infiltration. 
Note before 17 February 2018 subjects were dosed based on the protocol with dosing error. 
Incorrect TAP infiltration was noted by the independent data reviewing committee. Both errors 
affect the evaluation of the effectiveness of the study drug. All analyses based on the efficacy 
analysis set will be by randomized treatment regardless of the actual treatment received. 
 
 
9. 
STATISTICAL METHODS OF ANALYSIS 
 
9.1. 
General Principles 
The statistical analyses will be reported using summary tables, listings, and figures (TLFs). All 
analyses and tabulations will be performed using SAS Version 9.4 or later. Continuous 
variables will be summarized using descriptive statistics [sample size (n), mean, standard 
deviation (SD), minimum, median, and maximum]. Categorical variables will be tabulated with 
number and percentage of unique subjects. Unless otherwise noted, percentages will be 
calculated using the number of subjects in the respective treatment group and analysis set as 
the denominator and presented with only those categories appearing in the data. 
Individual subject data will be provided in listings. All listings will be sorted by treatment, site, 
subject, and, if applicable, collection date and time. 
 
9.1.1. ling Missing Values 
 
9.1.1.1. 
Total postsurgery opioid consumption 
For the calculation of the total postsurgical opioid consumption, both opioid rescue medication 
before hospital discharge and opioid pain medication in the daily diary after discharge will be 
included. If opioid is taken on the discharge day but time of dosing is missing, it will be imputed 
as time of discharge or 12:00 pm on the discharge day, whichever is later. If opioid is taken 
after the day of discharge and time of dosing is missing, it will be imputed as 12:00 pm the day 
after discharge. 
If patient does not return her patient daily diary at the end of study, then for the primary 
efficacy endpoint of total postsurgery opioid consumption through 72 hours (inclusive), if a 
patient is discharged  at  𝑥𝑥 < 36 hours  after  end  of  surgery,  her  total  postsurgical  opioid 
consumption through 72 hours will be calculated as  72𝐷𝐷0,𝑥𝑥/𝑥𝑥,  where  𝐷𝐷0,𝑥𝑥    is  the  opioid 
consumption  during  the  initial  𝑥𝑥  hours  (inclusive)  postsurgery.  If a patient is discharged 
at 36 ≤ 𝑥𝑥 ≤ 72 hours, her total postsurgery  opioid  consumption  through  72  hours  will  be 


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calculated  as  𝐷𝐷0,𝑥𝑥  + 𝐷𝐷2𝑥𝑥−72,𝑥𝑥,  where  𝐷𝐷2𝑥𝑥−72,𝑥𝑥   is  the  opioid  consumption from 2𝑥𝑥 − 72 
hours (exclusive) through 𝑥𝑥 hours (inclusive). For example, if a patient is discharged at x=70 
hours, her 
postsurgerical 0 to 72 hours opioid consumption will be calculated as her consumption during 
the first 70 hours plus the consumption between 70 and 72 hours, which is imputed by the 
consumption between 68 and 70 hours. 
 
9.1.1.2. 
VAS Pain Intensity Scores and Area Under the VAS-Time Curve 
Pain scores obtained during the opioid medication window will be replaced with the worst 
observation carried forward (wWOCF).  For this study the prescribed opioid rescue medication 
is oxycodone. However, morphine, hydromorphone, or other opioids may be used. The 
durations of the analgesic effect for various opioids are listed in Error! Reference source not 
found.. 
 
Table 2: Opioid Rescue Medication Window 
Medication 
Route 
Window Used to Impute VAS 
Oxycodone, Oxycocet, Percocet, 
acetaminophen-oxycodone, Oxycontin 
PO, IM, IV, SC 
6 hours 
Morphine 
IV, PO, SC 
4 hours 
Hydromorphone (Dilaudid), Hydromorphone 
hydrochloride 
IV 
2 hours 
Hydromorphone (Dilaudid), Hydromorphone 
hydrochloride 
PO, IM, SC 
4 hours 
Hydrocodone 
PO 
6 hours 
Fentanyl 
IV, PO, IM 
6 hours 
Hydrocodone combination product - Vicodin, 
Norco, Lorcet, Lortab, hydrocodone- 
acetaminophen 
PO 
6 hours 
Codeine combination product - Tylenol 3, 
acetaminophen-coedine, Paracetamol Forte, 
Tylenol 4 
PO 
6 hours 
Ultram, Tramadol, Tramacol hydrochloride 
PO 
6 hours 
PO = oral, IV = intravenous, IM = Intramuscular, SC = subcutaneous, VAS = visual analog scale. 
 
If other rescue medications not listed above are given, the window will be determined post- 
hoc. If a combination opioid product is given, the window will be determined by the opioid part 
of the medication. 
 
For the secondary analysis endpoint of VAS pain score, missing data at each scheduled time 
point will be imputed assuming VAS scores missing at random. Rubin’s (1987) multiple 
imputation procedure will be applied to replace each missing value with a set of plausible 
values that represent the uncertainty about the right value to impute. For the AUC and SPIS 


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calculation, the windowed worst observation carried forward (wWOCF) multiple imputation 
procedure will be used in the following order: 
 
a) Windowed worst observation carried forward (wWOCF) for rescue medications. 
For subjects who take a rescue medication, their VAS scores recorded within the 
window of controlled type of rescue medication (see Error! Reference source not 
found.) will be replaced by the ‘worst’ observation. The worst observation will be the 
highest VAS score from  the end of previous rescue  window or the  end of surgery 
whichever is later. The VAS score of rescue will be included in this calculation. Note (1) 
the VAS score in the window that is higher than the worst value to be carried forward, 
this “higher” value will not be overwritten. Instead, the worst value will be replaced by 
this “higher” value and continue carrying forward until the end of the window. (2) if the 
scheduled VAS score within the window is missing, it will be imputed with this worst 
value. 
b) After the wWOCF imputation, described in Step a, subject data still missing with a non- 
monotone missing pattern (i.e., intermittent missing) will have missing scores imputed 
using the Markov Chain Monte Carlo (MCMC) method (Schafer 1997) within each 
treatment by SAS PROC MI. Multiple imputations will be conducted to simulate 30 
datasets with only monotone missing data. In order to achieve the stationary 
distribution and to avoid dependency within samples generated by MCMC method, the 
number of iteration for the  burn-in period will be  set to 2000 and the  number of 
iterations between two consecutive samples will be set to 1000 (i.e., NBITER=2000 and 
NITER=1000.) 
c) The resulting data from Step b will then have  the  monotone missing pattern. The 
remaining missing data will then be imputed by a parametric regression method (Rubin 
1987) that assumes multivariate normality distribution. 
Only missing data at the scheduled time points are imputed by above Steps b and c.  The 
imputed VAS score will have the time from end of surgery assigned exactly the 
scheduled time, eg, 48.0 hr and 72.0 hr. 
d) AUC of VAS score will be derived using all scheduled and unscheduled VAS scores 
e) The AUC and SPIS at various time intervals will be derived from the imputed VAS scores 
resulting from Step c. There will be 30 sets of AUC and SPIS from the 30 imputed data 
sets. See Section 9.7.1.4 and 9.7.1.5 for detail. 
f) The endpoints derived in Step d will be analyzed as described in Section 9.7.1 for each 
imputation. 


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g) Rubin’s (1987) synthesizing procedure for the multiple imputed data will be applied to 
synthesize analysis results for each imputation. SAS PROC MIANALYZE will be used for 
this procedure. The mean parameter estimates, the asymptotic variance for this mean 
from the imputed data analysis in Step e will be computed using Rubin and Schenker 
method (1986). 
 
 
The SAS pseudo-code for multiple imputations and analysis is as follows. 
** Step 1 use Markov-Chain Monte-Carlo (MCMC) method to create a monotonic missing pattern 
** Note the value for the random seed is fixed to be 123 so that the results are reproducible, MIN=0 and 
MAX=10 are to bound the imputed VAS score within 0-10, ROUND=0.1 is to round the imputed VAS 
score with 1 decimal place. The Box-Cox transformation is to reduce the skewness of the data 
distribution ** 
proc mi data=adef seed=123 nimpute=30 out=output_step1 min=0 
max=10 round=0.1; 
by treatment; 
mcmc impute=monotone nbiter=2000 niter=1000; 
var t6 t12 t18 t24 t30 t36 t42 t48 t72 ; 
transform boxcox (t6 t12 t18 t24 t30 t36 t42 t48 t72 / 
c=0.5 lambda=0) ;* this is log(t+0.5) transformation ; 
run; 
 
** Step 2 – use regression on output dataset from Step 1 to impute missing values **; 
proc mi data=output_step1 seed=987 nimpute=1 out=output_step2 
min=0 max=10 round=0.1; 
by _imputation_ treatment ; 
monotone reg(t12 = t6 / details); 
monotone reg(t18 = t6 t12 / details); 
monotone reg(t24 = t6 t12 t18/ details); 
monotone reg(t30 = t6 t12 t18 t24/ details); 
monotone reg(t36 = t6 t12 t18 t24 t30/ details); 
monotone reg(t42 = t6 t12 t18 t24 t30 t36/ details); 
monotone reg(t48 = t6 t12 t18 t24 t30 t36 t42/ details); 
monotone reg(t72 = t6 t12 t18 t24 t30 t36 t42 t48/ 
details); 
var t6 t12 t18 t24 t30 t36 t42 t48 t72; 
transform boxcox (t6 t12 t18 t24 t30 t36 t42 t48 t72 / 
c=0.5 lambda=0) ; 
run; 
 
** Step 3 derive endpoint_variable using appropriate techniques by variable _IMPUTATION_ **; 
 
*** Step 4 analyze imputed data set **; 
ods output Diffs=diff LSMeans=lsm ; 
proc mixed data=auc1 ; 
by impute ; 
class usubjid trtpn siteid ; 
model aval = trtpn siteid age height ; 


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run ; 
lsmestimate trtpn "Trt1-Trt2 Noninferior" 1 -1 / lower 
testvalue=36 cl alpha=0.025 ; 
lsmestimate trtpn "Trt1-Trt2 Superior" 
1 -1 / lower 
testvalue=0 cl alpha=0.025 ; 
lsmeans trtpn / pdiff cl alpha=0.05 ; 
 
ods output ParameterEstimates=lsmdif ; 
proc mianalyze data=diff alpha=0.05 ; 
modeleffects estimate ; 
stderr stderr ; 
run ; 
 
ods output ParameterEstimates=lsmeans ; 
proc mianalyze data=lsm alpha=0.05 ; 
by trtpn ; 
modeleffects estimate ; 
stderr stderr ; 
run ; 
 
** Step 5 builds report from SUMMARYSTATSB and MIXEDSTATSB **; 
 
 
9.1.1.3. 
Exposure, Surgery, and Rescue Medication Date or Time 
It is expected that all necessary information on study drug exposure, surgery, and postsurgical 
rescue medication dates and times will be complete. Any such information that is missing and 
cannot be obtained through query resolution may be imputed, on a case-by-case basis, in a 
conservative manner that minimizes bias. For example, if pain medication taken on Day 1 has 
no time of administration recorded, the imputed time will be the end of surgery plus 1 minute. 
 
9.1.1.4. 
Adverse Event or Concomitant Medications Dates or Times 
For AEs with missing or partially missing start date/time, the following imputation rules will be 
applied for the determination of treatment-emergent status: 
For partial start date/time: 
• If the year is unknown, then the date will be assigned the date and time of first dose of 
study treatment. 
• If the year is known to be different from the year of the first dose, then missing month 
and day will be imputed as the first month and first day of the month. 
• If the year is known to be the year of the first dose, 
a) If the month is unknown or is the same as the month of the first dose, then the 
missing month and day will be imputed by the month and day of the first dose. 


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b) If the month is known to be different from the month of the first dose, then the 
missing day is imputed as 01 (first day of the month). 
• If the time is unknown, then: 
a) If the date (day, month, and year) matches the date of the administration of 
study drug, then the time of the study treatment will be used to impute the 
missing time. 
b) Otherwise, ’00:00’ will be assigned. 
For medications with missing or partially missing dates, Section 9.5 provides rules for the 
determination of prior or concomitant status. 
 
9.1.1.5. 
Adverse Event Severity or Relationship to Study Drug 
If severity of an AE is not reported, then for tables of AEs by severity, the event will be classified 
as ‘Severe’ and will be footnoted for the table to indicate this imputation. If relationship to 
study drug is not reported for an AE, then for tables of study-drug related AEs, the event will be 
assigned the relationship of ‘definite’. Tables presenting related AEs will include all AEs with 
relationships of ‘possible’, ‘probable’ or ‘definite’ as assessed by the investigator. 
 
9.1.1.6. 
Time to Event 
For calculating time to an event when only the hour is reported, the minutes will be set to zero. 
 
9.1.2. ling Erroneous Values 
Subject 263-0134’s 200mg oxycodone record (7 July 2018 16:00) will be removed due to data 
entry error. This subject data are locked in the eCRF, hence cannont be removed via database 
query/resolution. 
 
9.1.3. Multiplicity Adjustments 
For the efficacy analyses, EXPAREL+Bupivacaine HCl TAP infiltration following spinal anesthesia 
will be compared to bupivacaine HCl TAP infiltration following spinal anesthesia using the 1- 
sided 0.025 alpha level for the efficacy analysis set. 
No multiplicity adjustments will be made. 
 
9.1.4. By-Center Analyses 
By-site summaries will be presented for disposition, demographics, primary efficacy endpoint 
and secondary efficacy endpoints. In the by-site analysis, analysis stratified by site or adjusted 
for site as covariate, the small sites below will be pooled into one psudo site, numbered as 
SITEID 999: 


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• 
SITEID 264, 265, 266, 267, 269, 276, and 277. 
 
 
9.2. 
Subject Disposition 
Subject disposition summaries will include the number of subjects 
• Screened, 
o Screen failure 
o Enrolled (ie, randomized) 
• Randomized 
o Randomized not treated, 
o Randomized treated, 
• In the safety analysis set, 
• Subjects whose TAP infiltration were performed 
o Inorrectly based on ultrasound image 
• Subjects who were dosed before 17 February 2018, 
• In the efficacy analysis set, 
• Protocol 
o Enrolled under Amendment 2 or 3 
o Enrolled under Amendment 1 
o Enrolled under Original Protocol 
• Completed the study as planned, 
• Discontinued from the study, and 
o Reasons for discontinuation from the study. 
Percentages will be reported for the screen failures and enrolled using the number of subjects 
screened as the denominator; other percentages will use the number of subjects randomized 
and treated as denominator, unless otherwise noted. 
The safety analysis set and enrollment data will be presented as treated.  All other data will be 
presented as randomized. 
The disposition summary will present the data for each treatment group.  This summary table 
will present overall sites and for each site separately. 
 
 
9.3. 
Description of Demographics and Baseline Characteristics 
 
9.3.1. Demographics 
The summary of demographic data will present: 


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• Age (years) – descriptive statistics 
• Sex – n (%) 
• Ethnicity – n (%) 
• Race – n (%) 
• Country – n (%) 
Age is calculated from the date the subject signed the informed consent form (ICF) and birth.  It 
is presented as the number of years between, rounding down to the nearest integer year. 
The demographic summary will present the data for each treatment group.  Summaries will be 
provided for each (safety and efficacy) analysis set separately. 
 
9.3.2. Baseline Characteristics 
The summary of baseline characteristic data will present: 
• American Society of Anesthesiologists (ASA) Classification – n (%) 
• Baseline ECG interpretation 
• Height (cm) 
• Weight (kg) 
• Body Mass Index (BMI) (kg/m2) 
• Baseline vital signs 
o Heart rate (bpm) 
o Systolic blood pressure (mmHg) 
o Diastolic blood pressure (mmHg) 
The formula for BMI is 𝑤𝑤⁄(ℎ2), where w is weight in kilograms and h is height in  meters. 
Weight in pounds will be converted to kilograms using the conversion factor of 2.2046 pounds 
to 1 kilogram.  Height in inches will be converted to centimeters using the conversion factor of 
2.54 centimeters to 1 inch. 
Baseline characteristics summaries will present the data for each treatment group.  Summaries 
will be provided for each (safety and efficacy) analysis set separately. 
Descriptive statistics (n, mean, SD, median, minimum  and maximum) will be  provided for 
continuous variables. The number and percent of subjects will be tabulated for the categorical 
variables. 
 
9.4. 
Surgery Characteristics 
Surgery  characteristics  including  duration  of  surgery  will  be  summarized  using  descriptive 
statistics. Summaries will be provided for each (safety and efficacy) analysis set. 


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Duration of surgery is calculated as the difference between the end of surgery and start of 
surgery times and reported in hours. 
 
 
9.5. 
Intraoperative, Prior and Concomitant Medications 
All medications will be coded using the World Health Organization Drug Dictionary (WHODDE 
Sep 2018) and will be classified according to the anatomical therapeutic chemical classification 
term (ATC4) and preferred term (PT). 
Pre-operative and intraoperative medications are defined as medications given as part of the 
surgical procedure. These may include anesthesia, opioids or other medications with start and 
stop dates on the day of surgery and start and stop times overlapping with the surgery start and 
stop times. 
Prior and Concomitant medications are medications collected on the Prior/Concomitant 
Medication eCRF page. 
Prior medications are defined as medications with a stop date and time prior to the start of 
study drug administration. 
Concomitant medications are defined as medications taken after the start of study drug 
administration (i.e., started prior to the start of study drug administration and continued after 
or started after the start of study drug administration). 
For the determination of the prior and concomitant status, the follow fules will be followed for 
incomplete dates. 
• If the medication stop date is partially missing, 
o If  the  year  and  month  indicate  the  stop  date  is  before  study  drug  drug 
administration, it is Prior medication. 
o Otherwise, it is concomitant medication. 
• If the medication stop date is completely missing, it is concomitant medication. 
Pre- and intraoperative, prior, and concomitant medications will be summarized separately 
using n (%) of subjects for each treatment group and across treatment groups by ATC4 term 
and PT for the safety analysis set. Subjects may have more than one medication per ATC4 and 
PT. At each level of subject summarization, a subject will be counted once if one or more 
medications are reported by the same subject at that level. 
All 
medications (Combined Spinal Epidural Medications, 
Pre-Operative Medications, 
Intraoperative Medications, Multimodal Pain Medication, Rescue Medications,  Prescription 
Daily Pain Medications, and Prior/Concomitant Medications) will be included in the data listing. 


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9.6. 
Measurements of Treatment Compliance 
Study treatment is administered by the site personnel, therefore compliance is assured. 
 
9.7. 
Efficacy Analysis 
For Primary and Secondary Efficacy Analyses, descriptive statistics that are appropriate for the 
efficacy variable will also be shown by site, but no statistical analyses will be performed within a 
site. All efficacy analyses will be performed on the efficacy analysis set. 
 
9.7.1.  Efficacy Endpoints 
 
9.7.1.1. 
Primary Efficacy 
The  primary  endpoint  is  the  total  postsurgical  opioid  consumption  (mg)  in  oral  morphine 
equivalent dose (OMED) through 72 hours. 
 
9.7.1.2. 
Secondary Efficacy 
The following secondary endpoints will be analyzed as described in Section 9.1.3: 
• AUC of the VAS pain intensity scores through 72 hours presented as AUC0-72. 
• Total postsurgical opioid consumption through 24 and 48 hours, and Day 7 (168 hours) 
and Day 14 (336 hours). 
• Percentage of opioid-free subjects from end of surgery through 72 hours. 
• Percentages of opioid-sparing subjects from end of surgery through 72 hours. 
• Time to first opioid rescue medication from end of surgery. 
 
9.7.1.3. 
Tertiary Efficacy 
• The AUC of the VAS pain intensity scores from 0 to 12 hours, 0 to 24 hours, 0 to 
48 hours, 24 to 48 hours, 24 to 72 hours and 48 to 72 hours 
• Sum of VAS pain intensity scores at rest from end of surgery through 72 hours presented 
as SPIS0-72. 
• Sum of VAS pain intensity scores at rest from postsurgical 0 to 12 hours, 0 to 24 hours, 0 
to 48 hours, 0 to 72 hours, 24 to 48 hours, 24 to 72 hours and 48 to 72 hours presented 
as SPIS0-12, SPIS0-24, SPIS0-48, SPIS0-72, SPIS24-48, SPIS24-72, SPIS48-72. 
• Integrated rank assessment using the VAS pain intensity score at rest at postsurgery 24, 
48, and 72 hours and the total amount of postsurgical opioids consumed from end of 
surgery through 24, 48, and 72 hours (Silverman 19935). 
• Overall benefit of analgesia scores (OBAS) at each assessed time point. 


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• Time spent in the post-anesthesia care unit (PACU). 
• Time to first unassisted ambulation. 
• Proportion of subjects meeting Modified Post  Anesthesia Discharge Scoring System 
(MPADSS) criteria for discharge readiness at each assessed time point. 
• Overall assessment of the subject’s satisfaction with postsurgical pain control (using a 
5-point Likert scale) at 72 hours after surgery (or at hospital discharge if earlier than 
72 hours). 
• Responses to the QoR-15 questionnaire at 72 hours after surgery (or at hospital 
discharge if earlier than 72 hours). 
• Number of unscheduled phone calls or office visits related to pain from discharge 
through Day 14 
 
9.7.1.4. 
Area under the Curve 
Area under the pain-time curve is derived using the trapezoidal rule (see formula below) on the 
pain scores adjusted for rescue medication use using the observed and imputed values (see 
Section 9.1.1.2). AUC will start with the first pain assessment obtained after surgery and use all 
following pain assessments up to 72 hours post surgery including those collected prior to 
rescue medication and unscheduled. Exact assessment times will be used in deriving AUC. 
𝑛𝑛 
𝐴𝐴𝐴𝐴𝐴𝐴 = ೦೦( 𝑝𝑝𝑖𝑖 + 𝑝𝑝(𝑖𝑖−1))(𝑡𝑡𝑖𝑖 − 𝑡𝑡(𝑖𝑖−1))೦ /2 
𝑖𝑖=2 
Where pi is the VAS pain score at time i and ti is the time, in hours, from end of surgery.  Note t1 is 6 hours post 
surgery. It is the first time VAS score is collected. 
In calculating AUC0-72, if the exact 72 hour VAS score is not collected, it will be interpolated 
using the two nearest before and after data points.  If the last 72 hour assessment is before 
72.0 hours, then the exact 72 hour VAS score for the AUC calculation will use this last 
observation carried forward.  Similarly for the 6 hour VAS score, if it is not collected at the exact 
6 hour post surgery, it will be interpolated using the two nearest before and after data points. 
If the first 6 hour assessment is after 6.0 hour, then the exact 6 hour VAS score for the AUC 
calculation will use this first observation carried backward. 
 
9.7.1.5. 
Summed Pain Intensity Score 
SPIS will be calculated using the observed or imputed VAS scores only at the scheduled time 
points, 
𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆0−72    = 
೦ 
𝑉𝑉𝑉𝑉𝑉𝑉. 
6,12,18,24,30,36,42,48,72 ℎ𝑟𝑟𝑟𝑟 


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Refer to Section 7 Time Periods for the derivation of scheduled time points. For the multiply- 
imputed VAS scores, the average will be used for the SPIS calculation. No synthesizing 
procedure (Section 9.1.1.2 Step g) will be applied for this analysis. 
 
9.7.1.6. 
Opioid Dose Conversion 
Opioids dose will be converted to oral morphine equivalent dose (OMED mg) using the 
conversion factor from Error! Reference source not found. for all summaries.  Total opioid dose 
is the oral morphine equivalent sum of all opioids taken after surgery up to the time point of 
interest. Subjects with no opioid use during the period in question will be assigned a dose of 0 
mg for summaries. 
 
 
Table 3. Conversion Factors to IV and Oral Morphine Equivalent Dose from Other Opioids 
Medication 
Unit 
Route 
IV Morphine 
Conversion 
(Multiplication) 
Factor 
Oral Morphine 
Conversion 
(Multiplication) 
Factor 
Oxycodone, Oxycocet, Percocet, 
acetaminophen-oxycodone 
mg 
PO 
0.5 
1.5 
Morphine 
mg 
IV,IM,SC 
1 
3 
Morphine 
mg 
PO 
0.33 
1 
Hydromorphone (Dilaudid) 
mg 
IV,IM,SC 
6.67 
20 
Hydromorphone (Dilaudid) 
mg 
PO 
1.3 
4 
Fentanyl 
mg 
IV,PO,IM 
100 
300 
Hydrocodone combination product - Vicodin, 
Norco, Lorcet, Lortab, hydrocodone- 
acetaminophen, Ketobemidone 
mg 
PO 
0.33 
1 
Codeine combination product - Tylenol 3, 
acetaminophen-coedine, Paracetamol Forte, 
Tylenol 4 
mg 
PO 
0.05 
0.15 
Ultram, Tramadol, Tramacol hydrochloride 
mg 
PO, IM 
0.08 
0.25 
Demerol, Meperidine, Pethidine 
mg 
IV, SC 
0.1 
0.3 
Demerol, Meperidine, Pethidine 
mg 
PO 
0.033 
0.1 
Ketobemidone, Oxycodone 
mg 
IV 
1 
3 
Nalbuphine/Nallouphine (Nubain/Manfine) 
mg 
IV, IM,SC 
1 
3 
PO = oral, IV = intravenous, IM = Intramuscular, SC = subcutaneous, VAS = visual analog scale. 
If other rescue medications not listed above are given, the window will be determined post-hoc. If a 
combination opioid product is given, the window will be determined by the opioid part of the 
medication. 


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9.7.1.7. 
Overall Benefit of Analgesia Score (OBAS) 
The OBAS is derived as follows: 
1. Add all the scores of questions 1 to 6. 
2. To this number, add four. 
3. Subtract the score of question 7 from this number. 
If a response is missing to any question in the OBAS, the total score will not be calculated. 
 
9.7.1.8. 
Safety Endpoints 
• Incidence of AEs/SAEs starting after the start of anesthesia through Day 14. 
• Vital signs at scheduled time points. 
 
9.7.2.  Methods of Analysis 
For Primary and Secondary Efficacy Analyses, descriptive statistics appropriate for the efficacy 
variable will be presented overall and by site. No statistical comparison will be made within a 
site. 
 
9.7.2.1. 
Primary Efficacy Analysis 
Postsurgical opioid consumption (OMED mg) will be summarized by treatment group for the 
total dose consumed between 6 and 72 hours after the end of surgery. For the frequency count 
of number of subjects receiving opioid medications, subjects will be counted only once 
regardless of how many times subjects have received the medications. This summary table will 
show summaries overall. 
Tests for the treatment effect will be based on the following null hypothesis (Ho) and two-sided 
alternative hypothesis (Ha): 
Ho: μs = μp versus Ha: μs ≠ μp 
where μs and μp are the mean of the 0-72 hour Postsurgical opioid consumption (OMED mg) for 
the EXPAREL+Bupivacaine TAP infiltration following spinal anesthesia, and Bupivacaine TAP 
infiltration following spinal anesthesia, respectively. A one-sided test will be performed at 2.5% 
level of significance comparing the two treatment groups. The treatment effect of 
EXPAREL+Bupivacaine will be considered significantly better than that of Bupivacaine if the null 
hypothesis of no difference is rejected and a difference in the observed mean is in favor of 
EXPAREL+Bupivacaine (mean for EXPAREL+Bupivacaine less than the mean for Bupivacaine). 
To test for significant differences between EXPAREL+Bupivacaine and Bupivacaine, an analysis 
of covariance (ANCOVA) model with treatment and site as the main effects, age and height as 
covariates will be used. The LS means for each treatment group, LS mean difference between 


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the two treatment groups, two-sided 95% CI for the LS mean difference, and the one-sided p- 
value will be reported. 
In addition to the presentation for the between group difference, the percent reduction in total 
postsurgical OMED will also be presented. The % reduction is derived as follows, 
% Reduction = {LSMBupivacaine – LSMEXPAREL+Bupivacaine}/LSMBupivacaine 
where LSM is least square mean estimated from ANCOVA. 
The primary analysis for the primary endpoint is based on the Efficacy evaluable population. 
 
9.7.2.1.1. 
Subgroup Analysis of Primary Efficacy Endpoint 
The analysis of the primary endpoint will be repeated for selected subgroups such as 
• 
Age (<35, and ≥35), 
• Race (White and Non-White), 
• 
BMI (<25, 25 to <30, and ≥30+ kg/m2) 
• Number of prior C-sections (0, 1+), 
• Discharge Time (Discharged on or before Day 3, Discharged on or after Day 4), and 
• Subjects with or without anxiety medical history. 
Note  because  of  the  small  sample  sizes,  all  subgroup  analysis  will  be  performed  without 
adjusting/stratifiying by site 
 
9.7.2.2. 
Secondary Efficacy Analyses 
 
9.7.2.2.1. 
Opioid-Sparing at 72 Hours and Opioid-free at 48 Hours 
The Percentage of opioid-sparing subjects through 72 hours and percentage of opioid-free 
subjects through 72 hours will be additionally analyzed using the logistic regression model with 
treatment, site, age, and height as explanatory variables. Odds ratio (EXPAREL+Bupivacaine / 
Bupivacaine), and 95% CI for the odds ratio and p-value will be presented. In addition, the 
number and percentage of subject’s opioid-free and opioid-sparing will also be tabulated. 
Pseudo-code for logistic regression method: 
ods output OddsRatios=or /* ODDS RATIO AND 95% CL*/ 
Diffs=diff(keep=probz) /* 1-SIDED P-VALUE */ 
LSMeans=lsm(keep=trtpn mu) /* PROB OF YES */ ; 
proc logistic data=ef1 plots=none ; 
class siteid trtpn / param=glm ; 
model avalc(event="Yes")=trtpn siteid age heightbl ; 
lsmeans trtpn / pdiff=controll('2') ilink ; 
run ; 


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9.7.2.2.2. 
AUC for Pain Intensity Score 
AUC0-72 for pain intensity from 0 to 72 hours will be analyzed using ANCOVA with treatment and 
site as main effects, age and height as covariates. Note higher AUC means more pain over time. 
Based on the model, the LS mean and SE of the LS mean will be reported for each treatment. 
The LS Mean for treatment difference for EXPAREL+Bupivacaine minus Bupivacaine and 95% CI 
for the LSM difference will be used to test the following two hypotheses: 
• Hypothesis 1 (non-inferiority): 
o Ho: EXPAREL+Bupivacaine group is inferior to Bupivacaine group with respect to 
AUC for pain intensity. 
o Ha: EXPAREL+Bupivacaine group is not inferior to Bupivacaine group with 
respect to AUC for pain intensity. 
• Hypothesis 2 (superiority): 
o Ho: EXPAREL+Bupivacaine group is not different from Bupivacaine group with 
respect to AUC for pain intensity. 
o Ha: EXPAREL+Bupivacaine group is superior to Bupivacaine group with respect to 
AUC for pain intensity. 
The statistical test will be conducted using a stepdown approach by inspecting the 95% 
confidence interval for the between EXPAREL+Bupivacaine and Bupivacaine group difference as 
follows: 
• Non-inferiority Test for Hypothesis 1. 
o If the upper bound of the 2-sided 95% confidence interval for the LSM for the 
difference of AUC0-72 (EXPAREL+Bupivacaine) – AUC0-72 (Bupivacaine) is > NIM, 
where NIM (non-inferiority margin) = 50% x 72 hrs, then stop the hypothesis 
tests and declare that the non-inferiority result is not achieved. 
o If the upper bound of the 2-sided 95% CI is ≤ NIM then declare that the non- 
inferiority of EXPAREL+Bupivacaine to Bupivacaine is achieved. Move on to test 
for Hypothesis 2. 
• Superiority Test for Hypothesis 2 
o If the upper bound of the 2-sided 95% CI is ≥0, then stop the test and declare 
that the superiority of EXPAREL+Bupivacaine to Bupivacaine is not achieved. 
o If the 
upper 
bound 
is 
<0 
then 
declare 
that 
the 
superiority 
of 
EXPAREL+Bupivacaine to Bupivacaine is achieved. 


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In the table presentation for the between group comparion, if the superiority test passes, only 
the 1-sided superiority test p-value will be displayed. If the superiority test fails, only the 1- 
sided non-inferiority test p-value will be displayed. 
Additionally, descriptive statistics of the AUC of VAS pain score will also be shown by site but no 
statistical analyses will be performed within a site. 
 
9.7.2.2.3. 
Time to First Opioid Rescue Medication 
Time to first opioid rescue medication will be computed in hours as the date and time of the 
first opioid rescue medication minus the date and time of the end of surgery. If a subject is not 
administered an opioid rescue medication, the time to first administration will be censored at 
their last visit/follow up time (last VAS, start time of last concomitant medication, start time of 
last prescription daily pain medication, start time of last AE, hospital discharge, Subject 
Satisfaction with Postsurgical Pain Control questionnaire, QoR-15, and last OBAS). Note missing 
time will be set to 12:00 PM of the day. 
Time to first opioid rescue will be analyzed by the Cox regression model with treatment and site 
as factors, and age and height as covariates. The between group comparison will be carried out 
by the 𝜒𝜒2 test. The n (%) of subjects administered an opioid as well as the n (%) of censored 
observations  will  be  presented  for  each  treatment  group.  Median,  quartiles,  and  their 
associated 95% confidence intervals will be estimated from the adjusted survival curve with 
site, age, and height as confounders (Nieto and Coresh 1996). In addition, the plot of adjusted 
survival curve will be presented for both treatment groups. 
 
9.7.2.2.4. 
Total Postsurgical Opioid Consumption through 24 and 48 Hours, and Day 7 (168 
Hours) and Day 14 (336 Hours) 
These endpoints will be analyzed similar to Section 9.7.2.1. 
 
 
9.7.2.3. 
Tertiary Efficacy Analyses 
 
9.7.2.3.1. 
AUC  in  Visual  Analog  Scale  (VAS)  from  0 to  12 Hours,  0 to  24 Hours,  0  to 
48 Hours, 24 to 48 Hours, and 48 to 72 Hours 
These endpoints will be analyzed similar to Section 9.7.2.2.2. 
 
9.7.2.3.2. 
Summ of VAS Pain Intensity Scores at Rest from End of Surgery through 72 Hours 
(SPIS0-72) 


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Summed Pain Intensity Score through 72 hours (SPIS0-72) will be analyzed similarly to Section 
9.7.2.2.2. The non-inferiority margin for this analysis is defined as 50% x 9, where 9 is the 
number of time points in the SPIS0-72 calculation. 
 
9.7.2.3.3. 
Opioid-Free at 72 Hours 
These endpoints will be analyzed similar to Section 9.7.2.2.1. 
 
9.7.2.3.4. 
Sum of VAS Pain Intensity Scores (SPIS) at Rest from 0 to 12 Hours, 0 to 24 Hours, 
0 to 48 Hours, 24 to 48 Hours, and 48 to 72 Hours 
These endpoints will be analyzed similar to Section Error! Reference source not found.. 
 
9.7.2.3.5. 
Integrated Rank Assessment Using the VAS Pain Intensity Score at Rest 
In this analysis, SPIS0-72 is combined with the cumulative dose (oral MED) of the rescue opioid 
medications up to the time of the 72 hour pain assessment. If opioid pain medication 
information stops being collected before the pain assessment time, the projected amount will 
be calculated and used as described in Section 9.1.1.1. The integrated analysis of the pain score 
and opioid rescue medication will be carried out according to the methods of D.G. Silverman 
et al (1993) as follows. 
• Both the SPIS score and the amount of opioid medication will be separately ranked in 
the combined treatment groups (the average of respective ranks will be used in the case 
of ties). 
• Each subject’s SPIS rank and total opioid medication usage rank will then be subtracted 
by the mean rank [(n+1)/2] of all subjects and expressed as a percent (%) difference 
from the mean rank, where n is the total number of subjects in the analysis. 
• A subject’s integrated score is the sum of the % difference in the SPIS score and the % 
difference in the total opioid pain medication usage. 
The integrated score will be summarized with descriptive statistics by treatment and analyzed 
for the between treatment difference using the method described in Section Error! Reference 
source not found.. 
 
9.7.2.3.6. 
Overall Benefit of Analgesia (OBAS) 
The OBAS total score will be summarized and individual question responses tabulated by 
treatment at each assessment time points. For the OBAS total score, the between group 
comparison will be carried out at each time point using the Cochran-Mantel-Haenszel (CMH) 
test for row mean score difference (RMS) with modified ridit score. 
 
9.7.2.3.7. 
Time Spent in the Post-Anesthesia Care Unit (PACU) 


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The time spent (hours) in PACU is defined as date/time of admission to PACU subtracted by 
date/time of discharge from PACU. This endpoint will be analyzed by treatment group using 
ANCOVA as described in Section Error! Reference source not found.. 
 
9.7.2.3.8. 
Time to First Unassisted Ambulation 
Time to first unassisted ambulation will be computed in hours as the date and time of the first 
unassisted ambulation minus the date and time of the end of surgery. If a subject is not 
administered an ambulation, the time to first unassisted ambulation will be censored at 72 
hours after surgery or at the time of last follow-up, whichever is early. Time to first unassisted 
ambulation will be analyzed by the method similar to time to first opioid rescue medication 
secondary endpoint (see Section 9.7.2.2.3). 
 
9.7.2.3.9. 
Discharge Readiness 
Percentage of subjects meeting MPADSS criteria for discharge readiness (total score  ≥9, 
Section 7) will be analyzed similarly to Section 9.7.2.2.1 using logistic regression at each 
assessed time point. 
If a subject is discharge ready at an early timepoint, the subject will be considered discharge 
ready at all subsequent (future) timepoints. If a subject has a discharge readiness total score of 
less than 9 or if the total score is missing, the subject will be considered not discharge ready, 
unless they were previously considered discharge ready. 
 
9.7.2.3.10. 
Subject Satisfaction with Overall Analgesia 
Subject satisfaction with overall analgesia (obtained using a 5-point Likert scale) will be 
summarized with mean and SD and tabulated with n (%) by treatment and assessment time 
point. The between group comparison will be carried out using the same method as described 
in Section 9.7.2.3.6. 
 
9.7.2.3.11. 
QoR-15 Questionnaire 
This analysis will only be done on subjects with correct QoR-15. Listing of subjects with correct 
QoR-15 and incorrect QoR-15 will be provided. 
Quality of Recovery questionnaire is comprised of two Parts. Part A has 10 items and Part B has 
5 items, both on the feeling and experience in the last 24 hours. For each subject, the mean 
score of Part A and the mean score of Part B will be calculated using all the available item 
scores. If ≥4 item scores are missing for Part A, or ≥2 item scores are missing for Part B, the 
respective mean score will be set to missing. The total score for the questionnaire is defined as 
the average of the Part A and Part B mean scores. If either Part A or Part B mean score is 
missing, the total score is set to missing. See Appendix 1 for the QoR-15 questionnaire. 


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The total score as well as scores for Questions 3, 4, 14, 15 will be summarized (n, mean, SD, 
median, minimum and maximum) for each treatment group at 72 hours postsurgery or prior to 
hospital discharge, whichever occurs first. The between group comparison will be carried out 
using the same method as described in Section 9.7.2.3.6. 
 
9.7.2.3.12. 
Phone Calls after Discharge 
The number of unscheduled pain-related phone calls per subject after discharge through 
postsurgical Day 14 will be summarized with mean and SD and tabulated with n (%) of subjects 
with 0, 1, 2, 3, etc. phone call by treatment. The between group comparison will be carried out 
using the same method as described in Section 9.7.2.3.6. 
 
9.7.2.3.13. 
Total Opioid Consumption through Day 7 and Day 14 
Subject’s opioid consumption in hospital and on patient diary after discharge will be summed 
together to get total opioid consumption through Day 7 and Day 14. These two endpoints will 
be derived as the sum of total opioid consumption through 72 hours (primary efficacy 
endpoint) and from 72 hours (exclusive) through Day 7 and Day 14 (inclusive), respectively. The 
opioid consumption from 72 hrs through Day 7 and Day 14 will be based on the Prescription 
Daily Pain Medication recorded in the Patient Diary. No imputation or projection will be carried 
out for the missing diaries. These two endpoints will be analyzed similar to Section 9.7.2.1. 
 
 
9.7.2.4. 
By-Subgroup Analysis 
In addition, total opioid consumption through 72 hours will be analyzed for the following 
subgroup. 
• 
Age (<35, 35+ years) 
• Race (White, Non-White) 
• 
BMI (<25, 25 to <30, and 30+ kg/m2) 
• Number of prior C-sections (0, 1+) 
• Discharge Time (Discharged on or before Day 3, Discharged on or after Day 4) 
• Medical history of anxiety (yes, no) 
Note because of the small sample sizes, all subgroup analysis will be performed without 
adjusting/stratifiying by site. 
 
9.8. 
Safety Analyses 
Safety assessments in this study consist of adverse events (AEs) and vital signs (VS) 


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9.8.1. Adverse Events 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA 
v21.1). 
An AE will be considered TEAE if it starts on/after the time of the study drug administration. 
If an AE has a partial onset date and time the imputed start dates and time will be used to 
determine treatment-emergence (Section 9.1.1.4). All AE summaries will present TEAEs only. 
AEs that are not treatment-emergent will be included in listings but not summarized. 
AEs will be summarized using subject incidence table. An overview of TEAE will be presented. 
This table will include n (%) of subjects with 
 
• Any TEAE 
o Maximum severity: Mild 
o Maximum severity: Moderate 
o Maximum severity: Severe 
• At least one related TEAE 
• At least one serious TEAE 
• Subjects discontinued due to a TEAE 
• Died on study 
Additionally, n (%) are calculated based on the number of unique subjects within each MedDRA 
category (eg, preferred term) by treatment group. A subject reporting multiple events of the 
same category will be counted only once for that category. For summary purpose, AE 
relationship to the study drug will be grouped into “Unrelated” for “unrelated” or “unlikely 
related” and “Related” for “possibly”, “probably”, or “definitely related”. For subjects with 
more than one event coded to the same PT, the subjects will be counted for the categories with 
the strongest relationship and the greatest severity. The following subject incidence tables will 
be presented. 
 
• TEAEs by PT (Preferred Term) sorted by the decreasing order of subject incidence in 
the combined group 
• TEAEs by SOC (System Organ Class) and PT sorted alphabetically 
• TEAEs by study drug-relationship by SOC and PT 
• TEAEs by severity and by SOC and PT 
• TEAE of special interest (TEAESI) by SOC and PT 


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A subject data listing will be provided for all adverse events. Included in the listing are the 
reported term, PT, SOC, TEAE flag, study day when AE starts, duration, relationship, severity, 
action taken, outcome, and seriousness category. 
 
Separate data listings will be provided for subjects who die on study, experience SAEs, have 
TEAEs leading to study discontinuation, or AEs of special interest. 
 
AE of special interest will be extracted based on the MedDRA terms below. 


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Table 4. Adverse Events of Special Interest 
Group MedDRA System Organ Class 
MedDRA Preferred Terms 
FALL 
Injury, poisoning and procedural complications 
Fall 
LAST 
Cardiac Disorders 
Arrhythmia 
Cardiac Disorders 
Atrial Fibrillation 
Cardiac Disorders 
Atrial Tachycardia 
Cardiac Disorders 
Atrioventricular Block 
Cardiac Disorders 
Atrioventricular Block First Degree 
Cardiac Disorders 
Bradycardia 
Cardiac Disorders 
Bundle Branch Block Left 
Cardiac Disorders 
Bundle Branch Block Right 
Cardiac Disorders 
Cardiac Arrest 
Cardiac Disorders 
Cardiac Failure Acute 
Cardiac Disorders 
Cardiac Failure Congestive 
Cardiac Disorders 
Conduction Disorder 
Cardiac Disorders 
Myocardial Infarction 
Cardiac Disorders 
Sinus Arrest 
Cardiac Disorders 
Sinus Arrhythmia 
Cardiac Disorders 
Sinus Bradycardia 
Cardiac Disorders 
Sinus Tachycardia 
Cardiac Disorders 
Supraventricular Tachyarrhythmia 
Cardiac Disorders 
Supraventricular Tachycardia 
Cardiac Disorders 
Tachyarrhythmia 
Cardiac Disorders 
Tachycardia 
Cardiac Disorders 
Ventricular Extrasystoles 
Cardiac Disorders 
Ventricular Tachycardia 
Nervous System 
Dizziness 
Nervous System 
Dysgeusia 
Nervous System 
Somnolence 
Nervous System 
Tremors 
 
A listing of the mapping of the system organ class and preferred terms to verbatim terms will 
be presented. 
 
9.8.2. Vital Signs 
Vitals signs are resting heart rate (bpm), systolic blood pressure (mmHg), and diastolic blood 
pressure (mmHg). Vital signs will be summarized by treatment group at each assessment time 
point. Summaries will present both actual and change-from-baseline results. 


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9.8.3. Interim Analysis 
The objective of the interim analysis is to evaluate efficacy and re-estimate the sample size. 
The first planned interim analysis, with 80 subjects out of planned 152 subjects for the primary 
efficacy analysis, was to test the null hypothesis of no between-group difference using the 
O’Brien-Fleming’s 2-sided boundary of 0.0078. Predictive probability (Saville et al 2014) was 
computed to evaluate the futility of the trial. 
The possible outcomes of the interim analysis are 
• Stop trial for futility, if the predictive probability is <30% 
• Stop trial for overwhelming efficacy, if the p-value is <0.0078 
• Continue the study with the planned total sample size of 144 subjects, if the predictive 
probability is ≥70% 
• Continue the study with total sample size increased up to 200 subjects, if the predictive 
probability is ≥30% but <70%. The  expansion in the  sample size  is to achieve the 
predictive probability >70% 
If the study continues to its completion, the critical value for the final analysis is as follows. 
 
 
Table 5. Critical Values (2-sided) for the Final Analysis 
Maximum Sample Size 
144 
152 
160 
168 
176 
184 
192 
200 
Critical Value 
0.0472 
0.0476 
0.0480 
0.0484 
0.0486 
0.0488 
0.0490 
0.0492 
 
For detail of the interim analysis, please refer to “402-C-411_interim_SAP_final” dated 
07June2017 and “402-C-411_2nd_interim_SAP_draft_final.docx.pdf” dated 15August2018. 
Results of the Interim Analysis 
The first interim  analysis was carried out after 80 patients (40 per group) enrolled under 
Amendment 2 or later version of the protocol and provided their primary efficacy outcome 
(Section 9.7.1.1). All randomized subjects who underwent planned surgery and received study 
drug were included in this interim analysis. After this analysis, it was decided to continue the 
trial without change to the sample size. The second interim analysis was carried out when 120 
patients enrolled under Amendment 2 or later version and provided their primary efficacy 
outcome and key secondary outcome (VAS pain intensity score). As result of this analysis, total 
sample size was increased to 184. 


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10. 
SAMPLE SIZE CALCULATIONS 
The sample size for this study was based Quale et al (2016). The coefficient of variation (CV) 
from this poster was approximately 60%. Assuming a log-normal distribution for total opioid 
consumption with a 60% CV, 5% alpha, a 1:1 randomization ratio, and 80% power 72 subjects 
per treatment arm is sufficient to detect a 30% difference between treatments. Assuming 5% 
of the subjects are not evaluable a total sample size of approximately 152 subjects are needed 
to ensure 144 evaluable subjects 


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11. 
REFERENCES 
Newcombe, RG, Interval Estimation for the Difference between Independent Proportions: Comparison 
of Eleven Methods. Statist. Med. 17, 873-890 (1998). 
 
Nieto, FJ and J Coresh. Adjusting Survival Curvs for Confounders: A Review and a New Method. American 
Journal of Epidemiology. 1996. Vol. 143, No. 10. 
 
Rubin, DB. (1987). Multiple Imputation for Nonresponse in Surveys. New York: John Wiley & Sons. 
 
Quale, M, G Cunningham, C Foster, and J Hutchins. Addition of transversus abdominis plane infiltration 
with liposomal bupivacaine to intrathecal morphine for postoperative analgesia after Caesarean 
delivery: a retrospective study. Abstract 1497. American Society of Regional Anesthesia and Pain 
Management. 41st Annual Regional Anesthesiology and Acute Pain Medicine Meeting. 31-Mar-2016 to 
02-Apr-2016. New Orleans, LA, US. 
 
Saville, BR, JT Connor, GD Ayers, J Alvarez. The Utility of Bayesian Predictive Probabilities for Interim 
Monitoring of Clinical Trials. Clinical Trials. May 2014, p485-493, Vol. 11, No. 4. 
 
Schafer, JL. (1997). Analysis of Incomplete Multivariate Data. New York: Chapman & Hall. 
 
Silverman, DG, TZ O'Connor, SJ Brull. Integrated assessment of pain scores and rescue morphine use 
during studies of analgesic efficacy. Anesth Analg. 1993;77:168-170. 


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12. 
TIME AND EVENTS SCHEDULE OF STUDY PROCEDURES 
Please see the Protocol for the full “Time and Events Schedule of Study Procedures”. 


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13. 
LAYOUT OF TABLES, LISTINGS AND FIGURES 
The following are planned summary tables. Tables will be numbered according to the 
nomenclature used to support the CSR. The final table numbering may be different from the 
SAP. No amendment will be made for changes in table numbering. All headers,  titles, 
footnotes, and footers specified in the table mock-ups will be displayed in the produced output 
unless otherwise specified. Notes to programmers will not be included in the tables. 
Tables and listings will have 10 point font size. Listings font size may be reduced to 9 point if 
needed. The TLFs will have either Times New Roman, Courier New or SAS Monospace type 
face. All final TLFs will be provided in both PDF and Word (or RTF) file formats. 
Percentages should not appear if the count is zero. 
Italicized text in the TLF mock-ups indicate notes to programmers and is not to appear on any 
TLF. 
Note headers and footers on mock-ups are reflective of the SAP document and are not 
intended to appear on the TLFs. 
Titles on the TLFs in the mock-ups are presented left-justified as a single line of text. However, 
the presentation for final TFLs should be center-justified with the TLF number on one line and 
the remaining titles on multiple lines of text where the line breaks are delimited by hyphens (-) 
in the TLF mock-ups titles. For example, for Table 14.2-1.1.1 the title in the mock-up appears 
as: 
Table 14.2-1.1.1: Analysis of Postsurgical Total Opioid Consumption (MED mg) 
through 72 hours – Efficacy Analysis Set 
but should appear as follows on the final TLF: 
Table 14.2-1.1.1 
Analysis of Postsurgical Total Opioid Consumption (OMED mg) through 72 hours 
Efficacy Analysis Set 
The title format in the mock-ups is due to limitations of MS Word. The mock-up format enables 
MSWord to generate a table of contents for the mock-ups. 
For categorical variables, if subjects have missing values (example Race), a “missing” category 
will be added as appropriate. 
All tables will present treatment EXPAREL 266 mg (for EXPAREL+Bupivacaine) and IR 
Bupivacaine as separate columns. 
On all figures, EXPAREL 266 mg will be represented in red with solid lines and dots, and 
Bupivacaine will be represented in blue with solid lines and filled squares. 


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On all listings the treatments, in the order of appearance, are: EXPAREL 266 mg, IR Bupivacaine 
and, if applicable, NOT RANDOMIZED. Always insert a page break between treatments. 
On all listings sort within treatment by site, subject, with further sorts dependent on listing. 
The  shell  provides  a  general  guidance  for  how  the  data  will  be  presented. 
The  actual 
presentation may be modified to accommodate the page size restriction. 
For TFLs with multiple pages, page numbers will be included. 
All TFLs will have SAS program names and folder names and date/time stamp in the footnote 
for tracking purpose. 


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Statistical Analysis Plan 
 
 
 
14. 
LIST OF TABLES 
Table 14.1-1: Summary Of Subject Disposition – All Screened Subjects 
42 
Table 14.1-2.1: Summary Of Subject Demographics - Safety Analysis Set 
44 
Table 14.1-2.2: Summary Of Subject Demographics – Efficacy Analysis Set 
45 
Table 14.1-3.1: Summary Of Subject Baseline Characteristics - Safety Analysis Set 
48 
Table 14.1-3.2: Summary Of Subject Baseline Characteristics - Efficacy Analysis Set 
48 
Table 14.1-4.1: Summary Of Surgery Characteristics - Safety Analysis Set 
49 
Table 14.1-4.2: Summary Of Surgery Characteristics – Efficacy Analysis Set 
50 
Table 14.1-5: Incidence Of Intraoperative Medications - Efficacy Analysis Set 
51 
Table 14.2-1.1a: Analysis Of Postsurgical Total Opioid Consumption (Omed Mg) Through 72 Hours – 
Efficacy Analysis Set 
52 
Table 14.2-1.1b: Summary Of Postsurgical Total Opioid Consumption (Omed Mg) Through 72 Hours By 
Site - Efficacy Analysis Set 
53 
Table 14.2-1.2a: Analysis Of Postsurgical Total Opioid Consumption (Omed Mg) Through 24 And 48 
Hours, And Day 7 (168 Hours) And Day 14 (336 Hours) - Efficacy Analysis Set 
54 
Table 14.2-1.2b: Summary Of Postsurgical Total Opioid Consumption (Omed Mg) Through 24 And 48 
Hours, And Day 7 (168 Hrs) And Day 14 (336 Hours) By Site - Efficacy Analysis Set 
55 
Table 14.2-1.3a: Analysis Of Postsurgical Total Opioid Consumption (Omed Mg) Through Day 7 – 
Efficacy Analysis Set 
56 
Table 14.2-1.4a: Analysis Of Postsurgical Total Opioid Consumption (Omed Mg) Through Day 14 – 
Efficacy Analysis Set 
56 
Table 14.2-1.5a: Subgroup Analysis Of Postsurgical Total Opioid Consumption (Omed Mg) Through 72 
Hours By Age – Efficacy Analysis Set 
57 
Table 14.2-1.5b: Subgroup Summary Of Postsurgical Total Opioid Consumption (Omed Mg) Through 72 
Hours By Age – Efficacy Analysis Set 
58 
Table 14.2-1.6a: Subgroup Analysis Of Postsurgical Total Opioid Consumption (Omed Mg) Through 72 
Hours By Race – Efficacy Analysis Set 
59 
Table 14.2-1.6b: Subgroup Summary Of Postsurgical Total Opioid Consumption (Omed Mg) Through 72 
Hours By Race – Efficacy Analysis Set 
59 
Table 14.2-1.7a: Subgroup Analysis Of Postsurgical Total Opioid Consumption (Omed Mg) Through 72 
Hours By Bmi Status – Efficacy Analysis Set 
59 
Table 14.2-1.7b: Subgroup Summary Of Postsurgical Total Opioid Consumption (Omed Mg) Through 72 
Hours By Bmi Status – Efficacy Analysis Set 
59 
Table 14.2-1.8a: Subgroup Analysis Of Postsurgical Total Opioid Consumption (Omed Mg) Through 72 
Hours By Number Of Prior C-Sections – Efficacy Analysis Set 
59 
Table 14.2-1.8b: Subgroup Summary Of Postsurgical Total Opioid Consumption (Omed Mg) Through 72 
Hours By Number Of Prior C-Sections – Efficacy Analysis Set 
59 
Table 14.2-1.9a: Subgroup Analysis Of Postsurgical Total Opioid Consumption (Omed Mg) Through 72 
Hours By Discharge Time – Efficacy Analysis Set 
59 


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Table 14.2-1.9b: Subgroup Summary Of Postsurgical Total Opioid Consumption (Omed Mg) Through 72 
Hours By Discharge Time – Efficacy Analysis Set 
59 
Table 14.2-1.10a: Subgroup Analysis Of Postsurgical Total Opioid Consumption (Omed Mg) Through 72 
Hours By Anxiety Medical History – Efficacy Analysis Set 
60 
Table 14.2-1.10b: Subgroup Summary Of Postsurgical Total Opioid Consumption (Omed Mg) Through 
72 Hours By Anxiety Medical History – Efficacy Analysis Set 
60 
Table 14.2-2.1: Analysis Of Opioid-Sparing Subjects Through 72 Hours - Efficacy Analysis Set 
61 
Table 14.2-2.2: Summary Of Opioid-Sparing Subjects Through 72 Hours By Site - Efficacy Analysis Set62 
Table 14.2-3.1a: Analysis Of Auc For Vas Pain Intensity Scores Through 72 Hours – Efficacy Analysis 
Set 
63 
Table 14.2-3.1b: Summary Of Auc For Vas Pain Intensity Scores Through 72 Hours By Site – Efficacy 
Analysis Set 
64 
Table 14.2-3.2a: Analysis Of Auc For Vas Pain Intensity Scores At Rest From 0 To 12 Hours, 0 To 24 
Hours, 0 To 48 Hours, 24 To 48 Hours, And 48 To 72 Hours - Efficacy Analysis Set 
65 
Table 14.2-3.2b: Summary Of Auc For Vas Pain Intensity Scores At Rest From 0 To 12 Hours, 0 To 24 
Hours, 0 To 48 Hours, 24 To 48 Hours, And 48 To 72 Hours - Efficacy Analysis Set 
66 
Table 14.2-4: Analysis Of Time To First Opioid Rescue Medication Use (Hours) - Efficacy Analysis Set67 
Table 14.2-5.1: Analysis Of Opioid-Free Subjects Through 72 Hours - Efficacy Analysis Set 
68 
Table 14.2-5.2: Summary Of Opioid-Free Subjects Through 72 Hours By Site - Efficacy Analysis Set 
68 
Table 14.2-6.1a: Analysis Of Summed Pain Intensity Scores (Spis) Through 72 Hours– Efficacy Analysis 
Set 
68 
Table 14.2-6.1b: Summary Of Summed Pain Intensity Scores (Spis) Through 72 Hours By Site – Efficacy 
Analysis Set 
68 
Table 14.2-7a: Analysis Of Integrated Rank Assessment Using Spis At Rest And Omed Of Rescue 
Medications Through 24, 48, And 72 Hours - Efficacy Analysis Set 
69 
Table 14.2-7b: Summary Of Integrated Rank Assessment Using Spis At Rest And Omed Of Rescue 
Medications Through 24, 48, And 72 Hours - Efficacy Analysis Set 
70 
Table 14.2-8a: Analysis Of Overall Benefit Of Analgesia Scale (Obas) By Timepoint And Question - 
Efficacy Analysis Set 
71 
Table 14.2-8b: Summary Of Overall Benefit Of Analgesia Scale (Obas) By Timepoint And Question - 
Efficacy Analysis Set 
72 
Table 14.2-9a: Analysis Of Time Spent In Post-Anesthesia Care Unit (Pacu) – Efficacy Analysis Set 
73 
Table 14.2-9b: Summary Of Time Spent In Post-Anesthesia Care Unit (Pacu) – Efficacy Analysis Set 
74 
Table 14.2-10: Summary Of Time To First Unassisted Ambulation - Efficacy Analysis Set 
75 
Table 14.2-11a: Analysis Of Subjects Meeting Modified Post Anesthesia Discharge Scoring System 
(Mpadss) Criteria For Discharge Readiness At Each Assessed Timepoint - Efficacy Analysis 
Set 
76 
Table 14.2-11b: Summary Of Subjects Meeting Modified Post Anesthesia Discharge Scoring System 
(Mpadss) Criteria For Discharge Readiness At Each Assessed Timepoint - Efficacy Analysis 
Set 
77 


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Statistical Analysis Plan 
 
 
Table 14.2-12: Summary Of Overall Assessment Of Subject’s Satisfaction With Postsurgical Pain Control 
At 72 Hours After Surgery - Efficacy Analysis Set 
78 
Table 14.2-13a: Analysis Of Quality Of Recovery Questionnaire At 72 Hours Postsurgery - Efficacy 
Analysis Set (Only Include Subjects Who Completed The Correct Qor-15 Form) 
79 
Table 14.2-13b: Summary Of Quality Of Recovery Questionnaire At 72 Hours Postsurgery - Efficacy 
Analysis Set (Only Include Subjects Who Completed The Correct Qor-15 Form) 
81 
Table 14.2-14a: Analysis Of Subjects With Unscheduled Pain-Related Phone Calls - Efficacy Analysis  
Set 
83 
Table 14.2-14b: Summary Of Number Of Unscheduled Pain-Related Phone Calls - Efficacy Analysis Set84 
Table 14.3-1.1: Overview Of Treatment-Emergent Adverse Events (Teaes) - Safety Analysis Set 
85 
Table 14.3-1.2.1: Summary Of Incidence Of Treatment-Emergent Adverse Events (Teaes) By Preferred 
Term - Safety Analysis Set 
86 
Table 14.3-1.2.2: Summary Of Subject Incidence Of Treatment-Emergent Adverse Events (Teaes) By 
System Organ Class And Preferred Term - Safety Analysis Set 
87 
Table 14.3-1.3: Summary Of Subject Incidence Of Treatment-Emergent Adverse Events (Teaes) By 
System Organ Class, Preferred Term, And Worst Severity - Safety Analysis Set 
88 
Table 14.3-1.4: Summary Of Subject Incidence Of Treatment-Emergent Adverse Events (Teaes) By 
System Organ Class, Preferred Term, And Strongest Relationship To Study Drug - Safety 
Analysis Set 
89 
Table 14.3-1.5: Summary Of Subject Incidence Of Treatment-Emergent Adverse Events Of Special 
Interest (Teaesi) By Preferred Term - Safety Analysis Set 
90 
Table 14.3-2: Summary Of Vital Signs By Timepoint – Safety Analysis Set 
91 
Table 14.3-3.1: Incidence Of Prior Medications – Safety Analysis Set 
93 
Table 14.3-3.2: Incidence Of Concomitant Medications – Safety Analysis Set 
93 


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Statistical Analysis Plan 
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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-411 
Table 14.1-1: Summary of Subject Disposition – All Screened Subjects 
 Site: Overall  
 
 
EXPAREL 266 
(N=XX) 
n (%) 
mg 
IR Bupivacaine 
(N=XX) 
n (%) 
Total 
(N=XX) 
n (%) 
Screened [1] 
xx 
Screen Failure 
xx (xx.x) 
Enrolled 
xx (xx.x) 
Randomized 
xx 
xx 
xx 
Not Treated 
Treated 
xx 
xx 
xx 
xx 
xx 
xx 
TAP Infiltration Error per Ultrasound Image 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Study Drug Administered Before 17 February 2018 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Safety Analysis Set [2]# 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Efficacy Analysis Set [3]@ 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Protocol 
Enrolled under Protocol v3 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Enrolled under Protocol v2 
Enrolled under Protocol v1 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Completed Study@ 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Discontinued from Study@ 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Reasons for Discontinuation 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Death 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Adverse Event 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Lack of Efficacy 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Lost to Follow-up 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Withdrawal by Subject 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Other 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 


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# = as treated 
@ = as randomized 
[1] Signed the informed consent form 
[2] Received study drug 
[3] Received study drug and surgery 
Percentages for screen failure and enrolled based on number screened; others on number randomized. 
Subjects randomized to EXPAREL 266 mg but treated with IR Bupivacaine: list subjects 
Subjects randomized to IR Bupivacaine but treated with EXPAREL 266 mg: list subjects 
 
Note to programmer: First page will present overall sites; subsequent pages will present each site – one 
site per page. For reasons for discontinuation only those reasons that appear in the data will appear on 
the table. For individual sites the label should be the site number. 
For the footnotes “Subjects treated 
with...” if no subjects were mistreated, then omit footnote. 


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402-C-411 (C-section TAP) 
Statistical Analysis Plan 
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44 of 123 
03 January 2019 
 
 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-411 
Table 14.1-2.1: Summary of Subject Demographics - Safety Analysis Set 
 
Site: Overall 
Statistic 
EXPAREL+Bupivacaine 
IR Bupivacaine 
Total 
(N=XX) 
(N=XX) 
(N=XX) 
Age (yrs) 
n 
xx 
xx 
xx 
Mean 
xx.x 
xx.x 
xx.x 
SD 
x.xx 
x.xx 
x.xx 
Minimum 
xx 
xx 
xx 
Median 
xx.x 
xx.x 
xx.x 
Maximum 
xx 
xx 
xx 
Sex 
Female 
n (%) 
 
Male 
n (%) 
 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Ethnicity 
Hispanic or Latino 
n (%) 
 
Not Hispanic or Latino 
n (%) 
 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Race 
American Indian/Alaska Native 
n (%) 
 
Black/African American 
n (%) 
 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Asian 
White 
n 
n 
(%) 
(%) 
xx 
xx 
(xx.x) 
(xx.x) 
xx 
xx 
(xx.x) 
(xx.x) 
xx 
 
xx 
(xx.x) 
(xx.x) 
Native Hawaiian/Pacific Islander 
n (%) 
xx 
xx 
(xx.x) 
(xx.x) 
xx 
xx 
(xx.x) 
(xx.x) 
xx 
 
xx 
(xx.x) 
(xx.x) 
 
 
 


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Note to programmer: Only categories available in the data will appear on the table. 
First page will 
present overall sites; subsequent pages will present each site – one site per page. For individual sites 
the label should be the site number. 
 
Use this mock-up also for table: 
 
Table 14.1-2.2: Summary of Subject Demographics – Efficacy Analysis Set 


Pacira Pharmaceuticals, Inc. 
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402-C-411 (C-section TAP) 
Statistical Analysis Plan 
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03 January 2019 
 
 
 
Pacira Pharmaceuticals 
(Page 1 of 3) 
Protocol: 402-C-411 
Table 14.1-3.1: Summary of Subject Baseline Characteristics - Safety Analysis Set 
 
Statistic 
EXPAREL 266 
(N=XX) 
mg 
IR Bupivacaine 
(N=XX) 
Total 
(N=XX) 
ECG 
Normal, NCS 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
Abnormal, NCS 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
Abnormal, CS 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
VAS Score (cm) 
n 
Mean 
SD 
Minimum 
xx 
xx.x 
x.xx 
xx 
xx 
xx.x 
x.xx 
xx 
xx 
xx.x 
x.xx 
xx 
Median 
Maximum 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
ASA Classification 
1 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
2 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
3 
≥ 4 
n (%) 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Height(cm) 
n 
Mean 
SD 
Minimum 
Median 
xx 
xx.x 
x.xx 
xx 
xx.x 
xx 
xx.x 
x.xx 
xx 
xx.x 
xx 
xx.x 
x.xx 
xx 
xx.x 
Maximum 
xx 
xx 
xx 


Pacira Pharmaceuticals, Inc. 
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Statistical Analysis Plan 
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Pacira Pharmaceuticals 
(Page 2 of 3) 
Protocol: 402-C-411 
Table 14.1-3.1: Summary of Subject Baseline Characteristics - Safety Analysis Set 
 
 
 
Statistic 
EXPAREL 266 mg 
(N=XX) 
IR Bupivacaine 
(N=XX) 
Total 
(N=XX) 
Weight (kg) 
n 
Mean 
SD 
Minimum 
Median 
xx 
xx.x 
x.xx 
xx 
xx.x 
xx 
xx.x 
x.xx 
xx 
xx.x 
xx 
xx.x 
x.xx 
xx 
xx.x 
Maximum 
xx 
xx 
xx 
Body Mass Index (kg/m2) 
Maximum 
xx 
xx 
xx 
n 
xx 
xx 
xx 
Mean 
xx.x 
xx.x 
xx.x 
SD 
x.xx 
x.xx 
x.xx 
Minimum 
xx 
xx 
xx 
Median 
xx.x 
xx.x 
xx.x 
Maximum 
xx 
xx 
xx 
Maximum 
xx 
xx 
xx 
 
 


Pacira Pharmaceuticals, Inc. 
EXPAREL 
402-C-411 (C-section TAP) 
Statistical Analysis Plan 
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Pacira Pharmaceuticals 
(Page 3 of 3) 
Protocol: 402-C-411 
Table 14.1-3.1: Summary of Subject Baseline Characteristics - Safety Analysis Set 
 
Statistic 
EXPAREL 266 
(N=XX) 
mg 
IR Bupivacaine 
(N=XX) 
Total 
(N=XX) 
Heart Rate (bpm) 
n 
Mean 
SD 
Minimum 
Median 
Maximum 
xx 
xx.x 
x.xx 
xx 
xx.x 
xx 
xx 
xx.x 
x.xx 
xx 
xx.x 
xx 
xx 
xx.x 
x.xx 
xx 
xx.x 
xx 
Systolic Blood Pressure (mmHg) 
n 
Mean 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
SD 
Minimum 
Median 
x.xx 
xx 
xx.x 
x.xx 
xx 
xx.x 
x.xx 
xx 
xx.x 
Maximum 
xx 
xx 
xx 
Diastolic Blood Pressure (mmHg) 
n 
xx 
xx 
xx 
Mean 
SD 
xx.x 
x.xx 
xx.x 
x.xx 
xx.x 
x.xx 
Minimum 
Median 
Maximum 
Maximum 
xx 
xx.x 
xx 
xx 
xx 
xx.x 
xx 
xx 
xx 
xx.x 
xx 
xx 
 
 
 
Use Table 14.1-2.1 shell for 
 
Table 14.1-3.2: Summary of Subject Baseline Characteristics - Efficacy Analysis Set 


Pacira Pharmaceuticals, Inc. 
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Statistical Analysis Plan 
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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-411 
 Table 14.1-4.1: Summary of Surgery Characteristics - Safety Analysis Set  
 
 
Characteristic 
Statistic 
EXPAREL 266 
(N=XX) 
mg 
IR Bupivacaine 
(N=XX) 
Total 
(N=XX) 
Duration of Surgery (hours) 
n 
Mean 
SD 
Median 
Minimum 
Maximum 
xx 
xx.x 
x.xx 
xx 
xx.x 
xx 
xx 
xx.x 
x.xx 
xx 
xx.x 
xx 
xx 
xx.x 
x.xx 
xx 
xx.x 
xx 
Tourniquet 
Used Not 
Used 
n (%) 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
Duration (hours) 
n 
Mean 
SD 
Median 
Minimum 
Maximum 
xx 
xx.x 
x.xx 
xx 
xx.x 
xx 
xx 
xx.x 
x.xx 
xx 
xx.x 
xx 
xx 
xx.x 
x.xx 
xx 
xx.x 
xx 
Drain 
Used Not 
Used 
n (%) 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
Duration (hours) 
n 
Mean 
SD 
Median 
Minimum 
Maximum 
xx 
xx.x 
x.xx 
xx 
xx.x 
xx 
xx 
xx.x 
x.xx 
xx 
xx.x 
xx 
xx 
xx.x 
x.xx 
xx 
xx.x 
xx 
 
 


Pacira Pharmaceuticals, Inc. 
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Use this mock-up also for tables: 
 
Table 14.1-4.2: Summary of Surgery Characteristics – Efficacy Analysis Set 


Pacira Pharmaceuticals, Inc. 
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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-411 
 Table 14.1-5: Incidence of Intraoperative Medications - Efficacy Analysis Set  
 
 
EXPAREL 266 mg 
IR Bupivacaine 
Total 
Anatomical Therapeutic Class 
Preferred Name 
(ATC) 
(N=XX) 
n (%) 
(N=XX) 
n (%) 
(N=XX) 
n (%) 
 
Subjects taking at least one medication 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
ATC1 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
PN1.1 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
PN1.2 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
ATC2 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
PN2.1 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
PN2.2 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
ETC. 
 
 
Medications are coded using World Health Organization Drug Dictionary (WHODD Sepember 2018). 
Sorted by descending total incidence by ATC and preferred name within ATC. 
Intraoperatives medications are those indicated as such by the investigator. 
Subjects using the same prior medication more than once are counted only once at each summary level. 


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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-411 
Table 14.2-1.1a: Analysis of Postsurgical Total Opioid Consumption (OMED mg) Through 72 hours – Efficacy 
Analysis Set 
 
 
 
Statistic 
EXPAREL 266 mg 
(N=XX) 
IR Bupivacaine 
(N=XX) 
LS Mean [1] 
Standard Error of LS Mean [1] 
xxx.x 
xxx.xx 
xxx.x 
xxx.xx 
% Reduction [2] 
xxx.x 
LSM Treatment Difference Difference 
95% Confidence Interval [1][3] 
P-value, 1-sided [1][3] 
[1][3] 
xx.x 
(xx.x, xx.x) 
0.xxx 
LS = Least Square; LSM2 = LS Means in IR Bupivacaine group; LSM1 = LS Means in EXPAREL 266 mg group. 
[1] From an ANCOVA with main effects of treatment and site and covariates of age and height on total opioid 
consumption. Subjects without any opioid use are assigned a value of 0 mg for summaries. 
[2] % Reduction in Total Opioid Dose is calculated as (LSM2-LSM1)/LSM2*100%. 
[3] Test of Ha: LSM (EXPAREL 266 mg) < LSM (IR Bupivacaine). 


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Table 14.2-1.1b: Summary of Postsurgical Total Opioid Consumption (OMED mg) Through 72 hours by Site - 
Efficacy Analysis Set 
 
 
 
Site 
Statistic 
EXPAREL 266 mg 
(N=XX) 
IR Bupivacaine 
(N=XX) 
 
 
101 
n 
xx 
xx 
Mean 
xx.x 
xx.x 
SD 
x.xx 
x.xx 
Median 
xx.x 
xx.x 
Min, Max 
xx, xx 
xx, xx 
 
102 
n 
xx 
xx 
Mean 
xx.x 
xx.x 
SD 
x.xx 
x.xx 
Median 
xx.x 
xx.x 
Min, Max 
xx, xx 
xx, xx 
 
... 
... 
... 
... 
 
999 
n 
xx 
xx 
Mean 
xx.x 
xx.x 
SD 
x.xx 
x.xx 
Median 
xx.x 
xx.x 
Min, Max 
xx, xx 
xx, xx 
 
Overall 
n 
xx 
xx 
Mean 
xx.x 
xx.x 
SD 
x.xx 
x.xx 
Median 
xx.x 
xx.x 
Min, Max 
xx, xx 
xx, xx 
 
 
 
Note to programmer: Present for each site. 
Do not split a site’s statistics across pages. 


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Table 14.2-1.2a: Analysis of Postsurgical Total Opioid Consumption (OMED mg) Through 24 and 48 hours, and 
Day 7 (168 hours) and Day 14 (336 hours) - Efficacy Analysis Set 
 
EXPAREL 266 mg 
IR Bupivacaine 
Statistic 
(N=XX) 
(N=XX) 
0-24 hrs 
LS Mean [1] 
Standard Error of LS Mean [1] 
xxx.x 
xxx.xx 
xxx.x 
xxx.xx 
% Reduction [2] 
xxx.xx 
LSM Treatment Difference Difference 
[1][3] 
xx.x 
95% Confidence Interval [1][3] 
(xx.x, xx.x) 
P-value, 1-sided [1][3] 
 
0.xxx 
 
0-48 hrs 
LS Mean [1] 
xxx.x 
xxx.x 
Standard Error of LS Mean [1] 
xxx.xx 
xxx.xx 
% Reduction [2] 
xxx.xx 
LSM Treatment Difference Difference 
[1][3] 
xx.x 
95% Confidence Interval [1][3] 
(xx.x, xx.x) 
P-value, 1-sided [1][3] 
 
0.xxx 
 
. . . 
 
 
LS = Least Square; LSM2 = LS Means in IR Bupivacaine group; LSM1 = LS Means in EXPAREL 266 mg group. 
[1] From an ANCOVA with main effects of treatment and site and covariates of age and height on total opioid 
consumption. Subjects without any opioid use are assigned a value of 0 mg for summaries. 
[2] % Reduction in Total Opioid Dose is calculated as (LSM2-LSM1)/LSM2*100%. 
[3] Test of Ha: LSM (EXPAREL 266 mg) < LSM (IR Bupivacaine). 
 
 
Note to programmer: Time periods to appear on this table, in order, are 0-24 hrs, 0-48 hrs, 0-Day 7 (168 
hrs) and 0-Day 14 (336 hrs). Do not split a time period statistics across pages. 


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Table 14.2-1.2b: Summary of Postsurgical Total Opioid Consumption (OMED mg) Through 24 and 48 Hours, and Day 
7 (168 hrs) and Day 14 (336 hours) by Site - Efficacy Analysis Set 
 
Site 
EXPAREL 266 mg 
IR Bupivacaine 
Time Interval 
Statistic 
(N=XX) 
(N=XX) 
 
101 
 
0-24 hrs 
N 
xx 
xx 
Mean 
xxx.x 
xxx.x 
SD 
xxx.xx 
xxx.xx 
Median 
xxx.x 
xxx.x 
Min, Max 
xx, xx 
xx, xx 
 
0-48 hrs 
N 
xx 
xx 
Mean 
xxx.x 
xxx.x 
SD 
xxx.xx 
xxx.xx 
Median 
xxx.x 
xxx.x 
Min, Max 
xx, xx 
xx, xx 
 
0-Day 7 (168 hrs) 
 
0-Day 14 (336 hrs) 
 
999 
0-24 hrs 
. . . 
 
0-48 hrs 
. . . 
 
 
Overall 
. . . 
 
 


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Use Table 14.2-1.1a and 1.1b shells for 
 
 
 
Table 14.2-1.3a: Analysis of Postsurgical Total Opioid Consumption (OMED mg) Through Day 7 – Efficacy 
Analysis Set 
 
 
 
Table 14.2-1.4a: Analysis of Postsurgical Total Opioid Consumption (OMED mg) Through Day 14 – Efficacy 
Analysis Set 


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Table 14.2-1.5a: Subgroup Analysis of Postsurgical Total Opioid Consumption (OMED mg) Through 72 hours by 
Age – Efficacy Analysis Set 
 
 
 
Age 
Statistic 
EXPAREL 266 mg 
(N=XX) 
IR Bupivacaine 
(N=XX) 
 
 
<35 years 
LS Mean [1] 
xxx.x 
xxx.x 
Standard Error of LS Mean [1] 
xxx.xx 
xxx.xx 
% Reduction [2] 
xxx.x 
LSM Treatment Difference Difference 
[1][3] 
xx.x 
95% Confidence Interval [1][3] 
(xx.x, xx.x) 
P-value, 1-sided [1][3] 
 
0.xxx 
 
>= 35 years 
LS Mean [1] 
xxx.x 
xxx.x 
Standard Error of LS Mean [1] 
xxx.xx 
xxx.xx 
% Reduction [2] 
xxx.x 
LSM Treatment Difference Difference 
[1][3] 
xx.x 
95% Confidence Interval [1][3] 
(xx.x, xx.x) 
P-value, 1-sided [1][3] 
 
0.xxx 
 
 
LS = Least Square; LSM2 = LS Means in IR Bupivacaine group; LSM1 = LS Means in EXPAREL 266 mg group. 
[1] From an ANCOVA with main effects of treatment and covariates of age and height on total opioid 
consumption. Subjects without any opioid use are assigned a value of 0 mg for summaries. 
[2] % Reduction in Total Opioid Dose is calculated as (LSM2-LSM1)/LSM2*100%. 
[3] Test Ha: LSM (EXPAREL 266 mg) < LSM (IR Bupivacaine). 


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Table 14.2-1.5b: Subgroup Summary of Postsurgical Total Opioid Consumption (OMED mg) Through 72 hours by Age 
– Efficacy Analysis Set 
 
 
EXPAREL 266 mg 
IR Bupivacaine 
 
Age 
Statistic 
(N=XX) 
(N=XX) 
<35 years 
N 
xx 
xx 
Mean 
xxx.x 
xxx.x 
SD 
xxx.xx 
xxx.xx 
Median 
xxx.x 
xxx.x 
Min, Max 
xx, xx 
xx, xx 
 
>= 35 years 
N 
xx 
xx 
Mean 
xxx.x 
xxx.x 
SD 
xxx.xx 
xxx.xx 
Median 
Min, Max 
xxx.x 
xx, xx 
xxx.x 
xx, xx 
 
 


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Use Table 14.2-1.5a and 1.5b shell for (see SAP Section 9.7.2.1.1 for subgroup categories) 
 
Table 14.2-1.6a: Subgroup Analysis of Postsurgical Total Opioid Consumption (OMED mg) Through 72 hours by 
Race – Efficacy Analysis Set 
 
 
Table 14.2-1.6b: Subgroup Summary of Postsurgical Total Opioid Consumption (OMED mg) Through 72 hours by 
Race – Efficacy Analysis Set 
 
 
Table 14.2-1.7a: Subgroup Analysis of Postsurgical Total Opioid Consumption (OMED mg) Through 72 hours by 
BMI Status – Efficacy Analysis Set 
 
 
Table 14.2-1.7b: Subgroup Summary of Postsurgical Total Opioid Consumption (OMED mg) Through 72 hours by 
BMI Status – Efficacy Analysis Set 
 
 
Table 14.2-1.8a: Subgroup Analysis of Postsurgical Total Opioid Consumption (OMED mg) Through 72 hours by 
Number of Prior C-Sections – Efficacy Analysis Set 
 
 
Table 14.2-1.8b: Subgroup Summary of Postsurgical Total Opioid Consumption (OMED mg) Through 72 hours by 
Number of Prior C-Sections – Efficacy Analysis Set 
 
 
Table 14.2-1.9a: Subgroup Analysis of Postsurgical Total Opioid Consumption (OMED mg) Through 72 hours by 
Discharge Time – Efficacy Analysis Set 
 
 
Table 14.2-1.9b: Subgroup Summary of Postsurgical Total Opioid Consumption (OMED mg) Through 72 hours by 
Discharge Time – Efficacy Analysis Set 


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Table 14.2-1.10a: Subgroup Analysis of Postsurgical Total Opioid Consumption (OMED mg) Through 72 hours by 
Anxiety Medical History – Efficacy Analysis Set 
 
 
Table 14.2-1.10b: Subgroup Summary of Postsurgical Total Opioid Consumption (OMED mg) Through 72 hours by 
Anxiety Medical History – Efficacy Analysis Set 


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Table 14.2-2.1: Analysis of Opioid-Sparing Subjects through 72 hours - Efficacy Analysis Set 
 
 
 
Statistic 
EXPAREL 266 mg 
(N=XX) 
IR Bupivacaine 
(N=XX) 
No Opioid-Spared Percentage [1] 
(%) 
xx.x 
xx.x 
Opioid-Spared Percentage 
(%) 
Odds Ratio [2] 
xx.x 
xx.x 
xx.x 
95% CI for Odds Ratio 
(xx.x, xx.x) 
P-value, 1-sided [3] 
 
0.xxxx 
 
 
[1] LS Means probability from the logistic regression with treatment, site, age, and height as explanatory 
variables. 
[2] OR of EXPAREL 266 mg over IR Bupivacaine. 
[3] Test of Ha: Odds Ratio >1. 


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Table 14.2-2.2: Summary of Opioid-Sparing Subjects through 72 hours by Site - Efficacy Analysis Set 
 
 
Site 
Opioid Use 
Statistic 
EXPAREL 266 mg 
(N=XX) 
IR Bupivacaine 
(N=XX) 
 
 
101 
 
Opioid-Spared 
n (%) 
xx (xx.x) 
xx (xx.x) 
No Opioid-Spared 
n (%) 
xx (xx.x) 
xx (xx.x) 
 
... 
999 
 
 
 
Overall 
 
Opioid-Spared 
n (%) 
xx (xx.x) 
xx (xx.x) 
No Opioid-Spared 
n (%) 
xx (xx.x) 
xx (xx.x) 
 
 
Note to programmer: Present for each site. 
Do not split a site’s statistics across pages. 
Opioid-Spared 
n (%) 
xx (xx.x) 
xx (xx.x) 
No Opioid-Spared 
n (%) 
xx (xx.x) 
xx (xx.x) 


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Table 14.2-3.1a: Analysis of AUC for VAS Pain Intensity Scores Through 72 hours – Efficacy Analysis Set - 
Multiple Imputation Results 
 
 
 
Statistic 
EXPAREL 266 mg 
(N=XX) 
IR Bupivacaine 
(N=XX) 
LS Mean [1] 
xxx.x 
xxx.x 
Standard Error of LS Mean 
xxx.xx 
xxx.xx 
LSM Treatment Difference Difference 
95% Confidence Interval [2] 
[1] 
xx.x 
(xx.x, xx.x) 
Noninferiority Test P-value, 1-sided 
0.xxx 
Superiority Test P-value, 1-sided 
0.xxx 
 
 
LS = least squares. 
AUC = area under the curve calculated using the trapezoidal method. 
VAS = 10 cm visual analog scale for pain, where 0 = no pain and 10 = worst possible pain. 
[1] From an ANCOVA with main effects of treatment and site and covariates of age and height. 
[2] The non-inferiority of EXPAREL 266 mg to IR Bupivacaine is demonstrated if the upper limit is <=36. The 
superiority is demonstrated if the upper limit is <0. 
 
Programming note: if Superiority test fails, ie, p>0.05, then keep non-inferiority test and remove 
superiority test. Otherwise, remove non-inferiority test and keep superiority test. 


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Table 14.2-3.1b: Summary of AUC for VAS Pain Intensity Scores Through 72 hours by Site – Efficacy Analysis 
Set 
 
Site 
Statistic 
EXPAREL 266 
(N=XX) 
mg 
IR Bupivacaine 
(N=XX) 
101 
N 
xx 
xx 
Mean 
SD 
Median 
Min, Max 
xxx.x 
xxx.xx 
xxx.x 
xx, xx 
xxx.x 
xxx.xx 
xxx.x 
xx, xx 
... 
... 
... 
... 
999 
N 
xx 
xx 
Mean 
xxx.x 
xxx.x 
SD 
Median 
Min, Max 
xxx.xx 
xxx.x 
xx, xx 
xxx.xx 
xxx.x 
xx, xx 
Min, Max 
xx 
xx 
Overall 
N 
Mean 
SD 
Median 
xx 
xxx.x 
xxx.xx 
xxx.x 
xx 
xxx.x 
xxx.xx 
xxx.x 
Min, Max 
xx, xx 
xx, xx 
AUC = area under the curve calculated using the trapezoidal method. 
VAS = 10 cm visual analog scale for pain, where 0 = no pain and 10 = worst possible pain. 


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Table 14.2-3.2a: Analysis of AUC for VAS Pain Intensity Scores at Rest from 0 to 12 hours, 0 to 24 hours, 0 
 to 48 hours, 24 to 48 hours, and 48 to 72 hours - Efficacy Analysis Set  
 
 
Time Point 
Statistic 
EXPAREL 266 mg 
(N=XX) 
IR Bupivacaine 
(N=XX) 
 
 
0-24 
LS Mean [1] 
xxx.x 
xxx.x 
Standard Error of LS Mean 
xxx.xx 
xxx.xx 
LSM Treatment Difference [1] 
 xx.x 
95% Confidence Interval 
(xx.x, xx.x) 
P-value, 1-sided [2] 
0.xxxx 
 
Etc. 
LS Mean [1] 
xxx.x 
xxx.x 
Standard Error of LS Mean 
xxx.xx 
xxx.xx 
LSM Treatment Difference [1] 
xx.x 
95% Confidence Interval 
(xx.x, xx.x) 
P-value, 1-sided [2] 
0.xxxx 
LS = least squares; 
AUC = area under the curve calculated using the trapezoidal method; 
VAS = 10 cm visual analog scale for pain, where 0 = no pain and 10 = worst possible pain; 
[1] From an ANCOVA with main effects of treatment and site and covariates of age and height. 
[2] Test of Ha: LSM (EXPAREL 266 mg) < LSM (IR Bupivacaine). 
 
 
Note to programmer: VAS Pain Intensity Score to be presented on this table are, in order, 0-12, 0-24, 0-48, 
24-48, 24-48 and 48-72. Do not break statistics across pages. 


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Table 14.2-3.2b: Summary of AUC for VAS Pain Intensity Scores at Rest from 0 to 12 hours, 0 to 24 hours, 0 
to 48 hours, 24 to 48 hours, and 48 to 72 hours - Efficacy Analysis Set 
 
Time Point 
Statistic 
EXPAREL 266 mg 
(N=XX) 
IR Bupivacaine 
(N=XX) 
 
 
0-24 
n 
xx 
xx 
Mean 
xx.x 
xx.x 
SD 
x.xx 
x.xx 
Median 
xxx.x 
xxx.x 
Min, Max 
xx, xx 
xx, xx 
 
Etc. 
n 
Mean 
SD 
xx 
xx.x 
x.xx 
xx 
xx.x 
x.xx 
Median 
Min, Max 
xxx.x 
xx, xx 
xxx.x 
xx, xx 
 
 
Note to programmer: VAS Pain Intensity Score to be presented on this table are, in order, 0-12, 0-24, 0-48, 
24-48, 24-48 and 48-72. Do not break statistics across pages. 


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Table 14.2-4: Analysis of Time to First Opioid Rescue Medication Use (hours) - Efficacy Analysis Set 
 
 
 
Statistic 
EXPAREL 266 mg 
(N=XX) 
IR Bupivacaine 
(N=XX) 
 
 
Number of Subjects on 
Rescue Medication (Opioid) 
n (%) 
xx (xx.x) 
xx (xx.x) 
No Rescue Medication (censored) 
n (%) 
xx (xx.x) 
xx (xx.x) 
 
Time to Rescue 
Quartiles [1] 
First (25% rescued) 
Estimate 
 
xx.xx 
 
xx.xx 
(95% CI) 
(xx.xx, xx.xx) 
(xx.xx, xx.xx) 
 
Median (50% rescued) 
Estimate 
 
xx.xx 
 
xx.xx 
(95% CI) 
(xx.xx,xx.xx) 
(xx.xx,xx.xx) 
 
Third (75% rescued) 
Estimate 
 
xx.xx 
 
xx.xx 
(95% CI) 
(xx.xx,xx.xx) 
(xx.xx,xx.xx) 
 
Minimum 
Observed 
xx.xx 
xx.xx 
Maximum 
Observed 
xx.xx* 
xx.xx 
 
P-value, 2-sided [2] 
0.xxxx 
 
 
* indicates censored observation. 
CI = confidence interval 
[1] Estimates from the adjusted survival curve with site, age, and height as confounders. 
[2] P-value for the EXPAREL 266 mg to IR Bupivacaine comparison using the Cox regression model with 
treatment and site as factors and age and height as covariates. 


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Use Table 14.2-2.1 shell for 
 
Table 14.2-5.1: Analysis of Opioid-Free Subjects Through 72 hours - Efficacy Analysis Set 
 
 
 
Use Table 14.2-2.2 shell for 
 
Table 14.2-5.2: Summary of Opioid-Free Subjects Through 72 hours by Site - Efficacy Analysis Set 
 
 
 
 
 
 
Use Table 14.2-3.1a and 3.1b shell for 
 
Table 14.2-6.1a: Analysis of Summed Pain Intensity Scores (SPIS) Through 72 hours– Efficacy Analysis Set - 
Multiple Imputation Results 
 
Replace “<=36” with “<=4.5” in Footnote 2. 
 
 
Table 14.2-6.1b: Summary of Summed Pain Intensity Scores (SPIS) Through 72 hours by Site – Efficacy 
Analysis Set - Multiple Imputation Results 


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Table 14.2-7a: Analysis of Integrated Rank Assessment Using SPIS at Rest and OMED of Rescue Medications 
Through 24, 48, and 72 hours - Efficacy Analysis Set 
 
Time Period 
Statistic 
EXPAREL 266 
(N=XX) 
mg 
IR Bupivacaine 
(N=XX) 
0–72 hours 
LS Mean [1] 
Standard Error of LS Mean [1] 
xxx.x 
xxx.xx 
xxx.x 
xxx.xx 
LSM Treatment Difference Difference [1][2] 
xx.x 
95% Confidence Interval [1][2] 
P-value, 1-sided [1][2] 
(xx.x, xx.x) 
0.xxx 
0-48 hours 
. . . 
 
0-24 hours 
. . . 
 
 
 
 
LS = least squares; 
VAS = 10 cm visual analog scale for pain, where 0 = no pain and 10 = worst possible pain; 
[1] From an ANCOVA with main effects of treatment and site covariates of age and height. 
[2] Test of Ha: LSM (EXPAREL 266 mg) < LSM (IR Bupivacaine). 


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Table 14.2-7b: Summary of Integrated Rank Assessment Using SPIS at Rest and OMED of Rescue Medications 
Through 24, 48, and 72 hours - Efficacy Analysis Set 
 
Time Period 
Statistic 
EXPAREL 266 
(N=XX) 
mg 
IR Bupivacaine 
(N=XX) 
0-72 hours 
n 
Mean 
SD 
Median 
Min, Max 
xx 
xx.x 
x.xx 
xx.x 
xx, xx 
xx 
xx.x 
x.xx 
xx.x 
xx, xx 
0-48 hours 
. . . 
 
0-24 hours 
. . . 
 
 
 


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Table 14.2-8a: Analysis of Overall Benefit of Analgesia Scale (OBAS) by Timepoint and Question - Efficacy 
 Analysis Set  
 
 
Timepoint 
EXPAREL 266 mg 
IR Bupivacaine 
Question 
Statistic 
(N=XX) 
(N=XX) 
 
24 hours 
 
Total Score 
LS Mean [1] 
Standard Error of LS Mean 
xxx.x 
xxx.xx 
xxx.x 
xxx.xx 
LSM Treatment Difference [1] 
95% Confidence Interval 
xx.x 
(xx.x, xx.x) 
P-value, 1-sided [2] 
0.xxxx 
 
1. Current Pain 
LS Mean [1] 
Standard Error of LS Mean 
xxx.x 
xxx.xx 
xxx.x 
xxx.xx 
LSM Treatment Difference [1] 
95% Confidence Interval 
P-value, 1-sided [2] 
xx.x 
(xx.x, xx.x) 
0.xxxx 
Total score = sum of scores from questions 1 to 6 plus 4 minus question 7 score. 
[1] From an ANCOVA with main effects of treatment and site and covariates of age and height. 
[2] For Total and Questions 1 to 6 scores, Test of Ha: LSM (EXPAREL 266 mg) < LSM (IR Bupivacaine). For 
Question 7 score, Test of Ha: LSM (EXPAREL 266 mg) > LSM (IR Bupivacaine). 
 
 
Note to programmer: Timepoints to appear on this table, in order, are 24 and 72 hours and Day 10. 
Questions to appear on this table, in order, are ‘Total Score’, ‘1. Current Pain’, ‘2. Vomiting’, ‘3. 
Itching’, ‘4. Sweating’, ‘5. Freezing’, ‘6. Dizziness’, and ‘7. Satisfaction’. 
Do not split a question’s 
statistics across pages. P-Values should only be generated for ‘Total score’. 


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Table 14.2-8b: Summary of Overall Benefit of Analgesia Scale (OBAS) by Timepoint and Question - Efficacy 
 Analysis Set  
 
 
Timepoint 
EXPAREL 266 mg 
IR Bupivacaine 
Question 
Statistic 
(N=XX) 
(N=XX) 
 
24 hours 
 
Total Score 
n 
xx 
xx 
Mean 
xx.x 
xx.x 
SD 
Median 
xx.xx 
xx 
xx.xx 
xx 
Min, Max 
xx, xx 
xx, xx 
 
1. Current Pain 
n 
xx 
xx 
Mean 
SD 
Median 
xx.x 
xx.xx 
xx.x 
xx.x 
xx.xx 
xx.x 
Min, Max 
xx, xx 
xx, xx 
Total score = sum of scores from questions 1 to 6 plus 4 minus question 7 score. 
 
 
Note to programmer: Timepoints to appear on this table, in order, are 24 and 72 hours and Day 10. 
Questions to appear on this table, in order, are ‘Total Score’, ‘1. Current Pain’, ‘2. Vomiting’, ‘3. 
Itching’, ‘4. Sweating’, ‘5. Freezing’, ‘6. Dizziness’, and ‘7. Satisfaction’. 
Do not split a question’s 
statistics across pages. 


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 Table 14.2-9a: Analysis of Time Spent in Post-Anesthesia Care Unit (PACU) – Efficacy Analysis Set  
 
 
Statistic 
EXPAREL 266 mg 
(N=XX) 
IR Bupivacaine 
(N=XX) 
LS Mean [1] 
xxx.x 
xxx.x 
Standard Error of LS Mean [1] 
xxx.xx 
xxx.xx 
LSM Treatment Difference Difference 
95% Confidence Interval [1][2] 
[1][2] 
xx.x 
(xx.x, xx.x) 
P-value, 1-sided [1][2] 
0.xxxx 
[1] From an ANCOVA with main effects of treatment and site and covariates of age and height on time spent 
in PACU. 
[2] Test of Ha: LSM (EXPAREL 266 mg) < LSM (IR Bupivacaine). 


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Pacira Pharmaceuticals 
(Page X of Y) 
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 Table 14.2-9b: Summary of Time Spent in Post-Anesthesia Care Unit (PACU) – Efficacy Analysis Set  
 
 
Statistic 
EXPAREL 266 
(N=XX) 
mg 
IR Bupivacaine 
(N=XX) 
N 
Mean 
xx 
xxx.x 
xx 
xxx.x 
SD 
xxx.xx 
xxx.xx 
Median 
xxx.x 
xxx.x 
Min, Max 
xx, xx 
xx, xx 
 
 


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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-411 
 Table 14.2-10: Summary of Time to First Unassisted Ambulation - Efficacy Analysis Set  
 
 
Statistic 
EXPAREL 266 mg 
(N=XX) 
IR Bupivacaine 
(N=XX) 
 
 
Number of Subjects 
Achieved Unassisted Ambulation 
n (%) 
xx (xx.x) 
xx (xx.x) 
Did not Achieve Unassisted Ambulation 
n (%) 
xx (xx.x) 
xx (xx.x) 
 
Time to First Unassisted Ambulation 
Quartiles [1] 
First (25% Discharge Ready) 
Estimate 
xx.xx 
xx.xx 
(95% CI) 
(xx.xx,xx.xx) 
(xx.xx,xx.xx) 
 
Median (50% Discharge Ready) 
Estimate 
xx.xx 
xx.xx 
(95% CI) 
(xx.xx,xx.xx) 
(xx.xx,xx.xx) 
 
Third (75% Discharge Ready) 
Estimate 
xx.xx 
xx.xx 
(95% CI) 
(xx.xx,xx.xx) 
(xx.xx,xx.xx) 
 
Minimum 
Observed 
xx.xx 
xx.xx 
Maximum 
Observed 
xx.xx* 
xx.xx 
P-value, 2-sided [2] 
 
0.xxxx 
* indicates censored observation 
CI = confidence interval 
[1] Estimates from the adjusted survival curve with site, age, and height as confounders. 
[2] P-value from the EXPAREL 266 mg to IR Bupivacaine comparison using the Cox regression model with 
treatment and site as factors and age and height as covariates. 


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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-411 
Table 14.2-11a: Analysis of Subjects Meeting Modified Post Anesthesia Discharge Scoring System (MPADSS) 
 Criteria for Discharge Readiness at Each Assessed Timepoint - Efficacy Analysis Set  
 
 
EXPAREL 266 mg 
IR Bupivacaine 
Time Point 
Statistic 
(N=XX) 
(N=XX) 
24 
Criterion 
Criterion 
Met [1] 
not Met 
(%) 
(%) 
[2] 
xx.x 
xx.x 
xx.x 
xx.x 
 
Odds Ratio [3] 
xx.xx 
95% CI for Odds Ratio 
xx.xxx 
P-value, 1-sided [4] 
0.xxxx 
 
Etc. 
Criterion Met (%) 
xx.x 
xx.x 
Criterion not Met (%) 
xx.x 
xx.x 
 
Odds Ratio 
xx.xx 
95% CI for Odds Ratio 
xx.xxx 
P-value, 1-sided 
0.xxxx 
 
 
 
 
 
 
 
[1] Discharge-ready criterion is the MPADSS total score ≥9. Subjects who did not have assessment are 
considered “not ready”. 
[2] LS Means probability from the logistic regression with treatment, site, age, and height as explanatory 
variables. 
[3] Ratio of EXPAREL 266 mg over IR Bupivacaine in the odds of having 0 phone call. 
[4] Test of Ha: Odds Ratio >1 
 
 
 
Note to programmer: Repeat for all valid Time periods for which data is available. 
Do not split a time 
period statistics across pages. 


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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-411 
Table 14.2-11b: Summary of Subjects Meeting Modified Post Anesthesia Discharge Scoring System (MPADSS) 
Criteria for Discharge Readiness at Each Assessed Timepoint - Efficacy Analysis Set 
 
Time Point 
 
 
Statistic 
EXPAREL 266 mg 
(N=XX) 
n (%) 
IR Bupivacaine 
(N=XX) 
n (%) 
24 
Criterion Met [1] (%) 
xx (xx.x) 
xx (xx.x) 
Criterion not Met (%) 
xx (xx.x) 
xx (xx.x) 
Etc. 
Criterion Met (%) 
xx (xx.x) 
xx (xx.x) 
Criterion not Met (%) 
xx (xx.x) 
xx (xx.x) 
[1] Discharge-ready criterion is the MPADSS total score ≥9. Subjects who did not have assessment are 
considered “not ready”. 
 
 
 
 
Note to programmer: Repeat for all valid Time periods for which data is available. 
Do not split a time 
period statistics across pages. 


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Pacira Pharmaceuticals 
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Table 14.2-12: Summary of Overall Assessment of Subject’s Satisfaction with Postsurgical Pain Control at 72 
 
hours After Surgery - Efficacy Analysis Set 
Score 
Statistic 
EXPAREL 266 
(N=XX) 
mg 
IR Bupivacaine 
(N=XX) 
Summary 
n 
xx 
xx 
Mean 
xx.x 
xx.x 
SD 
x.xx 
x.xx 
Median 
xx.x 
xx.x 
Min, Max 
xx, xx 
xx, xx 
P-value, 2-sided[1] 
0.xxxx 
Score 
1: Extremely dissatisfied 
n (%) 
xx (xx.x) 
xx (xx.x) 
2: Dissatisfied 
n (%) 
xx (xx.x) 
xx (xx.x) 
3: Neither satisfied nor dissatisfied 
n (%) 
xx (xx.x) 
xx (xx.x) 
4: Satisfied 
n (%) 
xx (xx.x) 
xx (xx.x) 
5: Extremely Satisfied 
n (%) 
xx (xx.x) 
xx (xx.x) 
[1] P-value from CMH test performed using the “scores=modridit” option with site as stratification 
 
 
Note to programmer: include all subjects at 72 hours after surgery (or at hospital discharge if earlier 
than 72 hours). 


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Pacira Pharmaceuticals 
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Protocol: 402-C-411 
Table 14.2-13a: Analysis of Quality of Recovery Questionnaire at 72 hours Postsurgery - Efficacy Analysis 
 Set (Only Include Subjects who Completed the Correct QoR-15 Form)  
 
 
Statistic 
EXPAREL 266 mg 
(N=XX) 
IR Bupivacaine 
(N=XX) 
Overall  Summary 
LS Mean [1] 
xxx.x 
xxx.x 
Standard Error of LS Mean 
xxx.xx 
xxx.xx 
LSM Treatment Difference [1] 
xx.x 
95% Confidence Interval 
P-value, 1-sided [2] 
(xx.x, xx.x) 
0.xxxx 
 
 
Question 3 (Feeling rested: 
0=none, 10=all the time) 
 
LS Mean [1] 
xxx.x 
xxx.x 
 
Standard Error of LS Mean 
xxx.xx 
xxx.xx 
LSM Treatment Difference [1] 
 xx.x 
95% Confidence Interval 
(xx.x, xx.x) 
P-value, 1-sided [2] 
0.xxxx 
 
 
Question 4 (Have had a good sleep: 
0=none, 10=all the time) 
LS Mean [1] 
xxx.x 
xxx.x 
 
Standard Error of LS Mean 
xxx.xx 
xxx.xx 
LSM Treatment Difference [1] 
 xx.x 
95% Confidence Interval 
(xx.x, xx.x) 
P-value, 1-sided [2] 
0.xxxx 
 
 
Question 14 (Feeling worried or 
anxious: 10=none, 0=all the time) 
LS Mean [1] 
xxx.x 
xxx.x 
 
Standard Error of LS Mean 
xxx.xx 
xxx.xx 
LSM Treatment Difference [1] 
 xx.x 
95% Confidence Interval 
(xx.x, xx.x) 
P-value, 1-sided [2] 
0.xxxx 


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Question 15 (Feeling sad or 
depressed: 10=none, 0=all the 
time) 
LS Mean [1] 
xxx.x 
xxx.x 
 
 
Standard Error of LS Mean 
xxx.xx 
xxx.xx 
LSM Treatment Difference [1] 
 xx.x 
95% Confidence Interval 
(xx.x, xx.x) 
P-value, 1-sided [2] 
0.xxxx 
 
 
 
[1] From an ANCOVA with main effects of treatment and site and covariates of age and height. 
[2] Test of Ha: LSM (EXPAREL 266 mg) < LSM (IR Bupivacaine). 


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Pacira Pharmaceuticals 
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Protocol: 402-C-411 
Table 14.2-13b: Summary of Quality of Recovery Questionnaire at 72 hours Postsurgery - Efficacy Analysis 
Set (Only Include Subjects who Completed the Correct QoR-15 Form) 
 
Statistic 
EXPAREL 266 mg 
(N=XX) 
IR Bupivacaine 
(N=XX) 
 
 
Overall  Summary 
n 
xx 
xx 
Mean 
xx.x 
xx.x 
SD 
x.xx 
x.xx 
Median 
xx 
xx 
Min, Max 
xx,xx 
xx, xx 
 
 
Question 3 (Feeling rested: 0=none, 10=all the time) 
n 
xx 
xx 
Mean 
xx.x 
xx.x 
SD 
x.xx 
x.xx 
Median 
xx 
xx 
Min, Max 
xx,xx 
xx, xx 
 
 
Question 4 (Have had a good sleep: 0=none, 10=all the 
time) 
n 
xx 
xx 
Mean 
xx.x 
xx.x 
SD 
x.xx 
x.xx 
Median 
xx 
xx 
Min, Max 
xx,xx 
xx, xx 
Question 14 (Feeling 
0=all the time) 
worried or anxious: 10=none, 
n 
xx 
xx 
Mean 
xx.x 
xx.x 
SD 
x.xx 
x.xx 
Median 
xx 
xx 
Min, Max 
xx,xx 
xx, xx 


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Statistic 
EXPAREL 266 mg 
(N=XX) 
IR Bupivacaine 
(N=XX) 
 
 
Question 15 (Feeling sad or depressed: 10=none, 0=all 
the time) 
n 
xx 
xx 
Mean 
xx.x 
xx.x 
SD 
x.xx 
x.xx 
Median 
xx 
xx 
Min, Max 
xx,xx 
xx, xx 
[1] P-value from CMH test performed using the “scores=modridit” option with site as stratification 
factors. 


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Pacira Pharmaceuticals 
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Protocol: 402-C-411 
 Table 14.2-14a: Analysis of Subjects with Unscheduled Pain-Related Phone Calls - Efficacy Analysis Set  
 
Statistic 
EXPAREL 266 mg 
(N=XX) 
IR Bupivacaine 
(N=XX) 
0 
(%) [1] 
xx.x 
xx.x 
>=1 (%) 
xx.x 
xx.x 
 
Odds Ratio [2] 
xx.xx 
95% CI for Odds Ratio 
xx.xxx 
P-value, 1-sided [3] 
0.xxxx 
 
 
[1] LS Means probability from the logistic regression with treatment, site, age, and height as explanatory 
variables. 
[2] Ratio of EXPAREL 266 mg over IR Bupivacaine in the odds of having 0 phone call. 
[3] Test of Ha: Odds Ratio >1 


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Protocol: 402-C-411 
Table 14.2-14b: Summary of Number of Unscheduled Pain-Related Phone Calls - Efficacy Analysis Set 
 
 
Number of Calls 
EXPAREL 266 mg 
(N=XX) 
n (%) 
IR Bupivacaine 
(N=XX) 
n (%) 
0 
xx (xx.x) 
xx (xx.x) 
1 
xx (xx.x) 
xx (xx.x) 
2 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 


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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-411 
 
Table 14.3-1.1: Overview of Treatment-Emergent Adverse Events (TEAEs) - Safety Analysis Set 
 
 
Number of 
EXPAREL 266 mg 
(N=XX) 
n (%) 
IR Bupivacaine 
(N=XX) 
n (%) 
Total 
(N=XX) 
n (%) 
 
 
Subjects with Any TEAE 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Maximum Severity of Mild 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Maximum Severity of Moderate 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Maximum Severity of Severe 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
At Least One Related 
 
At Least One Serious 
 
Subject with Any TEAESI 
 
Subjects Discontinued due 
 
Died on Study 
 
 
 
 
Note to programmer: All categories on this table should appear, even if not present in the data. 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
to TEAE 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 


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Protocol: 402-C-411 
Table 14.3-1.2.1: Summary of Incidence of Treatment-Emergent Adverse Events (TEAEs) by Preferred Term - 
Safety Analysis Set 
 
 
Preferred Term 
EXPAREL 266 mg 
(N=XX) 
n (%) 
IR Bupivacaine 
(N=XX) 
n (%) 
Total 
(N=XX) 
n (%) 
Subjects with ≥1 TEAE 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
PT1 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
PT2 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
PT3 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
... 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
Adverse events coded using the Medical Dictionary for Regulatory Activities (MedDRA v21.1). 
Sorted by descending order of Total incidence. 
Subjects experiencing the same TEAE more than once are counted only once at each summary level. 


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Protocol: 402-C-411 
Table 14.3-1.2.2: Summary of Subject Incidence of Treatment-Emergent Adverse Events (TEAEs) by System Organ 
Class and Preferred Term - Safety Analysis Set 
 
System Organ Class 
Preferred Term 
EXPAREL 266 mg 
(N=XX) 
n (%) 
IR Bupivacaine 
(N=XX) 
n (%) 
Total 
(N=XX) 
n (%) 
 
 
Subjects 
 
SOC1 
PT1.1 
PT1.2 
 
SOC2 
PT2.1 
PT2.2 
 
ETC. 
 
 
Adverse events coded using the Medical Dictionary for Regulatory Activities (MedDRA v21.1). 
Sorted by system organ class and preferred term in alphabetical order. 
Subjects experiencing the same TEAE more than once are counted only once at each summary level. 
with ≥1 TEAE 
xx 
xx 
(xx.x) 
(xx.x) 
xx 
xx 
(xx.x) 
(xx.x) 
xx 
xx 
(xx.x) 
(xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 


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Protocol: 402-C-411 
Table 14.3-1.3: Summary of Subject Incidence of Treatment-Emergent Adverse Events (TEAEs) by System Organ 
Class, Preferred Term, and Worst Severity - Safety Analysis Set 
 
System Organ Class 
Preferred Term 
Worst Severity 
EXPAREL 266 mg 
(N=XX) 
n (%) 
IR Bupivacaine 
(N=XX) 
n (%) 
Total 
(N=XX) 
n (%) 
 
 
Subjects with ≥1 TEAE 
 
 
 
 
SOC1 
 
 
 
 
PT1.1 
 
 
 
 
PT1.2 
 
 
 
 
... 
 
Adverse events coded using the Medical Dictionary for Regulatory Activities (MedDRA v21.1). 
Sorted by descending order of Total incidence by system organ class and preferred term. 
Subjects experiencing the same TEAE more than once are counted only once at each summary level. 
Mild 
Moderate 
Severe 
xx 
xx 
xx 
(xx.x) 
(xx.x) 
(xx.x) 
xx 
xx 
xx 
(xx.x) 
(xx.x) 
(xx.x) 
xx 
xx 
xx 
(xx.x) 
(xx.x) 
(xx.x) 
Mild 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Moderate 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Severe 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Mild 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Moderate 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Severe 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Mild 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Moderate 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Severe 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 


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Protocol: 402-C-411 
Table 14.3-1.4: Summary of Subject Incidence of Treatment-Emergent Adverse Events (TEAEs) by System Organ 
Class, Preferred Term, and Strongest Relationship to Study Drug - Safety Analysis Set 
 
System Organ Class 
Preferred Term 
 
Strongest 
Relation 
EXPAREL 266 mg 
(N=XX) 
n (%) 
IR Bupivacaine 
(N=XX) 
n (%) 
Total 
(N=XX) 
n (%) 
Subjects with ≥1 TEAE 
Not Related 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Related 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
SOC1 
Not Related 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Related 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
PT1.1 
 
 
 
Adverse events coded using the Medical Dictionary for Regulatory Activities (MedDRA v21.1). 
Sorted by descending total incidence by system organ class and preferred term within system organ class. 
Subjects experiencing the same TEAE more than once are counted only once at each summary level. 
“Related” is “possible”, “probable”, or “definite” and “Not Related” is “unlikely” or “unrelated” by the 
investigator’s assessment. 
Not Related 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Related 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 


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Table 14.3-1.5: Summary of Subject Incidence of Treatment-Emergent Adverse Events of Special Interest 
(TEAESI) by Preferred Term - Safety Analysis Set 
Group 
Preferred Term 
EXPAREL 266 
(N=XX) 
n (%) 
mg 
IR Bupivacaine 
(N=XX) 
n (%) 
Total 
(N=XX) 
n (%) 
Subjects with ≥1 TEAESI 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
FALL 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Cardiac TEAESI 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Angina 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Myocardial infarction 
... 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Neurologic TEAESI 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Tinnitus 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Perioral numbness 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
... 
Adverse events coded using the Medical Dictionary for Regulatory Activities (MedDRA 21.1). 
Sorted by system organ class and preferred term in alphabetical order. 
Subjects experiencing the same TEAE more than once are counted only once at each summary level. 
 
 
 
Note to programmer: see SAP the list of AESI 


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Pacira Pharmaceuticals 
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Protocol: 402-C-411 
 
Table 14.3-2: Summary of Vital Signs by Timepoint – Safety Analysis Set 
Heart Rate (bpm) 
 
Timepoint 
Value 
Statistic 
EXPAREL 266 mg 
(N=XXX) 
IR Bupivacaine 
(N=XXX) 
Total 
(N=XXX) 
Baseline 
Actual 
n 
Mean 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
SD 
x.xx 
x.xx 
x.xx 
Minimum 
xx 
xx 
xx 
Median 
Maximum 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
 
 
OR 
Baseline [1] 
n 
Mean 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
SD 
x.xx
x.xx 
x.xx 
Minimum 
Median 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
Maximum 
xx 
xx 
xx 
Actual 
n 
xx 
xx 
xx 
Mean 
xx.x 
xx.x 
xx.x 
SD 
Minimum 
x.xx
xx 
x.xx 
xx 
x.xx 
xx 
Median 
Maximum 
xx.x 
xx 
xx.x 
xx 
xx.x 
xx 
Change 
n 
Mean 
xx 
xx.x 
xx 
xx.x 
xx 
xx.x 
SD 
Minimum 
x.xx
xx 
x.xx 
xx 
x.xx 
xx 
Median 
xx.x 
xx.x 
xx.x 
Maximum 
xx 
xx 
xx 
[1] Baseline (prior to surgery) for subjects with data at the timepoint. 


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Note to programmer: Vital signs are ‘Resting Heart Rate (bpm)’, ‘Systolic Blood Pressure (mmHg)’ and 
‘Diastolic Blood Pressure (mmHg)’. Timepoints to appear on this table are, in order of appearance, Baseline 
(prior to surgery), OR, PACU and Discharge. 
Do not split timepoint statistics across pages. 


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Note to programmer: Use mock-up 14.1-5.1 for tables: 
 
Table 14.3-3.1: Incidence of Prior Medications – Safety Analysis Set. 
 
On this table change the footnote ‘Intraoperatives medications are those indicated as such by the 
investigator’ to read ‘Prior medications are those stopped before start of study drug administration.’ 
 
Table 14.3-3.2: Incidence of Concomitant Medications – Safety Analysis Set. 
 
On this table change the footnote ‘Intraoperatives medications are those indicated as such by the 
investigator’ to read ‘Concomitant medications are those taken after the start of study drug administration 
and are not designated intraoperative medications.’ 


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15. 
LIST OF LISTINGS 
Listing 16.2-1: Subject Disposition – All Randomized Subjects 
95 
Listing 16.2-2: Randomization And Analysis Sets – All Randomized Subjects 
96 
Listing 16.2-3: Demographics – All Randomized Subjects 
97 
Listing 16.2-4: Height And Weight – All Randomized Subjects 
98 
Listing 16.2-5: Surgery – All Randomized Subjects 
99 
Listing 16.2-6: Visual Analog Scale (Vas) – All Randomized Subjects 
100 
Listing 16.2-7.1: Postsurgical Total Opioid Dose (Omed Mg) And Opioid-Free Status – All Randomized 
Subjects 
101 
Listing 16.2-7.2: Postsurgical Opioid Dosing – All Randomized Subjects 
102 
Listing 16.2-8.1: Quality Of Recovery (Qor-15) – 
103 
Listing 16.2-8.2: Quality Of Recovery (Qor-15) – All Randomized Subjects 
104 
Listing 16.2-9: Overall Benefit Of Analgesia – All Randomized Subjects 
105 
Listing 16.2-10: Subject Satisfaction With Post-Surgical Pain Control At 72 Hours – All Randomized 
Subjects 
106 
Listing 16.2-11: Modified Post-Anesthesia Discharge Scoring System (Mpadss) – All Randomized 
Subjects 
107 
Listing 16.2-12: Day 14 Phone Call – All Randomized Subjects 
108 
Listing 16.2-13: Vital Signs Assessment – All Randomized Subjects 
109 
Listing 16.2-14: Electrocardiogram Findings At Baseline – Investigator Assessment – All Randomized 
Subjects 
110 
Listing 16.2-15.1: All Adverse Events – All Randomized Subjects 
111 
Listing 16.2-15.2: Treatment-Emergent Adverse Events – All Randomized Subjects 
111 
Listing 16.2-15.3: All Serious Adverse Events – All Randomized Subjects 
111 
Listing 16.2-15.4: Treatment-Emergent Adverse Events Of Special Interest – All Randomized Subjects111 
Listing 16.2-16.1: Prior Medications – All Randomized Subjects 
112 
Listing 16.2-16.2: Concomitant Medications – All Randomized Subjects 
112 
Listing 16.2-17: Medical History – All Subjects 
113 
Listing 16.2-18: Intraoperative Opioids – Randomized Subjects 
114 
Listing 16.2-19: Study Drug Administration – Randomized Subjects 
115 
Listing 16.2-20: Urine Drug Screen, Alcohol Blood Test And Pregnancy Test – All Subjects 
116 
Listing 16.2-21: Admission And Discharge – Randomized Subjects 
117 
Listing 16.2-22: Important Protocol Deviations - Randomized Subjects 
118 
Listing 16.2-23: Unique Adverse Events Terms And Associated Coded Terms 
119 
Listing 16.2-24: Unique Medication Terms And Associated Coded Terms 
120 


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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-411 
Listing 16.2-1: Subject Disposition – All Randomized Subjects 
 
TREATMENT: treatment-name 
 
Date of 
Subject 
Last Visit (Day) 
End of Study Status 
Specify 
 
 
XXX-YYYY 
DDMONYYYY (XX) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note to programmer: End of study status for subject who early terminated from the study is the primary 
reason for termination. If subject discontinued due to an AE then the reason should read ‘ADVERSE EVENT, AE 
# X’. If subject discontinued due to death the reason should read ‘DEATH ON DDMONYYYY’. For those reasons 
that also collected a specify text, that text belongs in the specify column. 


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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-411 
Listing 16.2-2: Randomization and Analysis Sets – All Randomized Subjects 
 
Randomization 
Subject 
Date and Time 
Number 
Safety 
Efficacy 
XXX-YYYY 
DDMONYYYYTHH:MM 
XXXXX 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note to programmer: Analysis set will by ‘Y’ if subject in set, blank otherwise. 


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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-411 
Listing 16.2-3: Demographics – All Randomized Subjects 
 
TREATMENT: treatment-name 
 
 
Subject 
Initials 
Birth Date 
Age(yrs) 
Sex 
Race 
Ethnicity 
ASA Class 
 
 
XXX-YYYY 
AMZ 
DDMONYYYY 
XX 
XXXXXX 
XXXXXXXXX 
XXXXXXXXX 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note to programmer: If race is ‘other’ then race should be ‘Other: other-specify-text’. 


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03 January 2019 
 
 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-411 
Listing 16.2-4: Height and Weight – All Randomized Subjects 
 
TREATMENT: treatment-name 
Body Mass Index 
Subject 
Collection Date (Day) 
Height (cm) 
Weight (kg) 
(kg/m2) 
XXX-YYYY 
DDMONYYYYTHH:MM (-XX) 
XXX.X 
XXX.X 
XX.X 
 
 
 
 
 
 
 
 
 
 
 
 


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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-411 
Listing 16.2-5: Surgery – All Randomized Subjects 
TREATMENT: treatment-name 
Start 
Stop 
Duration 
Incision 
Length 
IR Bupivacaine 
Anesthesia 
Subject 
Date (Day) 
Time 
Time 
(hrs) 
Location 
(cm) 
Admin Time 
Type 
XXX-YYYY 
DDMONYYYY (XX) HH:MM 
HH:MM 
X.X 
XXXXX 
XX.X 
HH:MM 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note to programmer: If anesthesia type is ‘other’ then text should read ‘other: specify-text’. 


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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-411 
Listing 16.2-6: Visual Analog Scale (VAS) – All Randomized Subjects 
 
TREATMENT: treatment-name 
Time From Dose 
Subject 
Date Time (Day) 
Scheduled 
(hr) 
Actual 
(hr) 
Deviation 
(hrs) 
VAS 
(cm) 
Pain-Free 
(VAS ≤ 1.5cm) 
XXX-YYYY 
DDMONYYYYTHH:MM (X) 
XX.XX 
XX.XX 
XXXX 
XX.X 
Y 
 
 
 
 
 
 
 
 
 
 
 
 
VAS: 0=No pain to 10=Worst Pain Imaginable 
ND=Not Done NA=Not Applicable 
* = out of window 
 
 
Note to programmer: Sort by VAS collection date and time. If VAS was taken due to rescue medication dosing, 
put RESCUE in scheduled column and hours from dose in actual column – leave deviation column blank. Do not 
split a subject’s data across pages if it can be avoided. 
Pain-free will have Y if VAS ≤ 1.5 otherwise 
blank. An asterisk (*) will be placed next to the deviation if an assessment is out of window. 
See Table 
of Time and Events for windows. 


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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-411 
 Listing 16.2-7.1: Postsurgical Total Opioid Dose (OMED mg) and Opioid-free Status – All Randomized Subjects   
Subject 
0 to ≤72 hrs 
0 to ≤24 hrs 
0 to ≤48 hrs 
>24 to ≤48hrs 
>48 to ≤72hrs 
Opioid-Free 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total dose is dose from end of surgery through timepoint. 
 
 
Note to programmer: If medication is ‘Other’, text should read ‘Other: specify-text’. 
Sort by date and 
time within subject. 
XXX-YYYY 
XXXX.X 
XXXX.X 
XXXX.X 
XXXX.X 
XXXX.X 
NO 
XXX-YYYY 
- 
- 
- 
- 
- 
YES 


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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-411 
Listing 16.2-7.2: Postsurgical Opioid Dosing – All Randomized Subjects 
 
TREATMENT: treatment-name 
Subject 
Date and Time 
Time to 
Dosing (hr) Medication 
Dose 
(units) 
Conversion 
Factor 
Dose 
(OMED mg) 
Route 
XXX-YYYY 
DDMONYYYYTHH:MM 
XXX.X 
XXXXXXXXXXXX 
(XXXXX) 
X.XX 
XXX.X 
XXXXXXX 
DDMONYYYYTHH:MM 
XXX.X 
XXXXXXXXXXXX 
(XXXXX) 
X.XX 
XXX.X 
XXXXXXX 
DDMONYYYYTHH:MM 
XXX.X 
XXXXXXXXXXXX 
(XXXXX) 
X.XX 
XXX.X 
XXXXXXX 
DDMONYYYYTHH:MM 
XXX.X 
XXXXXXXXXXXX 
(XXXXX) 
X.XX 
XXX.X 
XXXXXXX 
 
 
 
 
 
 
 
 
 
Time to rescue is time from end of surgery to rescue medication dose. 
 
 
Note to programmer: If medication is ‘Other’, text should read ‘Other: specify-text’. 
Sort by date and 
time within subject. 


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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-411 
Listing 16.2-8.1: Quality of Recovery (QoR-15) – Question Text 
 
Question No. 
Question Text 
 
1 
Able to breathe easily 
2 
Been able to enjoy food 
3 
Feeling rested 
4 
Have had a good sleep 
5 
Able to look after personal toilet and hygiene unaided 
6 
Able to communicate with family or friends 
7 
Getting support from hospital doctors and nurses 
8 
Able to return to work or usual home activities 
9 
Feeling comfortable and in control 
10 
Having a feeling of general well-being 
11 
Moderate pain 
12 
Severe pain 
13 
Nausea or vomiting 
14 
Feeling worried or anxious 
15 
Feeling sad or depresse 
 


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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-411 
Listing 16.2-8.2: Quality of Recovery (QoR-15) – All Randomized Subjects 
 
TREATMENT: treatment-name 
 
Assessment 
Question 
Subject 
Date and Time 
(Day) 
Scheduled 
Actual 
(hrs) 
Deviation 
(hrs) 
1 2 3 4 5 6 7 8 10 11 12 13 14 15 
Total 
Score 
XXX-YYYY 
DDMONYYYYTHH:MM 
(XX) 
DDMONYYYYTHH:MM 
(XX) 
72 hrs 
Discharge 
XX.X 
XX.X 
XX.X 
XX.X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
XX 
XX 
 
 
Note to programmer: Sort by date and time within subject. 


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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-411 
Listing 16.2-9: Overall Benefit of Analgesia – All Randomized Subjects 
 
TREATMENT: treatment-name 
 
Assessment 
Question 
 
Subject 
Date and Time (Day) 
Schedule 
(hrs) 
Actual 
(hrs) 
Deviation 
(hrs) 
1 
2 
3 
4 
5 
6 
7 
Total 
Score 
XXX-YYYY 
DDMONYYYYTHH:MM (XX) 
24 
XX.X 
XX.X 
X 
X 
X 
X 
X 
X 
X 
XX 
DDMONYYYYTHH:MM (XX) 
72 
XX.X 
XX.X 
X 
X 
X 
X 
X 
X 
X 
XX 
DDMONYYYYTHH:MM (XX) 
240 (D10) 
XXX.X 
XX.X 
X 
X 
X 
X 
X 
X 
X 
XX 
Total score = sum of questions 1 to 6 scores minus question 7 score plus 4. 
1) Please rate your current pain at rest on a scale between 0=minimal pain and 4=maximum imaginable pain 
2) Please grade any distress and bother from vomiting in the past 24 h (0=not at all to 4=very much) 
3) Please grade any distress and bother from itching in the past 24 h (0=not at all to 4=very much) 
4) Please grade any distress and bother from sweating in the past 24 h (0=not at all to 4=very much) 
5) Please grade any distress and bother from freezing in the past 24 h (0=not at all to 4=very much) 
6) Please grade any distress and bother from dizziness in the past 24 h (0=not at all to 4=very much) 
7) How satisfied are you with your pain treatment during in the past 24 h (0=not at all to 4=very much) 
 
 
Note to programmer: Sort by date and time within subject. 


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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-411 
Listing 16.2-10: Subject Satisfaction with Post-Surgical Pain Control at 72 hours – All Randomized Subjects 
Treatment: treatment-name 
 
Subject 
Date and Time (Day) 
Rating 
Score 
XXX-YYYY 
DDMONYYYYTHH:MM (XX) 
EXTREMELY DISSATISFIED 
1 
XXX-YYYY 
DDMONYYYYTHH:MM (XX) 
DISSATISFIED 
2 
XXX-YYYY 
DDMONYYYYTHH:MM (XX) 
NEITHER SATISFIED NOR DISSATISFIED 
3 
 
XXX-YYYY 
DDMONYYYYTHH:MM (XX) 
SATISFIED 
4 
XXX-YYYY 
DDMONYYYYTHH:MM (XX) 
EXTREMELY SATISIFIED 
5 
XXX-YYYY 
DDMONYYYYTHH:MM (XX) 
EXTREMELY SATISIFIED 
5 
 
 
 
 
 
 
 
 
Time to rescue is time from end of surgery to rescue medication dose. 
 
 
Note to programmer: Sort by date and time within subject. 


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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-411 
Listing 16.2-11: Modified Post-Anesthesia Discharge Scoring System (MPADSS) – All Randomized Subjects 
TREATMENT: treatment-name 
 
Assessment 
Question 
 
Subject 
Date and Time (Day) 
Schedule 
(hrs) 
Actual 
(hrs) 
Deviation 
(hrs) 
1 
2 
3 
4 
5 
Total 
Score 
 
 
XXX-YYYY 
DDMONYYYYTHH:MM (XX) 
24 
XX.X 
XX.X 
X 
X 
X 
X 
X 
XX 
DDMONYYYYTHH:MM (XX) 
48 
XX.X 
XX.X 
X 
X 
X 
X 
X 
XX 
 
 
 
*=out of window 
Total score = sum of scores. 
1) Vital signs: 2 = ≤ 20%; 1 = 20-40%; 0 = >40% of preoperative value. 
2) Ambulation: 2 = steady gait/no dizziness; 1 = with assistance; 0 = none/dizziness 
3) Nausea and Vomiting: 2 = minimal; 1 = moderate; 0 = severe 
4) Pain: 2 = minimal; 1 = moderate; 0 = severe 
5) Surgical bleeding: 2 = minimal; 1 = moderate; 0 = severe 
 
 
Note to programmer: Sort by date and time within subject. 


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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-411 
Listing 16.2-12: Day 14 Phone Call – All Randomized Subjects 
TREATMENT: treatment-name 
Day 14 Phone Call 
No. of Pain-Related 
Unscheduled 
Schedule Actual Deviation 
Phone 
No. of ER 
No. of Hosp 
AE 
Subject 
Date 
(days) 
(days) 
(days) 
Calls 
Visits 
Visit 
Readmission 
Assessed 
XXX-YYYY DDMONYYYY 
14 
XX.X 
XX.X 
XX 
XX 
XXXX 
XXXX 
Y 
XXX-YYYY DDMONYYYY 
14 
XX.X 
XX.X 
XX 
XX 
XXXX 
XXXX 
Y 
XXX-YYYY DDMONYYYY 
14 
XX.X 
XX.X 
XX 
XX 
XXXX 
XXXX 
N 
 
Note to programmer: If the leading question “were there any …” is No, then “No. of …” is 0. 


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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-411 
Listing 16.2-13: Vital Signs Assessment – All Randomized Subjects 
 
TREATMENT: treatment-name 
 
Heart Rate 
Blood Pressure (mmHg) 
 
Assessment 
(bpm) 
Systolic 
Diastolic 
Subject 
 
Date and Time 
Schedule 
(hrs) 
Actual 
(hrs) 
Dev. 
(hrs) 
Actual 
Change 
 
Actual 
Change 
Actual 
Change 
XXX-YYYY 
 
DDMONYYYYTHH:MM 
Screening 
- 
- 
XX 
- 
 
XXX 
- 
XX 
- 
DDMONYYYYTHH:MM 
Baseline 
- 
- 
XX 
- 
XXX 
- 
XX 
- 
DDMONYYYYTHH:MM 
OR 
- 
- 
XX 
XX 
XXX 
-X 
XX 
X 
DDMONYYYYTHH:MM 
PACU 
XXX.XX 
XXX 
XX 
-XX 
XXX 
X 
XX 
-X 
*=out of window 
@=potentially clinically significant value 
Change is change from baseline (Preop). 
 
 
Note to programmer: Sort by Date and time within subject. An asterisk (*) will be placed next to the 
deviation if an assessment is out of window. 
See Table of Time and Events for windows. 


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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-411 
Listing 16.2-14: Electrocardiogram Findings at Baseline – Investigator Assessment – All Randomized Subjects 
Treatment: treatment-name 
Actual 
Deviation 
 
Subject 
Date and Time 
(hrs) 
(hrs) 
Finding 
XXX-YYYY 
DDMONYYYYTHH:MM 
- 
- 
Normal 
DDMONYYYYTHH:MM 
- 
- 
Abnormal, clinically significant 
DDMONYYYYTHH:MM 
- 
- 
Abnormal, not clinically significant 
DDMONYYYYTHH:MM 
DDMONYYYYTHH:MM 
XXX.XX 
XXX.XX 
XXX 
XXX 
Normal 
Normal 
*=out of window 
 
 
 
Note to programmer: Sort by Date and date and time within subject. An asterisk (*) will be placed next to 
the deviation if an assessment is out of window. 
See Table of Time and Events for windows. 


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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-411 
Listing 16.2-15.1: All Adverse Events – All Randomized Subjects 
 
Treatment: treatment-name 
Subject 
TEAE Data Type 
Data 
XXX-YYYY 
N 
Start (Day) 
Stop (Day) 
AE Number 
DDMONYYYYTHH:MM (XX) 
DDMONYYYYTHH:MM (XX) 
X 
System Organ Class 
Preferred 
Verbatim Severity 
Relationship        
to Study 
Drug 
XXXXXXXXXXXXXXXXXX 
XXXXXXXXXXXXXXXXXXXX 
XXXXXXXXXXXXXXXXXXXXXX 
XXXXXXXX 
XXXXXXXX 
Action Taken 
Outcome 
Serious 
Serious Cause(s) 
AE of Special Interest 
XXXXXXXXXXXXXXXXXXXXX 
XXXXXXXXXXXXXX 
Yes/No 
Hospitalization 
Yes/No 
TEAE: Treatment-emergent AE (Y=TEAE/N=Not TEAE) 
 
 
Note to programmer: If AE is ongoing, put ONGOING in stop row. 
Do not split an AE across pages. Insert a 
page break between subjects. Use this mock-up for the following listings: 
 
Listing 16.2-15.2: Treatment-emergent Adverse Events – All Randomized Subjects 
Listing 16.2-15.3: All Serious Adverse Events – All Randomized Subjects 
Listing 16.2-15.4: Treatment-emergent Adverse Events of Special Interest – All Randomized Subjects 


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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-411 
Listing 16.2-16.1: Prior Medications – All Randomized Subjects 
 
Treatment: treatment-name 
Subject 
Category 
Data Type 
Data 
XXX-YYYY 
Start (Day) 
Stop (Day) 
Medication Number 
DDMONYYYYTHH:MM (XX) 
DDMONYYYYTHH:MM (XX) 
X 
ATC Level 1 
ATC Level 2 
ATC Level 3 
ATC Level 4 
Preferred Name 
XXXXXXXXXXXXXXXXXX 
XXXXXXXXXXXXXXXXXXXX 
XXXXXXXXXXXXXXXXXXXXXX 
XXXXXXXXXXXXXXXXXXXX 
XXXXXXXXXXXXXXXXXXXXX 
Verbatim 
Route 
Frequency 
Given for AE or MH? 
XXXXXXXXXXXXXXXXXXXX 
XXXXXXXX 
XXXXXXXX 
XXXXXXXXXXXXXXXXXXXXX AE # XX (or MH # XX) 
 
 
 
 
 
 
 
 
ATC=Anatomical therapeutic class 
 
 
Note to programmer: If medication is ongoing, put ONGOING in stop row. 
Do not split a medication across 
pages. Insert a page break between subjects. Values for category column are: CONCOMITANT; 
SURGICAL/ANESTHESIA; NON-MEDICATION; PRIOR. 
Use this mock-up for the following listings: 
 
Listing 16.2-16.2: Concomitant Medications – All Randomized Subjects 


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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-411 
Listing 16.2-17: Medical History – All Subjects 
 
Treatment: treatment-name 
Subject 
Data Type 
Data 
XXX-YYYY 
Start (Day) 
Stop (Day) 
System Organ Class 
DDMONYYYY (XX) 
DDMONYYYY (XX) 
XXXXXXXXXXXXXXXXXX 
Preferred 
History Verbatim 
XXXXXXXXXXXXXXXXXXXX 
XXXXXXXXXXXXXXXXXXXXXX 
 
Start (Day) 
DDMONYYYY (XX) 
Stop (Day) 
DDMONYYYY (XX) 
System Organ Class 
XXXXXXXXXXXXXXXXXX 
Preferred 
XXXXXXXXXXXXXXXXXXXX 
History Verbatim 
XXXXXXXXXXXXXXXXXXXXXX 
 
 
 
 
 


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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-411 
Listing 16.2-18: Intraoperative Opioids – Randomized Subjects 
TREATMENT: treatment-name 
Subject 
Administered 
Name 
Dose 
Unit 
Route 
XXX-YYYY 
XXX-YYYY 
YES 
NO 
OPIOID-NAME 
XXX.XX 
(UNITS) 
XXXX 
 
 
 
 
 
 
 
 
 
 
 


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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-411 
Listing 16.2-19: Study Drug Administration – Randomized Subjects 
TREATMENT: treatment-name 
Subject 
Date 
Start 
Time 
Stop 
Time 
Total Volume 
(mL) 
XXX-YYYY 
DDMONYYYY 
HH:MM 
HH:MM 
XXX 
 
 
 
 
 
 
 
 
 
 
 
 


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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-411 
Listing 16.2-20: Urine Drug Screen, Alcohol Blood Test and Pregnancy Test – All Subjects 
TREATMENT: treatment-name 
Subject 
Visit 
Urine Drug 
Blood 
Alcohol 
Pregnancy 
XXX-YYYY 
Screening 
XXXXXXXX 
XXXXXXXX 
XXXXXXXX 
Day 0 (Preop) 
XXXXXXXX 
XXXXXXXX 
XXXXXXXX 
XXX-YYYY 
Screening Day 
0 (Preop) 
XXXXXXXX 
XXXXXXXX 
XXXXXXXX 
XXXXXXXX 
XXXXXXXX 
XXXXXXXX 
XXX-YYYY 
Screening Day 
0 (Preop) 
XXXXXXXX 
XXXXXXXX 
XXXXXXXX 
XXXXXXXX 
XXXXXXXX 
XXXXXXXX 
XXX-YYYY 
Screening Day 
0 (Preop) 
XXXXXXXX 
XXXXXXXX 
XXXXXXXX 
XXXXXXXX 
XXXXXXXX 
XXXXXXXX 
 
 


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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-411 
Listing 16.2-21: Admission and Discharge – Randomized Subjects 
 
TREATMENT: treatment-name 
 
Date and Time (Day) 
 
Subject 
Admission 
Discharge 
 
 
XXX-YYYY 
DDMONYYYYTHH:MM (XX) 
DDMONYYYYTHH:MM (XX) 
XXX-YYYY 
DDMONYYYYTHH:MM (XX) 
DDMONYYYYTHH:MM (XX) 
XXX-YYYY 
DDMONYYYYTHH:MM (XX) 
DDMONYYYYTHH:MM (XX) 
 
 
*=out of window 
Total score = sum of scores. 
1) Vital signs: 2 = ≤ 20%; 1 = 20-40%; 0 = >40% of preoperative value. 
2) Ambulation: 2 = steady gait/no dizziness; 1 = with assistance; 0 = none/dizziness 
3) Nausea and Vomiting: 2 = minimal; 1 = moderate; 0 = severe 
4) Pain: 2 = minimal; 1 = moderate; 0 = severe 
5) Surgical bleeding: 2 = minimal; 1 = moderate; 0 = severe 


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Listing 16.2-22: Important Protocol Deviations - Randomized Subjects 
TREATMENT: treatment-name 
Site 
Subject 
Date (day) 
Epoch 
Deviation Code 
Description 
XXX 
XXX-YYYY 
DDMONYYYY (XX) 
XXX 
Mistakenly Unblinding 
XXXXXXXXXXXXXXXXXX 
XXXXXXXXXXXXXXXXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note to programmer: Subjects may have multiple deviations. 
Sort deviations by subject and date. 
Select dvdecod “Mistakenly Unblinding”, “Restricted Medications Taken”, “Non-Compliance/Ultrasound”, 
“Primary Efficacy Assessments”, “Other Important Deviations”, “Improper Informed Consent Procedure” 


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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-327 
Listing 16.2-23: Unique Adverse Events Terms and Associated Coded Terms 
 
MedDRA Terms 
SOC 
Preferred Term 
Verbatim(s) 
SOC1 
XXXXXXXXXXXXXXXXXXXXXXXXXXX 
PT1.1 
XXXXXXXXXXXXXXXXXXXXXXXXXXX 
XXXXXXXXXXXXXXXXXXXXXXXXXXX 
XXXXXXXXXXXXXXXXXXXXXXXXXXX 
PT1.2 
XXXXXXXXXXXXXXXXXXXXXXXXXXX 
XXXXXXXXXXXXXXXXXXXXXXXXXXX 
SOC2 
PT2.1 
XXXXXXXXXXXXXXXXXXXXXXXXXXX 
XXXXXXXXXXXXXXXXXXXXXXXXXXX 
Coded using MedDRA v21.1. 
Note to programmer: Sort by SOC and preferred term in alphabetical order 


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Protocol: 402-C-327 
Listing 16.2-24: Unique Medication Terms and Associated Coded Terms 
 
Who Drug Dictionary Terms 
ACT1 
ACT2 
ACT3 
ACT4 
Preferred name 
Verbatim(s) 
ATC1 
ATC1.2 
PN1.2.1 
XXXXXXXXXXXXXXXXXXXXXXXXXX 
XXXXXXXXXXXXXXXXXXXXXXXXXX 
PN1.2.2 
XXXXXXXXXXXXXXXXXXXXXXXXXX 
 
ATC2 
ATC2.2 
ATC2.3 
ATC2.4 
PN2.2.3.4.1 
XXXXXXXXXXXXXXXXXXXXXXXXXX 
XXXXXXXXXXXXXXXXXXXXXXXXXX 
 
Coded using WHO Drug Dictionary September 2018. 
 
 
Note to programmer: Sort by ATC1, ATC2, ATC3, ATC4 and preferred name in alphabetical order 


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16. 
LIST OF FIGURES 
FIGURE 1: BAR CHART OF TOTAL POSTSURGERY OPIOID CONSUMPTION (MED) – EFFICACY 
ANALYSIS SET 
122 
FIGURE 2: PLOT OF MEAN PAIN INTENSITY SCORE (VAS) VS TIME THROUGH 72 HOURS – EFFICACY 
ANALYSIS SET 
122 
FIGURE 3: PLOT OF TIME TO FIRST OPIOID RESCUE MEDICATION – EFFICACY ANALYSIS SET 
122 
FIGURE 4: PLOT OF % OF OPIOID-FREE PATIENTS – EFFICACY ANALYSIS SET 
122 


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Statistical Analysis Plan 
 
 
 
Use Figure mock-up xx for the following the x-axis should track through 76 hours: 
Figure 1: Bar Chart of Total Postsurgery Opioid Consumption (MED) – Efficacy Analysis Set 
 
Use Figure mock-up xx for the following (the x-axis should track through 76 hours): 
Figure 2: Plot of Mean Pain Intensity Score (VAS) vs Time through 72 hours – Efficacy Analysis Set 
 
Use Figure mock-up xx for the following (use actual hours since the end of surgery and not scheduled hours, 
include all VAS scores collected, the x-axis should track through 76 hours): 
Figure 3: Plot of Time to First Opioid Rescue Medication – Efficacy Analysis Set 
 
 
 
Use Figure mock-up xx for the following (use actual hours since the end of surgery and not scheduled hours, 
include all VAS scores collected, the x-axis should track through 100 hours): 
Figure 4: Plot of % of Opioid-free Patients – Efficacy Analysis Set 


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17. 
Appendix