Clinical trial NCT03682302
Conditions: Postoperative Pain Management
Keywords: Pediatric
Sponsor: Pacira Pharmaceuticals, Inc
Start date: 2019-04-02; Completion date: 2019-09-24
Enrollment: 98 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
Primary Objective: To evaluate the pharmacokinetics (PK) of EXPAREL in pediatric subjects aged 6 to less than 17 years undergoing various types of surgeries.

Secondary Objective: To evaluate the safety of EXPAREL in pediatric subjects aged 6 to less than 17 years undergoing various types of surgeries.

Detailed description:
This is a Phase 3, two-part, multi-center, open-label study designed to evaluate the PK and safety profile of EXPAREL in pediatric subjects aged 6 to less than 17 years when administered intraoperatively at the end of surgery via local infiltration. 90 pediatric subjects undergoing spine and/or cardiac surgeries are planned for enrollment.

Part 1 is a multicenter, randomized, open-label study in subjects aged 6 to less than 17 years undergoing spine or cardiac surgeries. There will be 2 treatment groups: Group 1 will include subjects aged 12 to less than 17 years, while Group 2 will include subjects aged 6 to less than 12 years

Part 2 is a multicenter, randomized, open-label, safety study in subjects aged 6 to less than 17 years undergoing spine or cardiac surgeries. There will be 2 treatment groups: Group 1 will include subjects aged 12 to less than 17 years, while Group 2 will include subjects aged 6 to less than 12 years.

Subjects will be screened within 30 days prior to study drug administration. During the screening visit, subjects will be assessed for past or present neurologic, cardiac, and general medical conditions that, in the opinion of the investigator, would preclude them from study participation.

Subjects will undergo their pre-planned spinal or cardiac surgeries per the institution's standard of care. On Day 1, eligible subjects will receive the study drug intraoperatively at the end of surgery via local infiltration into the surgical site. Dosing of EXPAREL will be based on body weight, with a starting dose of 4 mg/kg (maximum 266 mg).

There is no required length of stay in the hospital; subjects may be discharged based on the medical judgment of the treating physician.

A follow-up phone call will be scheduled for all subjects on Day 7. A final follow-up visit will be made on Day 30 to all subjects who would have received the study drug.

Arms: arm 1: Single dose of EXPAREL 4 mg/kg (not to exceed a maximum total dose of 266 mg) via local infiltration at the end of spine surgery. arm 2: Single dose of bupivacaine hydrochloride (HCl) 2 mg/kg (not to exceed a maximum total dose of 175 mg) via local infiltration at the end of spine surgery. arm 3: Single dose of EXPAREL 4 mg/kg (not to exceed a maximum total dose of 266 mg) via local infiltration at the end of spine surgery. arm 4: Single dose of EXPAREL 4 mg/kg (not to exceed a maximum total dose of 266 mg) via local infiltration at the end of cardiac surgery.
Interventions: intervention 1: Exparel intervention 2: 0.5% Bupivacaine HCl
Intervention descriptions: intervention 1: EXPAREL 4mg/kg (maximum 266 mg) intervention 2: Bupivacaine HCl 2mg/kg

Protocol documents:
Prot_000.pdf: 
Pacira Pharmaceuticals, Inc. 
 
 
EXPAREL 
Document: 
Clinical Study Protocol 
Official Title: 
A Multicenter Study to Evaluate the Pharmacokinetics and Safety of 
EXPAREL for Postsurgical Analgesia in Pediatric Subjects Aged 6 to 
Less Than 17 years (PLAY) 
NCT Number: 
NCT03682302 
Document Date: 
October 1, 2018 
 


 
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Pacira Pharmaceuticals, Inc. 
402-C-319 (Pediatric Infiltration) 
EXPAREL® 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
2 of 58 
 01-OCT-2018  
 
1.
SIGNATURE PAGE 
 
 
 
 
 
Richard Scranton, MD, MPH 
Chief Medical Officer 
 
 
 
 
 
 
Date 
Michael Rozycki, PhD 
Vice President, Regulatory Affairs 
 
 
 
 
 
 
Date 
Julia Yang, MD 
Vice President, Clinical Research 
 
 
 
 
 
 
Date 
Hassan Danesi, MD, MBA 
Sr. Medical Director  
 
 
 
 
 
 
Date 
Vincent Yu, PhD 
Sr. Director, Biometrics 
 
 
Date 
 
Vincent Yu
Digitally signed by Vincent Yu 
DN: cn=Vincent Yu, o=Pacira, 
ou=Biometrics, 
email=vincent.yu@pacira.com, c=US 
Date: 2018.10.01 12:05:45 -04'00'
Julia Yang
Digitally signed by Julia Yang 
DN: cn=Julia Yang, o=Pacira, 
ou=Clinical Research, 
email=Julia.Yang@pacira.com, c=US 
Date: 2018.10.01 15:03:44 -04'00'
Hassan Danesi
Digitally signed by Hassan Danesi 
DN: cn=Hassan Danesi, o=Pacira 
Pharmaceuticals, ou=Medical, 
email=hassan.danesi@pacira.com, c=US 
Date: 2018.10.01 15:07:58 -04'00'
Michael 
Rozycki
Digitally signed by Michael Rozycki 
DN: cn=Michael Rozycki, 
o=Regulatory Affairs, ou=Clinical 
Regulatory, 
email=michael.rozycki@pacira.com, 
c=US 
Date: 2018.10.01 15:15:52 -04'00'
Richard 
Scranton
Digitally signed by Richard Scranton 
DN: cn=Richard Scranton, o=Pacira 
Pharmaceuticals Inc., ou=Chief Scientific 
Officer, email=Richard.Scranton@pacira.com, 
c=US 
Date: 2018.10.01 15:48:35 -04'00'


Pacira Pharmaceuticals, Inc. 
402-C-319 (Pediatric Infiltration) 
EXPAREL® 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
3 of 58 
 01-OCT-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 Product: 
EXPAREL  
Name of Active Ingredient: 
Bupivacaine, 1.3%, 13.3 mg/mL 
Title of Study: A Multicenter Study to Evaluate the Pharmacokinetics and Safety of EXPAREL for Postsurgical 
Analgesia in Pediatric Subjects Aged 6 to Less Than 17 Years
Principal Investigators: To be determined 
Study Centers: Multicenter study in the United States (US) 
Publications (Reference): None 
Objectives: 
Primary objective: The primary objective is to evaluate the pharmacokinetics (PK) of EXPAREL in pediatric 
subjects aged 6 to less than 17 years undergoing various types of surgeries. 
 
Secondary objective: The secondary objective is to evaluate the safety of EXPAREL in pediatric subjects aged 6 to 
less than 17 years undergoing various types of surgeries. 
Methodology: 
This is a two-part study to evaluate the PK and safety of EXPAREL in pediatric subjects aged 6 to less than 
17 years.  Part 1 will evaluate PK and safety in subjects aged 6 to less than 17 years, while Part 2 will assess safety 
in subjects aged 6 to less than 17 years.   
 
In Part 1, subject enrollment will be conducted in parallel to include the older age group (12 to <17 years old; 
Group 1) and the younger age group (6 to <12 years old; Group 2).  
 
Subject enrollment for Part 2 (of each group) will commence upon complete enrollment of Part 1 (of that group).  
In Part 2, subject enrollment will be conducted in parallel to include the older age group (12 to <17 years old; 
Group 1) and the younger age group (6 to <12 years old; Group 2).   
 
Dosing of EXPAREL will be based on body weight, with a starting dose of 4 mg/kg (maximum 266 mg).  
 
 
Surgery Type, Dose, and Number of Subjects [n] 
 
Part 1 (PK and Safety) 
Part 2 (Safety) 
Group 1  
(subjects aged 
12 to <17 
years) 
Spine Surgery 
 
EXPAREL 4 mg/kg [15] 
bupivacaine HCl 2 mg/kg [15] 
Spine Surgery 
 
EXPAREL 4 mg/kg [15] 
bupivacaine HCl 2 mg/kg [15] 
Group 2  
(subjects aged 
6 to <12 years) 
Spine or Cardiac Surgery 
 
EXPAREL 4 mg/kg [15] 
Spine or Cardiac Surgery 
 
EXPAREL 4 mg/kg [15] 
 
Part 1 (Pharmacokinetics- PK) – Subjects aged 6 to less than 17 years 
Part 1 is a multicenter, randomized, open-label study in subjects aged 6 to less than 17 years undergoing spine or 
cardiac surgeries.  There will be two treatment groups: Group 1 will include subjects aged 12 to less than 17 years, 
while Group 2 will include subjects aged 6 to less than 12 years.  Safety will be assessed as a secondary objective. 


Pacira Pharmaceuticals, Inc. 
402-C-319 (Pediatric Infiltration) 
EXPAREL® 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
4 of 58 
 01-OCT-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 Product: 
EXPAREL  
Name of Active Ingredient: 
Bupivacaine, 1.3%, 13.3 mg/mL 
 
Part 1, Group 1, is an active-controlled, open-labeled, PK evaluation study in subjects aged 12 to less than 
17 years undergoing spine surgery.  The active comparator will be bupivacaine HCl.  The sample size is a total of 
30 subjects (15 subjects per treatment group).  Subjects will be randomized 1:1 to receive either a single dose of 
EXPAREL 4 mg/kg (maximum 266 mg) or bupivacaine HCl 2 mg/kg (not exceeding a maximum bupivacaine HCl 
dose of 175 mg total) intraoperatively at the end of surgery via local infiltration.  
 
Part 1, Group 2, is a single-arm (EXPAREL 4 mg/kg), open-labeled, PK evaluation study in subjects aged 6 to 
less than 12 years undergoing spine or cardiac surgery.  The sample size is a total of 15 subjects.  Subjects will 
receive a single dose of EXPAREL 4 mg/kg (maximum 266 mg) intraoperatively at the end of surgery via local 
infiltration.  
 
The total sample size for Part 1 is 45 subjects aged 6 to less than 17 years, with 30 subjects in Group 1 and 
15 subjects in Group 2. 
Part 2 (Safety) – Subjects aged 6 to less than 17 years 
Part 2 is a multicenter, randomized, open-label, safety study in subjects aged 6 to less than 17 years undergoing 
spine or cardiac surgeries.  There will be two treatment groups: Group 1 will include subjects aged 12 to less than 
17 years, while Group 2 will include subjects aged 6 to less than 12 years.  
 
Part 2, Group 1, is an active-controlled, open-labeled, safety evaluation study in subjects aged 12 to less than 
17 years undergoing spine surgery.  The active comparator will be bupivacaine HCl.  The sample size is a total of 
30 subjects (15 subjects per treatment group).  Subjects will be randomized 1:1 to receive either a single dose of 
EXPAREL 4 mg/kg (maximum 266 mg) or bupivacaine HCl 2 mg/kg (not exceeding a maximum bupivacaine HCl 
dose of 175 mg total) intraoperatively at the end of surgery via local infiltration. 
 
Part 2, Group 2, is a single-arm (EXPAREL 4 mg/kg), open-labeled study in subjects aged 6 to less than 12 years 
undergoing spine or cardiac surgery.  The sample size is a total of 15 subjects.  Subjects will receive a single dose 
of EXPAREL 4 mg/kg (maximum 266 mg) intraoperatively at the end of surgery via local infiltration.  
 
The total sample size for Part 2 is 45 subjects aged 6 to less than 17 years, with 30 subjects in Group 1 and 
15 subjects in Group 2.  
 
The overall safety assessment will include all 45 subjects from Part 1 and all 45 subjects from Part 2, with a total 
of 90 subjects. 
 
Subjects will be screened within 30 days prior to study drug administration.  During the screening visit, subjects 
will be assessed for past or present neurologic, cardiac, and general medical conditions that, in the opinion of the 
investigator, would preclude them from study participation.  After the informed consent form (ICF) is signed by 
the subject’s legal guardian and written assent is provided by the subject (if capable), medical history, surgical 
history, physical examination, 12-lead electrocardiogram (ECG), vital sign measurements, neurological 
assessment, clinical laboratory tests (hematology, chemistry, and urinalysis), pain intensity score, urine pregnancy 
test for females of childbearing potential, urine drug screen and alcohol breath test will be conducted. 
 
On Day 1, eligible subjects will receive the study drug intraoperatively at the end of surgery via local infiltration to 


Pacira Pharmaceuticals, Inc. 
402-C-319 (Pediatric Infiltration) 
EXPAREL® 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
5 of 58 
 01-OCT-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 Product: 
EXPAREL  
Name of Active Ingredient: 
Bupivacaine, 1.3%, 13.3 mg/mL 
produce local analgesia.  Use of intraoperative opioids, acetaminophen, ketorolac, or other non-steroidal 
anti-inflammatory drugs (NSAIDs), will be permitted in accordance with the study site’s standard of care.  Avoid 
additional use of local anesthetics within 96 hours following the administration EXPAREL.    
 
There is no required length of stay in the hospital; subjects may be discharged based on the medical judgment of 
the treating physician.  For subjects discharged from the hospital before all protocol-specified assessments till 
96 hours are completed, a nurse will perform follow-up visits at the subject’s home to perform the required 
postsurgical assessments and collect PK samples till 96 hours. 
 
A follow-up phone call will be scheduled for all subjects on Day 7.  For the assessment of adverse events (AEs), a 
final follow-up visit will be made on Day 30 to all subjects who would have received the study drug.  
 
Postsurgical Pain Management 
Use of postsurgical pain medication in cases of insufficient analgesia will be permitted according to the 
institution’s standard of care.  The investigator must record all postsurgical pain management medications 
provided to the subjects till the hospital discharge.  Avoid additional use of local anesthetics within 96 hours 
following the administration EXPAREL.    
 
Postsurgical Assessments 
Postsurgical assessments to be done till 96 hours include pain intensity using the 11-point Numeric Rating Scale at 
Rest (NRS-R; Appendix 1) for subjects aged 12 to less than 17 years and the Color Analog Scale (CAS; 
Appendix 2) for subjects aged 6 to less than 12 years; neurological assessment (Appendix 3); clinical laboratory 
tests (Appendix 4); and vital signs.   
 
AEs will be recorded from the time the ICF is signed/assent is given till Day 30.   
 
In case a cardiac or neurological AE of special interest (AESI) or serious AE (SAE) occurs during the study, if the 
investigator or medical monitor considers that the event may be related to study treatment or suggests the possible 
occurrence of local anesthetic systemic toxicity (LAST; with or without the need for treatment [e.g., intralipids]), 
or if a plausible etiology for the event cannot be found, an unscheduled PK blood sample must be collected and a 
12-lead ECG, vital signs, and clinical laboratory tests (hematology and complete metabolic profile [CMP]) 
according to the study site’s standard of care may be conducted.  See Section 13.1.7 and Appendix 6 for additional 
information on handling of AESIs. 
 
Cardiac AESIs include chest pain, abnormal/irregular heart rate, and shortness of breath requiring intervention.  
Neurologic AESIs include seizure, altered mental status/altered sensorium, rigidity, dysarthria, tremors, tinnitus, 
visual disturbance, and severe or worsening dizziness (see below).  Additionally, the following events may be of 
special interest if they persist or occur beyond 72 hours post dose: dizziness, hyperesthesia, muscular twitching, 
and tingling/paresthesia. 
 
Dizziness will be assessed as mild, moderate, or severe based on the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) Version 5.0.  Mild dizziness is defined as mild unsteadiness or 
sensation of movement; moderate dizziness is defined as moderate unsteadiness or sensation of movement limiting 
instrumental activities of daily living (ADL); and severe dizziness is defined as severe unsteadiness or sensation of 
movement that limits self-care ADLs.  Dizziness will be captured as an AESI if it is severe or worsens or persists 


Pacira Pharmaceuticals, Inc. 
402-C-319 (Pediatric Infiltration) 
EXPAREL® 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
6 of 58 
 01-OCT-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 Product: 
EXPAREL  
Name of Active Ingredient: 
Bupivacaine, 1.3%, 13.3 mg/mL 
beyond 72 hours post dose.  
 
Cardiac or neurological AEs that do not meet one of these three criteria for AESI should be reported as described 
in Section 14.1 (Adverse Events) and captured in the database as an AE. 
 
Pharmacokinetic Assessment (Part 1 only) 
A population PK sampling scheme will be used to limit the number of blood draws for each individual subject.  On 
Day 1, eligible subjects will be assigned to one of the two PK sampling groups shown below based on surgery type 
(see the table below for PK sample collection schedule).  A total of 8 blood samples will be collected from each 
subject at the specific time windows shown for the determination of bupivacaine plasma concentrations.  Having 
two separate PK sampling sequences for spine and cardiac surgeries will help to guard against clustering of PK 
samples. 
 
Table: PK Sample Collection 
Surgery 
Type 
PK Sample Timing (Based on the End of Study Drug Administration) 
Sample 1 
Sample 2 
Sample 3 
Sample 4 
Sample 5 
Sample 6 
Sample 7 
Sample 8 
Spine 
15±5 min 
30±5 min 
45±5 min 
1-1.25 h 
2-3 h 
10-18 h 
24-36 h 
42-60 h 
Cardiac 
15±5 min 
30±5 min 
45±5 min 
1-1.25 h 
15-25 h 
30-40 h 
45-55 h 
64-72 h 
h: hour; min: minutes; PK: pharmacokinetic. 
 
These sampling time points will not only characterize overall PK of bupivacaine from EXPAREL, but will also 
characterize the PK of immediate release bupivacaine and thoroughly characterize the early peak for both 
treatments.  
 
Note that a new needle stick may not be necessary for each blood draw.  The subject may be fitted with a 
peripheral venous line at the discretion of the investigator to facilitate the collection of blood for PK assessment. 
 
In the situation where PK blood draws and other assessments coincide with or occur at about the same time, the 
blood draw for PK analysis must be conducted first, and the pain intensity assessment conducted second, as 
applicable, followed by other assessments. 
 
Data Safety Monitoring Board  
A Data Safety Monitoring Board (DSMB) will be set up to monitor the safety and dosing data on an ongoing basis 
for all treatment groups.   
 
Number of Subjects (Planned): 
Approximately 90 subjects are planned for this study: 45 in Part 1 and 45 in Part 2.  Overall, 60 subjects will 
receive EXPAREL and 30 subjects will receive immediate release bupivacaine. 
Eligibility Criteria: 
Inclusion Criteria 
1.
Subjects whose parent(s) or guardian(s) has/have signed and dated the ICF for the subject to participate in 
the study, and subjects who have provided written assent to participate in the study (if capable). 
2.
American Society of Anesthesiologists (ASA) Class 1-3. 


Pacira Pharmaceuticals, Inc. 
402-C-319 (Pediatric Infiltration) 
EXPAREL® 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
7 of 58 
 01-OCT-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 Product: 
EXPAREL  
Name of Active Ingredient: 
Bupivacaine, 1.3%, 13.3 mg/mL 
3.
Male or female subjects 6 to less than 17 years of age on the day of surgery. 
4.
Body mass index (BMI) at screening within the 5th to 95th percentile for age and sex (see Appendix 5). 
5.
A negative pregnancy test for female subjects of childbearing potential must be available prior to the start of 
surgery.  The pregnancy test must be conducted in the preoperative holding area according to the study 
site’s standard of care. 
6.
Subjects and their parent(s)/guardian(s) must be able to speak, read, and understand the language of the ICF 
and any instruments used for collecting subject-reported outcomes to enable accurate and appropriate 
responses to study assessments, and provide informed consent/assent.  
7.
Subjects must be able to adhere to the study visit schedule and complete all study assessments. 
Exclusion Criteria 
1.
Currently pregnant, breastfeeding, or planning to become pregnant during the study or within 1 month after 
study drug administration. 
2.
History of hypersensitivity or idiosyncratic reactions to amide-type local anesthetics or to opioid 
medication.  
3.
Contraindication to bupivacaine HCl or other amide-type local anesthetics or to opioid medication. 
4.
Administration of EXPAREL or bupivacaine HCl within 30 days prior to study drug administration. 
5.
Subjects with coagulopathies or immunodeficiency disorders. 
6.
History of, suspected, or known addiction to or abuse of drugs or alcohol within the past 2 years.  
7.
Clinically significant medical or psychiatric disease that, in the opinion of the investigator, indicates an 
increased vulnerability to study drugs and/or procedures. 
8.
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. 
In addition, the subject will be ineligible to receive study drug if he or she meets the following criterion during 
surgery: 
9.
Any clinically significant event or condition uncovered during the surgery (e.g., excessive bleeding, acute 
sepsis) that might render the subject medically unstable or complicate the subject’s postsurgical course. 
Test Product, Dose, Mode of Administration, and Lot Number: 
Name: EXPAREL (bupivacaine liposome injectable suspension).  
Active ingredient: Bupivacaine 1.3%, 13.3 mg/mL 
Dosage: Single dose of EXPAREL 4 mg/kg  
Lot number: To be determined 
Mode of administration: Intraoperative local infiltration 
Reference Product, Dose, Mode of Administration, and Lot Number:  
Name: Bupivacaine HCl  
Active ingredient: Bupivacaine HCl  
Dosage: 2 mg/kg, not to exceed a maximum dose of 175 mg 
Lot number: Commercial product to be provided by Pacira 
Mode of administration: Intraoperative local infiltration
Duration of Subject Participation in the Study: 
Participation will begin at the signing of the ICF/obtaining written assent.  No more than 30 days should pass 
between signing of the ICF/obtaining written assent and the administration of study drug.  The time from study 
drug administration till the end of participation is 30 ± 3 days.  Therefore, subjects may participate in the study for 


Pacira Pharmaceuticals, Inc. 
402-C-319 (Pediatric Infiltration) 
EXPAREL® 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
8 of 58 
 01-OCT-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 Product: 
EXPAREL  
Name of Active Ingredient: 
Bupivacaine, 1.3%, 13.3 mg/mL 
up to 63 days.  
Pharmacokinetic Analysis (Part 1 only):
A total of 8 blood samples will be collected from each subject at specific time windows for the determination of 
plasma bupivacaine concentrations.  Population PK modeling will be performed using all PK data collected during 
the study.  The population PK model will characterize overall PK of bupivacaine from EXPAREL and will also 
characterize the PK of immediate release bupivacaine.   
Pharmacokinetic Endpoints (Part 1 only):  
The following PK endpoints will be predicted from the model:  
x
Area under the plasma concentration-versus-time curve (AUC) 
x
Maximum plasma concentration (Cmax) 
x
The apparent terminal elimination half-life (t1/2el)
x
Apparent clearance (CL/F) 
x
Apparent volume of distribution (Vd/F) 
Safety Assessments: 
The following safety assessments will be conducted at the time points specified: 
x
Vital signs (temperature, resting heart rate, respiratory rate, oxygen saturation, and blood pressure) at 
screening; at baseline (on Day 1 prior to surgery); upon arrival in the post-anesthesia care unit (PACU); at 2, 
4, 8, 12, 24, 36, 48, 60, 72, and 96 hours after the end of study drug administration; at hospital discharge; 
and on Day 30. 
x
Neurological assessment at screening; at 2, 4, 8, 12, 24, 36, 48, 60, 72, and 96 hours after the end of study 
drug administration; at hospital discharge; and on Day 30 (Part 1 only, see Appendix 3).  
x
Clinical laboratory tests (hematology, chemistry, and urinalysis) at screening; at baseline (on Day 1 prior to 
surgery); and at 96 hours after the end of study drug administration (see Appendix 4). 
x
AEs from the time the ICF is signed/assent is obtained till Day 30. 
Safety Endpoints: 
The following safety endpoints will be assessed based on the safety measurements conducted at the specified time 
points: 
x
Change from baseline in vital signs (temperature, resting heart rate, respiratory rate, oxygen saturation, and 
blood pressure). 
x
Summary of neurological assessments (proportion of subjects who are oriented, and proportion of subjects 
who have any neurologic events).  Note: Events identified during the neurologic assessment should be 
recorded as AEs. 
x
Change from baseline in clinical laboratory data. 
x
Incidence of treatment-emergent AEs (TEAEs) and SAEs till Day 30. 
Other Assessments:  
The following efficacy measurements will be done for exploratory purposes only:   
x
Pain intensity scores at screening; at 4, 8, 12, 24, 36, 48, 60, 72, and 96 hours after the end of study drug 
administration; immediately prior to each administration of postoperative opioid pain management medication 
till 96 hours; and at hospital discharge.  If a subject is too anesthetized at the time of a scheduled pain intensity 
assessment, the assessment should be skipped.  Pain intensity will be measured as follows:  


Pacira Pharmaceuticals, Inc. 
402-C-319 (Pediatric Infiltration) 
EXPAREL® 
Clinical Study Protocol 
 
 
CONFIDENTIAL 
9 of 58 
 01-OCT-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 Product: 
EXPAREL  
Name of Active Ingredient: 
Bupivacaine, 1.3%, 13.3 mg/mL 
o
11-point NRS-R for subjects aged 12 to less than 17 years (Appendix 1) 
o
CAS for subjects aged 6 to less than 12 years (Appendix 2) 
x
Postsurgical opioid pain management medication use (time, dose) till 96 hours after the end of study drug 
administration. 
Other Endpoints:  
Analysis of other endpoints will be conducted for exploratory purposes only.  The efficacy endpoints listed below 
will be assessed based on the efficacy measurements conducted at the time points specified. 
x
Pain intensity scores. 
x
Area under the curve (AUC) of pain intensity scores. 
x
Total opioid consumption in morphine equivalents. 
x
Time to first postsurgical use of opioid medication.   
Statistical Methods: 
A comprehensive statistical analysis plan will be developed for this study.  Descriptive statistics (number of 
subjects, mean, standard deviation, median, minimum, and maximum) will be provided for continuous data.  
Tabulations (number and percentage of subjects) by category will be provided for categorical data.  This study is 
not powered for efficacy. 
 
A prospective population PK analysis plan will be developed.  Nonlinear mixed-effect modeling will be used to 
analyze the sparse concentration-versus-time data.    
 
Population and individual PK parameters will be estimated.  Individual PK parameters estimated for each subject 
will be used to compute PK exposures (AUC and Cmax).  All PK parameters will be presented in listings and 
descriptive summary statistics, including the arithmetic mean, median, range, standard deviation, and coefficient of 
variation.  Details and results of this mixed-effect modeling analysis will be reported separately. 
 
Sample Size 
The sample size was based on the number of subjects necessary to characterize the PK profile of EXPAREL in 
pediatric subjects with the precision required by the Food and Drug Administration. 


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Table 1: Time and Events Schedule of Study Procedures 
Screen 
Visit
D1
Preop OR
15
min
30
min 1 h
2 h 4 h 8 h 12 h 24 h 36 h 48 h 60 h 72 h 96 h
Hosp
Dis
D7
Call
D30
Visit
Time Window 
Within
30 days
±5
min
±5
min
±15
min
±15
min
±15
min
±30
min ±1 h ±1 h ±2 h ±2 h ±2 h ±2 h ±4 h
  
±1 d 
±3 d 
Obtain signed informed consent/assent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assess/confirm eligibility 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record medical history and surgical history  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record demographics and baseline characteristics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test (for females of childbearing 
potential; Part 1 only) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine drug screen and alcohol breath test at the 
investigator’s discretion (Part 1 only).  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
12-lead ECG1 
X2
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical laboratory tests (hematology, chemistry, 
urinalysis)3 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Perform neurological assessment 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Measure and record vital signs4 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Record age-specific pain intensity score5 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Collect PK blood samples per time windows in Table 2
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prepare study medication 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administer study medication; record dosage, volume, 
size of incision, and administration start and stop times
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record intraoperative opioids administered and doses 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record surgery start and stop times 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record times and doses of all pain management 
medication administered  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record date and time of discharge 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 


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Screen 
Visit
D1
Preop OR
15
min
30
min 1 h
2 h 4 h 8 h 12 h 24 h 36 h 48 h 60 h 72 h 96 h
Hosp
Dis
D7
Call
D30
Visit
Time Window 
Within
30 days
±5
min
±5
min
±15
min
±15
min
±15
min
±30
min ±1 h ±1 h ±2 h ±2 h ±2 h ±2 h ±4 h
  
±1 d 
±3 d 
Document any unscheduled phone calls, unscheduled 
office visits, or ER visits related to pain after discharge
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Record prior and concomitant medications6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Record AEs beginning at the time the ICF or assent is 
signed1,3,4,7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Note: Postsurgical assessments will be conducted at the time points specified after the end of study drug administration.   
In the situation where PK blood draws and other assessments coincide or occur at about the same time, the blood draw for PK analysis must be conducted first, and the pain 
intensity assessment conducted second, as applicable, followed by any other assessments. 
1 ECG abnormalities that are clinically significant should be recorded as AEs.  May also conduct a 12-lead ECG if a subject experiences an AESI (i.e., cardiac AE or neurological 
AE), or an SAE; see footnote 7. 
2 A baseline 12-lead ECG must be recorded prior to surgery and may be performed either at the screening visit or in the preoperative holding area on Day 1. 
3 May also conduct clinical laboratory tests if a subject experiences an AESI or an SAE; see footnote 7. 
4 Vital signs (temperature, resting heart rate, respiratory rate, oxygen saturation and blood pressure) will be measured after the subject has rested in a supine position for at least 
5 minutes.  May also measure vital signs if a subject experiences an AESI (i.e., cardiac AE or neurological AE), or an SAE; see footnote 7. 
5 Pain intensity will be measured using the 11-point NRS-R for subjects aged 12 to less than 17 years (Appendix 1) and CAS for subjects aged 6 to less than 12 years 
(Appendix 2).  The preoperative pain intensity assessment should be conducted immediately prior to each administration of postoperative opioid pain management medication till 
96 hours.  If a subject is too anesthetized at the time of a scheduled pain intensity assessment, the assessment should be skipped. 
6 Instruct subject to discontinue prohibited medications.  Record date/time of all medications starting at least 30 days prior to study drug administration till 96 hours after study 
drug administration.  Record medications administered for treatment of an AE till Day 30. 
7 In case a cardiac or neurological AE of special interest (AESI) or serious AE (SAE) occurs during the study, if the investigator or medical monitor considers that the event may 
be related to study treatment or suggests the possible occurrence of local anesthetic systemic toxicity (LAST; with or without the need for treatment [e.g., intralipids]), or if a 
plausible etiology for the event cannot be found, an unscheduled PK blood sample must be collected and a 12-lead ECG, vital signs, and clinical laboratory tests (hematology and 
complete metabolic profile [CMP]) according to the study site’s standard of care may be conducted.  See Section 13.1.7 and Appendix 6 for additional information on handling of 
AESIs.  Cardiac or neurological events that do not meet one of these three criteria should be reported as described in Section 14.1.  
Cardiac AESIs include chest pain, abnormal/irregular heart rate, and shortness of breath requiring intervention.  Neurologic AESIs include seizure, altered mental status/altered 
sensorium, rigidity, dysarthria, tremors, tinnitus, visual disturbance, and severe or worsening dizziness.  Additionally, the following events may be of special interest if they persist 
or occur beyond 72 hours post dose: dizziness, hyperesthesia, muscular twitching, and tingling/paresthesia.  Severity of dizziness will be assessed based on NCI CTCAE 
(Version 5.0).  Dizziness will be captured as an AESI if it is severe or worsens or persist beyond 72 hours post dose (see Section 13.1.7). 
Abbreviations: 
AE: adverse event; AESI: AE of special interest; CAS: Color Analog Scale; CTCAE: Common Terminology Criteria for Adverse Events; d: day(s); ECG: electrocardiogram; 
ER: emergency room; h: hour; Hosp Dis: hospital discharge; ICF: informed consent form; min: minutes; NCI: National Cancer Institute; NRS-R: Numeric Rating Scale at Rest; 
OR: operating room; PK: pharmacokinetic; SAE: serious adverse event. 
 


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3.
TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL .................................................................................................. I
1.
SIGNATURE PAGE ...........................................................................................................2
2.
SYNOPSIS ...........................................................................................................................3
3.
TABLE OF CONTENTS ...................................................................................................12
4.
LIST OF ACRONYMS/ABBREVIATIONS AND DEFINITIONS OF TERMS ............16
4.1.List of Acronyms/Abbreviations ................................................................................16
4.2.Definition of Terms ....................................................................................................17
5.
ETHICS..............................................................................................................................18
5.1.Institutional Review Board/Independent ethics committee ........................................18
5.2.Ethical Conduct of the Study ......................................................................................18
5.3.Subject Information, Consent, and Assent .................................................................18
6.
INVESTIGATORS AND STUDY ADMINISTRATION STRUCTURE ........................19
7.
INTRODUCTION .............................................................................................................19
7.1.Indication ....................................................................................................................20
7.2.Current Therapies/Treatments ....................................................................................20
7.3.EXPAREL (bupivacaine liposome injectable suspension) .........................................21
7.4.Summary of Human Clinical Experience with EXPAREL ........................................21
7.5.Postmarketing Exposure in Adults and Children ........................................................23
8.
OBJECTIVES ....................................................................................................................24
8.1.Primary Objective .......................................................................................................24
8.2.Secondary Objectives .................................................................................................24
9.
OVERALL STUDY DESIGN AND PLAN ......................................................................24
9.1.Overall Study Design and Plan ...................................................................................24
9.2.Duration of the Study and Subject Participation ........................................................28
9.3.Data Safety Monitoring Board ....................................................................................28
9.4.Discussion of Study Design ........................................................................................28
10.
STUDY POPULATION ....................................................................................................29
10.1.
Inclusion Criteria ............................................................................................29
10.2.
Exclusion Criteria ...........................................................................................29
10.3.
Removal of Subjects from Therapy or Assessment ........................................30
10.3.1.
Withdrawal Secondary to Adverse Events ..............................................30


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10.3.2.
Voluntary or Study Investigator Withdrawal ..........................................30
11.
TREATMENTS .................................................................................................................31
11.1.
Treatments to be Administered .......................................................................31
11.2.
Administration Instructions/Procedures .........................................................32
11.2.1.
Study Drug Administration Considerations ............................................32
11.3.
Identity of Investigational Products ................................................................32
11.3.1.
Description of EXPAREL .......................................................................32
11.3.2.
Description of Reference Product ...........................................................33
11.3.3.
Description of Diluents ............................................................................33
11.4.
Method of Assigning Subjects to Treatment ..................................................33
11.4.1.
Randomization Scheme ...........................................................................33
11.4.2.
Randomization Procedures for Treatment Assignment ...........................33
11.4.3.
Replacement of Subjects .........................................................................33
11.5.
Selection of Doses in the Study ......................................................................33
11.6.
Prior and Concomitant Therapy and Medications ..........................................33
11.6.1.
Before Study Drug Administration .........................................................34
11.6.2.
During Surgery ........................................................................................34
11.6.3.
After Surgery ...........................................................................................34
11.7.
Treatment Compliance ....................................................................................34
11.8.
Accountability of Study Drug .........................................................................35
12.
STUDY ENDPOINTS AND MEASUREMENTS ............................................................35
12.1.
Pharmacokinetic Analysis ..............................................................................35
12.2.
Pharmacokinetic Endpoints ............................................................................35
12.3.
Safety Assessments .........................................................................................35
12.4.
Safety Endpoints .............................................................................................36
12.5.
Other Measurements .......................................................................................36
12.6.
Other Endpoints ..............................................................................................36
12.7.
Appropriateness of Measures .........................................................................37
13.
STUDY PROCEDURES ...................................................................................................37
13.1.
Instructions for Conducting Procedures and Measures ..................................37
13.1.1.
Pain Intensity Assessment .......................................................................37
13.1.2.
Neurological Examination .......................................................................37
13.1.3.
Clinical Laboratory Tests ........................................................................37


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13.1.4.
Vital Signs ...............................................................................................38
13.1.5.
Physical Examination ..............................................................................38
13.1.6.
Electrocardiograms ..................................................................................38
13.1.7.
Adverse Events of Special Interest ..........................................................38
13.2.
Screening Procedures ......................................................................................39
13.3.
Baseline Procedures (Day 1 Prior to Surgery) ................................................39
13.4.
Intraoperative Procedures ...............................................................................40
13.5.
Postoperative Assessments till 96 Hours ........................................................40
13.6.
Hospital Discharge ..........................................................................................41
13.7.
Day 7 Phone Call ............................................................................................41
13.8.
Day 30 Visit ....................................................................................................42
14.
ADVERSE EVENT REPORTING....................................................................................42
14.1.
Adverse Events ...............................................................................................42
14.1.1.
Definitions ...............................................................................................42
14.1.2.
Recording Adverse Events ......................................................................43
14.1.3.
Severity of Adverse Events .....................................................................44
14.1.4.
Relationship of Adverse Events to Study Drug .......................................44
14.1.5.
Outcome of Adverse Events ....................................................................44
14.1.6.
Action Taken with Subject Because of an Adverse Event ......................45
14.2.
Serious Adverse Events ..................................................................................45
14.2.1.
Definition of a Serious Adverse Event ....................................................45
14.2.2.
Reporting Serious Adverse Events ..........................................................46
15.
STATISTICAL METHODS ..............................................................................................47
15.1.
Study Hypothesis ............................................................................................47
15.2.
Study Endpoints ..............................................................................................47
15.3.
Determination of Sample Size ........................................................................47
15.4.
Analysis Populations ......................................................................................47
15.5.
Handling Subject Dropouts and Discontinuations ..........................................47
15.6.
Statistical Analyses .........................................................................................47
15.6.1.
Baseline Characteristics ...........................................................................47
15.6.2.
Efficacy Analyses ....................................................................................47
15.6.3.
Pharmacokinetic Analysis .......................................................................48
15.6.4.
Safety Analyses .......................................................................................48


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15.7.
Significance Testing .......................................................................................48
16.
REFERENCES ..................................................................................................................49
17.
INVESTIGATOR AGREEMENT.....................................................................................51
18.
APPENDICES ...................................................................................................................52
Appendix 1:
Numeric Rating Scale at Rest (NRS-R) ..................................................53
Appendix 2:
Color Analog Scale (CAS) ......................................................................54
Appendix 3:
Neurological Assessment ........................................................................55
Appendix 4:
Clinical Laboratory Tests ........................................................................56
Appendix 5:
BMI Normal Ranges (5th to 95th Percentile) ............................................57
Appendix 6:
Flow Diagram for Handling of AESIs .....................................................58
 
 
LIST OF TABLES 
Table 1: Time and Events Schedule of Study Procedures .............................................................10
Table 2: PK Sample Collection ......................................................................................................27
 
 
 


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4.
LIST OF ACRONYMS/ABBREVIATIONS AND DEFINITIONS OF 
TERMS 
4.1.
List of Acronyms/Abbreviations 
ADL 
Activities of daily living 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
ASA 
American Society of Anesthesiology 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
BMI 
Body mass index 
CAS 
Color Analog Scale 
CFR 
Code of Federal Regulations 
CK 
Creatine kinase 
CPK 
Creatine phosphokinase 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
ER 
Emergency room 
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  
JCAHO 
Joint Commission on Accreditation of Healthcare Organizations 
LDH 
Lactate dehydrogenase 
NCI 
National Cancer Institute 
NDA 
New Drug Application 
NRS-R 
Numeric rating scale – at rest 
NSAID 
Non-steroidal anti-inflammatory drug 


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OR 
Operating room 
PACU 
Post-anesthesia care unit 
PCA 
Patient-controlled analgesia 
PK 
Pharmacokinetic 
PMR 
Post Marketing Requirement 
PPD 
Premier PerspectiveTM Database 
PTAE 
Pre-treatment adverse event 
SAE  
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard Deviation 
TIBC 
Total iron binding capacity 
TEAE 
Treatment-emergent adverse event 
UIBC 
Unsaturated iron binding capacity 
US 
United States 
WHO 
World Health Organization 
 
4.2.
Definition of Terms 
Pharmacokinetic terms are defined in Section 12.2. 
 
 


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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 (including Subpart D regarding additional safeguards for 
children in clinical investigations), 54, 56, and 312, and the ICH GCP.  Study documents will be 
maintained in accordance with applicable regulations. 
5.3.
Subject Information, Consent, and Assent 
Before a subject undergoes any study-specific screening procedures, the investigator or designee 
will thoroughly explain to the subject’s parent/guardian the purpose of the study, the associated 
procedures, and any expected effects and potential adverse reactions.  A copy of the IRB- or 
IEC-approved ICF will be provided to the subject’s parent/guardian, who will be given sufficient 
time and opportunity to inquire about the details of the study and decide whether or not to enroll 
their child.  The subject’s parent/guardian, and the study staff with whom he or she discusses the 
ICF, will sign and date the ICF.  If the subject is capable of providing assent, he or she will be 
provided with an explanation of the study and an IRB- or IEC-approved written assent form to 
read.  Once the investigator is assured that the subject understands the concepts involved, the 
subject will be asked to give assent (if applicable) to participate in the study.  The subject’s 
parent/guardian must sign the ICF and the subject must give assent (if applicable) before any 
study-specific procedures are performed.  A copy of the fully signed ICF will be given to the 
parent/guardian and a copy of the assent form (if applicable) will be given to the subject. 
The investigator will explain to the subject’s parent/guardian that they are completely free to 
decline entering their child into the study and to withdraw their child from the study at any time, 
for any reason, without risking his or her medical care.  The subject may also independently 
withdraw assent to participate in the study.  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 2013).   


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6.
INVESTIGATORS AND STUDY ADMINISTRATION STRUCTURE 
Information regarding the investigators, sites, laboratories, and other service providers is 
available upon request to the IRB/IECs and regulatory agencies. 
7.
INTRODUCTION
With the identification of acute pain by the World Health Organization (WHO) as a problem of 
global proportions (Gureje 1998) and the publication of the Joint Commission on Accreditation 
of Healthcare Organizations (JCAHO) pain standards, there is increasing acceptance of pain as 
the fifth vital sign, on par with blood pressure, pulse, temperature, and respiration rate 
(Lynch 2001). 
Postsurgical pain is one of the most common forms of acute pain (Schug 1993; Carr 1999).  
In contrast to chronic pain, for which no adaptive value has been demonstrated, acute pain is the 
normal physiological response to tissue insult or injury and has adaptive value by serving as a 
warning of danger or damage.  Most acute pain is either treatable or avoidable, especially when it 
occurs in a clinical setting.  However, if acute pain is poorly or inappropriately treated, it may 
progress to chronic pain (Perkins 2000; Petersen-Felix 2002).  Thus, effectively modulating the 
response to acute pain may be considered a primary step in the prevention of chronic pain 
(Stephen 2003).  The suboptimal management of acute pain has been recognized as a problem by 
clinicians for more than 50 years (Papper 1952; Marks 1973) and has been formally identified as 
a public health concern by various societies and government institutions worldwide.   
In 1992, the US Agency for Health Care Policy and Research developed guidelines for the 
management of postoperative pain in the hopes of increasing awareness of the consequences of 
poor pain control in the postoperative setting and promoting better pain management techniques 
(Stephen 2003).  These consequences, which include delayed healing, longer hospitalization, and 
the development of chronic pain, are significant not only from the patient’s perspective (decrease 
in functionality and quality of life) but also from the health economic perspective (increase in 
healthcare resource utilization and costs). 
Each year, more than 5 million children undergo surgery in the US, and it is estimated that up to 
75% of these patients experience significant postoperative pain and receive postoperative 
analgesia (Owen 1990).  Opioid use is ubiquitous among hospitalized patients undergoing 
surgical procedures (Kessler 2013).  One consequence is a growing epidemic of opioid use, 
misuse, and diversion (Morris 2015; Joranson 2006).  Specific to the pediatric population, 
prescription opioid use before the 12th grade is a predictor of future opioid misuse, with a 33% 
increase in future risk of misuse after high school (Miech 2015).  
A multimodal approach to postoperative analgesia, using a combination of agents (e.g., opioids, 
local anesthetics, non-steroidal anti-inflammatory drugs [NSAIDs]), and delivery techniques 
(patient-controlled analgesia [PCA], epidural and regional blocks) is currently recognized as 


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best practice for pain management (Breivik 1995a; Breivik 1995b; American Society of 
Anesthesiologists [ASA] Task Force 1995; Dahl 2000).  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.   
A New Drug Application (NDA) for EXPAREL was submitted as a 505(b)(2) application and 
subsequently approved by the US FDA on October 28, 2011 (NDA 022-496).  As part of the 
approval for EXPAREL, Pacira is required to conduct pediatric studies as a Post Marketing 
Requirement (PMR). 
7.1.
Indication
EXPAREL was initially approved by the US FDA in 2011 for single-dose administration into the 
surgical site to produce postsurgical analgesia.  The indication was amended and approved by the 
US FDA in 2018 to read: “EXPAREL is indicated for single-dose infiltration in adults to 
produce postsurgical local analgesia and as an interscalene brachial plexus block to produce 
postsurgical regional analgesia.  Safety and efficacy have not been established in other nerve 
blocks.”   
EXPAREL was developed to provide a prolonged period of decreased pain and decreased opioid 
use with a single-dose administration without the use of indwelling catheters.  
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 (ASA Task Force 1995). 
7.2.
Current Therapies/Treatments 
Current modalities of postsurgical analgesic treatment include infiltration and nerve block with 
local anesthetic agents, usually combined with the systemic administration of analgesics 
(multimodal therapy).  Multimodal therapy usually includes opioid medications, NSAIDs, and/or 
acetaminophen provided through a variety of routes including intravenous, transdermal patch, 
and oral administration.  Opioids are widely used and considered amongst the most powerful 
analgesics; however, they also 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 the US 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 


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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), and conserve healthcare 
resources.  As such, the JCAHO 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.  However, AEs related to opioid administration (e.g., nausea, vomiting, ileus, 
confusion) represent one important reason 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).  Furthermore, management of opioid-related events often requires medical 
attention (e.g., 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 less than 8 hours.  EXPAREL 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 has been noted in 
infiltration studies to have a bimodal curve (Apseloff 2013), with an initial peak occurring at 
approximately 0 to 2 hours and a second peak at approximately 24 to 48 hours (Hu 2013).  
7.4.
Summary of Human Clinical Experience with EXPAREL 
The EXPAREL clinical development program assessed the efficacy and safety across a wide 
range of body regions and applications, investigating its use in the management of acute pain 
when administered as a peripheral nerve block for regional analgesia, and as a field block for 
local analgesia.  Pacira has conducted 31 clinical studies (13 Phase 1, 7 Phase 2, and 11 Phase 3).  
Across the 31 completed studies in the clinical program, safety data were collected on 
3644 subjects (2141 subjects received EXPAREL, 850 subjects received IR bupivacaine alone, 
and 653 subjects received placebo). 
Across these studies, a total of 2141 adult human subjects received EXPAREL at doses ranging 
from 9 to 665 mg and by various routes, including field block, peripheral nerve block, 
subcutaneous, and epidural routes of administration.  EXPAREL was well tolerated and had a 


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favourable safety profile when administered as a field block or as an interscalene brachial plexus 
nerve block in varying degrees of vascularity in subjects undergoing various surgical procedures.  
The frequency and types of events are consistent with the profile of other local anaesthetics.  
At doses up to 665 mg of EXPAREL, no central nervous system or cardiovascular system AEs 
observed with high doses of bupivacaine HCl solution have been observed with 
EXPAREL.  Two thorough QTc studies have been conducted; EXPAREL did not cause 
significant QTc prolongation even at the highest dose evaluated.   
Across all studies, the types and the incidence rates of treatment-emergent AEs (TEAEs) were 
similar between the EXPAREL All Doses group (all doses combined) and the bupivacaine HCl 
group.  The incidence rate for each of the three most common TEAEs (nausea, constipation, and 
vomiting) was lower in the EXPAREL All Doses group than in the bupivacaine HCl group.   
In terms of efficacy, three positive Phase 3 studies (402-C-316, 402-C-317, 402-C-331) 
demonstrated statistically significant improvements in pain intensity scores compared to placebo 
or bupivacaine HCl in the postoperative period when administered as a field block (infiltration).  
All three studies also showed a statistically significant reduction compared to placebo or 
bupivacaine in total opioid consumption; Studies 316, 317 and 331 additionally show a 
significantly higher percentage of opioid-free patients and a significantly longer time to first 
opioid use compared to placebo or IR bupivacaine. 
EXPAREL was demonstrated to produce statistically significant and clinically meaningful 
analgesia in adult patients in two pivotal placebo-controlled Phase 3 studies (317 and 316) 
involving both orthopedic and soft tissue procedures over 36 and 72 hours, respectively.  The 
primary endpoints (area under the curve [AUC] of the numeric rating scale at rest [NRS-R] pain 
intensity scores till 72 hours [316] and till 24 hours [317]) were met.  Key secondary endpoints 
(percentage of subjects who received no supplementary opioid medication; total amount of 
postoperative consumption of opioid medication; and time to first use of opioid medication) were 
also met, demonstrating prolonged analgesia and reduction of opioid use by various measures.  
Robust nature of the efficacy results in both pivotal studies, 316 and 317, was demonstrated 
across subgroups of subjects with various prognostic features and across demographic 
subgroups.   
Study 331 was a Phase 3, multicenter, randomized, double-blind, active-controlled trial of 
EXPAREL in adult subjects undergoing primary unilateral TKA under spinal anesthesia to 
investigate pain control and total opioid consumption following a field block.  Study 331 
compared EXPAREL 266 mg admixed with bupivacaine HCl 100 mg to an active comparator of 
bupivacaine HCl 100 mg alone.  Seventy (70) subjects treated with EXPAREL+ bupivacaine and 
69 subjects treated with bupivacaine alone were analyzed.  The co-primary efficacy endpoints 
were the AUC of VAS from 12 to 48 hours and the total opioid consumption (in oral morphine 
equivalents) from 0 to 48 hours.  The cumulative pain intensity in the EXPAREL + bupivacaine 
group (Mean AUC12-48 = 180.8) was statistically significantly lower than the bupivacaine alone 
group (mean AUC12-48 = 209.3), so the first co-primary efficacy endpoint was met (P = 0.0381).  


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The LS geometric mean total opioid consumption from 0 to 48 hours after surgery was 
statistically significantly lower in the EXPAREL + bupivacaine group than the bupivacaine alone 
group, so the second co-primary efficacy endpoint was met (16.7 mg vs 84.0 mg; P = 0.0029).  
In addition, EXPAREL was associated with a higher proportion of subjects who were opioid free 
through 72 hours (10% vs 0%; P < 0.01) and also significantly prolonged the time to first opioid 
rescue (median 4.1 hours vs 2.9 hours; P = 0.023) compared to bupivacaine HCl. 
An analysis was performed to compare the incidence of opioid-related AEs between the 
EXPAREL and bupivacaine HCl groups in all bupivacaine-controlled, parallel-group infiltration 
studies in adults (SIMPLE TKA [total knee arthroplasty] 311, SKY0402-C-208, SIMPLE 
Hemorrhoidectomy 312, SKY0402-C-209, SKY0402-C-207, SKY0402-C-201, and SIMPLE 
Breast Augmentation 315).  There was a statistically significantly lower incidence of 
opioid-related AEs in the EXPAREL ≤266 mg group compared to the bupivacaine HCl group till 
72 hours post dose.  This was consistent with the statistically significantly lower total 
postoperative consumption of opioids in the EXPAREL ≤266 mg group till 72 hours post dose.  
Fewer subjects in the EXPAREL ≤266 mg group had at least one opioid-related AE compared to 
the bupivacaine HCl group (25.6% versus 45.6%; p<0.0001).  The total opioid medication 
administered (adjusted geometric mean) till 72 hours post dose was statistically significantly 
lower in the EXPAREL ≤266 mg group (7.94 mg) compared to the bupivacaine HCl group 
(15.84 mg); p<0.0001.  The EXPAREL >266 mg group did not show a statistically significant 
advantage favoring EXPAREL; the mean (standard deviation [SD]) of the average number of 
opioid-related AEs per subject was 0.58 (0.522), and the total opioid medication administered 
(adjusted geometric mean) till 72 hours post dose was 22.82 mg in the EXPAREL >266 mg 
group. 
Please see the EXPAREL Full Prescribing Information for safety information regarding the use 
of EXPAREL for the treatment of postsurgical pain in the setting of infiltration. 
Please refer to the Investigator’s Brochure for additional information regarding the completed 
studies.   
7.5.
Postmarketing Exposure in Adults and Children 
As of May-2018, more than 4 million patients have received EXPAREL in the postmarketing 
setting.  While EXPAREL is not approved for use in patients less than 18 years of age, there is 
evidence that it has been widely used off-label in pediatric cases. 
The Premier PerspectiveTM Database (PPD) is the largest inpatient drug utilization database in 
the US and contains de-identified hospital chargemaster data from approximately 600 hospitals, 
which accounts for approximately 15% of all hospitalizations nationwide (McDonald 2013).  
Recent inquiries into the PPD between 01-Jan-2011 and 31-Mar- 2017 found that it contains data 
for 2461 patients aged less than 18 years who had been exposed to EXPAREL in both inpatient 
and outpatient settings, including 1796 patients between 6 and <17 years of age.   


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In addition, The Cleveland Clinic (Cleveland, Ohio) currently uses EXPAREL off-label as part 
of its postsurgical multimodal analgesia for patients under the age of 18 years across several 
surgical procedures.  A retrospective chart analysis is being conducted to evaluate the safety 
profile and clinical benefit of EXPAREL in this setting. 
8.
OBJECTIVES 
8.1.
Primary Objective 
The primary objective is to evaluate the pharmacokinetics (PK) of EXPAREL in pediatric 
subjects aged 6 to less than 17 years undergoing surgery. 
8.2.
Secondary Objectives 
The secondary objective is to evaluate the safety of EXPAREL in pediatric subjects aged 6 to 
less than 17 years undergoing surgery. 
9.
OVERALL STUDY DESIGN AND PLAN 
9.1.
Overall Study Design and Plan 
This is a two-part study to evaluate the PK and safety of EXPAREL in pediatric subjects aged 
6 to less than 17 years.  Part 1 will evaluate PK and safety in subjects aged 6 to less than 
17  years, while Part 2 will assess safety in subjects aged 6 to less than 17 years.   
In Part 1, subject enrollment will be conducted in parallel to include the older age group (12 to 
<17 years old; Group 1) and the younger age group (6 to <12 years old; Group 2).  
Subject enrollment for Part 2 (of each group) will commence upon complete enrollment of Part 1 
(of that group).  In Part 2, subject enrollment will be conducted in parallel to include the older 
age group (12 to <17 years old; Group 1) and the younger age group (6 to <12 years old; 
Group 2).   
Dosing of EXPAREL will be based on body weight, with a starting dose of 4 mg/kg (maximum 
266 mg).  
 
Surgery Type, Dose, and Number of Subjects [n] 
 
Part 1 (PK and Safety) 
Part 2 (Safety) 
Group 1  
(subjects aged 12 to 
<17 years) 
Spine Surgery 
 
EXPAREL 4 mg/kg [15] 
bupivacaine HCl 2 mg/kg [15] 
Spine Surgery 
 
EXPAREL 4 mg/kg [15] 
bupivacaine HCl 2 mg/kg [15] 
Group 2  
(subjects aged 6 to 
<12 years) 
Spine or Cardiac Surgery 
 
EXPAREL 4 mg/kg [15] 
Spine or Cardiac Surgery 
 
EXPAREL 4 mg/kg [15] 
 
Part 1 (Pharmacokinetics- PK) - Subjects aged 6 to less than 17 years  


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Part 1 is a multicenter, randomized, open-label study in 45 subjects aged 6 to less than 17 years 
of age undergoing spine or cardiac surgeries.  There will be two treatment groups: Group 1 will 
include subjects aged 12 to less than 17 years of age, while Group 2 will include subjects aged 
6 to less than 12 years of age.  
Part 1, Group 1, is an active-controlled, open-labeled, PK evaluation study in subjects aged 
12 to less than 17 years undergoing spine surgery.  The active comparator will be bupivacaine 
HCl.  The sample size is a total of 30 subjects (15 subjects per treatment group).  Subjects will be 
randomized 1:1 to receive either a single dose of EXPAREL 4 mg/kg (maximum 266 mg) or 
bupivacaine HCl 2 mg/kg (not exceeding a maximum bupivacaine HCl dose of 175 mg total) 
intraoperatively at the end of surgery via local infiltration.  
Part 1, Group 2, is a single-arm (EXPAREL 4 mg/kg), open-labeled, PK evaluation study in 
subjects aged 6 to less than 12 years undergoing spine or cardiac surgery.  The sample size is a 
total of 15 subjects.  Subjects will receive a single dose of EXPAREL 4 mg/kg (maximum 
266 mg) intraoperatively at the end of surgery via local infiltration.  
The total sample size for Part 1 is 45 subjects aged 6 to less than 17 years, with 30 subjects in 
Group 1 and 15 subjects in Group 2. 
Part 2 (Safety) – Subjects aged 6 to less than 17 years
Part 2 is a multicenter, randomized, open-label, safety study in 45 subjects aged 6 to less than 
17 years undergoing spine or cardiac surgeries.  There will be two treatment groups: Group 1 
will include subjects aged 12 to less than 17 years, while Group 2 will include subjects aged 6 to 
less than 12 years.  
Part 2, Group 1, is an active-controlled, open-labeled, safety evaluation study in subjects aged 
12 to less than 17 years undergoing spine surgery.  The active comparator will be bupivacaine 
HCl.  The sample size is a total of 30 subjects (15 subjects per treatment group).  Subjects will be 
randomized 1:1 to receive either a single dose of EXPAREL 4 mg/kg (maximum 266 mg) or 
bupivacaine HCl 2 mg/kg (not exceeding a maximum bupivacaine HCl dose of 175 mg total) 
intraoperatively at the end of surgery via local infiltration.   
Part 2, Group 2, is a single-arm (EXPAREL 4 mg/kg), open-labeled study in subjects aged 6 to 
less than 12 years undergoing spine or cardiac surgery.  The sample size is a total of 15 subjects.  
Subjects will receive a single dose of EXPAREL 4 mg/kg (maximum 266 mg) intraoperatively at 
the end of surgery via local infiltration.  
The total sample size for Part 2 is 45 subjects aged 6 to less than 17 years, with 30 subjects in 
Group 1 and 15 subjects in Group 2.  
The overall safety assessments will include all 45 subjects from Part 1 and all 45 subjects from 
Part 2, with a total of 90 subjects. 
Subjects will be screened within 30 days prior to study drug administration.  During the 
screening visit, subjects will be assessed for past or present neurologic, cardiac, and general 


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medical conditions that, in the opinion of the investigator, would preclude them from study 
participation.  After the ICF is signed by the subject’s legal guardian and written assent is 
provided by the subject (if capable), medical history, surgical history, physical examination, 
12-lead electrocardiogram (ECG), vital sign measurements, neurological assessment, clinical 
laboratory tests (hematology, chemistry, and urinalysis), pain intensity score, urine pregnancy 
test for females of childbearing potential, urine drug screen and alcohol breath test will be 
conducted. 
On Day 1, eligible subjects will receive the study drug intraoperatively at the end of surgery via 
local infiltration to produce local analgesia.  Use of intraoperative opioids, acetaminophen, 
ketorolac, or other NSAIDs, will be permitted in accordance with the study site’s standard of 
care.  
Avoid additional use of local anesthetics within 96 hours following the administration 
EXPAREL. 
There is no required length of stay in the hospital; subjects may be discharged based on the 
medical judgment of the treating physician.  For subjects discharged from the hospital before all 
protocol-specified assessments till 96 hours are completed, a nurse will perform follow-up visits 
at the subject’s home to perform the required postsurgical assessments and collect PK samples 
till 96 hours. 
A follow-up phone call will be scheduled for all subjects on Day 7.  For the assessment of AEs, a 
final follow-up visit will be made on Day 30 to all subjects who would have received the study 
drug.  
Postsurgical Pain Management 
Use of postsurgical pain medication in cases of insufficient analgesia will be permitted according 
to the institution’s standard of care.  The investigator must record all postsurgical pain 
management medications provided to the subjects till the hospital discharge.  
Avoid additional use of local anesthetics within 96 hours following the administration 
EXPAREL.  
Postsurgical Assessments 
Postsurgical assessments to be conducted till 96 hours include pain intensity using the 11-point 
NRS-R (Appendix 1) for subjects aged 12 to less than years and the Color Analog Scale (CAS; 
Appendix 2) for subjects aged 6 to less than 12 years; neurological assessment (Appendix 3); 
clinical laboratory tests (Appendix 4); and vital signs.   
AEs will be recorded from the time the ICF is signed/assent is given till Day 30.   
In case a cardiac or neurological AE of special interest (AESI) or serious AE (SAE) occurs 
during the study, if the investigator or medical monitor considers that the event may be related to 
study treatment or suggests the possible occurrence of local anesthetic systemic toxicity (LAST; 


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with or without the need for treatment [e.g., intralipids]), or if a plausible etiology for the event 
cannot be found, an unscheduled PK blood sample must be collected and a 12-lead ECG, vital 
signs, and clinical laboratory tests (hematology and complete metabolic profile [CMP]) 
according to the study site’s standard of care may be conducted.  See Section 13.1.7 and 
Appendix 6 for additional information on handling of AESIs.  Cardiac or neurological AEs that 
do not meet one of these three criteria for AESI should be reported as described in Section 14.1 
and captured in the database as an AE. 
Cardiac AESIs include chest pain, abnormal/irregular heart rate, and shortness of breath 
requiring intervention.  Neurologic AESIs include seizure, altered mental status/altered 
sensorium, rigidity, dysarthria, tremors, tinnitus, visual disturbance, and severe or worsening 
dizziness (see below).  Additionally, the following events may be of special interest if they 
persist or occur beyond 72 hours post dose: dizziness, hyperesthesia, muscular twitching, and 
tingling/paresthesia.  
Dizziness will be assessed as mild, moderate, or severe based on the National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0.  Mild dizziness 
is defined as mild unsteadiness or sensation of movement; moderate dizziness is defined as 
moderate unsteadiness or sensation of movement limiting instrumental activities of daily living 
(ADL); and severe dizziness is defined as severe unsteadiness or sensation of movement that 
limits self-care ADLs.  Dizziness will be captured as an AESI if it is severe or worsens or persist 
beyond 72 hours post dose.  
Pharmacokinetic Assessment (Part 1 only) 
A population PK sampling scheme will be used to limit the number of blood draws for each 
individual subject.  On Day 1, eligible subjects will be assigned to one of the two PK sampling 
groups shown below based on surgery type (Table 2).  A total of 8 blood samples will be 
collected from each subject at the specific time windows shown for the determination of 
bupivacaine plasma concentrations.  Having two PK sampling sequences for spine and cardiac 
surgeries will help to guard against clustering of PK samples.  
Table 2: PK Sample Collection 
Surgery 
Type 
PK Sample Timing (Based on the End of Study Drug Administration) 
Sample 1 
Sample 2 
Sample 3 
Sample 4 
Sample 5 
Sample 6 
Sample 7 
Sample 8 
Spine 
15±5 min 
30±5 min 
45±5 min 
1-1.25 h 
2-3 h 
10-18 h 
24-36 h 
42-60 h 
Cardiac 
15±5 min 
30±5 min 
45±5 min 
1-1.25 h 
15-25 h 
30-40 h 
45-55 h 
64-72 h 
h: hour; min: minutes; PK: pharmacokinetic. 
 
These sampling time points will not only characterize overall PK of bupivacaine from 
EXPAREL, but will also characterize the PK of immediate release bupivacaine and thoroughly 
characterize the early peak for both treatments.  


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Note that a new needle stick may not be necessary for each blood draw.  The subject may be 
fitted with a peripheral venous line at the discretion of the investigator to facilitate the collection 
of blood for PK assessment. 
In the situation where PK blood draws and other assessments coincide or occur at about the same 
time, the blood draw for PK analysis must be conducted first, and the pain intensity assessment 
conducted second, as applicable, followed by other assessments. 
9.2.
Duration of the Study and Subject Participation 
Participation will begin at the signing of the ICF/obtaining written assent.  No more than 30 days 
should pass between signing of the ICF/obtaining written assent and the administration of study 
drug.  The time from study drug administration till the end of participation is 30 ± 3 days.  
Therefore, subjects may participate in the study for up to 63 days. 
9.3.
Data Safety Monitoring Board 
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).  
A Data Safety Monitoring Board (DSMB) will be set up to monitor the safety and dosing data on 
an ongoing basis for all treatment groups, with additional expedited DSMB review conducted as 
necessary.   
9.4.
Discussion of Study Design 
This study is designed to formulate specific guidance regarding dose for the safe administration 
of EXPAREL in the pediatric population aged 6 to less than 17 years.  EXPAREL doses 
recommended for adults are expressed as absolute values or ranges, whereas doses for pediatric 
subjects will be based on body weight, consistent with general prescription standards used in 
pediatric practice.  
A population PK modeling of the infiltration studies in adults and simulations to support 
child/adolescent dosing was performed.  Predicted values generated by the final model 
adequately described observed bupivacaine concentrations following administration of 
EXPAREL.  According to this model, a dose of 4 mg/kg would produce bupivacaine 
concentrations in pediatric patients aged 6 to less than 17 years analogous to those observed in 
the adult infiltration studies.  
In addition, the available data from The Cleveland Clinic (as discussed in Section 7.5) shows that 
the average dose among 375 pediatric patients was 4.1 ± 1.8 mg/kg, with no significant AEs 
attributed to EXPAREL use.  This study is designed to further characterize the PK profile and to 
confirm the safety of the 4 mg/kg dose of EXPAREL. 
A population PK sampling scheme will be used to limit the number of blood draws.  A total of 
8 blood samples will be collected from each subject at the specific post-dose time windows 
shown in Table 2 for the determination of bupivacaine plasma concentrations.   


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10.
STUDY POPULATION 
Subjects must meet all eligibility criteria to be enrolled in this study.  
10.1. Inclusion Criteria 
Subjects eligible for study entry must meet all of the following criteria: 
1. Subjects whose parent(s) or guardian(s) has/have signed and dated the ICF for the subject 
to participate in the study, and subjects who have provided written assent to participate in 
the study (if capable). 
2. American Society of Anesthesiologists (ASA) Class 1-3. 
3. Male or female subjects 6 to less than 17 years of age on the day of surgery. 
4. Body mass index (BMI) at screening within the 5th to 95th percentile for age and sex (see 
Appendix 5). 
5. A negative pregnancy test for female subjects of childbearing potential must be available 
prior to the start of surgery.  The pregnancy test must be conducted in the preoperative 
holding area according to the study site’s standard of care.   
6. Subjects and their parent(s)/guardian(s) must be able to speak, read, and understand the 
language of the ICF and any instruments used for collecting subject-reported outcomes to 
enable accurate and appropriate responses to study assessments, and provide informed 
consent/assent.  
7. Subjects must be able to 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 any of the following criteria is met:  
1. Currently pregnant, breastfeeding, or planning to become pregnant during the study or 
within 1 month after study drug administration. 
2. History of hypersensitivity or idiosyncratic reactions to amide-type local anesthetics or to 
opioid medication.  
3. Contraindication to bupivacaine HCl or other amide-type local anesthetics or to opioid 
medication. 
4. Administration of EXPAREL or bupivacaine HCl within 30 days prior to study drug 
administration. 
5. Subjects with coagulopathies or immunodeficiency disorders. 
6. History of, suspected, or known addiction to or abuse of drugs or alcohol within the past 
2 years.  


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7. Clinically significant medical or psychiatric disease that, in the opinion of the 
investigator, indicates an increased vulnerability to study drugs and/or procedures. 
8. 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. 
In addition, the subject will be ineligible to receive study drug if he or she meets the following 
criterion during surgery:  
9. Any clinically significant event or condition uncovered during the surgery 
(e.g., excessive bleeding, acute sepsis) that might render the subject medically unstable or 
complicate the subject’s postoperative course.  
10.3. Removal of Subjects from Therapy or Assessment 
Every reasonable effort should be made to maintain subject compliance and participation in the 
study.  Subjects who withdraw from the study after receiving study drug should undergo safety 
assessments till the end of the study (Day 30).   
If a subject who withdraws from the study has an ongoing AE, every effort must be made to 
follow 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 him or her incapable of continuing with the 
remaining study assessments, then he or she will be discontinued from further participation in the 
study.  A final evaluation visit should be performed so that the subject’s study participation can 
be terminated in a safe and orderly manner.  Otherwise, the subject’s parent or guardian will be 
instructed to notify the study personnel of any abnormalities during the intervals between study 
visits and to come to the study site if medical evaluation is needed and the urgency of the 
situation permits.  Any subject exhibiting undesirable AEs will receive appropriate treatment at 
the discretion of the investigator.   
This study involves a single administration of the 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 will be obtained by the 
investigator. 
10.3.2. Voluntary or Study Investigator Withdrawal 
Subjects (or their parent or guardian) are free to discontinue participation in the study at any 
time, without prejudice to future treatment.  Nevertheless, subjects will be encouraged to 
complete at least the study safety assessments.  In addition, a subject may be discontinued from 


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the study if he or she refuses to comply with study procedures.  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 he or she 
can be withdrawn in a safe and orderly manner.  In the final evaluation, vital signs (temperature, 
resting heart rate, respiratory rate, oxygen saturation, and blood pressure) and any changes in the 
subject's health status will be recorded.   
After termination from the study, the subject may be followed for safety including monitoring of 
AEs till Day 30.   
11.
TREATMENTS 
11.1. Treatments to be Administered 
Study Drug 
Dosing of EXPAREL for this study will be based on body weight, with a starting dose of 
4 mg/kg.  This weight-based dosing applies to Part 1 and Part 2 of the study. 
The study drug will be administered prior to wound closure.  The investigator must document the 
size of the incision.  Each infiltration site should be spaced 1.0 to 1.5 cm apart and approximately 
1 to 1.5 mL should be delivered into both deep and superficial areas.  Following infiltration, the 
tissue should visibly expand with minimal leakage.   
All eligible subjects will receive a single dose of EXPAREL intraoperatively at the end of 
surgery via local infiltration into the surgical site.  EXPAREL can be administered as is or may 
be expanded with normal (0.9%) saline to increase the volume up to a final concentration of 
0.89 mg/mL (i.e., 1:14 dilution by volume).  The total volume of expansion will be dependent on 
the incision length.  Details regarding the expansion of EXPAREL are provided in the Study 
Drug Infiltration Guide. 
Total Volume of Expansion  
The investigator must document the total volume used for each surgery. 
x
EXPAREL 4 mg/kg + normal saline (20–60 mL based on the incision size) = total 
volume. 
For example: If the infiltration sites are 1.5 cm apart, then a 10 cm incision would be 
10 × 2 sides × 3 layers = 60 cm.  If there is 1 mL infiltrated every 1.5 cm, the total 
volume would be 40 mL. 
In Part 1, all eligible subjects will receive a single dose of EXPAREL intraoperatively at the end 
of surgery via local infiltration.  EXPAREL can be administered as is or expanded to increase 
volume up to a final concentration of 0.89 mg/mL (i.e., 1:14 dilution by volume) with normal 


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saline (0.9% sodium chloride solution).  The total volume of expansion will be dependent on the 
size of the wound.   
In Part 2, all eligible subjects randomized to EXPAREL will receive a single dose of EXPAREL 
intraoperatively at the end of surgery via local infiltration.  Dosing will be informed by the 
results of Part 1 and any recommendations based on the complete safety review. 
Subjects randomized to the active control group will receive bupivacaine HCl 2 mg/kg, with a 
maximum dose of 175 mg. 
Postsurgical Pain Management 
The use of postsurgical pain medication in cases of insufficient analgesia is permitted according 
to the institution’s standard of care.  The investigator must record all pain management 
medications administered during hospitalization.  Avoid additional use of local anesthetics 
within 96 hours following administration of EXPAREL    
11.2. Administration Instructions/Procedures 
All injections must be performed with an infiltrative moving needle technique, with frequent 
aspirations to reduce the chance for accidental intravascular injection.  If an aspiration draws 
blood, the needle must be moved and placed in a different location until the aspiration is 
negative.  The study drug should be infiltrated in small increments into both deep and superficial 
layers to ensure uniform distribution along the entire length of the surgical wound. 
11.2.1. Study Drug Administration Considerations 
As there is a potential risk of severe adverse effects associated with the administration of local 
anesthetics, the study site must be equipped to treat subjects with evidence of cardiac toxicity.   
EXPAREL may not be administered to a subject if the vial has been open for more than 4 hours.  
In order to prevent the study drug from settling, gently inverting and re-inverting the syringe 
several times prior to administration is recommended.  No agents should be admixed with 
EXPAREL.  
11.3. Identity of Investigational Products 
11.3.1. Description of EXPAREL 
EXPAREL is formulated as a sterile, non-pyrogenic, white to off-white, preservative-free, 
homogeneous suspension of bupivacaine encapsulated into multivesicular lipid-based particles 
(the DepoFoam drug delivery system).   
Bupivacaine is present at a nominal concentration of 13.3 mg/mL.  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 and 8°C (36°F to 46°F). 


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11.3.2. Description of Reference Product 
The reference product will be bupivacaine HCl.  All information on the drug administered, dose, 
frequency, and duration will be captured in the electronic case report form (eCRF). 
11.3.3. Description of Diluents 
Normal saline (0.9% sodium chloride solution) for injection will be used for the expansion of 
study drug.   
11.4. Method of Assigning Subjects to Treatment 
11.4.1. Randomization Scheme 
Approximately 90 subjects are planned for this study: 45 in Part 1 and 45 in Part 2.  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.  
11.4.2. Randomization Procedures for Treatment Assignment 
Once a subject is identified as being qualified to participate in the study (see Section 10), and is 
at the study site for surgery, the authorized site staff or designee will obtain a randomization 
assignment.  The subject will be considered randomized into the study once the study treatment 
assignment is received. 
11.4.3. Replacement of Subjects 
Subjects who are withdrawn from the study before receiving study drug 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. 
11.5. Selection of Doses in the Study 
The dose of EXPAREL (4 mg/kg) was selected to provide similar exposure in pediatric subjects 
as was seen in adults.  A Population PK model was developed using all data obtained from the 
infiltration studies in adult subjects (SKY0402-C-201, SKY0402-C-208, SKY0402-C-316, 
SKY0402-C-317, and SKY0402-C-401).  Simulations from this model were performed to 
predict bupivacaine plasma concentrations in pediatric subjects aged 6 to less than 17 years.  The 
dose of EXPAREL administered will not exceed 266 mg, regardless of the weight of the subject. 
The selection of the 4 mg/kg dose is also supported by real world evidence collected at the 
Cleveland Clinic, where 375 pediatric patients have received EXPAREL at a mean dose of 
4.1 ± 1.8 mg/kg, with no significant AEs attributed to EXPAREL use. 
11.6. Prior and Concomitant Therapy and Medications
All medications taken within 30 days prior to study drug administration till Day 30 after study 
drug administration or until the subject is withdrawn from the study, whichever is sooner, will be 


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recorded on the eCRF.  Additionally, any medications administered in association with an AE 
will be recorded till Day 30.   
11.6.1. Before Study Drug Administration 
Permitted Prior Medications and Therapy 
x
Prophylactic antibiotics are permitted according to the surgeon’s preference. 
Restricted Prior Medications and Therapy 
x
Use 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 is not permitted. 
11.6.2. During Surgery 
Permitted 
x
Use of intraoperative opioids, acetaminophen, ketorolac, or other NSAIDs.  
Restricted 
x
No drugs should be admixed with the study drug (e.g., epinephrine, dexamethasone, 
clonidine). 
x
Avoid additional use of local anesthetics within 96 hours following administration of 
EXPAREL.  
11.6.3. After Surgery 
Permitted 
x
Postsurgical pain management will consist of institution’s standard of care in case of 
insufficient analgesia. 
x
Parenteral antiemetic medication may be administered, as needed.
Restricted 
x
Avoid additional use of local anesthetics within 96 hours following administration of 
EXPAREL.
All postsurgical analgesics administered must be documented till 96 hours after surgery. 
11.7. Treatment Compliance 
Study drug will be administered intraoperatively by the study staff and, thus, compliance is 
ensured. 


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11.8. Accountability of Study Drug 
Any shipment of EXPAREL for the study will contain an investigational drug transmittal and 
receipt form to assist the investigator or designee (e.g., pharmacist) in maintaining current and 
accurate inventory records.  At a minimum, the pharmacist 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 an unblinded 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 unblinded study monitor and 
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. Pharmacokinetic Analysis 
A total of 8 blood samples will be collected per subject at specific time windows (Table 2) for 
the determination of plasma concentrations.  Population PK modeling will be performed using all 
PK data collected during the study.  The population PK model will estimate EXPAREL 
individual and population PK parameters and exposure, inter-individual variability of PK 
parameters, and intra-individual variability of bupivacaine concentrations. 
12.2. Pharmacokinetic Endpoints 
A population PK analysis will be performed.  The following model-predicted PK endpoints will 
be determined:  
x
Area under the plasma concentration-versus-time curve (AUC) 
x
Maximum plasma concentration (Cmax) 
x
The apparent terminal elimination half-life (t1/2el)
x
Apparent clearance (CL/F) 
x
Apparent volume of distribution (Vd/F) 
12.3. Safety Assessments 
The following safety measurements will be conducted at the time points specified: 
x
Vital signs (temperature, resting heart rate, respiratory rate, oxygen saturation, and blood 
pressure) at screening; upon arrival in the post-anesthesia care unit (PACU); at 2, 4, 8, 12, 
24, 36, 48, 60, 72, and 96 hours after the end of study drug administration; at hospital 
discharge; and on Day 30. 


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x
Neurological assessment at screening; at 2, 4, 8, 12, 24, 36, 48, 60, 72, and 96 hours after 
the end of study drug administration; at hospital discharge; and on Day 30 (Part 1 only, 
Appendix 3). 
x
Clinical laboratory tests (hematology, chemistry, and urinalysis) at screening; at baseline 
(on Day 1 prior to surgery) and at 96 hours after the end of study drug administration (see 
Appendix 4). 
x
AEs from the time the ICF is signed/assent is obtained till Day 30. 
12.4. Safety Endpoints 
The following safety endpoints will be assessed based on the safety measurements conducted at 
the specified time points: 
x
Change from baseline in vital signs (temperature, resting heart rate, respiratory rate, 
oxygen saturation, and blood pressure). 
x
Summary of neurological assessments (proportion of subjects who are oriented, and 
proportion of subjects who have any neurologic events).  Note: Events identified during 
the neurologic assessment should be recorded as AEs. 
x
Change from baseline in clinical laboratory data. 
x
Incidence of TEAEs and SAEs till Day 30. 
12.5. Other Measurements 
The following efficacy measurements will be done for exploratory purposes only:   
x
Pain intensity scores at screening; at 4, 8, 12, 24, 36, 48, 60, 72, and 96 hours after the end of 
study drug administration; immediately prior to each administration of postoperative opioid 
pain management medication till 96 hours; and at hospital discharge.  If a subject is too 
anesthetized at the time of a scheduled pain intensity assessment, the assessment should be 
skipped.  Pain intensity scores will be collected using the following instruments:  
o
11-point NRS-R for subjects aged 12 to less than 17 years (Appendix 1) 
o
CAS for subjects aged 6 to less than 12 years (Appendix 2) 
x
Postoperative opioid pain management medication use (time, dose) till hospital discharge. 
12.6. Other Endpoints 
Analysis of these other endpoints will be conducted for exploratory purposes only.  The efficacy 
endpoints listed below will be assessed based on the efficacy measurements conducted at the 
time points specified. 
x
Pain intensity scores  
x
The AUC of pain intensity scores 


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x
Total opioid consumption in morphine equivalents  
x
Time to first postsurgical use of opioid medication.   
12.7. Appropriateness of Measures 
The 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 study procedures is provided in Table 1.  PK Sampling times are 
provided in Table 2.   
13.1. Instructions for Conducting Procedures and Measures 
All post-dose assessments will be timed from the end of study drug administration. 
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 the last 
suture/staple.  Postsurgical is defined as after the end of surgery.  
13.1.1. Pain Intensity Assessment 
Pain intensity will be assessed using age-specific tools at screening; at 4, 8, 12, 24, 36, 48, 60, 
72, and 96 hours after the end of study drug administration; immediately prior to each 
administration of postoperative opioid pain management medication till 96 hours; and at hospital 
discharge.  Pain intensity scores will be collected using the following instruments: 
x
11-point NRS-R for subjects aged 12 to less than 17 years (Appendix 1) 
x
CAS for subjects aged 6 to less than 12 years (Appendix 2) 
13.1.2. Neurological Examination 
A neurological assessment will be conducted during Part 1 only at the following time points: at 
screening; at 2, 4, 8, 12, 24, 36, 48, 60, 72, and 96 hours after the end of study drug 
administration; at hospital discharge; and on Day 30.  The examination will include the subject's 
orientation.  Additionally, subjects aged 6 years or older will be asked whether he or she is 
experiencing any numbness of the lips, the tongue, or around the mouth; hearing problems; or 
muscle twitching (see Appendix 3).  If the subject answers "yes" to any of these questions, the 
event should be recorded as an AE and additional safety procedures should be conducted as 
appropriate (see Section 13.1.7).    
13.1.3. Clinical Laboratory Tests 
The scheduled clinical laboratory tests (hematology, chemistry, and urinalysis) will be conducted 
at screening; baseline (on Day 1 prior to surgery); and at 96 hours after the end of study drug 
administration (see Appendix 4).  Clinical laboratory tests, as appropriate, may also be conducted 
if a subject experiences an AESI, or an SAE (see Section 13.1.7).  


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13.1.4. Vital Signs 
The scheduled vital signs (temperature, resting heart rate, respiratory rate, oxygen saturation, 
and blood pressure) will be measured after the subject has rested in a supine position for at least 
5 minutes at screening; upon arrival at the PACU; at 2, 4, 8, 12, 24, 36, 48, 60, 72, and 96 hours 
after the end of study drug administration; at hospital discharge; and on Day 30.  Vital signs may 
also be measured if a subject experiences an AESI or an SAE (see Section 13.1.7).  The subject 
will remain in a supine position during the assessment. 
13.1.5. Physical Examination 
A full physical examination will be conducted at screening.  Superficial abnormalities that may 
interfere with participation in the study will be noted.  A follow-up physical examination will be 
conducted on Day 30 and will include examination of the surgical site.   
13.1.6. Electrocardiograms 
A 12-lead ECG will be conducted at screening or on Day 1 before surgery.  A 12-lead ECG 
according to the study site’s standard of care may also be conducted if a subject experiences an 
AESI or an SAE (see Section 13.1.7).   
13.1.7. Adverse Events of Special Interest 
All AEs will be recorded from the time the ICF is signed/assent is given till Day 30.  In case a 
cardiac or neurological AE of special interest (AESI) or serious AE (SAE) occurs during the 
study, if the investigator or medical monitor considers that the event may be related to study 
treatment or suggests the possible occurrence of local anesthetic systemic toxicity (LAST; with 
or without the need for treatment [e.g., intralipids]), or if a plausible etiology for the event cannot 
be found, an unscheduled PK blood sample must be collected and a 12-lead ECG, vital signs, 
and clinical laboratory tests (hematology and complete metabolic profile [CMP]) according to 
the study site’s standard of care may be conducted.  See Appendix 6 for additional information 
on handling of AESIs.  
Cardiac AESIs include chest pain, abnormal/irregular heart rate, and shortness of breath 
requiring intervention.  Neurologic AESIs include seizure, altered mental status/altered 
sensorium, rigidity, dysarthria, tremors, tinnitus, visual disturbance, and severe or worsening 
dizziness (see below).  Additionally, the following events may be of special interest if they 
persist or occur beyond 72 hours post dose: dizziness, hyperesthesia, muscular twitching, and 
tingling/paresthesia.  
Dizziness will be assessed as mild, moderate, or severe based on the NCI CTCAE Version 5.0.  
Mild dizziness is defined as mild unsteadiness or sensation of movement; moderate dizziness is 
defined as moderate unsteadiness or sensation of movement limiting instrumental ADL; and 
severe dizziness is defined as severe unsteadiness or sensation of movement that limits self-care 
ADLs.  Dizziness will be captured as an AESI if it is severe or worsens or persist beyond 
72 hours post dose. 


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Cardiac or neurological AEs that do not meet one of these three criteria for AESI should be 
reported as described in Section 14.1 and captured in the database as an AE.  
13.2. Screening Procedures 
x
Explain study purpose and procedures. 
x
Obtain written informed consent/assent before performing any study-related procedures. 
x
Assess eligibility. 
x
Record relevant medical/surgical history, demographics, and baseline characteristics. 
x
Conduct urine pregnancy test for females of childbearing potential (Part 1 only). 
x
Perform physical examination. 
x
Perform neurological assessment (see Appendix 3; Part 1 only).  
x
Conduct clinical laboratory tests (hematology, chemistry, and urinalysis) (see Appendix 4). 
x
Conduct a urine drug screen and alcohol breath test at the investigator’s discretion.  Subjects 
with a positive result will be excluded from the study. 
x
Measure vital signs (temperature, resting heart rate, respiratory rate, oxygen saturation, and 
blood pressure) after subject has rested in a supine position. 
x
Conduct 12-lead ECG after subject has rested in a supine position. 
x
Record a pain intensity score using one of the following instruments: 
o
11-point NRS-R for subjects aged 12 to less than 17 years (Appendix 1) 
o
CAS for subjects aged 6 to less than 12 years (Appendix 2) 
x
Record concomitant medications. 
x
Record AEs starting at the signing of the ICF/assent. 
All subjects who are screened for enrollment, but do not meet eligibility criteria, who decline to 
participate, or whose parent or guardian decline the subject’s participation, will be documented 
on a screening log with the reason for non-participation. 
13.3. Baseline Procedures (Day 1 Prior to Surgery) 
x
Confirm eligibility. 
x
Update relevant medical and surgical history. 
x
Conduct urine pregnancy test for females of childbearing potential.  A negative pregnancy 
test result must be available before surgery. 
x
Measure vital signs (temperature, resting heart rate, respiratory rate, oxygen saturation, and 
blood pressure) after subject has rested in a supine position. 


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x
Conduct 12-lead ECG after subject has rested in a supine position. 
x
Conduct clinical laboratory tests (hematology, chemistry, and urinalysis; Appendix 4). 
x
Conduct a urine drug screen and alcohol breath test at the investigator’s discretion (Part 1 
only).  Subjects with a positive result will be excluded from the study. 
x
Record changes to concomitant medications since screening. 
x
Record AEs and any treatment(s) for the events. 
13.4. Intraoperative Procedures 
x
Confirm eligibility based on exclusion criterion 9 (i.e., verify that no significant 
intraoperative events have occurred). 
x
Prepare study drug.  
x
Administer study drug at the end of surgery.  
x
Record start and stop times of study drug administration. 
x
Record dosage of study drug administered and expansion volume if applicable. 
x
Record use of intraoperative opioids. 
x
Record surgery start and stop times.  
x
Record size of incision. 
x
Record concomitant medications. 
x
Record AEs and any treatment(s) for the events. 
Refer to Section 13.1.7 for additional procedures in the event a cardiac or neurological AE of 
special interest or SAE occurs. 
13.5. Postoperative Assessments till 96 Hours 
x
Record age-specific pain intensity score at 4, 8, 12, 24, 36, 48, 60, 72, and 96 hours after the 
end of study drug administration; and immediately prior to each administration of 
postoperative opioid pain management medication.  Pain assessments should be obtained 
before blood draws at the overlapping time points.  If a subject is too anesthetized at the time 
of a scheduled pain intensity assessment, the assessment should be skipped.  Pain intensity 
scores will be collected using the following instruments: 
o
11-point NRS-R for subjects aged 12 to less than 17 years (Appendix 1) 
o
CAS for subjects aged 6 to less than 12 years (Appendix 2) 
x
Perform neurological assessment at 2, 4, 8, 12, 24, 36, 48, 60, 72, and 96 hours after the end 
of study drug administration (see Appendix 3).  


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x
Measure vital signs (temperature, resting heart rate, respiratory rate, oxygen saturation, and 
blood pressure) at 2, 4, 8, 12, 24, 36, 48, 60, 72, and 96 hours after the end of study drug 
administration. 
x
Collect blood sample for PK analysis at the procedure-specific time windows shown in 
Table 2; record the date and time each sample is collected. 
x
Collect blood sample for clinical laboratory testing (hematology, chemistry, and urinalysis) 
at 96 hours after the end of study drug administration (see Appendix 4). 
x
Record supplemental pain medications and concomitant medications used by the subject. 
x
Administer postoperative opioid pain management medication upon request, as needed.  
Record pain score prior to administration of such medication. 
x
Record date, time, and amount of all opioid pain management medication administered. 
x
Record other concomitant medications. 
x
Record AEs and any treatment(s) for the events. 
Refer to Section 13.1.7 for additional procedures in the event a cardiac or neurological AE of 
special interest or SAE occurs. 
Note: Subjects will be discharged from the hospital as indicated by their physician, and a nurse 
will perform follow-up visits at the subject’s home to perform postsurgical assessments and 
collect PK samples till 96 hours. 
13.6. Hospital Discharge 
x
Record age-specific pain intensity score  
x
Perform neurological assessment (see Appendix 3; Part 1 only). 
x
Measure vital signs (temperature, resting heart rate, respiratory rate, oxygen saturation, and 
blood pressure)  
x
Record AEs and any treatment(s) for the events 
x
Record concomitant and discharge medications 
x
Record date and time of discharge 
13.7. Day 7 Phone Call 
x
Document any unscheduled phone calls, unscheduled office visits, or ER visits related to 
pain. 
x
Record AEs and any treatment(s) for the events.  
x
Record concomitant medications. 


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13.8. Day 30 Visit 
x
Perform follow-up physical examination. 
x
Perform neurological assessment (see Appendix 3; Part 1 only). 
x
Measure vital signs (temperature, resting heart rate, respiratory rate, oxygen saturation, and 
blood pressure) after subject has rested in a supine position.  
x
Document any unscheduled phone calls, unscheduled office visits, or ER visits related to 
pain after discharge. 
x
Record AEs and any treatment(s) for the events.  
x
Record concomitant medications. 
14.
ADVERSE EVENT REPORTING 
Consistent with the current regulatory guidance provided by the US FDA CFR Part 312 and the 
ICH GCP, AE and SAE are defined in Section 14.1.1 and Section 14.2.1, respectively.   
The concepts of AEs and SAEs 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 used primarily to identify, during the conduct of the study, those SAEs that may 
require expedited reporting to regulatory authorities. 
See Section 13.1.7 for a description of AESIs. 
14.1. Adverse Events
14.1.1. Definitions
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 (e.g., 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 (e.g., 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.  AEs 
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 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 
(e.g., migraine) is considered an AE.   


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An AE that occurs after the ICF is signed and before the start of the study drug administration is 
identified as a pre-treatment AE (PTAE).  An AE that occurs after the administration of the study 
treatment is considered a TEAE.   
Adverse Reaction: Any AE caused by a drug.  Adverse reactions are a subset of all suspected 
adverse reactions for which there is a reason to conclude that the drug caused the event. 
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 (i.e., PTAEs and TEAEs), with an 
onset after the subject signs the ICF.  For the purpose of this study, all AEs that occur till Day 30 
must be recorded regardless of whether or not they are considered related to the 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 case report form (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; i.e., lined 
through and initialed).  Whenever possible, abnormal laboratory results should be reported as 
their clinical corollary (e.g., low potassium should be recorded as hypokalemia). 
A continuous AE with varying grades of severity should be recorded as one AE.  The highest 
grade of severity experienced by that subject during the course of the continuous AE should 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 (i.e., 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 (e.g., 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 subject due to an AE, and the 
outcome of the AE, including the date and time of resolution, if applicable.   


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14.1.3. Severity of Adverse Events 
In general, the severity of an AE should 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. 
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 will assess the relationship of the AE to study drug after careful medical 
consideration on a case-by-case basis.  General guidelines for determining the causality of an AE 
to the study drug are provided below: 
Unrelated: 
A causal relationship between the study drug and the AE can be easily ruled out 
(e.g., 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). 
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: 
The initial event resolved, but has a continuing abnormal condition 
as a result of the AE. 
Not Recovered/ 
Not Resolved: 
At the time of the 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 the 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 (e.g., 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 (e.g., treatment, diagnostic 
tests, laboratory tests, or therapy) for each reported AE. 
x
None. 
x
Medication. 
x
Non-pharmaceutical therapy.  (The specific therapy used must be recorded in the CRF.) 
x
Discontinued from study. 
x
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 
Serious Adverse Event (SAE): An AE or suspected adverse reaction is considered “serious” if, in 
the view of either the investigator or Sponsor, it results in any of the following outcomes: 
x
Death1 
x
A life-threatening adverse event2 
x
Inpatient hospitalization or prolongation of existing hospitalization3 
x
A persistent or significant incapacity4 
x
Congenital anomaly/birth defect 
x
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 (i.e., 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 30, 
whether or not related to EXPAREL, must be reported by the investigator or designee to Pacira 
Drug Safety within 24 hours of discovery by either email (drugsafety@pacira.com) or fax 
(973-201-0649).  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 subject-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 30, 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 Hypothesis 
No formal hypothesis testing will be conducted. 
15.2. Study Endpoints  
The endpoints to be assessed in this study are listed in Section 12.2 (Pharmacokinetic 
Endpoints), Section 12.4 (Safety Endpoints), and Section 12.6 (Other Endpoints). 
15.3. Determination of Sample Size  
The sample size was based on the number of subjects necessary to characterize the PK profile of 
EXPAREL in pediatric subjects with the precision required by the FDA. 
15.4. Analysis Populations 
The following study populations are planned:  
x
The PK population will consist of all subjects who receive study drug and provide at least 
one quantifiable plasma concentration.  
x
The safety population will consist of all subjects who underwent the planned surgery and 
received study treatment.   
15.5. Handling Subject Dropouts and Discontinuations 
Subjects who discontinue after dosing will not be replaced. 
15.6. Statistical Analyses 
Continuously valued data will be summarized using descriptive statistics (n [number of subjects 
contributing data], mean, SD, median, minimum, and maximum).  Discretely valued data will be 
tabulated (n and percentage) by category.  The denominator for all percentages will be the 
number of subjects who underwent the planned surgery. 
15.6.1. Baseline Characteristics 
Baseline characteristics will be summarized or tabulated as appropriate. 
15.6.2. Efficacy Analyses 
Pain intensity scores will be summarized by time point.   


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Area under the pain scale versus time curve will be calculated using the trapezoidal rule and 
summarized. 
15.6.3. Pharmacokinetic Analysis 
A prospective population PK analysis plan will be developed.  Nonlinear mixed-effect modeling 
with NONMEM® software (Beal 2011) will be used to analyze the sparse 
concentration-versus-time data.  Population and individual PK parameters will be estimated.  
Individual PK parameters estimated for each subject will be used to compute PK exposures 
(AUC and Cmax).  PK parameters will be presented in listings and descriptive summary statistics, 
including the arithmetic mean, median, range, standard deviation, and coefficient of variation.  
Details and results of this mixed-effects modeling analysis will be reported separately. 
15.6.4. Safety Analyses 
The incidence of AEs will be tabulated by system organ class and preferred term.  Subjects 
reporting the same AE more than once will be counted only once within each tabulation category 
for that AE. 
15.7. Significance Testing 
Not applicable. 


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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81. 
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. 
Apseloff G, Onel E, Patou G. Time to onset of analgesia following local infiltration of liposome 
bupivacaine in healthy volunteers: a randomized, single-blind, sequential cohort, crossover 
study. Int J Clin Pharmacol Ther. 2013;51:367373. 
Beal S, Sheiner LB, Boeckmann A, Bauer RJ. NONMEM User’s Guides. (1989-2011), Icon 
Development Solutions, Ellicott City, Maryland, USA, 2011. 
Breivik H, Hogstrom H, Niemi G, et al. Safe and effective post-operative pain relief: 
introduction and continuous quality-improvement of comprehensive post-operative pain 
management programs. Bailliére’s Clin Anaesthesiol. 1995a;9:423–60. 
Breivik H. Benefits, risks and economics of post-operative pain management programs. 
Baillière’s Clin Anaesthesiol. 1995b;9:403–422. 
Carr DB, Goudas LC. Acute pain. Lancet. 1999;353: 2051–2058. 
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. 
Dahl V, Raeder JC. Non-opioid postoperative analgesia. Acta Anaesthesiol Scand. 
2000;44:1191–203. 
EXPAREL Full Prescribing Information, December 2015. 
EXPAREL Investigator’s Brochure, Edition 18, 31 August 2016. 
Gureje O, Von Korff M, Simon GE, Gater R. Persistent pain and well-being: A World Health 
Organization study in primary care. JAMA. 1998;280:147–151. 
Hu D, Onel E, Singla N, et al. Pharmacokinetic profile of liposome bupivacaine injection 
following a single administration at the surgical site. Clin Drug Investig. 2013;33:109–115. 
Joranson De and Gilson AM. Wanted: a public health approach to prescription opioid abuse and 
diversion. Pharmacoepidemiol Drug Saf. 2006;15: 632–4. 
Kessler ER, Shah M, Gruschkus SK et al. Cost and quality implications of opioid-based 
postsurgical pain control using administrative claims data from a large health system: Opioid-
related adverse events and their impact on clinical and economic outcomes. Pharmacotherapy. 
2013;33(4):383–91. 


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Lynch M. Pain as the fifth vital sign. Comprehensive assessment leads to proper treatment. 
Adv Nurse Pract. 2001;9:28–36. 
Marks RM, Sacher EJ. Undertreatment of medical inpatient pain with narcotic analgesics. 
Ann Intern Med. 1973;78:173–81. 
McDonald JS, Kallmes DF, Lanzino G, Cloft HJ. Protamine Does Not Increase Risk of Stroke in 
Patients With Elective Carotid Stenting. Stroke. 2013;44(7):2028-30. 
Miech R, Johnston L, O’Malley et al. Prescription opioids in adolescence and future opioid 
misuse. Pediatrics. 2015;136 (5): e1-e9. 
Morris BJ and Mir HR. The opioid epidemic: Impact on orthopaedic surgery. J Am Acad Orthop 
Surg. 2015;23(5):267–71. 
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. 
Owen H, McMillan V, Rogowski D. Postoperative pain therapy: a survey of patients' 
expectations and their experiences. Pain. 1990;41(3):303–7. 
Papper EM, Brodie BB, Rovenstein EA. Postoperative pain: its use in the comparative evaluation 
of analgesics. Surgery. 1952;32:107–9. 
Perkins FM, Kehlet H. Chronic pain as an outcome of surgery. A review of predictive factors. 
Anesthesiology. 2000;93:1123–33. 
Petersen-Felix S, Curatolo M. Neuroplasticity — an important factor in acute and chronic pain. 
Swiss Med Weekly. 2002;132:273–8. 
Schug SA, Large RG. Economic considerations in pain management. Pharmacoeconomics. 
1993;3:260–7;9.  
Stephen J, Laskin C, Pashos B et al. The burden of acute postoperative pain and the potential role 
of the COX-2-specific inhibitors. Rheumatology. 2003;42(3): iii40–iii52. 
2005;159:33-6. 
Viscusi ER. New and emerging treatment options for acute postoperative pain in the inpatient 
setting: Barriers to effective pain management. Medscape Pharmacists 2009. Accessed 04 
January 2011. Available at: http://www.medscape.org/viewarticle/713472_2. 
 


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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: 
x
To assume responsibility for the proper conduct of the study at this site; 
x
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. or 
designee.  I also agree to comply with Good Clinical Practice and all regulatory 
requirements; 
x
Not to implement any changes to the protocol without agreement from Pacira 
Pharmaceuticals, Inc. 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);  
x
That I am thoroughly familiar with the appropriate use of the investigational product(s), 
as described in this protocol, and with other relevant information (e.g., the Investigator’s 
Brochure); 
x
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; 
x
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 Pharmaceuticals, Inc. 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 Pharmaceuticals, Inc. and/or 
the investigational product(s) will be disclosed to the regulatory authorities by Pacira 
Pharmaceuticals, Inc. 
 
____________________________________ 
_____________________________ 
Signature of Investigator 
 
 
 
 
 
 


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18.
APPENDICES 


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Appendix 1: Numeric Rating Scale at Rest (NRS-R) 
Subjects aged 12 to less than 17 years will be evaluated for pain using the NRS-R at screening; at 
4, 8, 12, 24, 36, 48, 60, 72, and 96 hours after the end of study drug administration; immediately 
prior to each administration of postoperative opioid pain management medication till 96 hours; 
and at hospital discharge.  If a subject is too anesthetized at the time of a scheduled pain intensity 
assessment, the assessment should be skipped.   
 
Pain Intensity Scale 
 
On a scale of 0 to 10, where 0 = no pain and 10 = worst possible pain, circle the number that best 
describes how much pain are you having right now?  (Circle one number only.) 
 
0
          1            2            3            4            5            6            7            8            9           10
No pain                                                                                                                     Worst possible pain 
 


Pacira Pha
EXPAREL
 
 
CONFIDE
Appendi
Subjects 
8, 12, 24
prior to e
and at ho
assessme
 
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armaceuticals, I
L® 
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, 36, 48, 60, 
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ss than 12 ye
72, and 96 h
stration of po
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one number o
 
g Scale (CAS
ears will be 
hours after th
ostoperative 
ubject is too 
ld be skippe
elow, where 0
e the number
only.) 
54 of 58
S) 
evaluated fo
he end of stu
opioid pain 
anesthetized
d.   
0 (green colo
r that best de
or pain using
udy drug adm
 managemen
d at the time 
or) means no
escribes how
402-C-319 (P
Cli
g the CAS at
ministration;
nt medicatio
of a schedul
 pain and 10
much pain a
Pediatric Infiltr
inical Study Pr
01-OCT
t screening; a
; immediatel
on till 96 hou
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T-2018 
at 4, 
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ensity 
ng


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Appendix 3:  
Neurological Assessment 
The neurological assessment will be conducted at screening; at 2, 4, 8, 12, 24, 48, 60, 72, and 
96 hours; at hospital discharge; and on Day 30. 
 
The examination will include the subject
's orientation.    
Is the subject oriented?  
 
  Yes  
  No        Not Assessable 
If the subject is not oriented, the event should be recorded as an AE.  
 
Additionally, the subject will be asked the following questions: 
Since your last assessment have you had numbness of the lips, the tongue, or around the 
mouth?          
 
  Yes  
  No 
Since your last assessment have you had a metallic taste in your mouth?    
 
  Yes  
  No 
Since your last assessment, have you had problems with your hearing not related to the 
use of a hearing aid?   
  Yes  
  No 
Since your last assessment, have you had problems with your vision not related to the use 
of eye glasses? 
  Yes  
  No 
Since your last assessment, have your muscles been twitching?    
 
  Yes  
  No 
If the subject answers “yes” to any of these questions, the event should be recorded as an AE and 
additional safety procedures should be conducted (see Section 13.1.7).  


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Appendix 4: 
Clinical Laboratory Tests 
The scheduled clinical laboratory tests (hematology, chemistry, and urinalysis) will be conducted 
at screening; at baseline (on Day 1 prior to surgery); and at 96 hours.   
Additionally, appropriate clinical laboratory tests should be conducted if a subject experiences 
a cardiac or neurological AE of special interest or an SAE (see Section 13.1.7).  
 
General Chemistry Analysis 
General Hematology (CBC with 
Differential) Components 
Urinalysis 
Albumin 
White blood cells 
Color 
Alkaline phosphatase 
Red blood cells 
Appearance 
Alanine transaminase (ALT)  
Hemoglobin 
Specific gravity 
Amylase 
Hematocrit 
pH 
Aspartate transaminase (AST)  
Mean corpuscular volume 
Protein 
Bilirubin, direct 
Mean corpuscular hemoglobin 
Glucose 
Bilirubin, total 
Blood urea nitrogen 
Mean corpuscular hemoglobin 
concentration 
Ketones 
Bilirubin 
Calcium 
Red cell distribution width 
Blood 
Carbon dioxide (bicarbonate) 
Platelets 
Urobilinogen 
Chloride 
Mean platelet volume 
Nitrite 
Cholesterol 
Absolute/percent neutrophil count 
Leukocyte esterase 
Creatine kinase (CK), total (or creatine 
phosphokinase [CPK]) 
Absolute/percent lymphocyte count 
Absolute/percent monocyte count 
 
Creatinine, serum 
Absolute/percent eosinophil count 
Gamma-glutamyl transpeptidase (GGT) 
Absolute/percent basophil count 
Glucose 
Iron 
Unsaturated/Total Iron binding capacity 
(UIBC/TIBC) 
Lactate dehydrogenase (LDH) 
Lipase 
Magnesium 
Phosphorus 
Potassium 
Sodium 
Total protein 
Transferrin 
Triglycerides 
Uric acid 
 


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Appendix 5: 
BMI Normal Ranges (5th to 95th Percentile) 
 
Age (years) 
Males 
Females 
2 
14.7 – 19.3 
14.4 – 19.1 
3 
14.3 – 18.2 
14.0 – 18.3 
4 
14.0 – 17.8 
13.7 – 18.0  
5 
13.8 – 18.0 
13.5 – 18.2 
6 
13.8 – 18.4 
13.4 – 18.8 
7 
13.7 – 19.2 
13.4 – 19.6 
8 
13.8 – 20.0 
13.5 – 20.7 
9 
14.0 – 21.0  
13.8 – 21.8 
10 
14.2 – 22.1 
14.0 – 22.9 
11 
14.5 – 23.2 
14.4 – 24.1 
12 
15.0 – 24.2 
14.8 – 25.2 
13 
15.4 – 25.2 
15.3 – 26.2 
14 
16.0 – 26.0 
15.8 – 27.2 
15 
16.5 – 26.8 
16.3 – 28.1 
16 
17.1 – 27.6 
16.8 – 28.9 
Adapted from: Centers for Disease Control and Prevention, National Center for Health Statistics, 
http://www.cdc.gov/growthcharts/clinical_charts.htm  
 


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Appendix 6: 
Flow Diagram for Handling of AESIs 
 
 
 
 
 
AESI or SAE 
(Review by Study Investigator)
Yes
No 
Review by Pacira 
Medical Monitor 
No 
Yes
Periodic DSMB review of all events (AESI, 
SAE, AE)
Reported as 
AE 
Event-driven 
DSMB 
review as 
required
Unscheduled PK blood 
sample; possible 12-lead 
ECG, vital signs, and 
clinical laboratory tests
Possibly related 
to study drug, 
potential LAST, or 
plausible etiology 
not found
Unscheduled PK blood 
sample; possible 12-lead 
ECG, vital signs, and 
clinical laboratory tests
Possibly related  
to study drug, 
potential LAST, or 
plausible etiology 
not found 

SAP_001.pdf: 
Pacira Pharmaceuticals, Inc. 
 
 
EXPAREL 
Document: 
Statistical Analysis Plan 
Official Title: 
A Multicenter Study to Evaluate the Pharmacokinetics and Safety of 
EXPAREL for Postsurgical Analgesia in Pediatric Subjects Aged 6 to 
Less Than 17 years (PLAY) 
NCT Number: 
NCT03682302 
Document Date: 
October 30, 2019 
 


 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
A Multicenter Study to Evaluate the Pharmacokinetics and Safety of EXPAREL for 
Postsurgical Analgesia in Pediatric Subjects Aged 6 to Less Than 17 Years 
 
 
 
 
Protocol No.: 402-C-319 
IND No.: 69,198  
Study Phase: 3 
Study Drug: EXPAREL (bupivacaine liposome injectable 
suspension) 
Date/Version: 30 October 2019/Version 11.0  
Prepared by: Michael Edwardes, Ph.D. 
Sponsor: Everest Clinical Research Corporation 
150 Clove Road 
Little Falls, NJ 07424 
Tel: 919-263-9028 
 
 
 
 
 
 
 
 
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. 




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TABLE OF CONTENTS
1. 
INTRODUCTION ................................................................................................................................ 6 
2. 
STUDY OBJECTIVES......................................................................................................................... 6 
2.1 
Primary Objective....................................................................................................................... 6 
2.2 
Secondary Objective................................................................................................................... 6 
3. 
STUDY OVERVIEW........................................................................................................................... 6 
4. 
DEFINITIONS...................................................................................................................................... 9 
5. 
ANALYSIS POPULATIONS............................................................................................................... 9 
6. 
STATISTICAL METHODS OF ANALYSIS .................................................................................... 10 
6.1 
General Principles..................................................................................................................... 10 
6.1.1 
Handling Missing Values........................................................................................... 10 
6.1.1.1 
Exposure, Surgery, and Rescue Opioid Medication Date or Time............ 10 
6.1.1.2 
Postsurgical Opioid Medication................................................................. 10 
6.1.1.3 
Adverse Event or Concomitant Medications Dates or Times.................... 11 
6.1.1.4 
Adverse Event Severity or Relationship to Study Drug ............................ 11 
6.1.1.5 
Time of Events........................................................................................... 11 
6.2 
Subject Disposition................................................................................................................... 11 
6.3 
Description of Demographics and Baseline Characteristics..................................................... 12 
6.3.1 
Demographics............................................................................................................. 12 
6.3.2 
Baseline Characteristics ............................................................................................. 12 
6.4 
Surgery Characteristics............................................................................................................. 12 
6.5 
Intraoperative, Prior, and Concomitant Medications................................................................ 12 
6.6 
Measurements of Treatment Compliance................................................................................. 13 
6.7 
Pharmacokinetic Analysis ........................................................................................................ 13 
6.7.1 
Sample Collections for Pharmacokinetic Analysis .................................................... 13 
6.8 
Safety Analyses ........................................................................................................................ 15 
6.8.1 
Vital Signs.................................................................................................................. 15 
6.8.2 
Electrocardiograms..................................................................................................... 16 
6.8.3 
Neurological Assessments.......................................................................................... 16 
6.8.4 
Adverse Events........................................................................................................... 16 
6.8.5 
Laboratory Parameters ............................................................................................... 18 
6.9 
Efficacy Analysis...................................................................................................................... 19 
6.9.1 
Pain Intensity Score.................................................................................................... 19 
6.9.1.1 
Area under the Curve................................................................................. 19 
6.9.2 
Opioid Consumption .................................................................................................. 20 
6.9.2.1 
Time to First Postsurgical Use of Opioid Medication ............................... 21 
6.10 Interim Analysis ....................................................................................................................... 21 
6.10.1 
Sample Size Review................................................................................................... 21 
6.11 Deviations from the Protocol.................................................................................................... 21 


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7. 
REFERENCES.................................................................................................................................... 22 
8. 
SAS CODE ......................................................................................................................................... 23 
9. 
TIME AND EVENTS SCHEDULE OF STUDY PROCEDURES.................................................... 24 
10. LAYOUT OF TABLES, LISTINGS AND FIGURES ....................................................................... 26 
11. TABLE OF CONTENTS FOR TABLE MOCK-UPS........................................................................ 27 
12. TABLE OF CONTENTS FOR LISTING MOCK-UPS..................................................................... 64 
13. TABLE OF CONTENTS FOR FIGURE MOCK-UPS .................................................................... 104 


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LIST OF ABBREVIATIONS 
Abbreviation 
Description 
ADL 
Activities of daily living 
AE 
Adverse event 
AESI 
AE of special interest 
ASA 
American Society of Anesthesiology 
ATC 
Anatomical therapeutic class 
AUC 
Area under the curve 
BLOQ 
Below the limit of quantification 
BMI 
Body mass index 
bpm 
Beats per minute 
CAS 
Color Analog Scale 
CI 
Confidence interval 
CMP 
Complete metabolic panel 
CRF 
Case report form 
CSR 
Clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Coefficient of Variation 
ECG 
Electrocardiogram 
EMA 
European Medicines Agency 
FDA 
Food and Drug Administration 
GM 
Geometric Mean 
hr, h 
hour 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IM 
Intramuscular 
IV 
Intravenous 
MedDRA 
Medical dictionary for regulatory affairs 
min 
minutes 
MED mg 
Morphine equivalent dose in mg 
n 
Number of subjects 
NCI 
National Cancer Institute 
NRS-R 
Numerical Rating Scale at Rest 
PK 
Pharmacokinetics 
PO 
Oral 
PT 
Preferred Term 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SC 
Subcutaneous 
SD 
Standard deviation 
SOC 
System Organ Class 
TEAE 
Treatment-emergent adverse event 
TLF 
Table, listings and figures 
WHO 
World Health Organization 
WHO-DD 
World Health Organization – Drug Dictionary 
 


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1. INTRODUCTION
This Statistical Analysis Plan (SAP) describes the planned statistical analyses and reporting of the clinical 
study 402-C-319 titled “A Multicenter Study to Evaluate the Pharmacokinetics and Safety of EXPAREL®
for Postsurgical Analgesia in Pediatric Subjects Aged 6 to Less Than 17 Years”.
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 Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for 
Human Use: Guidance on Statistical Principles in Clinical Trials.1 All work planned and reported for this 
SAP will follow internationally accepted statistical practice guidelines, published by the American 
Statistical Association2 and the Royal Statistical Society3.
The purposes of this SAP are to:
x
Outline the analyses and presentations of data that will form the basis for drawing conclusions 
regarding the study objectives and hypotheses outlined in the protocol.
x
Explain 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 clinical study reports (CSRs), 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 were reviewed in preparation of this SAP:
x
Original Protocol 402-C-319 issued on 01Oct2018.
x
CRF version 4.0 issued on 17Mar2019.
x
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.
2. STUDY OBJECTIVES
2.1 Primary Objective
The primary objective is to evaluate the pharmacokinetics (PK) of EXPAREL in pediatric subjects aged 6 
to less than 17 years undergoing various types of surgeries.
2.2 Secondary Objective
The secondary objective is to evaluate the safety of EXPAREL in pediatric subjects aged 6 to less than
17 years undergoing various types of surgeries.
3. STUDY OVERVIEW
This is a two-part study to evaluate the PK and safety of EXPAREL in pediatric subjects aged 6 to less 
than 17 years. Part 1 will evaluate the PK and safety in subjects aged 6 to less than 17 years, while Part 2
will assess the safety in subjects aged 6 to less than 17 years. This is also a two-group study. Group 1 will 
include subjects aged from 12 to <17 years old undergoing spine surgery. Group 2 will include subjects 
aged from 6 to <12 years old undergoing spine or cardiac surgery. (Table 1)
In Part 1, subject enrollment will be conducted in parallel to include the older age group (12 to <17 years 
old; Group 1) and the younger age group (6 to <12 years old; Group 2).


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Subject enrollment for Part 2 (of each group) will commence upon completion of Part 1 (of that group). In 
Part 2, subject enrollment will be conducted in parallel to include the older age group (12 to <17 years 
old; Group 1) and the younger age group (6 to <12 years old; Group 2). 
Dosing of EXPAREL will be based on body weight, with a starting dose of 4 mg/kg (maximum 266 mg). 
Dosing of Bupivacaine HCl will be based on body weight, with a starting dose of 2 mg/kg (maximum 175 
mg). 
Table 1 
Study 319 Design  
 
Part 1 (PK and Safety) 
Part 2 (Safety) 
Group 1: subjects aged 12 to <17 years 
(Surgery: Spine Surgery) 
EXPAREL 4 mg/kg [N=15]; or 
bupivacaine HCl 2 mg/kg [N =15] 
EXPAREL 4 mg/kg [N =15]; or 
bupivacaine HCl 2 mg/kg [N =15] 
Group 2: subjects aged 6 to <12 years 
(Surgery: Spine or Cardiac Surgery) 
EXPAREL 4 mg/kg [N=15] 
EXPAREL 4 mg/kg [N =15] 
 
Part 1 (Pharmacokinetics [PK]) - Subjects aged 6 to less than 17 years 
Part 1 is a multicenter, randomized, open-label study in 45 subjects aged 6 to less than 17 years of age 
undergoing spine or cardiac surgeries. Part 1 is divided in 2 groups: Group 1 will include subjects aged 12 
to less than 17 years of age, while Group 2 will include subjects aged 6 to less than 12 years of age. 
Part 1, Group 1, is an active-controlled, open-labeled, PK evaluation study in subjects aged 12 to less than 
17 years undergoing spine surgery. The active comparator will be bupivacaine HCl. The planned sample 
size for Part 1, Group 1 is 30 subjects (15 subjects per treatment group). Subjects will be randomized 1:1 
to receive either a single dose of EXPAREL 4 mg/kg (maximum 266 mg) or bupivacaine HCl 2 mg/kg 
(not exceeding a maximum bupivacaine HCl dose of 175 mg total) intraoperatively at the end of surgery 
via local infiltration. 
Part 1, Group 2, is a single arm (EXPAREL 4 mg/kg), open-label, PK evaluation study in subjects aged 6 
to less than 12 years undergoing spine or cardiac surgery. The planned sample size for Part 1 Group 2 is 
15 subjects. Subjects will receive a single dose of EXPAREL 4 mg/kg (maximum 266 mg) 
intraoperatively at the end of surgery via local infiltration. 
Part 2 (Safety) - Subjects aged 6 to less than 17 years 
Part 2 is a multicenter, randomized, open-label study in 45 subjects aged 6 to less than 17 years of age 
undergoing spine or cardiac surgeries. Part 2 is divided in 2 groups: Group 1 will include subjects aged 12 
to less than 17 years of age, while Group 2 will include subjects aged 6 to less than 12 years of age. 
Part 2, Group 1, is an active-controlled, open-labeled, safety evaluation study in subjects aged 12 to less 
than 17 years undergoing spine surgery. The active comparator will be bupivacaine HCl. The planned 
sample size is 30 subjects (15 subjects per treatment group) for Part 2 Group 1. Subjects will be 
randomized 1:1 to receive either a single dose of EXPAREL 4 mg/kg (maximum 266 mg) or bupivacaine 
HCl 2 mg/kg (not exceeding a maximum bupivacaine HCl dose of 175 mg total) intraoperatively at the 
end of surgery via local infiltration. 
Part 2, Group 2, is a single arm (EXPAREL 4 mg/kg), open-label study in subjects aged 6 to less than 
12 years undergoing spine or cardiac surgery. The planned sample size for Part 2 Group 2 is 15 subjects. 
Subjects will receive a single dose of EXPAREL 4 mg/kg (maximum 266 mg) intraoperatively at the end 
of surgery via local infiltration. 
Screening Procedures 
Subjects will be screened within 30 days prior to study drug administration. During the screening visit, 
subjects will be assessed for past or present neurologic, cardiac, and general medical conditions that, in 


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the opinion of the investigator, would preclude them from study participation. After the Informed Consent 
Form (ICF) is signed by the subject’s legal guardian and written assent is provided by the subject (if 
capable), medical history, surgical history, physical examination, 12-lead electrocardiogram (ECG), vital 
sign measurements, neurological assessment, clinical laboratory tests (hematology, chemistry, and 
urinalysis), pain intensity score assessment, urine pregnancy test (for females of childbearing potential), 
urine drug screen and alcohol breath test will be conducted. 
Study Procedures 
On Day 1, eligible subjects will receive the study drug intraoperatively at the end of surgery via local 
infiltration to produce analgesia. Use of intraoperative opioids, acetaminophen, ketorolac, or other 
NSAIDs, will be permitted in accordance with the study site’s standard of care. 
Avoid additional use of local anesthetics within 96 hours following the administration EXPAREL. 
There is no required length of stay in the hospital; subjects may be discharged based on the medical 
judgement of the treating physician. For subjects discharged from the hospital before all protocol-
specified assessments until 96 hours are completed, a nurse will perform follow-up visits at the subject’s 
home to perform the required postsurgical assessments and collect PK samples until 96 hours. 
A follow-up phone call will be scheduled for all subjects on Day 7. For the assessment of AEs, a final 
follow-up visit will be made on Day 30 to all subjects who would have received the study drug. 
Postsurgical Pain Management 
Use of postsurgical pain medication in cases of insufficient analgesia will be permitted according to the 
institution’s standard of care. The investigator must record all postsurgical pain management medications 
provided to the subjects until the hospital discharge. 
Avoid additional use of local anesthetics within 96 hours following the administration EXPAREL. 
Postsurgical Assessments 
Postsurgical assessments to be conducted until 96 hours include pain intensity using 11-point Numerical 
Rating Scale at Rest (NRS-R) for subjects aged 12 to less than 17 years and the Color Analog Scale 
(CAS) for subjects age 6 to less than 12 years; neurological assessment, clinical laboratory tests, and vital 
signs. 
AEs will be recorded from the time of ICF is signed/assent is given until Day 30. 
The study protocol specified that if a cardiac or neurological AE of special interest (AESI) or serious AE 
(SAE) occurs during the study, if the investigator or medical monitor considers that the event may be 
related to study treatment or suggests the possible occurrence of local anesthetic systemic toxicity (LAST; 
with or without the need for treatment [e.g., intralipids]), or if a plausible etiology for the event cannot be 
found, an unscheduled PK blood sample must be collected and a 12-lead ECG, vital signs, and clinical 
laboratory tests (hematology and complete metabolic profile [CMP]) according to the study site’s 
standard of care may be conducted. Cardiac and neurological AEs that do not meet one of these three 
criteria for AESI should be reported and captured in the database as an AE. 
Cardiac AESIs include chest pain, abnormal/irregular heart rate, and shortness of breath requiring 
intervention. Neurologic AESIs include seizure, altered mental status/altered sensorium, rigidity, 
dysarthria, tremors, tinnitus, visual disturbance, and severe or worsening dizziness (see below). 
Additionally, the following events may be of special interest if they persist or occur beyond 72 hours post 
dose: dizziness, hyperesthesia, muscular twitching, and tingling/paresthesia. 
Dizziness will be assessed as mild, moderate, or severe based on the National Cancer Institute-Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0. Mild dizziness is defined as mild 


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unsteadiness or sensation of movement; moderate dizziness is defined as moderate unsteadiness or 
sensation of movement limiting instrumental activities of daily living (ADL); and severe dizziness is 
defined as severe unsteadiness or sensation of movement that limits self-care ADLs. Dizziness will be 
captured as an AESI if it is severe or worsens or persist beyond 72 hours post dose. 
4. DEFINITIONS 
Study Day 
If the date of the event is on or after the date of the end of study drug administration, Study Day is 
calculated as the date of the event minus the date of the end of study drug administration plus one (1). If 
the date of the event is before the date of the end of study drug administration, Study Day is the date of 
the event minus the date of the end of study drug administration. 
Treatment-emergent Adverse Events 
Treatment-emergent adverse events (TEAEs) are those with onset on or after the start time of study drug 
administration, and before or at the end of the study (expected to be Study Day 30±3 days). 
Time 0 (zero) 
Time 0 is defined as the time of the end of study drug administration, with the exception of AE’s and 
concomitant medications.  Time 0 for AE’s and concomitant medications are defined as the time of the 
start of study drug administration.   
Time Deviation 
For PK sampling time window, Time Deviation is the difference (actual – start/end of target window of 
assessment) between the actual and target window of assessment in the PK sampling. If sampling 
occurred before the beginning of target window of assessment, time deviation will be calculated by 
subtracting the actual time from the beginning of the target window of assessment. If the sampling 
occurred after the end of target window of assessment, time deviation will be calculated by subtracting 
the actual sampling time from the end of the target window of assessment.  Any samples occurring with 
the target window will have a time deviation of 0.   
Baseline 
Baseline measurement or assessment is defined as the last available measurement or assessment prior to 
the start of study drug administration. 
Last Follow-up Time 
For subjects who withdraw prematurely, the last follow-up time will be defined as the maximum of the 
last pain or any other study assessment, the last concomitant medication start or end datetime, and the last 
adverse event start or end datetime.  
5. ANALYSIS POPULATIONS 
The Safety Population will consist of all subjects who underwent the planned surgery and received study 
treatment. All analyses based on the safety population will be by actual treatment received.  
The PK Population will consist of subjects who received study drug and provided at least one quantifiable 
plasma concentration. All analyses will be by actual treatment received. 
All analyses of data collected for exploratory purposes (i.e., data related to pain intensity scores and 
opioid consumption) will be conducted using the safety population, and analyzed according to the actual 
treatment received. 


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6. STATISTICAL METHODS OF ANALYSIS 
6.1 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, with the exception that 
pharmacokinetics descriptive statistics will be performed using Sigmastat and Microsoft Excel. 
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 subjects. Unless otherwise noted, percentages will be based on the number of subjects 
in the treatment group or group within the analysis population. 
Individual subject data will be provided in listings. All listings will be sorted by group, treatment (Group 
1), surgery type (Group 2), site, subject and, if applicable, collection date and time. 
Unless otherwise stated, summaries will present data pooled from all sites. 
Unless otherwise noted, tabulations of categorical data will present only those categories appearing in the 
data. 
For tables presenting summaries of pain intensity scores, if more than one score is presented for a specific 
timeframe/timepoint of interest, the highest score within that specific timeframe/timepoint should be used. 
Unless otherwise stated, separate summaries and data listings will be presented for each age group 
(Group 1, Group 2).  Unless otherwise noted, summaries for Group 1 will be presented by treatment 
group and summaries for Group 2 will be presented by type of surgery (Spine or Cardiac). 
6.1.1 Handling Missing Values 
6.1.1.1 Exposure, Surgery, and Rescue Opioid 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 opioid rescue pain medication taken on Day 1 has no time of 
administration recorded, the imputed time will be the end of surgery. 
6.1.1.2 Postsurgical Opioid Medication 
Opioid rescue pain medication usage will be summarized based on oral morphine equivalent dosage 
(MED mg).  
If a subject is discontinues the study early (e.g., dies, withdraws consent, is withdrawn from the study, or 
is lost to follow-up) before the end of the analyses time interval (e.g., 72 hours after end of surgery), his 
or her total opioid rescue pain medication usage through the time interval will be a projected amount.  
For the calculation of the total amount of opioid medication used from the end of surgery through, for 
example, 72 hours, if a subject is discharged at ݔ<36 hours after end of surgery, the total postsurgical 
opioid consumption through 72 hours will be calculated as ͹ʹ כ
஽బǡೣ
௫ , where ܦ0,ݔ is the opioid 
consumption during the initial ݔ hours (inclusive) postsurgery.  If a subject is discharged at 36≤ݔ<72 
hours, the total postsurgical opioid consumption through 72 hours will be calculated as ܦ0,ݔ+ܦ2ݔ−72,ݔ, 
where ܦ2ݔ−72,ݔ is the opioid consumption from 2ݔ−72 hours (exclusive) through ݔ hours (inclusive).  For 
example, if a subject is discharged at x=70 hours, the postsurgical 0 to 72 hours opioid consumption will 
be calculated as the 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. 


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If an opioid medication is taken on the discharge day, but the 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 day of 
discharge, and the time of dosing is missing, it will be imputed as12:00 pm. 
6.1.1.3 Adverse Event or Concomitant Medications Dates or Times 
For AEs or concomitant medications with missing or partially missing start/stop date/time, the following 
imputation rules will be applied: 
For partial start date/time: 
x 
If the year is unknown, then the date will be assigned the year of the first dose of study treatment. If 
the entire study is conducted within the same year, then that year will be the imputed year. 
x 
If the month is unknown, then, if the year matches the year of the dose of study drug date, then the 
month and day of the dose of study drug date will be used to impute the missing month and 
corresponding day. Otherwise, ‘January’ will be assigned. 
x 
If the day is unknown, then, if the month and year match the month and year of the dose of study drug 
date, then the day of the dose of study drug date will be imputed. Otherwise, ‘01’ will be assigned. 
x 
If the time is unknown, then, if the date (day, month, and year) matches the date of the administration 
of study drug, then the end time of the study drug administration will be imputed. Otherwise, ’00:00’ 
will be assigned. 
For partial stop date/time: 
x 
If the year is unknown, then the date will be assigned the year that subject discontinued from study, 
and time will be set to the last time of the day (‘23:59’). 
x 
If the month is unknown, then month subject discontinued from study will be assigned. 
x 
If the day is unknown, then the last day of the month will be assigned. 
x 
If the time is unknown, then the last time of the day will be assigned (‘23:59’), with the exception of 
end times for epoch in any CDISC dataset, where next day and ’00:00’ would be assigned. 
6.1.1.4 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’. If relationship to study drug is not reported for an AE, then for tables of study-drug related 
treatment emergent AEs, the event will be assigned the relationship ‘definite’. If the AE starts before 
study drug administration, then the relationship ‘unrelated’ is presumed. Tables presenting related AEs 
will include all AEs with relationships of ‘possible’, ‘probable’ or ‘definite’ as assessed by the 
investigator.  
If severity or relationship is missing, then a sub-row will be added in the summary tables for imputed vs. 
severe or imputed vs. related. 
6.1.1.5 Time of Events  
For calculating the time of an event when only the hour is reported, the minutes will be set to zero. 
6.2 Subject Disposition 
Subject disposition summaries will include the number of subjects that were: 
x 
Screened 
x 
Randomized 
o Randomized, not treated 
o Randomized and treated 
x 
In the safety population 


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x 
In the PK population 
x 
Completed the study as planned 
x 
Discontinued from the study, and 
o Reasons for discontinuation from the study 
Percentages will be based on the number of subjects randomized.  
6.3 Description of Demographics and Baseline Characteristics  
6.3.1 Demographics  
The summary of demographic data will present: 
x 
Age (years) – descriptive statistics 
x 
Sex – n (%) 
x 
Ethnicity – n (%) 
x 
Race – n (%) 
Demographics in the PK Population and the Safety Population will be summarized by treatment group 
(EXPAREL or Bupivacaine HCl) for Group 1 and by surgery type (cardiac or spine) for Group 2. 
6.3.2 Baseline Characteristics 
The summary of baseline characteristic data will present: 
x 
American Society of Anesthesiologists (ASA) Classification 
x 
Baseline pain intensity scores 
x 
Height (cm) 
x 
Weight (kg) 
x 
Body Mass Index (BMI) (kg/m2) 
 
The formula for BMI isݓȀሺ݄ଶሻ, 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. Height in centimeters will be converted to meters using the conversion factor of 100 centimeters to 1 
meter. 
Baseline characteristics summaries will be summarized by treatment group for Group 1 and by surgery 
type for Group 2.   
Descriptive statistics (n, mean, SD, median, minimum and maximum) will be provided for pain scores, 
height, weight, and BMI at baseline. The number and percent of subjects will be tabulated for the various 
categories of ASA classification. 
6.4 Surgery Characteristics 
Surgery characteristics include duration of surgery and total incision length. Duration of surgery is 
calculated as the difference between the end of surgery and start of surgery times and reported in hours. 
Descriptive statistics will be provided for the duration of surgery and total incision length using the safety 
population, by treatment group for Group 1, and by surgery type for Group 2. Surgical characteristics will 
be included in data listings. 
6.5 Intraoperative, Prior, and Concomitant Medications 
Intraoperative, Prior, and concomitant medications will be coded using the World Health Organization 
Drug Dictionary (WHO-DD) and will be classified according to the default anatomical therapeutic 
chemical (ATC 4) classification term and preferred term (PT). 


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Intraoperative medications are medications collected on Intraoperative Medication eCRF page.
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 
times overlapping within the surgery start and stop times.
Prior medications are defined as medications with a stop date and time prior to the start of surgery. Prior 
medications are recorded on the prior/concomitant medication eCRF page.  
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) and recorded on the prior/concomitant or post surgical pain medication CRF 
page.
Intraoperative, prior and concomitant medications will be summarized separately using the number and 
percentage of subjects within each age group and treatment group of the study by ATC class and PT for 
the safety population. Subjects may have more than one medication per ATC category and PT. At each 
level of subject summarization, a subject will be counted once if one or more medications are reported by 
the subject at that level.
A data listing will be created for all medications, with a flag variable identifying intraoperative, prior, and 
concomitant medications.
A listing mapping the ATC class and PT to verbatim term will be presented.
6.6 Measurements of Treatment Compliance
Study treatment is administered by a party other than the subject, therefore compliance is assured.
6.7 Pharmacokinetic Analysis
6.7.1
Sample Collections for Pharmacokinetic Analysis
A sparse PK sampling scheme is used to limit the number of blood draws from individual subjects. On 
Day 1, eligible subjects will be assigned to one of two PK sampling groups shown in Table 2 based on 
surgery type. A total of 8 blood samples will be collected from each subject at the specific time windows 
shown for the determination of bupivacaine plasma concentrations. 
Table 2
PK Sampling Times
Surgery 
Type
PK Sample Timing (Based on the End of Study Drug Administration)
Sample 1
Sample 2
Sample 3
Sample 4
Sample 5
Sample 6
Sample 7
Sample 8
Spine
15±5 min
30±5 min
45±5 min
1-1.25 h
2-3 h
10-18 h
24-36 h
42-60 h
Cardiac
15±5 min
30±5 min
45±5 min
1-1.25 h
15-25 h
30-40 h
45-55 h
64-72 h
Abbreviations: h = hour; min = minutes; PK = pharmacokinetic
These sampling time points will not only characterize overall PK of bupivacaine from EXPAREL, but 
will also characterize the PK of immediate release bupivacaine and thoroughly characterize the early peak 
for both surgery types.
6.7.2
Pharmacokinetic Parameters Calculation Methods
Nonsterospecific assay is used for the measurement of bupivacaine concentration. Pharmacokinetic 
parameters will be calculated by noncompartmental analysis (NCA) method from concentration-time data 
following these guidelines:


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x 
Actual sampling times relative to study drug administration will be used for all calculations of the PK 
parameters. If there is any doubt as to the actual time a sample was taken, then the scheduled time 
will be used. 
x 
Concentrations from unscheduled PK blood samples will be used in the analysis of the parameters. 
x 
There will be no imputation of missing concentration data. 
x 
For the summaries of concentrations and for calculation of area under the curve (AUC) from 
bupivacaine plasma concentrations, concentrations below the limit of quantification (BLOQ) will be 
handled as follows: 
o Pre-dose values will be set to zero. 
o BLOQ values between the dosing time and the first time point above lower limit of 
quantification (LLOQ) will be set to 0. 
o BLOQ values at time points between two measurable concentration values will be set to ½ of 
LLOQ (lower limit of quantification). 
o All remaining BLOQ values will be set to missing. 
The following PK endpoints will be determined using non-compartmental methods:  
x 
Area under the plasma concentration-versus-time curve (AUC0-∞ and AUC0-last). The AUC0-last 
from the time of dosing to the time of the last quantifiable concentration will be calculated using the 
linear trapezoidal method.  The AUC0-∞ from the time of dosing (zero) to infinity will be calculated 
as sum of AUC0-last and residual area Ct/λz. 
x 
Maximum plasma concentration (Cmax) and time of Cmax (Tmax).  
x 
The apparent terminal elimination half-life (t1/2el).  t1/2el will be calculated as loge(2)/λz.The 
apparent terminal elimination rate constant (λz) will be estimated at terminal phase by linear 
regression after log-transformation of the concentrations: 
o Only those data points that are judged to describe the terminal log-linear decline will be used 
in the regression. 
o A minimum number of three data points in the terminal phase will be used in calculating λz 
with the line of regression starting post the Cmax data point (Cmax will not be part of the 
regression slope) and including the last point above LLOQ value (Ct). 
o An appropriate number of decimal places will be used for λz to enable the reported value of 
terminal half-life (t1/2el) to be calculated. 
x 
Apparent clearance (CL/F) will be estimated as Dose/AUC0-∞. 
x 
Apparent volume of distribution (Vd/F) will be estimated based on the teriminal phase as Dose/(λz͑
AUC0-∞). 
In addition, a population PK modeling will be performed using all PK data collected during the study. 
The population PK analysis plan will be developed separately. 
6.7.3 Pharmacokinetic Concentrations and Variables 
A complete data listing will be provided for all PK bupivacaine concentration data. Concentrations that 
are BLOQ will be indicated in the listing. 
A plot of bupivacaine concentration-time data, with original scale and semi-log scale overlain on the same 
page will be created for each individual subject. 
If different than the preceding plot, a plot of dose-normalized concentration-time data, with the original 
scale and semi-log scale overlaid on same page, will also be created for each individual subject. 
Plasma bupivacaine concentrations for each formulation will be summarized at each nominal time 
window (any out-of-window results would be shown only in a listing). The following descriptive statistics 


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will be presented: n, geometric mean, arithmetic mean, SD, %CV, median, minimum and maximum.
Results will be summarized by treatment group (EXPAREL or bupivacaine HCl) for Group 1 and by 
surgery type (cardiac or spine) for Group 2. Plots of mean bupivacaine concentration over time will be 
created with the original scale and semi-log scale overlain on the same page. If the number of subjects in 
a group is less or equal to 3, then individual concentration over time curves will be plotted instead of the 
mean concentration. For group 1, there will be two plots overlain for the two treatments. For group 2, 
there will be two separate plots for the two types of surgery.
Pharmacokinetics parameters will be presented in the data listings and descriptive summary statistics, 
including the arithmetic mean, median, minimum, maximum, standard deviation, %CV of mean, 
geometric mean, %CV of geometric mean. Differences will be compared between the two formulations 
using single factor ANOVA.
6.8 Safety Analyses
Safety assessments in this study consist of vital signs, 12-lead ECGs, neurological assessments, and AEs. 
Vital signs, ECGs, and neurological assessments will be serially collected (see Time and Events Schedule 
of Study Procedures, Section 9). Adverse events will be collected from the time of informed consent
through to the final Day 30 visit.
6.8.1
Vital Signs
Vitals signs are resting heart rate (bpm), systolic blood pressure (mmHg), diastolic blood pressure 
(mmHg), temperature (ºC), oxygen saturation (%), and respiratory rate (breaths/min). Vital signs will be 
summarized by treatment group (Group 1), and by surgery type (Group 2) at each assessment timepoint. 
Summaries will present both observed results by timepoint and change-from-baseline results. Baseline is 
defined as the last measurement on prior to the end of study drug administration . Baseline statistics will
be presented at each assessment timepoint for those subjects reporting data at that timepoint.
Time windows will be derived for each post baseline visit using the time intervals for the study time 
windows detailed in Table 3.
Table 3
Analysis Study Time Windows for Vital Signs Assessments
Study Time
Time Interval for Study Time Window
Baseline
≥ 0 minutes prior to dose
Post-dose 2 hours
1.75 – 2.25 hours after end of study drug administration
Post-dose 4 hours
3.75 – 4.25 hours after end of study drug administration
Post-dose 8 hours
7.5 – 8.5 hours after end of study drug administration
Post-dose 12 hours
11 – 13 hours after end of study drug administration
Post-dose 24 hours
23 – 25 hours after end of study drug administration
Post-dose 36 hours
34 – 38 hours after end of study drug administration
Post-dose 48 hours
46 – 50 hours after end of study drug administration
Post-dose 60 hours
58 – 62 hours after end of study drug administration
Post-dose 72 hours
70 – 74 hours after end of study drug administration
Post-dose 96 hours
92 – 100 hours after end of study drug administration
Day 30
27 – 33 days after end of study drug administration


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If there are multiple vital sign values for the same parameter prior to the end of study drug administration,
the last value will be chosen for Baseline. If there are multiple vital sign values in a post-end of study 
drug administration window, the value closest to the target time point will be chosen for analysis. 
Unscheduled visits can be mapped to a study time only if the scheduled assessment for that time was not 
done and an unscheduled visit falls into the time interval for the visit window. Data from both scheduled
and unscheduled visits will be listed.
6.8.2
Electrocardiograms
Investigators will classify ECG tracings as ‘normal, ‘abnormal not clinically significant’ or ‘abnormal 
clinically significant’. ECGs are assessed only at screening or on Day 1 prior to surgery, and a listing of 
ECG data will be provided. 
6.8.3
Neurological Assessments
Neurological assessments include orientation (orientated, disoriented, not assessable), numbness (of lips, 
tongue, or around mouth), metallic taste, hearing problems, vision problems, and muscle twitching. The 
number and percentage of subjects will be tabulated for each neurological assessment by treatment group 
for Group 1 and by surgery type for Group 2, at any time after baseline and at each assessment timepoint.
Time windows will be derived for each post baseline visit using the time intervals for the study time 
windows detailed in Table 4.
Table 4
Analysis Study Time Windows for Neurological Assessments
Study Time
Time Interval for Study Time Window
Baseline
≥ 0 minutes prior to dose
Post-dose 2 hours
1.75 – 2.25 hours after end of study drug administration
Post-dose 4 hours
3.75 – 4.25 hours after end of study drug administration
Post-dose 8 hours
7.5 – 8.5 hours after end of study drug administration
Post-dose 12 hours
11 – 13 hours after end of study drug administration
Post-dose 24 hours
23 – 25 hours after end of study drug administration
Post-dose 36 hours
34 – 38 hours after end of study drug administration
Post-dose 48 hours
46 – 50 hours after end of study drug administration
Post-dose 60 hours
58 – 62 hours after end of study drug administration
Post-dose 72 hours
70 – 74 hours after end of study drug administration
Post-dose 96 hours
92 – 100 hours after end of study drug administration
Day 30
27 – 33 days after end of study drug administration
If there are multiple neurological assessment values for the same parameter prior to the end of study drug 
administration, the last value will be chosen for Baseline. If there are multiple neurological assessment
values in a post-end of study drug administration window, the value closest to the target time point will be 
chosen for analysis. Unscheduled visits can be mapped to a study time only if the scheduled assessment 
for that time was not done and an unscheduled visit falls into the time interval for the visit window. Data 
from both scheduled and unscheduled visits will be listed.
6.8.4
Adverse Events
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA).
An AE will be considered TEAE if the onset date and time is between the start time of study drug 
administration and the final Day 30 visit.


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If an AE has a partial onset date and time the imputed start and stop dates and times will be used to 
determine treatment-emergence (e.g., stop date and time is before start time of study drug administration). 
All AE summaries will present TEAEs only; AEs that are not treatment-emergent will be included in 
listings but not summarized. 
The incidence of subjects reporting TEAEs will be tabulated by the number and percentage of subjects 
reporting the TEAE. Incidence is defined as a subject reporting at least one TEAE within the summary 
level. Summary levels are ‘at least one TEAE’, System Organ Class (SOC) and Preferred Term. Subjects 
will be counted only once within each reporting level on the table. For example, if a subject reports a 
TEAE of headache on two separate occasions, the subject will be counted only once in the headache row 
of the table. Similarly, if a subject reports two separate TEAEs within the same SOC the subject will only 
be counted once in the summary row for that SOC. A summary of subjects reporting at least one TEAE 
during the study will also be presented. 
The first row on every TEAE table will be the number and percentage of subjects reporting at least one 
TEAE. Subsequent rows will be presented in descending order of subject counts for the overall within 
each age group and treatment group, with the most common system organ class first, followed within 
each SOC by the PT in descending subject count order. For tables presenting the severity or relationship 
to study treatment of AE, the sort order will be determined by the number and percentage of subjects 
reporting the PT, thus the sort order of rows will remain the same for the relation or severity tables as the 
tables by preferred term. 
The following summaries will be presented for the AEs reported by the subjects: 
An overview of all TEAEs, serious TEAEs and TEAEs of Special Interest will present the number and 
percentage of subjects in the following categories: 
x 
Any TEAE 
o Maximum severity: Mild 
o Maximum severity: Moderate 
o Maximum severity: Severe 
x 
At least one related TEAE 
x 
At least one serious TEAE 
x 
At least one TEAE of special interest 
x 
Subjects discontinued due to a TEAE 
x 
Died on study (i.e., within 30 days of study drug administration) 
Subjects will be counted once in each of the above categories except for maximum severity. Subjects will 
be counted only once at the highest severity reported. For example, if a subject has a mild and severe 
headache and a moderate rash, the subject will be counted under maximum severity of severe only. 
Adverse event tables will present the data within each age group of the study. Incidence tables will be 
created for the following groups of TEAEs: 
x 
All TEAEs by System Organ Class (SOC) and Preferred term (PT) sorted in descending order of 
frequency 
x 
All TEAEs by relationship to study drug 
x 
All TEAEs by severity 
x 
All TEAEs of special interest 
x 
All serious TEAEs 
If there are no AEs to report on any of the above tables, the table should be created with the line ‘no 
adverse events were reported’ in the body of the table. 
Adverse events will be considered related if the investigator assessment of relationship to study treatment 
is either ‘possible’, ‘probable’ or ‘definite’. Adverse events will be considered unrelated if the 


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investigator assessment of relationship to study treatment is either ‘unrelated’, ‘unlikely related’. All AE 
summaries based on related AEs will be produced based on the investigator assessment of relatedness. 
Table 5 are the MedDRA terms for the adverse events of special interest according to the protocol. All 
AEs reported by investigators are based on this definition along with their clinical judgement.
A listing of the mapping of the system organ class and preferred terms to verbatim terms will be 
presented.
6.8.5
Laboratory Parameters
Clinical laboratory assessments (hematology, chemistry, and urinalysis) are collected at screening, 
baseline (prior to the end of study drug administration) and 96 hours after the end of study drug 
administration. Laboratory results will be summarized by treatment group (Group 1), and by type of 
surgery (Group 2) at each assessment timepoint. Summaries will present both actual and change-from-
baseline results. Baseline statistics will be presented at each assessment timepoint for those subjects 
reporting data at that timepoint.
Tabulations of the number and percentage of subjects with value of below normal, normal, or above 
normal will be provided by treatment group (Group 1), and type of surgery (Group 2), at each assessment 
timepoint.
Time windows will be derived for each post baseline visit using the time intervals for the study time 
windows detailed in Table 6
Table 6
Analysis Study Time Windows for Clinical Laboratory Assessments
Study Time
Time Interval for Study Time Window
Baseline
≥ 0 minutes prior to dose
Post-dose 96 hours
92 – 100 hours after end of study drug administration
Table 5. MedDRA Terms for AEs of Special Interest
MedDRA 21.1 Dictionary Terms
Group
Protocol term
Term Level
Term
Cardiac
Chest pain
Preferred term
Chest Pain
Abnormal/irregular heart rate
Preferred term
Heart Rate Irregular
Shortness of breath requiring intervention
Preferred term
Dyspnoea
Neurologic
Seizure
Preferred term
Seizure
Altered mental status
Preferred term
Mental Status Changes
Altered sensorium
Preferred term
Depressed level of consciousness
Rigidity
Preferred term
Muscle Rigidity
Dysarthria
Preferred term
Dysarthria
Tremors
Preferred term
Tremor
Tinnitus
Preferred term
Tinnitus
Visual disturbance
Preferred term
Visual Impairment
Dizziness*
Preferred term
Dizziness
Other
Dizziness#
Preferred term
Dizziness
Hyperesthesia#
Preferred term
Hyperaesthesia
Muscular twitching#
Preferred term
Muscle Twitching
Tingling#
Preferred term
Paresthesia
Paresthesia#
Preferred term
Paresthesia
* if severe or worsening
# if event persists or occurs after 72 hours after start of study treatment dose


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If there are multiple clinical laboratory assessment values for the same parameter prior to the end of study 
drug administration, the last value will be chosen for Baseline.  If there are multiple clinical laboratory
assessment values in a post-end of study drug administration window, the value closest to the target time 
point will be chosen for analysis.  Unscheduled visits can be mapped to a study time only if the scheduled 
assessment for that time was not done and an unscheduled visit falls into the time interval for the visit 
window. Data from both scheduled and unscheduled visits will be listed.
6.9 Efficacy Analysis
For exploratory efficacy analyses, descriptive statistics that are appropriate for the efficacy variable will 
be shown within each age group and treatment group (Group 1), type of surgery (Group 2), for the safety 
population.
6.9.1
Pain Intensity Score
Summary statistics will be presented for pain intensity scores at each assessment timepoint. These 
summaries will be based on the observed values at the scheduled time points. Data listings of pain 
intensity scores will also be provided.
Time windows will be derived for each post baseline visit using the time intervals for the study time 
windows detailed in Table 7.
Table 7
Analysis Study Time Windows for Pain Intensity Scores
Study Time
Time Interval for Study Time Window
Baseline
≥ 0 minutes prior to dose
Post-dose 4 hours
3.75 – 4.25 hours after end of study drug administration
Post-dose 8 hours
7.5 – 8.5 hours after end of study drug administration
Post-dose 12 hours
11 – 13 hours after end of study drug administration
Post-dose 24 hours
23 – 25 hours after end of study drug administration
Post-dose 36 hours
34 – 38 hours after end of study drug administration
Post-dose 48 hours
46 – 50 hours after end of study drug administration
Post-dose 60 hours
58 – 62 hours after end of study drug administration
Post-dose 72 hours
70 – 74 hours after end of study drug administration
Post-dose 96 hours
92 – 100 hours after end of study drug administration
If there are multiple pain intensity score values for the same parameter prior to the end of study drug 
administration, the last value will be chosen for Baseline. If there are multiple pain intensity score values 
in a post-end of study drug administration window, the value closest to the target time point will be 
chosen for analysis. Unscheduled visits can be mapped to a study time only if the scheduled assessment 
for that time was not done and an unscheduled visit falls into the time interval for the visit window. Data 
from both scheduled and unscheduled visits will be listed.
6.9.1.1
Area under the Curve
Area under the pain-time curve (AUC) is derived using the linear trapezoidal rule (see formula below) on
the pain scores. AUC will start with the first pain assessment obtained after surgery and use all following 
pain assessments including those collected prior to administration of opioid medication and unscheduled
assessments. Actual assessment times will be used in deriving AUC.


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ܣܷܥൌሾ෍ሺ
௡
௜ୀସ
݌௜൅݌ሺ௜ିଵሻሻሺݐ௜െݐሺ௜ିଵሻሻሿȀʹ
Where pi is the pain intensity score at time i, and ti is the time, in hours, from end of surgery. Note that i
starts at 4 as this represents the first measurement post-surgery.
Summary statistics will be presented for the following pain intensity AUCs: AUCAdjusted(4-24), AUCAdjusted (4-
48), AUCAdjusted (4-72), AUCAdjusted (4-96) and AUCAdjusted (4-Hospital Discharge).
6.9.2
Opioid Consumption
Opioid medications will be converted to oral morphine equivalent dose (MED mg) using the appropriate 
conversion factor from Table 8 for all summaries. Opioids are collected on the Post Surgical Pain 
Medication and Prior/Concomitant Medications eCRF pages. The amount of total opioid dose will be 
calculated as the sum of the oral morphine equivalent of all opioids taken after surgery up to the timepoint 
of interest. Subjects with no opioid use during the period in question will be assigned a dose of 0 for 
summaries and changed to the lesser of 0.1 or half of the smallest total amount observed in the study,
whichever is smaller, prior to being transformed with the natural logarithm for analysis. Total postsurgical 
opioid dose will be calculated through 24, 48, and 72 hours. In addition to the descriptive statistics for 
continuous data, geometric mean (GM) and coefficient of variation (CV) will also be included and mean 
and SD will be excluded.
For the calculation of the total dose through 72 hours, if a subject’s last follow-up time is 72-x hours, then 
the approach described in Section 6.1.1.2 is used.
Table 8 Oral Morphine Equivalents
Medication
Unit
Route
Oral Morphine Conversion 
Multiplication Factor
Morphine, Morphine Sulfate 
mg
IV,IM,SC
3
Morphine 
mg
PO
1
Morphine 
mg
R
1
Buprenorphine 
mcg
IM
75
Buprenorphine 
mcg
SL
37.5
Codeine (Tylenol 3, acetaminophen-coedine, 
Paracetamol Forte, Tylenol 4, …) 
mg
PO
0.15
Codeine Phosphate 
mg
IM
0.24
Demerol, Meperidine, Pethidine 
mg
IV,SC
0.3
Demerol, Meperidine, Pethidine 
mg
PO
0.1
Fentanyl, Remifentanil 
mcg
IV,PO,IM,TD
300
Hydromorphone 
mg
R
4
Hydromorphone (Dilaudid) 
mg
IV,IM,SC
20
Hydromorphone (Dilaudid) 
mg
PO
4
Hydromorphone (Dilaudid) 
mg
EP
45
Ketobemidone, Oxycodone 
mg
IV
3
Methadone 
mg
IM
3
Methadone 
mg
PO
1.5
Methadone 
mg
IV
6
Nalbuphine/Nallouphine (Nubain/Manfine) 
mg
IV,IM,SC
3
Oxycodone, Oxycocet, Percocet, acetaminophen-
oxycodone, Oxycodone HCl 
mg
PO
1.5
Oxymorphone 
mg
PO
3
Oxymorphone
mg
IM,SC
30
Pentazocine/Acetaminophen 
mg
PO
0.2
Pentazocine/Naloxone 
mg
PO
0.2


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Pentazocine 
mg
IM
1
Tapentadol
mg
PO
0.3
Ultram, Tramadol, Tramacol hydrochloride
mg
PO,IM
0.25
Vicodin, Norco, Lorcet, Lortab, hydrocodone-
acetaminophen, Ketobemidone
mg
PO
1
Key: EP = Epidural; IM = Intramuscular; IV = Intravenous; INS = Intra Nasal Spray; NA = Not Applicable; PO = Oral; R = Rectal; SC 
= Subcutaneous; SL = Sublingual; TBD = To Be Determined; TD = Transdermal
If other rescue medications are given, then the conversion to oral Morphine Equivalent will be determined post-hoc. If a combination 
opioid product is given, then the oral Morphine Equivalent will be determined by the opioid part of the medication. Opioids given post 
surgically with an indication such as ‘anesthesia maintenance’ will not be included.
6.9.2.1
Time to First Postsurgical Use of Opioid Medication
Time to first postsurgical use of 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 72 hours after 
surgery or at the time of last follow-up, whichever is earliest. Time to first opioid consumption will be 
summarized by the quartiles (25th, 50th, and 75th), minimum and maximum estimated using Kaplan-Meier 
methods within age group and part of the study. The quartile and the 95% confidence limits 
(CONFTYPE=LOGLOG) for each quartile will be presented.
A Kaplan-Meier plot of the time from end of surgery to first opioid rescue medication use will be presented 
within age group and part of the study, and a log-rank test p-value of treatment difference shown for group 
1.
6.10Interim Analysis
Not Applicable.
6.10.1 Sample Size Review
The sample size was based on the number of subjects necessary to characterize the PK of EXPAREL in 
pediatric subjects with the precision required by the Food and Drug Administration.
6.11Deviations from the Protocol
This SAP has an additional analysis that was not specified in the Protocol.  Pharmacokinetic parameters 
will be calculated with a NCA method as specified in Section 6.7.2.


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7. REFERENCES 
 US Federal Register. International Conference on Harmonisation; Guidance on Statistical Principles 
for Clinical Trials. Department of Health and Human Services: Food and Drug Administration 
[Docket No. 97D-0174]. Federal Register Volume 63, Number 179, pages 49583-49598. 16 
September 1998.  
 American Statistical Association. Ethical Guidelines for Statistical Practice. Prepared by the 
Committee on Professional Ethics, 07 August 1999. 
http://www.amstat.org/profession/ethicalstatistics.html 
 Royal Statistical Society. The Royal Statistical Society: Code of Conduct, August 1993. 
http://www.rss.org.uk/about/conduct.html. 
 


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8. SAS CODE 
Endpoint 
SAS Code 
AUC of Pain Intensity Score 
* AUC calculations; 
%macro AUC(st,en); 
 
data auc; 
   set adre(where=(&st.<=atptn<=&en.)); 
   by usubjid paramcd base avisitn adt ady t anl01fl; 
   retain prevval prevt; 
   if first.ady then do; 
      prevval=.; 
      prevt=.; 
   end; 
   else trapez=(aval+prevval)/2*(t-prevt); 
   prevval=aval; 
   prevt=t; 
run; 
proc means data=auc noprint; 
   by usubjid paramcd base avisitn adt ady 
/*pftsfl*/; 
   var aval trapez t; 
   output out=a&st.&en. sum(aval)=singl 
sum(trapez)=aval min(t)=mint max(t)=maxt; 
run; 
data a&st.&en.; 
   set a&st.&en.; 
   if .<mint<maxt then aval=aval; 
  else if 0<mint=maxt then aval=singl; 
   drop _: mint maxt singl; 
run; 
 
%mend AUC; 
 
%AUC(4,24);   /* AUC 4-24 */ 
%AUC(4,48);   /* AUC 4-48 */ 
%AUC(4,72);   /* AUC 4-72 */ 
%AUC(4,96);   /* AUC 4-96 */ 
***  AUC 4-Hospital Discharge: ***; 
***  For this run, make a subset of the data ***; 
***  first with only assessments taken on or ***; 
***  before hospital discharge ***; 
%AUC(4,96);   /* AUC 4-96 */ 
 
 


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9. TIME AND EVENTS SCHEDULE OF STUDY PROCEDURES 
 


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10. 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 templates 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 14.1-1 the title in the mock-up appears as: 
Table 14.1-1.1.1: Summary of Subject Disposition (Part 1, Group 1) – All 
Screened Subjects 
but should appear as follows on the final TLF: 
Table 14.1-1.1.1 
Summary of Subject Disposition (Part 1, Group 1) 
Safety Population 
 
The title format in the mock-ups is due to limitations of MSWord. The mock-up format enables 
MSWord to generate a table of contents for the mock-ups. 
Always insert a page break between parts of the study. 
Sort all listings within study part and age group by site, subject with further sorts dependent on 
listing. 
Table and listing shells follow. 
For categorical variables, if subjects are missing data for a certain category (example Race), a 
missing subcategory should be added under the respective category. 
For any subjects who are enrolled in the incorrect group for their age, add a footnote to all TFL’s for that 
group:  “Subject XXXX is XX years old but was incorrectly enrolled in Group X.” 


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11. TABLE OF CONTENTS FOR TABLE MOCK-UPS
Table 14.1-1.1.1: Summary of Subject Disposition (Group 1: 12 to <17 years) – All Screened 
Subjects............................................................................................................................................... 31 
Table 14.1-1.1.2: Summary of Subject Disposition (Group 2: 6 to < 12 years) – All Screened Subjects.. 31 
Table 14.1-2.1.1: Summary of Subject Demographics (Group 1: 12 to <17 years) - PK Population......... 32 
Table 14.1-2.1.2: Summary of Subject Demographics (Group 2: 6 to < 12 years) - PK Population.......... 32 
Table 14.1-2.2.1: Summary of Subject Demographics (Group 1: 12 to <17 years) - Safety Population.... 33 
Table 14.1-2.2.2: Summary of Subject Demographics (Group 2: 6 to < 12 years) - Safety Population..... 33 
Table 14.1-3.1.1: Summary of Subject Baseline Characteristics (Part 1, Group 1) - PK Population......... 34 
Table 14.1-3.1.1: Summary of Subject Baseline Characteristics (Group 1: 12 to <17 years) - PK 
Population ........................................................................................................................................... 35 
Table 14.1-3.1.1: Summary of Subject Baseline Characteristics (Group 1: 12 to <17 years) - PK 
Population ........................................................................................................................................... 36 
Table 14.1-3.1.1: Summary of Subject Baseline Characteristics (Group 1: 12 to <17 years) - PK 
Population ........................................................................................................................................... 37 
Table 14.1-3.1.2: Summary of Subject Baseline Characteristics (Group 2: 6 to < 12 years) - PK 
Population ........................................................................................................................................... 38 
Table 14.1-3.2.1: Summary of Subject Baseline Characteristics (Group 1: 12 to <17 years) - Safety 
Population ........................................................................................................................................... 38 
Table 14.1-3.2.2: Summary of Subject Baseline Characteristics (Group 2: 6 to < 12 years) - Safety 
Population ........................................................................................................................................... 38 
Table 14.1-4.1.1: Summary of Surgery Characteristics (Group 1: 12 to <17 years) - Safety Population .. 39 
Table 14.1-4.1.2: Summary of Surgery Characteristics (Group 2: 6 to < 12 years) - Safety Population ... 39 
Table 14.1-5.1.1: Tabulation of Incidence of Intraoperative Medications (Group 1: 12 to <17 years) -
Safety Population ................................................................................................................................ 40 
Table 14.1-5.1.2: Tabulation of Incidence of Intraoperative Medications (Group 2: 6 to < 12 years) -
Safety Population ................................................................................................................................ 40 
Table 14.2-1.1.1: Summary of Numeric Rating Scale Pain Intensity Scores (Group 1: 12 to <17 years) 
- Safety Population.............................................................................................................................. 41 
Table 14.2-1.1.2: Summary of Color Analog Scale Pain Intensity Scores (Group 2: 6 to < 12 years) -
Safety Population ................................................................................................................................ 41 
Table 14.2-2.1.1: Summary of AUC of Pain Intensity Scores (Group 1: 12 to <17 years) – Safety 
Population ........................................................................................................................................... 43 
Table 14.2-2.1.2: Summary of AUC of Pain Intensity Scores (Group 2: 6 to < 12 years) – Safety 
Population ........................................................................................................................................... 43 
Table 14.2-3.1.1: Summary of Total Opioid Consumption (MED mg) (Group 1: 12 to <17 years) -
Safety Population ................................................................................................................................ 44 
Table 14.2-3.1.2: Summary of Total Opioid Consumption (MED mg) (Group 2: 6 to < 12 years) -
Safety Population ................................................................................................................................ 44 
Table 14.2-4.1.1: Analysis of Time to First Postsurgical Opioid Medication Use (Group 1: 12 to <17 
years) - Safety Population................................................................................................................... 45 
Table 14.2-4.1.3: Analysis of Time to First Postsurgical Opioid Medication Use (Group 2: 6 to < 12 
years) - Safety Population................................................................................................................... 45 
Table 14.3-1.1.1: Summary of Vital Signs (Group 1: 12 to <17 years) – Safety Population ..................... 46 


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Table 14.3-1.1.2: Summary of Vital Signs (Group 2: 6 to < 12 years) – Safety Population ...................... 46 
Table 14.3-1.1.3: Summary of Vital Signs (Both Groups: 6 to < 17 years) – Spine Surgery – Safety 
Population ........................................................................................................................................... 47 
Table 14.3-2.1.1: Summary of Neurological Assessments by Timepoint (Group 1: 12 to <17 years) -
Safety Population ................................................................................................................................ 48 
Table 14.3-2.1.2: Summary of Neurological Assessments by Timepoint (Group 2: 6 to < 12 years) -
Safety Population ................................................................................................................................ 49 
Table 14.3-2.1.3: Summary of Neurological Assessments by Timepoint (Both Groups: 6 to < 17 
years) – Spine Surgery - Safety Population ........................................................................................ 49 
Table 14.3-3.1.1.1: Summary of Clinical Laboratory Data by Timepoint (Group 1: 12 to <17 years) –
Hematology - Safety Population......................................................................................................... 50 
Table 14.3-3.1.1.2: Summary of Clinical Laboratory Data by Timepoint (Group 2: 6 to < 12 years) –
Hematology - Safety Population......................................................................................................... 51 
Table 14.3-3.1.1.3: Summary of Clinical Laboratory Data by Timepoint (Both Groups: 6 to < 17 
years) - Spine Surgery – Hematology - Safety Population ................................................................. 51 
Table 14.3-3.2.1.1: Summary of Clinical Laboratory Data by Timepoint (Group 1: 12 to <17 years) –
Chemistry - Safety Population ............................................................................................................ 51 
Table 14.3-3.2.1.2: Summary of Clinical Laboratory Data by Timepoint (Group 2: 6 to < 12 years) –
Chemistry - Safety Population ............................................................................................................ 51 
Table 14.3-3.2.1.3: Summary of Clinical Laboratory Data by Timepoint (Both Groups: 6 to < 17 
years) – Spine Surgery – Chemistry - Safety Population.................................................................... 51 
Table 14.3-3.3.1.1: Summary of Clinical Laboratory Data by Timepoint (Group 1: 12 to <17 years) –
Urinalysis - Safety Population ............................................................................................................ 51 
Table 14.3-3.3.1.2: Summary of Clinical Laboratory Data by Timepoint (Group 2: 6 to < 12 years) –
Urinalysis - Safety Population ............................................................................................................ 51 
Table 14.3-3.3.1.3: Summary of Clinical Laboratory Data by Timepoint (Both Groups: 6 to < 17 
years) - Spine Surgery – Urinalysis - Safety Population..................................................................... 51 
Table 14.3-3.4.1.1: Tabulation of Clinical Laboratory Data by Timepoint (Group 1: 12 to <17 years) 
– Urinalysis - Safety Population ......................................................................................................... 52 
Table 14.3-3.4.1.2: Tabulation of Clinical Laboratory Data by Timepoint (Group 2: 6 to < 12 years) –
Urinalysis - Safety Population ............................................................................................................ 52 
Table 14.3-3.4.1.3: Tabulation of Clinical Laboratory Data by Timepoint (Both Groups: 6 to < 17 
years) – Spine Surgery – Urinalysis - Safety Population.................................................................... 53 
Table 14.3-3.5.1.1: Tabulation of Clinical Laboratory Range by Timepoint (Group 1: 12 to <17 years) 
– Hematology - Safety Population...................................................................................................... 54 
Table 14.3-3.5.1.2: Tabulation of Clinical Laboratory Range by Timepoint (Group 2: 6 to < 12 years) 
– Hematology - Safety Population...................................................................................................... 54 
Table 14.3-3.5.1.3: Tabulation of Clinical Laboratory Range by Timepoint (Both Groups: 6 to < 17 
years) – Spine Surgery – Hematology - Safety Population................................................................. 54 
Table 14.3-3.6.1.1: Tabulation of Clinical Laboratory Range by Timepoint (Group 1: 12 to <17 years) 
– Chemistry - Safety Population ......................................................................................................... 54 
Table 14.3-3.6.1.2: Tabulation of Clinical Laboratory Range by Timepoint (Group 2: 6 to < 12 years) 
– Chemistry - Safety Population ......................................................................................................... 54 
Table 14.3-3.6.1.3: Tabulation of Clinical Laboratory Range by Timepoint (Both Groups: 6 to < 17 
years) - Spine Surgery – Chemistry - Safety Population .................................................................... 55 


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Table 14.3-3.7.1.1: Tabulation of Clinical Laboratory Range by Timepoint (Group 1: 12 to <17 years) 
– Urinalysis - Safety Population ......................................................................................................... 55 
Table 14.3-3.7.1.2: Tabulation of Clinical Laboratory Range by Timepoint (Group 2: 6 to < 12 years) 
– Urinalysis - Safety Population ......................................................................................................... 55 
Table 14.3-3.7.1.3: Tabulation of Clinical Laboratory Range by Timepoint (Both Groups: 6 to < 17 
years) – Spine Surgery – Urinalysis - Safety Population.................................................................... 55 
Table 14.3-4.1.1: Overview of Treatment-Emergent Adverse Events (TEAEs) (Group 1: 12 to <17 
years) - Safety Population................................................................................................................... 56 
Table 14.3-4.1.2: Overview of Treatment-Emergent Adverse Events (TEAEs) (Group 2: 6 to < 12 
years) - Safety Population................................................................................................................... 56 
Table 14.3-4.1.3: Overview of Treatment-Emergent Adverse Events (TEAEs) - Safety Population ........ 56 
Table 14.3-4.1.4: Overview of Treatment-Emergent Adverse Events (TEAEs) (Both Groups: 6 to < 
17 years) – Spine Surgery - Safety Population ................................................................................... 56 
Table 14.3-4.2.1: Summary of Incidence of Treatment-Emergent Adverse Events (TEAEs) (Group 1: 
12 to <17 years) - Safety Population................................................................................................... 57 
Table 14.3-4.2.2: Summary of Incidence of Treatment-Emergent Adverse Events (TEAEs) (Group 2: 
6 to < 12 years) - Safety Population.................................................................................................... 57 
Table 14.3-4.2.3: Summary of Incidence of Treatment-Emergent Adverse Events (TEAEs) (Both 
Groups: 6 to < 17 years) - Spine Surgery - Safety Population............................................................ 57 
Table 14.3-4.3.1: Summary of Incidence of Treatment-Emergent Adverse Events (TEAEs) by 
Severity (Group 1: 12 to <17 years) - Safety Population.................................................................... 58 
Table 14.3-4.3.2: Summary of Incidence of Treatment-Emergent Adverse Events (TEAEs) by 
Severity (Group 2: 6 to < 12 years) - Safety Population..................................................................... 58 
Table 14.3-4.3.3: Summary of Incidence of Treatment-Emergent Adverse Events (TEAEs) by 
Severity (Both Groups: 6 to < 17 years) – Spine Surgery - Safety Population................................... 58 
Table 14.3-4.4.1: Summary of Incidence of Treatment-Emergent Adverse Events (TEAEs) by 
Relationship to Study Drug (Group 1: 12 to <17 years) - Safety Population ..................................... 59 
Table 14.3-4.4.2: Summary of Incidence of Treatment-Emergent Adverse Events (TEAEs) by 
Relationship to Study Drug (Group 2: 6 to < 12 years) - Safety Population ...................................... 59 
Table 14.3-4.4.3: Summary of Incidence of Treatment-Emergent Adverse Events (TEAEs) by 
Relationship to Study Drug (Both Groups: 6 to < 17 years) – Spine Surgery - Safety Population .... 60 
Table 14.3-5.1.1: Summary of Incidence of Serious Treatment-Emergent Adverse Events (TEAEs) 
(Group 1: 12 to <17 years) - Safety Population .................................................................................. 60 
Table 14.3-5.1.2: Summary of Incidence of Serious Treatment-Emergent Adverse Events (TEAEs) 
(Group 2: 6 to < 12 years) - Safety Population ................................................................................... 60 
Table 14.3-5.1.3: Summary of Incidence of Serious Treatment-Emergent Adverse Events (TEAEs) 
(Both Groups: 6 to < 17 years) – Spine Surgery - Safety Population ................................................. 60 
Table 14.3-6.1.1: Summary of Incidence of Treatment-Emergent Adverse Events (TEAEs) of Special 
Interest (Group 1: 12 to <17 years) - Safety Population ..................................................................... 60 
Table 14.3-6.1.2: Summary of Incidence of Treatment-Emergent Adverse Events (TEAEs) of Special 
Interest (Group 2: 6 to < 12 years) - Safety Population ...................................................................... 60 
Table 14.3-6.1.3: Summary of Incidence of Treatment-Emergent Adverse Events (TEAEs) of Special 
Interest (Both Groups: 6 to < 17 years) – Spine Surgery - Safety Population .................................... 60 
Table 14.3-7.1.1: Tabulation of Incidence of Prior Medications (Group 1: 12 to <17 years) - Safety 
Population ........................................................................................................................................... 60 


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Table 14.3-7.1.2: Tabulation of Incidence of Prior Medications (Group 2: 6 to < 12 years) - Safety 
Population ........................................................................................................................................... 61 
Table 14.3-7.1.3: Tabulation of Incidence of Prior Medications (Both Groups: 6 to < 17 years) –
Spine Surgery - Safety Population...................................................................................................... 61 
Table 14.3-8.1.1: Tabulation of Incidence of Concomitant Medications (Group 1: 12 to <17 years) –
Safety Population ................................................................................................................................ 61 
Table 14.3-8.1.2: Tabulation of Incidence of Concomitant Medications (Group 2: 6 to < 12 years) –
Safety Population ................................................................................................................................ 61 
Table 14.3-8.1.3: Tabulation of Incidence of Concomitant Medications (Both Groups: 6 to < 17 
years) – Spine Surgery – Safety Population........................................................................................ 61 
Table 14.4-1.1: Summary of EXPAREL Pharmacokinetic Parameters (Group 1: 12 to <17 years) –
PK Population ..................................................................................................................................... 62 
Table 14.4-1.2: Summary of EXPAREL Pharmacokinetic Parameters (Group 2: 6 to < 12 years) –
Spine Surgery - PK Population ........................................................................................................... 62 
Table 14.4-1.3: Summary of EXPAREL Pharmacokinetic Parameters (Group 2: 6 to < 12 years) –
Cardiac Surgery - PK Population........................................................................................................ 62 
Table 14.4-1.4: Summary of EXPAREL Pharmacokinetic Parameters (Both Groups: 6 to < 17 years) 
– Spine Surgery - PK Population ........................................................................................................ 62 
Table 14.4-3.1: Summary of EXPAREL Pharmacokinetic Plasma Concentrations (ng/mL) (Group 1: 
12 to <17 years) – PK Population ....................................................................................................... 63 
Table 14.4-3.2: Summary of EXPAREL Pharmacokinetic Plasma Concentrations (ng/mL) (Group 2: 
6 to < 12 years) – Spine Surgery - PK Population .............................................................................. 63 
Table 14.4-3.3: Summary of EXPAREL Pharmacokinetic Plasma Concentrations (ng/mL) (Group 2: 
6 to < 12 years) – Cardiac Surgery - PK Population........................................................................... 63 
Table 14.4-3.4: Summary of EXPAREL Pharmacokinetic Plasma Concentrations (ng/mL) (Both 
Groups: 6 to < 17 years) – Spine Surgery - PK Population ................................................................ 63 


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Table 14.1-1.1.1: Summary of Subject Disposition (Group 1: 12 to <17 years) – All Screened Subjects 
 
EXPAREL 
4 mg/kg 
[N=xx] 
Bupivacaine HCl 
2 mg/kg 
[N=xx] 
Total 
[N=xx] 
Screened [1] 
 
 
xx 
 
 
 
 
Randomized 
xx 
xx 
xx 
  Not Treated 
xx 
xx 
xx 
  Treated 
xx 
xx 
xx 
 
 
 
 
Safety Population – n (%) [2]# 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
PK Population – n (%) [3]@ 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
Completed Study – n (%)@ 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
Discontinued from Study – n (%)@ 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Reasons for Discontinuation – n (%)@ 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
    Death – n (%)@ 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
    Adverse Event – n (%)@ 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
    Lack of Efficacy – n (%)@ 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
    Lost to Follow-up – n (%)@ 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
    Withdrawal by Subject – n (%)@ 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
    Other – n (%)@ 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
# = as treated; @ = as randomized; 
[1] Signed the informed consent form; [2] Received study drug and surgery; [3] Received study drug and provide at least 
one quantifiable plasma concentration 
Percentages based on number randomized. 
Source: list SAS datasets used to create table 
 
ddmmmyyyyThh:mm 
SAS X.Y 
 
program_name 
 
Note to programmer: For reasons for discontinuation only those reasons that appear in the data will appear 
on the table. Use this template also for tables: 
Table 14.1-1.1.2: Summary of Subject Disposition (Group 2: 6 to < 12 years) – All Screened Subjects 
Note to programmer: Replace treatment columns by Spine Surgery and Cardiac Surgery for this table. 


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Protocol: 402-C-319 
Table 14.1-2.1.1: Summary of Subject Demographics (Group 1: 12 to <17 years) - PK Population 
 
 
 
Statistic 
EXPAREL 
4 mg/kg 
[N=xx] 
Bupivacaine HCl 
2 mg/kg 
[N=xx] 
 
Total 
[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 (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Male 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
Ethnicity 
 
 
 
 
  Hispanic or Latino 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Not Hispanic or Latino 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
Race 
 
 
 
 
  American Indian/Alaska Native 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Asian 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Black/African American 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Native Hawaiian/Pacific Islander  
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Not Reported 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Other 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  White 
n (%) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Source: list SAS datasets used to create table 
 
ddmmmyyyyThh:mm 
SAS X.Y 
 
program_name 
 
Note to programmer: If subjects are missing data for a category (example Race), a missing subcategory 
should be added under the respective category. Use this template also for tables: 
 
Table 14.1-2.1.2: Summary of Subject Demographics (Group 2: 6 to < 12 years) - PK Population 
Note to programmer: Replace treatment columns by Spine Surgery and Cardiac Surgery for this table. 


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Table 14.1-2.2.1: Summary of Subject Demographics (Group 1: 12 to <17 years) - Safety Population 
 
Table 14.1-2.2.2: Summary of Subject Demographics (Group 2: 6 to < 12 years) - Safety Population 
Note to programmer: Parts 1 and 2 combined. Replace treatment columns by Spine Surgery and Cardiac Surgery 
for this table. 
 
 


Pacira Pharmaceuticals, Inc. 
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34 of 111 
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Protocol: 402-C-319 
Table 14.1-3.1.1: Summary of Subject Baseline Characteristics (Part 1, Group 1) - PK Population 
 
Statistic 
EXPAREL 
4 mg/kg 
[N=xx] 
Bupivacaine HCl 
2 mg/kg 
[N=xx] 
 
Total 
[N=xx] 
Neurological Assessments 
 
 
 
 
   Subject oriented 
 
 
 
 
    Yes 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
    No 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
    Not assessable 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
 
 
 
  Numb lips, tongue, mouth 
 
 
 
 
    Yes 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
    No 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
 
 
 
  Metallic taste 
 
 
 
 
    Yes 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
    No 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
 
 
 
  Problems hearing 
 
 
 
 
    Yes 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
    No 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
 
 
 
  Problems with vision 
 
 
 
 
    Yes 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
    No 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
 
 
 
  Muscle twitch 
 
 
 
 
    Yes 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
    No 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
 
 
 
ECG 
 
 
 
 
  Normal 
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%) 
NCS = Not clinically significant 
CS = Clinically significant 
Source: list SAS datasets used to create table 
 
ddmmmyyyyThh:mm 
SAS X.Y 
 
program_name 


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35 of 111 
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Protocol: 402-C-319 
Table 14.1-3.1.1: Summary of Subject Baseline Characteristics (Group 1: 12 to <17 years) - PK Population 
 
Statistic 
EXPAREL 
4 mg/kg 
[N=xx] 
Bupivacaine HCl 
2 mg/kg 
[N=xx] 
 
Total 
[N=xx] 
Baseline NRS Pain Score 
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 
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 
n (%) 
   xx (xx.x) 
   xx (xx.x) 
   xx (xx.x) 
 
 
 
 
 
Height (cm) 
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 
 
 
 
 
 
Weight (kg) 
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 
 
 
 
 
 
Source: list SAS datasets used to create table 
 
ddmmmyyyyThh:mm 
SAS X.Y 
 
program_name 
 
 
 


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36 of 111 
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Protocol: 402-C-319 
Table 14.1-3.1.1: Summary of Subject Baseline Characteristics (Group 1: 12 to <17 years) - PK Population 
 
Statistic 
EXPAREL 
4 mg/kg 
[N=xx] 
Bupivacaine HCl 
2 mg/kg 
[N=xx] 
 
Total 
[N=xx] 
Body Mass Index (kg/m2) 
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 
 
 
 
 
 
Heart Rate (bpm) 
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 
 
 
 
 
 
Systolic Blood Pressure (mmHg) 
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 
 
 
 
 
 
Diastolic Blood Pressure (mmHg) 
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 
 
 
 
 
 
Source: list SAS datasets used to create table 
 
ddmmmyyyyThh:mm 
SAS X.Y 
 
program_name 
 
 


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Protocol: 402-C-319 
Table 14.1-3.1.1: Summary of Subject Baseline Characteristics (Group 1: 12 to <17 years) - PK Population 
 
Statistic 
EXPAREL 
4 mg/kg 
[N=xx] 
Bupivacaine HCl 
2 mg/kg 
[N=xx] 
 
Total 
[N=xx] 
Temperature (ºC) 
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 
 
 
 
 
 
Oxygen Saturation (%) 
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 
 
 
 
 
 
Respiratory Rate (breaths/min) 
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 
 
 
 
 
 
Source: list SAS datasets used to create table 
 
ddmmmyyyyThh:mm 
SAS X.Y 
 
program_name 
 
 


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Statistical Analysis Plan 
 
 
CONFIDENTIAL 
38 of 111 
30 October 2019 
Note to programmer: 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 template also for tables: 
 
Table 14.1-3.1.2: Summary of Subject Baseline Characteristics (Group 2: 6 to < 12 years) - PK Population 
Note to programmer: Replace treatment columns by Spine Surgery and Cardiac Surgery, replace Baseline NRS 
Pain Score by Baseline CAS Pain Sore for this table. 
 
 
Table 14.1-3.2.1: Summary of Subject Baseline Characteristics (Group 1: 12 to <17 years) - Safety 
Population 
Note to programmer: Parts 1 and 2 combined. Exclude neurological assessments. 
 
 
Table 14.1-3.2.2: Summary of Subject Baseline Characteristics (Group 2: 6 to < 12 years) - Safety 
Population 
Note to programmer: Parts 1 and 2 combined. Replace treatment columns by Spine Surgery and Cardiac Surgery, 
replace Baseline NRS Pain Score by Baseline CAS Pain Sore for this table.  
 
 


Pacira Pharmaceuticals, Inc. 
402-C-319 
EXPAREL® 
Statistical Analysis Plan 
 
 
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39 of 111 
30 October 2019 
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Protocol: 402-C-319 
Table 14.1-4.1.1: Summary of Surgery Characteristics (Group 1: 12 to <17 years) - Safety Population 
Characteristic 
Statistic 
EXPAREL 
4 mg/kg 
[N=xx] 
Bupivacaine HCl 
2 mg/kg 
[N=xx] 
 
Total 
[N=xx] 
Duration of Surgery (hours) 
n 
xx 
xx 
xx 
 
Mean 
xx.x 
xx.x 
xx.x 
 
SD 
x.xx 
x.xx 
x.xx 
 
Median 
xx 
xx 
xx 
 
Minimum 
xx.x 
xx.x 
xx.x 
 
Maximum 
xx 
xx 
xx 
 
 
 
 
 
Total Incision Length (cm) 
n 
xx 
xx 
xx 
 
Mean 
xx.x 
xx.x 
xx.x 
 
SD 
x.xx 
x.xx 
x.xx 
 
Median 
xx 
xx 
xx 
 
Minimum 
xx.x 
xx.x 
xx.x 
 
Maximum 
xx 
xx 
xx 
Source: list SAS datasets used to create table 
 
ddmmmyyyyThh:mm 
SAS X.Y 
 
program_name 
Note to programmer: Parts 1 and 2 combined. 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 
template also for following table: 
 
Table 14.1-4.1.2: Summary of Surgery Characteristics (Group 2: 6 to < 12 years) - Safety Population 
Note to programmer: Replace treatment columns by Spine Surgery and Cardiac Surgery for this table.  


Pacira Pharmaceuticals, Inc. 
402-C-319 
EXPAREL® 
Statistical Analysis Plan 
 
 
CONFIDENTIAL 
40 of 111 
30 October 2019 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-319 
Table 14.1-5.1.1: Tabulation of Incidence of Intraoperative Medications (Group 1: 12 to <17 years) - Safety 
Population 
Anatomical Therapeutic Class (ATC) 
  Preferred Name 
EXPAREL 
4 mg/kg 
n (%) 
Bupivacaine HCl 
2 mg/kg 
n (%) 
 
Total 
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) 
 
 
 
 
ETC. 
 
 
 
Medications are coded using World Health Organization Drug Dictionary (WHO-DD) September 2018. 
Sorted by descending total incidence by ATC for Total column.  Subjects using the same intraoperative 
medication (PT) more than once or multiple medications within an ATC class are counted only once at each 
ATC summary level. 
Intraoperative medications are those indicated as such by the investigator. 
Subjects using the same medication more than once are counted only once at each summary level. 
Source: list SAS datasets used to create table 
 
ddmmmyyyyThh:mm 
SAS X.Y 
 
program_name 
Note to programmer: Parts 1 and 2 combined. Use this template also for table following. 
Table 14.1-5.1.2: Tabulation of Incidence of Intraoperative Medications (Group 2: 6 to < 12 years) - Safety 
Population 
Note to programmer: Parts 1 and 2 combined. Replace treatment columns by Spine Surgery and Cardiac Surgery 
for this table. 


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Table 14.2-1.1.1: Summary of Numeric Rating Scale Pain Intensity Scores (Group 1: 12 to <17 years) - Safety 
Population 
 
 
Time Point 
 
 
Statistic 
EXPAREL 
4 mg/kg 
[N=xx] 
Bupivacaine HCl 
2 mg/kg 
[N=xx] 
 
Screening 
n 
xx 
xx 
 
 
Mean 
xx.x 
xx.x 
 
 
SD 
x.xx 
x.xx 
 
 
Minimum 
xx 
xx 
 
 
Median 
xx.x 
xx.x 
 
 
Maximum 
xx 
xx 
 
 
 
 
 
 
4 hours 
n 
xx 
xx 
 
 
Mean 
xx.x 
xx.x 
 
 
SD 
x.xx 
x.xx 
 
 
Minimum 
xx 
xx 
 
 
Median 
xx.x 
xx.x 
 
 
Maximum 
xx 
xx 
 
 
 
 
 
 
8 hours 
n 
xx 
xx 
 
 
Mean 
xx.x 
xx.x 
 
 
SD 
x.xx 
x.xx 
 
 
Minimum 
xx 
xx 
 
 
Median 
xx.x 
xx.x 
 
 Maximum 
xx 
xx 
 
Source: list SAS datasets used to create table 
 
ddmmmyyyyThh:mm 
SAS X.Y 
 
program_name 
 
Note to programmer: Other timepoints for this table are: 12 hours, 24 hours, 36 hours, 48 hours, 60 hours, 
72 hours, 96 hours, and Hospital Discharge. Use this template also for tables: 
 
Table 14.2-1.1.2: Summary of Color Analog Scale Pain Intensity Scores (Group 2: 6 to < 12 years) - Safety 
Population 


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Note to programmer: Replace treatment columns by Spine Surgery and Cardiac Surgery for this table. 


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Table 14.2-2.1.1: Summary of AUC of Pain Intensity Scores (Group 1: 12 to <17 years) – Safety Population 
 
 
Parameter 
Statistic 
EXPAREL  
4 mg/kg  
[N=xx] 
Bupivacaine 
HCl 
2 mg/kg  
[N=xx] 
AUC(4-24) 
N 
 
xx 
 
xx 
 
Mean 
 
xxx.x 
 
xxx.x 
 
SD 
 
xxx.xx 
 
xxx.xx 
 
Median 
 
xxx.x 
 
xxx.x 
 
Minimum 
 
xx 
 
xx 
 
Maximum 
 
xxx 
 
xxx 
AUC = area under the curve calculated using the trapezoidal method; 
 
 
Source: list SAS datasets used to create table 
 
ddmmmyyyyThh:mm 
SAS X.Y 
 
program_name 
 
Note to programmer: Other parameters to include in this table: AUC(4-48), AUC(4-72), AUC(4-96) and AUC(4-
Hospital Discharge).  Use this template also for: 
 
Table 14.2-2.1.2: Summary of AUC of Pain Intensity Scores (Group 2: 6 to < 12 years) – Safety Population 
Note to programmer: Replace treatment columns by Spine Surgery and Cardiac Surgery for this table. 
 
 
 
 
 
 


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Table 14.2-3.1.1: Summary of Total Opioid Consumption (MED mg) (Group 1: 12 to <17 years) - Safety 
Population 
Time Period [1] 
Statistic 
     EXPAREL 
     4 mg/kg 
     [N=xx] 
     Bupivacaine HCl 
     2 mg/kg 
     [N=xx] 
0-24 hrs 
n 
xx 
xx 
 
Geometric Mean 
xx.x 
xx.x 
 
%CV 
x.xx 
x.xx 
 
Minimum 
xx 
xx 
 
Median 
xx.x 
xx.x 
 
Maximum 
xx 
xx 
 
 
 
 
0-48 hrs 
n 
xx 
xx 
 
Geometric Mean 
xx.x 
xx.x 
 
%CV 
x.xx 
x.xx 
 
Minimum 
xx 
xx 
 
Median 
xx.x 
xx.x 
 
Maximum 
xx 
xx 
 
 
 
 
0-72 hrs 
n 
xx 
xx 
 
Geometric Mean 
xx.x 
xx.x 
 
%CV 
x.xx 
x.xx 
 
Minimum 
xx 
xx 
 
Median 
xx.x 
xx.x 
 
Maximum 
xx 
xx 
[1] Time 0 is defined as the time of the end of surgery. 
Source: list SAS datasets used to create table 
 
ddmmmyyyyThh:mm 
SAS X.Y 
 
program_name 
 
Table 14.2-3.1.2: Summary of Total Opioid Consumption (MED mg) (Group 2: 6 to < 12 years) - Safety 
Population 
Note to programmer: Use preceding Table as template. Replace treatment columns by Spine Surgery and Cardiac 
Surgery for this table. 
 


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Table 14.2-4.1.1: Analysis of Time to First Postsurgical Opioid Medication Use (Group 1: 12 to <17 years) - 
Safety Population 
 
Statistic 
EXPAREL 
4 mg/kg 
[N=xx] 
Bupivacaine HCl 
2 mg/kg 
[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 First Rescue [1] 
 
 
 
  Quartiles [2] 
 
 
 
    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 
* indicates censored observation 
 
CI = confidence interval 
Subjects who are not administered an opioid rescue medication by 72 hours are censored at 72 hours after 
surgery or at the time of last follow-up, whichever is earliest. 
[1] Time 0 is defined as the time of the end of surgery. 
[2] Estimates from Kaplan-Meier analysis.  
Source: list SAS datasets used to create table 
 
ddmmmyyyyThh:mm 
SAS X.Y 
 
program_name 
 
Table 14.2-4.1.3: Analysis of Time to First Postsurgical Opioid Medication Use (Group 2: 6 to < 12 years) - 
Safety Population 
Note to programmer: Use preceding Table as template. Replace treatment columns by Spine Surgery and Cardiac 
Surgery for this table. 
 
 


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Table 14.3-1.1.1: Summary of Vital Signs (Group 1: 12 to <17 years) – Safety Population  
Vital Sign  
Timepoint  
Value  
Statistic  
EXPAREL 
4 mg/kg 
[N=xx]  
Bupivacaine HCl 
2 mg/kg 
[N=xx] 
 
Resting Heart Rate (bpm)  
Baseline  
Actual  
  
n  
xx  
xx  
 
 
  
Mean  
xx.x  
xx.x  
 
 
  
SD  
x.xx  
x.xx  
 
 
  
Minimum  
xx  
xx  
 
 
  
Median  
xx.x  
xx.x  
 
 
  
Maximum  
xx  
xx  
 
 
 
 
2 hours  
Actual  
n  
xx  
xx  
 
 
  
Mean  
xx.x  
xx.x  
 
 
  
SD  
x.xx  
x.xx  
 
 
  
Minimum  
xx  
xx  
 
 
  
Median  
xx.x  
xx.x  
 
 
  
Maximum  
xx  
xx  
 
 
 
 
 
Change from Baseline  
n  
xx  
xx  
 
 
  
Mean  
xx.x  
xx.x  
 
 
  
SD  
x.xx  
x.xx  
 
 
  
Minimum  
xx  
xx  
 
 
  
Median  
xx.x  
xx.x  
 
 
  
Maximum  
xx  
xx  
[1] Baseline (Day 1 prior to surgery) for subjects with data at the timepoint.  
Source: list SAS datasets used to create table  
  
ddmmmyyyyThh:mm  
SAS X.Y  
  
program_name  
  
Note to programmer: Vital signs are ‘Resting Heart Rate (bpm)’, ‘Systolic Blood Pressure (mmHg)’,  
‘Diastolic Blood Pressure (mmHg)’, ‘Temperature (ºC)’, ‘Oxygen Saturation (%) and Respiratory rate 
(breaths/min)’. Timepoints to appear on this table are, in order of appearance, 2, 4, 8, 12, 24, 36, 48, 60, 
72, and 96 hours, Hospital Discharge, and Day 30.  Don’t split timepoint across pages.  
 
Table 14.3-1.1.2: Summary of Vital Signs (Group 2: 6 to < 12 years) – Safety Population 


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47 of 111 
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Note to programmer: Use preceding Table as template. Replace treatment columns by Spine Surgery and Cardiac 
Surgery for this table. 
Table 14.3-1.1.3: Summary of Vital Signs (Both Groups: 6 to < 17 years) – Spine Surgery – Safety Population 
 
 
 


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Table 14.3-2.1.1: Summary of Neurological Assessments by Timepoint (Group 1: 12 to <17 years) - Safety 
Population 
  
 
Timepoint  
Assessment  
Score  
EXPAREL 
4 mg/kg 
[N=xx] 
 n (%) 
Bupivacaine HCl 
2 mg/kg 
[N=xx] 
 n (%) 
Screening  
Oriented?  
No  
xx (xx.x)  
xx (xx.x)  
  
 
Yes  
Not Assessable 
xx (xx.x)  
xx (xx.x) 
xx (xx.x)  
xx (xx.x) 
 
 
 
  
Numbness of lips, tongue or mouth  No  
xx (xx.x)  
xx (xx.x)  
  
 
Yes  
xx (xx.x)  
xx (xx.x)  
 
 
 
 
 
 
 
Metallic taste  
No  
xx (xx.x)  
xx (xx.x)  
Yes   
xx (xx.x)   
xx (xx.x)   
 
 
 
  
Hearing problems  
No  
xx (xx.x)  
xx (xx.x)  
Yes   
xx (xx.x)   
xx (xx.x)   
 
 
 
  
Vision problems  
No  
xx (xx.x)  
xx (xx.x)  
Yes   
xx (xx.x)   
xx (xx.x)   
 
 
 
  
Muscle twitching  
No  
xx (xx.x)  
xx (xx.x)  
  
 
Yes  
xx (xx.x)  
xx (xx.x)  
Etc.  
 
 
 
Source: list SAS datasets used to create table  
  
ddmmmyyyyThh:mm  
SAS X.Y  
  
program_name  
Note to programmer: Timepoints to appear on this table are, in order of appearance, Screening, and 2, 4, 8, 
12, 24, 36, 48, 60, 72, and 96 hours, Hospital Discharge, and Day 30.  Do not split a timepoint across 
pages. Do not split timepoints across pages.  
 
Use Table 14.3-2.1.1 as template. Replace treatment columns by Spine Surgery and Cardiac Surgery for these 
tables: 


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Table 14.3-2.1.2: Summary of Neurological Assessments by Timepoint (Group 2: 6 to < 12 years) - Safety 
Population 
Table 14.3-2.1.3: Summary of Neurological Assessments by Timepoint (Both Groups: 6 to < 17 years) – Spine 
Surgery - Safety Population 
 
 


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50 of 111 
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Table 14.3-3.1.1.1: Summary of Clinical Laboratory Data by Timepoint (Group 1: 12 to <17 years) – 
Hematology - Safety Population 
Laboratory parameter (units) 
 
 
Timepoint 
Value 
Statistic 
EXPAREL 
4 mg/kg 
[N=xx] 
Bupivacaine HCl 
2 mg/kg 
[N=xx] 
Baseline [1] 
Actual 
n 
xx 
xx 
 
 
Mean 
xx.x 
xx.x 
 
 
SD 
x.xx 
x.xx 
 
 
Minimum 
xx 
xx 
 
 
Median 
xx.x 
xx.x 
 
 
Maximum 
xx 
xx 
 
 
 
 
 
96 hours 
Actual 
n 
xx 
xx 
 
 
Mean 
xx.x 
xx.x 
 
 
SD 
x.xx 
x.xx 
 
 
Minimum 
xx 
xx 
 
 
Median 
xx.x 
xx.x 
 
 
Maximum 
xx 
xx 
 
 
 
 
 
 
Change  
n 
xx 
xx 
 
 
Mean 
xx.x 
xx.x 
 
 
SD 
x.xx 
x.xx 
 
 
Minimum 
xx 
xx 
 
 
Median 
xx.x 
xx.x 
 
 
Maximum 
xx 
xx 
[1] Baseline (Day 1 prior to surgery) for subjects with data at the timepoint. 
Source: list SAS datasets used to create table 
 
ddmmmyyyyThh:mm 
SAS X.Y 
 
program_name 
 
Note to programmer: See protocol for list of lab analytes.  Analytes should be sorted in alphabetical 
order. Use as template for following tables.  
 


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Table 14.3-3.1.1.2: Summary of Clinical Laboratory Data by Timepoint (Group 2: 6 to < 12 years) – 
Hematology - Safety Population 
Note to programmer: Replace treatment columns by Spine Surgery and Cardiac Surgery for this table. 
 
Table 14.3-3.1.1.3: Summary of Clinical Laboratory Data by Timepoint (Both Groups: 6 to < 17 years) - Spine 
Surgery – Hematology - Safety Population 
 
 
Table 14.3-3.2.1.1: Summary of Clinical Laboratory Data by Timepoint (Group 1: 12 to <17 years) – Chemistry 
- Safety Population 
 
 
Table 14.3-3.2.1.2: Summary of Clinical Laboratory Data by Timepoint (Group 2: 6 to < 12 years) – Chemistry 
- Safety Population 
Note to programmer: Replace treatment columns by Spine Surgery and Cardiac Surgery for this table. 
Table 14.3-3.2.1.3: Summary of Clinical Laboratory Data by Timepoint (Both Groups: 6 to < 17 years) – Spine 
Surgery – Chemistry - Safety Population 
 
 
Table 14.3-3.3.1.1: Summary of Clinical Laboratory Data by Timepoint (Group 1: 12 to <17 years) – 
Urinalysis - Safety Population 
 
Table 14.3-3.3.1.2: Summary of Clinical Laboratory Data by Timepoint (Group 2: 6 to < 12 years) – 
Urinalysis - Safety Population 
Note to programmer: Replace treatment columns by Spine Surgery and Cardiac Surgery for this table. For 
urinalysis results only numeric results will appear. 
 
Table 14.3-3.3.1.3: Summary of Clinical Laboratory Data by Timepoint (Both Groups: 6 to < 17 years) - Spine 
Surgery – Urinalysis - Safety Population 
 


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Table 14.3-3.4.1.1: Tabulation of Clinical Laboratory Data by Timepoint (Group 1: 12 to <17 years) – 
Urinalysis - Safety Population 
Analyte 
  Timepoint 
Category 
Statistic 
EXPAREL 
4 mg/kg 
[N=xx] 
Bupivacaine HCl 
2 mg/kg 
[N=xx] 
 
 
Analyte 1 
Baseline [1] 
Cat 1 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
Cat 2 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
Etc. 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
 
 
 
 
 
96 hours 
Cat 1 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
Cat 2 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
Etc. 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
 
 
 
 
Analyte 2 
Baseline [1] 
Cat 1 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
Cat 2 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
Etc. 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
 
 
 
 
 
96 hours 
Cat 1 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
Cat 2 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
Etc. 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
Etc. 
 
 
 
 
 
[1] Baseline (prior to surgery) for subjects with data at the timepoint.                                      
Source: list SAS datasets used to create table 
 
ddmmmyyyyThh:mm 
SAS X.Y 
 
program_name 
 
Note to programmer: Do not split timepoint statistics across pages, if possible.  Present all available lab 
analytes. Categories are the superset of those reported in the data for both timepoints combined.  All 
categories should appear for both timepoints with zeros (0) as counts where needed. Use as template for 
following table.  
 
Table 14.3-3.4.1.2: Tabulation of Clinical Laboratory Data by Timepoint (Group 2: 6 to < 12 years) – 
Urinalysis - Safety Population 
Note to programmer: Replace treatment columns by Spine Surgery and Cardiac Surgery for this table. 


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30 October 2019 
 
Table 14.3-3.4.1.3: Tabulation of Clinical Laboratory Data by Timepoint (Both Groups: 6 to < 17 years) – 
Spine Surgery – Urinalysis - Safety Population 
 
 
 
 


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54 of 111 
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Table 14.3-3.5.1.1: Tabulation of Clinical Laboratory Range by Timepoint (Group 1: 12 to <17 years) – 
Hematology - Safety Population 
Laboratory parameter (units) 
 
 
Timepoint 
Normal 
Range 
Statistic 
 EXPAREL 
 4 mg/kg 
  [N=xx] 
Bupivacaine HCl 
  2 mg/kg 
  [N=xx] 
Baseline 
Below 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
Normal 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
Above 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
 
 
 
 
96 hours 
Below 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
Normal 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
 
Above 
n (%) 
xxx (xx.x%) 
xxx (xx.x%) 
Source: list SAS datasets used to create table 
 
ddmmmyyyyThh:mm 
SAS X.Y 
 
program_name 
 
Note to programmer: Do not split timepoint statistics across pages.  Present all available analytes.  
Analytes should be sorted in alphabetical order.  Use this template also for tables: 
 
Table 14.3-3.5.1.2: Tabulation of Clinical Laboratory Range by Timepoint (Group 2: 6 to < 12 years) – 
Hematology - Safety Population 
Note to programmer: Replace treatment columns by Spine Surgery and Cardiac Surgery for this table. 
Table 14.3-3.5.1.3: Tabulation of Clinical Laboratory Range by Timepoint (Both Groups: 6 to < 17 years) – 
Spine Surgery – Hematology - Safety Population 
 
 
Table 14.3-3.6.1.1: Tabulation of Clinical Laboratory Range by Timepoint (Group 1: 12 to <17 years) – 
Chemistry - Safety Population 
 
Table 14.3-3.6.1.2: Tabulation of Clinical Laboratory Range by Timepoint (Group 2: 6 to < 12 years) – 
Chemistry - Safety Population 


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55 of 111 
30 October 2019 
Note to programmer: Replace treatment columns by Spine Surgery and Cardiac Surgery for this table. 
Table 14.3-3.6.1.3: Tabulation of Clinical Laboratory Range by Timepoint (Both Groups: 6 to < 17 years) - 
Spine Surgery – Chemistry - Safety Population 
 
Table 14.3-3.7.1.1: Tabulation of Clinical Laboratory Range by Timepoint (Group 1: 12 to <17 years) – 
Urinalysis - Safety Population 
 
Table 14.3-3.7.1.2: Tabulation of Clinical Laboratory Range by Timepoint (Group 2: 6 to < 12 years) – 
Urinalysis - Safety Population 
Note to programmer: Replace treatment columns by Spine Surgery and Cardiac Surgery for this table. For 
urinalysis results only numeric results will appear on this table. 
Table 14.3-3.7.1.3: Tabulation of Clinical Laboratory Range by Timepoint (Both Groups: 6 to < 17 years) – 
Spine Surgery – Urinalysis - Safety Population 
 
 
 


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Table 14.3-4.1.1: Overview of Treatment-Emergent Adverse Events (TEAEs) (Group 1: 12 to <17 years) - Safety 
Population 
Number of 
EXPAREL 
4 mg/kg 
[N=xx] 
n (%) 
Bupivacaine HCl 
2 mg/kg 
[N=xx] 
n (%) 
Subjects with Any TEAE 
xx (xx.x) 
xx (xx.x) 
  Maximum Severity of Mild 
xx (xx.x) 
xx (xx.x) 
  Maximum Severity of Moderate 
xx (xx.x) 
xx (xx.x) 
  Maximum Severity of Severe 
xx (xx.x) 
xx (xx.x) 
  At least one Related 
xx (xx.x) 
xx (xx.x) 
  At least one Serious 
xx (xx.x) 
xx (xx.x) 
  At least one TEAE of Special Interest 
xx (xx.x) 
xx (xx.x) 
 
 
 
Subjects Discontinued due to TEAE 
xx (xx.x) 
xx (xx.x) 
 
 
 
Died on Study 
xx (xx.x) 
xx (xx.x) 
Related TEAEs are those AEs indicated as ‘possible’, ‘probable’ or ‘definite’ related by the investigator 
on the AE CRF. 
Source: list SAS datasets used to create table 
 
ddmmmyyyyThh:mm 
SAS X.Y 
 
program_name 
Note to programmer: All categories on this table should appear, even if not present in the data.  
 
Table 14.3-4.1.2: Overview of Treatment-Emergent Adverse Events (TEAEs) (Group 2: 6 to < 12 years) - Safety 
Population 
Note to programmer: Table 14.3.5.1.1 as template. Change columns to Spine Surgery and Cardiac Surgery. 
Table 14.3-4.1.3: Overview of Treatment-Emergent Adverse Events (TEAEs) - Safety Population 
Note to programmer: Combine Table 14.3.5.1.1 and 14.3-5.1.2. Show as 4 columns in one Table  
Table 14.3-4.1.4: Overview of Treatment-Emergent Adverse Events (TEAEs) (Both Groups: 6 to < 17 years) – 
Spine Surgery - Safety Population 
 
 


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Table 14.3-4.2.1: Summary of Incidence of Treatment-Emergent Adverse Events (TEAEs) (Group 1: 12 to <17 
years) - Safety Population 
System Organ Class 
  Preferred Term 
EXPAREL 
4 mg/kg 
[N=xx] 
n (%) 
Bupivacaine HCl 
  2 mg/kg 
[N=xx] 
n (%) 
 
Subjects with at least one TEAE 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
SOC1 
xx (xx.x) 
xx (xx.x) 
 
  PT1.1 
xx (xx.x) 
xx (xx.x) 
 
  PT1.2 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
SOC2 
xx (xx.x) 
xx (xx.x) 
 
  PT2.1 
xx (xx.x) 
xx (xx.x) 
 
  PT2.2 
xx (xx.x) 
xx (xx.x) 
 
 
xx (xx.x) 
xx (xx.x) 
 
ETC. 
 
 
 
Adverse events coded using the Medical Dictionary for Regulatory Activities (MedDRA 21.1). 
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. 
Source: list SAS datasets used to create table 
 
ddmmmyyyyThh:mm 
SAS X.Y 
 
program_name 
Note to programmer: For tables presenting severity or related, if the severity or relationship is missing, 
then a sub-row will be added into the table for imputed versus severe or imputed versus related. Use this 
template also for following tables: 
 
Table 14.3-4.2.2: Summary of Incidence of Treatment-Emergent Adverse Events (TEAEs) (Group 2: 6 to < 12 
years) - Safety Population 
Note to programmer: Replace treatment columns by Spine Surgery and Cardiac Surgery for this table. 
 
Table 14.3-4.2.3: Summary of Incidence of Treatment-Emergent Adverse Events (TEAEs) (Both Groups: 6 to < 17 
years) - Spine Surgery - Safety Population 


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Table 14.3-4.3.1: Summary of Incidence of Treatment-Emergent Adverse Events (TEAEs) by Severity (Group 1: 
12 to <17 years) - Safety Population 
System Organ Class 
  Preferred Term 
Severity 
 
EXPAREL 
4 mg/kg 
[N=xx] 
n (%) 
Bupivacaine HCl 
2 mg/kg 
[N=xx] 
n (%) 
Subjects with at least one TEAE 
Mild 
 
xx (xx.x) 
xx (xx.x) 
 
Moderate 
 
xx (xx.x) 
xx (xx.x) 
 
Severe 
 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
SOC1 
Mild 
 
xx (xx.x) 
xx (xx.x) 
 
Moderate 
 
xx (xx.x) 
xx (xx.x) 
 
Severe 
 
xx (xx.x) 
xx (xx.x) 
  PT1.1 
Mild 
 
xx (xx.x) 
xx (xx.x) 
 
Moderate 
 
xx (xx.x) 
xx (xx.x) 
 
Severe 
 
xx (xx.x) 
xx (xx.x) 
Adverse events coded using the Medical Dictionary for Regulatory Activities (MedDRA 21.1). 
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. 
Source: list SAS datasets used to create table 
 
ddmmmyyyyThh:mm 
SAS X.Y 
 
program_name 
Table 14.3-4.3.2: Summary of Incidence of Treatment-Emergent Adverse Events (TEAEs) by Severity (Group 2: 6 
to < 12 years) - Safety Population 
Note to programmer: Use preceding Table as template. Replace treatment columns by Spine Surgery and Cardiac 
Surgery for this table. 
 
Table 14.3-4.3.3: Summary of Incidence of Treatment-Emergent Adverse Events (TEAEs) by Severity (Both 
Groups: 6 to < 17 years) – Spine Surgery - Safety Population 
 
 
 
 


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Table 14.3-4.4.1: Summary of Incidence of Treatment-Emergent Adverse Events (TEAEs) by Relationship to 
Study Drug (Group 1: 12 to <17 years) - Safety Population 
System Organ Class 
  Preferred Term 
Relation 
EXPAREL 
4 mg/kg 
[N=xx] 
n (%) 
Bupivacaine HCl 
2 mg/kg 
[N=xx] 
n (%) 
 
Subjects with at least one TEAE 
Unrelated 
xx (xx.x) 
xx (xx.x) 
 
 
Unlikely 
xx (xx.x) 
xx (xx.x) 
 
 
Possible 
xx (xx.x) 
xx (xx.x) 
 
 
Probable 
xx (xx.x) 
xx (xx.x) 
 
 
Definite 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
SOC1 
Unrelated 
xx (xx.x) 
xx (xx.x) 
 
 
Unlikely 
xx (xx.x) 
xx (xx.x) 
 
 
Possible 
xx (xx.x) 
xx (xx.x) 
 
 
Probable 
xx (xx.x) 
xx (xx.x) 
 
 
Definite 
xx (xx.x) 
xx (xx.x) 
 
  PT1.1 
Unrelated 
xx (xx.x) 
xx (xx.x) 
 
 
Unlikely 
xx (xx.x) 
xx (xx.x) 
 
Adverse events coded using the Medical Dictionary for Regulatory Activities (MedDRA 21.1). 
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. 
Source: list SAS datasets used to create table 
 
ddmmmyyyyThh:mm 
SAS X.Y 
 
program_name 
Note to programmer: For tables presenting severity or related, if the severity or relationship is missing, 
then a sub-row will be added into the table for imputed versus severe or imputed versus related. For 
related tables add the following footnote to the table, “Related TEAEs are those AEs indicated as 
‘possible’, ‘probable’ or ‘definite’ related by the investigator on the AE CRF.” 
 
Table 14.3-4.4.2: Summary of Incidence of Treatment-Emergent Adverse Events (TEAEs) by Relationship to 
Study Drug (Group 2: 6 to < 12 years) - Safety Population 
Note to programmer: Use preceding Table as template. Replace treatment columns by Spine Surgery and Cardiac 
Surgery for this table. 
 


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Note to programmer: Replace treatment columns by Spine Surgery and Cardiac Surgery for all Tables ending in 
“2”.  
Table 14.3-4.4.3: Summary of Incidence of Treatment-Emergent Adverse Events (TEAEs) by Relationship to 
Study Drug (Both Groups: 6 to < 17 years) – Spine Surgery - Safety Population 
 
Note to programmer: Use mock-up 14.3-4.2.1 for the following: 
Table 14.3-5.1.1: Summary of Incidence of Serious Treatment-Emergent Adverse Events (TEAEs) (Group 1: 12 to 
<17 years) - Safety Population 
 
Table 14.3-5.1.2: Summary of Incidence of Serious Treatment-Emergent Adverse Events (TEAEs) (Group 2: 6 to 
< 12 years) - Safety Population 
 
Table 14.3-5.1.3: Summary of Incidence of Serious Treatment-Emergent Adverse Events (TEAEs) (Both Groups: 6 
to < 17 years) – Spine Surgery - Safety Population 
 
Note to programmer: Use mock-up 14.3-4.2.1 for the following: 
Table 14.3-6.1.1: Summary of Incidence of Treatment-Emergent Adverse Events (TEAEs) of Special Interest 
(Group 1: 12 to <17 years) - Safety Population 
 
Table 14.3-6.1.2: Summary of Incidence of Treatment-Emergent Adverse Events (TEAEs) of Special Interest 
(Group 2: 6 to < 12 years) - Safety Population 
 
Table 14.3-6.1.3: Summary of Incidence of Treatment-Emergent Adverse Events (TEAEs) of Special Interest 
(Both Groups: 6 to < 17 years) – Spine Surgery - Safety Population 
 
Note to programmer: Use mock-up 14.1-5.1.1 for the following: 
Table 14.3-7.1.1: Tabulation of Incidence of Prior Medications (Group 1: 12 to <17 years) - Safety 
Population 
 


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Table 14.3-7.1.2: Tabulation of Incidence of Prior Medications (Group 2: 6 to < 12 years) - Safety 
Population 
 
Note to programmer: On these tables change the footnote ‘Intraoperative medications are those indicated as 
such by the investigator’ to read ‘Prior medications are those stopped before start of study drug 
administration.’ 
Table 14.3-7.1.3: Tabulation of Incidence of Prior Medications (Both Groups: 6 to < 17 years) – Spine 
Surgery - Safety Population 
 
Table 14.3-8.1.1: Tabulation of Incidence of Concomitant Medications (Group 1: 12 to <17 years) – Safety 
Population.  
 
Table 14.3-8.1.2: Tabulation of Incidence of Concomitant Medications (Group 2: 6 to < 12 years) – Safety 
Population.  
 
Note to programmer: On these tables change the footnote ‘Intraoperative medications are those indicated as 
such by the investigator’ to read ‘Concomitant medications are those taken between the start of study drug 
administration and discharge from study and are not designated intraoperative medications.’ Note that a 
concomitant medication can start prior to start of study drug and be ongoing. 
Table 14.3-8.1.3: Tabulation of Incidence of Concomitant Medications (Both Groups: 6 to < 17 years) – Spine 
Surgery – Safety Population.  
 
 
 


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Table 14.4-1.1: Summary of EXPAREL Pharmacokinetic Parameters (Group 1: 12 to <17 years) – PK Population 
EXPAREL 
Bupivacaine HCl 
Statistic 
[N=xx] 
[N=xx] 
AUC(0-inf) (hr*ng/mL) 
n 
xx 
xx 
Mean (%CV) 
xx.x (xx.x) 
xx.x (xx.x) 
SD 
x.xx 
x.xx 
Median 
xx.x 
xx.x 
Geometric Mean (%CV) 
xx.x 
xx.x 
Minimum, Maximum 
xx, xx 
xx, xx 
p-value * 
0.xxx 
 
AUC(0-last) (hr*ng/mL) 
n 
xx 
xx 
Mean (%CV) 
xx.x (xx.x) 
xx.x (xx.x) 
SD 
x.xx 
x.xx 
Median 
xx.x 
xx.x 
Geometric Mean (%CV) 
xx.x 
xx.x 
Minimum, Maximum 
xx, xx 
xx, xx 
p-value * 
0.xxx 
* 2-sided t-test     
Source: list SAS datasets used to create table 
 
ddmmmyyyyThh:mm 
SAS X.Y 
 
program_name 
 Note to programmer: Other Pharmacokinetic parameters to appear on this table are, in order of 
 appearance: Cmax (ng/mL), Tmax, t1/2el (hr), CL/F (L/hr), and Vd (L). Use this template also for tables: 
 
Table 14.4-1.2: Summary of EXPAREL Pharmacokinetic Parameters (Group 2: 6 to < 12 years) – Spine Surgery - 
PK Population 
Table 14.4-1.3: Summary of EXPAREL Pharmacokinetic Parameters (Group 2: 6 to < 12 years) – Cardiac Surgery 
- PK Population 
Table 14.4-1.4: Summary of EXPAREL Pharmacokinetic Parameters (Both Groups: 6 to < 17 years) – Spine 
Surgery - PK Population 


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Table 14.4-3.1: Summary of EXPAREL Pharmacokinetic Plasma Concentrations (ng/mL) (Group 1: 12 to <17 years) 
– PK Population 
EXPAREL 
Bupivacaine HCl 
Statistic 
[N=xx] 
[N=xx] 
15 Minutes 
n 
xx 
xx 
Mean (%CV) 
xx.x (xx.x) 
xx.x (xx.x) 
SD 
x.xx 
x.xx 
Median 
xx.x 
xx.x 
Geometric Mean (%CV) 
xx.x (xx.x) 
xx.x (xx.x) 
Minimum, Maximum 
xx, xx 
xx, xx 
 
30 Minutes 
n 
xx 
xx 
Mean (%CV) 
xx.x (xx.x) 
xx.x (xx.x) 
SD 
x.xx 
x.xx 
Median 
xx.x 
xx.x 
Geometric Mean (%CV) 
xx.x (xx.x) 
xx.x (xx.x) 
Minimum, Maximum 
xx, xx 
xx, xx 
 Source: list SAS datasets used to create table 
 
ddmmmyyyyThh:mm 
 SAS X.Y 
 
program_name 
Note to programmer: Other Pharmacokinetic Plasma Concentration timepoints to appear on this table are, in 
order of appearance: 45 Minutes, 1 – 1.25 Hours, 2 – 3 Hours, 10 – 18 Hours, 24 – 36 Hours, and 42 – 60 
Hours. Use this template also for tables: 
Table 14.4-3.2: Summary of EXPAREL Pharmacokinetic Plasma Concentrations (ng/mL) (Group 2: 6 to < 12 years) 
– Spine Surgery - PK Population 
Table 14.4-3.3: Summary of EXPAREL Pharmacokinetic Plasma Concentrations (ng/mL) (Group 2: 6 to < 12 years) 
– Cardiac Surgery - PK Population 
 
Note to programmer: Change timepoints to: 15 Minutes, 30 Minutes, 45 Minutes, 1 – 1.25 Hours, 15 – 25 
Hours, 30 – 40 Hours, 45 – 55 Hours, and 64 – 72 Hours.  
Table 14.4-3.4: Summary of EXPAREL Pharmacokinetic Plasma Concentrations (ng/mL) (Both Groups: 6 to < 17 
years) – Spine Surgery - PK Population 


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12. TABLE OF CONTENTS FOR LISTING MOCK-UPS
Listing 16.2-1.1.1: Subject Disposition (Group 1: 12 to <17 years) – All Subjects ................................... 67 
Listing 16.2-1.1.2: Subject Disposition (Group 2: 6 to < 12 years) – All Subjects .................................... 67 
Listing 16.2-1.1.3: Screen Failures............................................................................................................. 68 
Listing 16.2-2.1.1: Randomization and Populations (Group 1: 12 to <17 years) – All Subjects................ 69 
Listing 16.2-2.1.2: Enrollment and Populations (Group 2: 6 to < 12 years) – All Subjects....................... 69 
Listing 16.2-3.1.1: Demographics (Group 1: 12 to <17 years) – All Subjects ........................................... 70 
Listing 16.2-3.1.2: Demographics (Group 2: 6 to < 12 years) – All Subjects ............................................ 70 
Listing 16.2-4.1.1: Height and Weight (Group 1: 12 to <17 years) – All Subjects .................................... 71 
Listing 16.2-4.1.2: Height and Weight (Group 2: 6 to < 12 years) – All Subjects ..................................... 71 
Listing 16.2-5.1.1: Surgery (Group 1: 12 to <17 years) – All Subjects...................................................... 72 
Listing 16.2-5.1.2: Surgery (Group 2: 6 to < 12 years) – All Subjects....................................................... 72 
Listing 16.2-6.1.1: Numeric Rating Scale at Rest Pain Intensity Score (Group 1: 12 to <17 years) –
All Subjects......................................................................................................................................... 73 
Listing 16.2-6.1.2: Color Analog Scale Pain Intensity Score (Group 2: 6 to < 12 years) – All Subjects... 73 
Listing 16.2-7.1.1.1: Opioid Medication Total Dose (MED mg) and Opioid-free Status (Group 1: 12 
to <17 years) - All Subjects................................................................................................................. 74 
Listing 16.2-7.1.1.2: Opioid Medication Total Dose (MED mg) and Opioid-free Status (Group 2: 6 to 
< 12 years) - All Subjects.................................................................................................................... 74 
Listing 16.2-7.2.1.1: Opioid Medication (Group 1: 12 to <17 years) – All Subjects ................................. 75 
Listing 16.2-7.2.1.2: Opioid Medication (Group 2: 6 to < 12 years) – All Subjects .................................. 75 
Listing 16.2-8.1.1: Day 7 Phone Call (Group 1: 12 to <17 years) – All Subjects ...................................... 76 
Listing 16.2-8.1.2: Day 7 Phone Call (Group 2: 6 to < 12 years) – All Subjects ....................................... 76 
Listing 16.2-8.1.3: Day 30 Visit (Group 1: 12 to <17 years) – All Subjects .............................................. 76 
Listing 16.2-8.1.4: Day 30 Visit (Group 2: 6 to < 12 years) – All Subjects............................................... 76 
Listing 16.2-9.1.1.1: EXPAREL Pharmacokinetic Concentrations (Raw) (Group 1: 12 to <17 years) –
All Subjects......................................................................................................................................... 77 
Listing 16.2-9.1.1.2: EXPAREL Pharmacokinetic Concentrations (Raw) (Group 2: 6 to < 12 years) –
Spine Surgery – All Subjects .............................................................................................................. 77 
Listing 16.2-9.1.1.3: EXPAREL Pharmacokinetic Concentrations (Raw) (Group 2: 6 to < 12 years) –
Cardiac Surgery – All Subjects........................................................................................................... 77 
Listing 16.2-9.3.1.1: Bupivacaine Pharmacokinetic Concentrations (Raw) (Group 1: 12 to <17 years) 
– All Subjects...................................................................................................................................... 77 
Listing 16.2-9.5.1.1: EXPAREL Pharmacokinetic Parameters (Group 1: 12 to <17 years) – PK 
Population ........................................................................................................................................... 78 
Listing 16.2-9.5.1.2: EXPAREL Pharmacokinetic Parameters (Group 2: 6 to < 12 years) – Spine 
Surgery – PK Population..................................................................................................................... 78 
Listing 16.2-9.5.1.3: EXPAREL Pharmacokinetic Parameters (Group 2: 6 to < 12 years) – Cardiac 
Surgery – PK Population..................................................................................................................... 78 
Listing 16.2-9.6.1.1: Bupivacaine Pharmacokinetic Parameters (Group 1: 12 to <17 years) – PK 
Population ........................................................................................................................................... 78 
Listing 16.2-10.1.1: Hematology (Group 1: 12 to <17 years) – All Subjects............................................. 79 
Listing 16.2-10.1.2: Hematology (Group 2: 6 to < 12 years) – All Subjects.............................................. 79 


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Listing 16.2-11.1.1: Chemistry (Group 1: 12 to <17 years) – All Subjects................................................ 79 
Listing 16.2-11.1.2: Chemistry (Group 2: 6 to < 12 years) – All Subjects................................................. 79 
Listing 16.2-12.1.1: Urinalysis – Numeric Results (Group 1: 12 to <17 years)– All Subjects................... 79 
Listing 16.2-12.1.2: Urinalysis – Numeric Results (Group 2: 6 to < 12 years)– All Subjects ................... 80 
Listing 16.2-13.1.1: Urinalysis – Character Results (Group 1: 12 to <17 years) – All Subjects................ 81 
Listing 16.2-13.1.2: Urinalysis – Character Results (Group 2: 6 to < 12 years) – All Subjects................. 81 
Listing 16.2-14.1.1: Vital Signs Assessment (Group 1: 12 to <17 years) – All Subjects........................... 82 
Listing 16.2-14.1.2: Vital Signs Assessment (Group 2: 6 to < 12 years) – All Subjects............................ 83 
Listing 16.2-15-1.1: Electrocardiogram Findings – Investigator Assessment (Group 1: 12 to <17 
years) – All Subjects ........................................................................................................................... 84 
Listing 16.2-15-1.2: Electrocardiogram Findings – Investigator Assessment (Group 2: 6 to < 12 
years) – All Subjects ........................................................................................................................... 84 
Listing 16.2-16.1.1: Neurological Assessment (Group 1: 12 to <17 years) – All Subjects........................ 85 
Listing 16.2-16.1.2: Neurological Assessment (Group 2: 6 to < 12 years) – All Subjects......................... 85 
Listing 16.2-17.1.1.1: All Adverse Events (Group 1: 12 to <17 years) – All Subjects .............................. 86 
Listing 16.2-17.1.1.2: All Adverse Events (Group 2: 6 to < 12 years) – All Subjects ............................... 86 
Listing 16.2-17.2.1.1.1: Treatment-emergent Adverse Events (Group 1: 12 to <17 years) – All 
Subjects............................................................................................................................................... 86 
Listing 16.2-17.2.1.1.2: Treatment-emergent Adverse Events (Group 2: 6 to < 12 years) – All 
Subjects............................................................................................................................................... 86 
Listing 16.2-17.2.2.1.1: Treatment-emergent Study Drug Related Adverse Events (Group 1: 12 to <17 
years) – All Subjects ........................................................................................................................... 87 
Listing 16.2-17.2.2.1.2: Treatment-emergent Study Drug Related Adverse Events (Group 2: 6 to < 12 
years) – All Subjects ........................................................................................................................... 87 
Listing 16.2-17.3.1.1: All Serious Adverse Events (Group 1: 12 to <17 years) – All Subjects ................. 87 
Listing 16.2-17.3.1.2: All Serious Adverse Events (Group 2: 6 to < 12 years) – All Subjects .................. 87 
Listing 16.2-17.4.1.1.1: Treatment-emergent Serious Adverse Events (Group 1: 12 to <17 years) – All 
Subjects............................................................................................................................................... 87 
Listing 16.2-17.4.1.1.2: Treatment-emergent Serious Adverse Events (Group 2: 6 to < 12 years) – All 
Subjects............................................................................................................................................... 87 
Listing 16.2-17.4.2.1.1: Treatment-emergent Study Drug Related Serious Adverse Events (Group 1: 
12 to <17 years) – All Subjects........................................................................................................... 87 
Listing 16.2-17.4.2.1.2: Treatment-emergent Study Drug Related Serious Adverse Events (Group 2: 6 
to < 12 years) – All Subjects............................................................................................................... 87 
Listing 16.2-17.5.1.1.1: Treatment-emergent Adverse Events of Special Interest, as Reported by 
Investigators (Group 1: 12 to <17 years) – All Subjects..................................................................... 87 
Listing 16.2-17.5.1.1.2: Treatment-emergent Adverse Events of Special Interest, as Reported by 
Investigators (Group 2: 6 to < 12 years) – All Subjects...................................................................... 87 
Listing 16.2-17.5.2.1.1: Treatment-emergent Study Drug Related Adverse Events of Special Interest 
(Group 1: 12 to <17 years) – All Subjects .......................................................................................... 87 
Listing 16.2-17.5.2.1.2: Treatment-emergent Study Drug Related Adverse Events of Special Interest 
(Group 2: 6 to < 12 years) – All Subjects ........................................................................................... 87 
Listing 16.2-17.5.3.1.1: Adverse Events of Special Interest, as Defined in the Protocol (Group 1: 12 to 
<17 years) – All Subjects.................................................................................................................... 89 


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Listing 16.2-17.5.3.1.2: Adverse Events of Special Interest, as Defined in the Protocol (Group 2: 6 to 
< 12 years) – All Subjects................................................................................................................... 89 
Listing 16.2-18.1.1.1: Prior Medications (Group 1: 12 to <17 years) – All Subjects................................. 90 
Listing 16.2-18.1.1.2: Prior Medications (Group 2: 6 to < 12 years) – All Subjects.................................. 90 
Listing 16.2-18.2.1.1: Concomitant Medications (Group 1: 12 to <17 years) – All Subjects .................... 90 
Listing 16.2-18.2.1.2: Concomitant Medications (Group 2: 6 to < 12 years) – All Subjects ..................... 90 
Listing 16.2-19.1.1: Medical/Surgical History (Group 1: 12 to <17 years) – All Subjects ........................ 91 
Listing 16.2-19.1.2: Medical/Surgical History (Group 2: 6 to < 12 years) – All Subjects......................... 91 
Listing 16.2-20.1.1: Intraoperative Medications (Group 1: 12 to <17 years) – All Subjects ..................... 92 
Listing 16.2-20.1.2: Intraoperative Medications (Group 2: 6 to < 12 years) – All Subjects ...................... 92 
Listing 16.2-21.1.1: Study Drug Administration (Group 1: 12 to <17 years) – All Subjects..................... 93 
Listing 16.2-21.1.2: Study Drug Administration (Group 2: 6 to < 12 years) – All Subjects...................... 93 
Listing 16.2-22.1.1: Urine Drug Screen, Alcohol Blood Test and Pregnancy Test (Group 1: 12 to <17 
years) – All Subjects ........................................................................................................................... 94 
Listing 16.2-22.1.2: Urine Drug Screen, Alcohol Blood Test and Pregnancy Test (Group 2: 6 to < 12 
years) – All Subjects ........................................................................................................................... 94 
Listing 16.2-23.1.1: Admission and Discharge (Group 1: 12 to <17 years) – All Subjects ....................... 95 
Listing 16.2-23.1.2: Admission and Discharge (Group 2: 6 to < 12 years) – All Subjects ........................ 95 
Listing 16.2-24.1.1: Informed Consent (Group 1: 12 to <17 years) – All Subjects.................................... 96 
Listing 16.2-24.1.2: Informed Consent (Group 2: 6 to < 12 years) – All Subjects..................................... 96 
Listing 16.2-25.1.1: Subject Eligibility (Group 1: 12 to <17 years) – All Subjects ................................... 97 
Listing 16.2-25.1.2: Subject Eligibility (Group 2: 6 to < 12 years) – All Subjects .................................... 97 
Listing 16.2-25a: Subject Eligibility Inclusion Criteria – All Subjects ...................................................... 98 
Listing 16.2-25b: Subject Eligibility Exclusion Criteria – All Subjects..................................................... 99 
Listing 16.2-26: Unique Adverse Event Terms and Associated Coded Terms ........................................ 100 
Listing 16.2-27: Unique Medication Terms and Associated Coded Terms.............................................. 101 
Listing 16.2-28.1.1: Protocol Deviations (Group 1: 12 to <17 years) – All Subjects............................... 102 
Listing 16.2-28.1.2: Protocol Deviations (Group 2: 6 to < 12 years) – All Subjects................................ 102 
Listing 16.2-29-1.1: Physical Exam (Group 1: 12 to <17 years) – All Subjects ...................................... 103 
Listing 16.2-29-1.2: Physical Exam (Group 2: 6 to < 12 years) – All Subjects ....................................... 103 


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Listing 16.2-1.1.1: Subject Disposition (Group 1: 12 to <17 years) – All Subjects 
TREATMENT: treatment-name 
Site Subject 
Part 
Date of 
Last Visit 
End of Study 
Status 
Specify 
 
 
 
 
 
 
xxx 
yyyy 
Part 1 
ddmmmyyyy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Part 2 
 
 
 
 
 
 
 
 
 
Source: list SAS datasets used to create table 
 
ddmmmyyyyThh:mm 
SAS X.Y 
 
program_name 
 
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 ddmmmyyyy’. For those reasons 
that also collected a specify text, that text belongs in the specify column. Use this template also for 
listing: 
 
Listing 16.2-1.1.2: Subject Disposition (Group 2: 6 to < 12 years) – All Subjects 
Note to programmer: Replace “TREATMENT” with “SURGERY TYPE”, followed by “Spine Surgery” or “Cardiac 
Surgery”.   
 
 


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Listing 16.2-1.1.3: Screen Failures 
Site 
Subject 
Date of 
Screening 
Reason(s) for Screen Failure 
 
 
 
 
 
xxx 
yyyy 
ddmmmyyyy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: list SAS datasets used to create table 
 
ddmmmyyyyThh:mm 
SAS X.Y 
 
program_name 
 
 


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Listing 16.2-2.1.1: Randomization and Populations (Group 1: 12 to <17 years) – All Subjects 
TREATMENT: treatment-name 
 
 
 
Randomization 
       Population 
Site Subject 
Part 
Date and Time 
Number 
Safety 
PK 
 
 
 
 
 
 
 
xxx 
yyyy 
Part 1 
ddmmmyyyyThh:mm 
xxxxx 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Part 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: list SAS datasets used to create table 
 
ddmmmyyyyThh:mm 
SAS X.Y 
 
program_name 
 
Note to programmer: Population will by ‘Y’ if subject in set, blank otherwise. Use this template also for 
listing: 
Listing 16.2-2.1.2: Enrollment and Populations (Group 2: 6 to < 12 years) – All Subjects 
Note to programmer: Change “Randomization” column header to “Enrollment”. 
 
 


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Listing 16.2-3.1.1: Demographics (Group 1: 12 to <17 years) – All Subjects 
TREATMENT: treatment-name 
 
Subject 
 
 
 
 
 
 
Site 
Number 
Init. 
Birth Date 
Age(yrs) 
Sex 
Race 
Ethnicity 
ASA Class 
 
 
 
 
 
 
 
 
xxx 
yyyy 
AMZ 
ddmmmyyyy 
xx 
X 
xxxxxxxxxxx 
xxxxxxxxx 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The following subjects were not placed in the correct group according to their age: xxxx, xxxx, . 
Source: list SAS datasets used to create table 
 
ddmmmyyyyThh:mm 
SAS X.Y 
 
program_name 
 
Note to programmer: If race is ‘other’ then race should be ‘Other: other-specify-text’. Use this 
template also for listing: 
Listing 16.2-3.1.2: Demographics (Group 2: 6 to < 12 years) – All Subjects 
 
 


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Protocol: 402-C-319 
Listing 16.2-4.1.1: Height and Weight (Group 1: 12 to <17 years) – All Subjects 
TREATMENT: treatment-name 
 
 
 
 
 
 
Body Mass 
Site 
Subject 
 
Collection Date 
Height (cm) 
Weight (kg) 
Index 
(kg/m2) 
 
 
 
 
 
 
xxx 
yyyy 
 
ddmmmyyyyThh:mm 
xxx.X 
xxx.X 
xx.X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: list SAS datasets used to create table 
 
ddmmmyyyyThh:mm 
SAS X.Y 
 
program_name 
 
Note to programmer: Use this template also for listing: 
Listing 16.2-4.1.2: Height and Weight (Group 2: 6 to < 12 years) – All Subjects 
 
 


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402-C-319 
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Statistical Analysis Plan 
 
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Protocol: 402-C-319 
Listing 16.2-5.1.1: Surgery (Group 1: 12 to <17 years) – All Subjects 
TREATMENT: treatment-name 
Site 
Subject 
Date 
Start 
Time 
Stop 
Time 
Duration 
(hrs) 
Procedure 
Name 
Incision 
Length 
(cm) 
Intraoperative 
Medications 
Administered? 
 
 
 
 
 
 
 
xxx 
yyyy 
ddmmmyyyy 
HH:MM 
HH:MM 
X.X 
xxxxx 
xx.X 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: list SAS datasets used to create table 
 
ddmmmyyyyThh:mm 
SAS X.Y 
 
program_name 
 
Note to programmer: If anesthesia type is ‘other’ then text should read ‘other: specify-text’. Procedure 
Name is ‘Cardiac’ or ‘Spine’. Use this template also for listing: 
 
Listing 16.2-5.1.2: Surgery (Group 2: 6 to < 12 years) – All Subjects 
 
 
 


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402-C-319 
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Statistical Analysis Plan 
 
CONFIDENTIAL 
73 of 111 
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Protocol: 402-C-319 
Listing 16.2-6.1.1: Numeric Rating Scale at Rest Pain Intensity Score (Group 1: 12 to <17 years) – All 
Subjects 
TREATMENT: treatment-name 
 
 
 
Time From Dose 
 
   
Site 
Subject 
Date and Time 
Scheduled(hr) 
Actual(hr) 
Deviation(hrs) Pain Score    
 
 
 
 
 
 
 
xxx 
yyyy 
ddmmmyyyyThh:mm 
xx.xx 
xx.xx 
xxxx 
xx.x 
   
 
 
ddmmmyyyyThh:mm 
Day 1 Pre-op  
xx.xx 
xxxx 
xx.x 
   
 
 
ddmmmyyyyThh:mm * 
4 hours  
xx.xx 
xxxx 
xx.x 
   
 
 
ND 
8 hours  
 
 
 
   
 
 
ddmmmyyyyThh:mm 
12 hours 
xx.xx 
xxxx 
xx.x 
   
 
 
ddmmmyyyyThh:mm 
Unscheduled 
xx.xx 
xxxx 
xx.x 
   
 
 
ddmmmyyyyThh:mm 
… 
xx.xx 
xxxx 
xx.x 
   
 
 
ddmmmyyyyThh:mm 
Hospital discharge 
xx.xx 
xxxx 
xx.x 
   
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
   
ND=Not Done;  
* = out of window 
Source: list SAS datasets used to create table 
 
ddmmmyyyyThh:mm 
SAS X.Y 
 
program_name 
 
Note to programmer: Sort by collection date and time. If Pain Intensity Score 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. An asterisk (*) will be 
placed next to the deviation if an assessment is out of window.  See Table of Time and Events for windows. 
Use this template also for listing: 
 
Listing 16.2-6.1.2: Color Analog Scale Pain Intensity Score (Group 2: 6 to < 12 years) – All Subjects 
 


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402-C-319 
EXPAREL® 
Statistical Analysis Plan 
 
CONFIDENTIAL 
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Protocol: 402-C-319 
Listing 16.2-7.1.1.1: Opioid Medication Total Dose (MED mg) and Opioid-free Status (Group 1: 12 to <17 
years) - All Subjects 
TREATMENT: treatment-name 
Site 
Subject 
0-24 hrs [1] 
0-48 hrs [1] 
0-72 hrs [1] 
Opioid-Free 
 
 
 
 
 
 
xxx 
yyyy 
xxxx.x 
xxxx.x 
xxxx.x 
NO 
xxx 
yyyy 
- 
- 
- 
YES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total dose is dose from end of surgery through timepoint. 
[1] Time 0 is defined as the time of the end of surgery. 
Source: list SAS datasets used to create table 
 
ddmmmyyyyThh:mm 
SAS X.Y 
 
program_name 
 
Note to programmer: Use this template also for listing: 
Listing 16.2-7.1.1.2: Opioid Medication Total Dose (MED mg) and Opioid-free Status (Group 2: 6 to < 12 
years) - All Subjects 
 
 


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402-C-319 
EXPAREL® 
Statistical Analysis Plan 
 
CONFIDENTIAL 
75 of 111 
30 October 2019 
Pacira Pharmaceuticals 
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Protocol: 402-C-319 
Listing 16.2-7.2.1.1: Opioid Medication (Group 1: 12 to <17 years) – All Subjects 
TREATMENT: treatment-name 
Site 
Subject 
Date and Time 
Time to  
Rescue (hr) 
Medication 
Dose 
(units) 
Conversion 
Factor 
Dose 
(MED 
mg) 
Route 
 
 
 
 
 
 
 
 
 
xxx 
yyyy 
ddmmmyyyyThh:mm 
xxx.x 
xxxxxxxxxxxx xx(xxxx) 
x.xx 
xxx.x xxxxxxx  
 
 
ddmmmyyyyThh:mm 
xxx.x 
xxxxxxxxxxxx xx(xxxx) 
x.xx 
xxx.x xxxxxxx  
 
 
ddmmmyyyyThh:mm 
xxx.x 
xxxxxxxxxxxx xx(xxxx) 
x.xx 
xxx.x xxxxxxx  
 
 
ddmmmyyyyThh:mm 
xxx.x 
xxxxxxxxxxxx xx(xxxx) 
x.xx 
xxx.x xxxxxxx  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Time to rescue is time from end of surgery to rescue medication dose. 
Source: list SAS datasets used to create table 
 
ddmmmyyyyThh:mm 
SAS X.Y 
 
program_name 
 
Note to programmer: Medication should be preferred term.  If medication or route is ‘Other’, text should 
read ‘Other: specify-text’.  Sort by date and time within subject. Use this template also for listing: 
 
Listing 16.2-7.2.1.2: Opioid Medication (Group 2: 6 to < 12 years) – All Subjects 
 
 
 
 
 


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402-C-319 
EXPAREL® 
Statistical Analysis Plan 
 
CONFIDENTIAL 
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30 October 2019 
Pacira Pharmaceuticals 
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Protocol: 402-C-319 
Listing 16.2-8.1.1: Day 7 Phone Call (Group 1: 12 to <17 years) – All Subjects 
TREATMENT: treatment-name 
  
 
 
 
 
Day 7 Phone Call 
 
Number of pain-
related 
 
 
 
Site 
Subject 
Date 
Schedule 
(days) 
Actual 
(days) 
Deviation 
(days) 
 
Phone 
Calls 
Office 
Visits  
Number of ER 
Visits 
AE Assessed 
 
 
 
 
 
 
 
 
XXX 
YYYY 
DDMONYYYY 
7 
XX.X 
XX.X 
 
XX 
XX 
 
XXXX 
Yes 
XXX 
YYYY 
DDMONYYYY 
7 
XX.X 
XX.X 
 
XX 
XX 
 
XXXX 
No 
XXX 
YYYY 
DDMONYYYY 
7 
XX.X 
XX.X 
 
XX 
XX 
 
XXXX 
No 
 
 
 
 
 
 
 
 
 
 
 
 
ER = Emergency Department 
Source: list SAS datasets used to create table 
 
DDMONYYYYTHH:MM 
SAS X.Y  
Note to programmer: Sort by date and time within subject. Use this template also for listing: 
 
Listing 16.2-8.1.2: Day 7 Phone Call (Group 2: 6 to < 12 years) – All Subjects 
Note to programmer: Replace treatment columns by Spine Surgery and Cardiac Surgery for this table. 
 
Listing 16.2-8.1.3: Day 30 Visit (Group 1: 12 to <17 years) – All Subjects 
Note to programmer: Change “Day 7 Phone Call” column to “Day 30 Visit”. 
 
Listing 16.2-8.1.4: Day 30 Visit (Group 2: 6 to < 12 years) – All Subjects 
Note to programmer: Change “Day 7 Phone Call” column to “Day 30 Visit”. Replace treatment columns by Spine 
Surgery and Cardiac Surgery for this table. 
 
 


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402-C-319 
EXPAREL® 
Statistical Analysis Plan 
 
CONFIDENTIAL 
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30 October 2019 
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Protocol: 402-C-319 
Listing 16.2-9.1.1.1: EXPAREL Pharmacokinetic Concentrations (Raw) (Group 1: 12 to <17 years) – All 
Subjects 
Site 
Subject 
Scheduled 
Timepoint 
(hrs) 
Date and Time 
Actual 
(hrs) 
Deviation 
(hrs) 
Concentration 
Original 
(ng/mL) 
 
 
 
 
 
 
 
xxx 
yyyy 
xx 
yyyy-MM-DDThh:mm 
- 
- 
xxxx.x 
 
 
xx 
yyyy-MM-DDThh:mm 
xx.x 
xx.x 
xxxx.x 
 
 
xx 
yyyy-MM-DDThh:mm 
xx.x 
xx.x 
xxxx.x 
 
 
xx-xx 
yyyy-MM-DDThh:mm 
xx.x 
xx.x 
xxxx.x 
 
 
xx-xx 
yyyy-MM-DDThh:mm 
xx.x 
xx.x 
xxxx.x 
 
 
xx-xx 
yyyy-MM-DDThh:mm 
xx.x 
xx.x 
xxxx.x 
 
 
xx-xx 
yyyy-MM-DDThh:mm 
xx.x 
xx.x 
xxxx.x 
 
 
xx-xx 
yyyy-MM-DDThh:mm 
xx.x 
xx.x 
xxxx.x 
 
 
 
 
 
 
 
BLOQ = Below limit of quantification. ND = Not determined. 
Source: list SAS datasets used to create table 
 
ddmmmyyyyThh:mm 
SAS X.Y 
 
program_name 
 
Note to programmer: Scheduled time points are different for spine and cardiac surgeries. Sort by date and 
time within subject. Use this template also for listings: 
Listing 16.2-9.1.1.2: EXPAREL Pharmacokinetic Concentrations (Raw) (Group 2: 6 to < 12 years) – Spine 
Surgery – All Subjects 
Listing 16.2-9.1.1.3: EXPAREL Pharmacokinetic Concentrations (Raw) (Group 2: 6 to < 12 years) – Cardiac 
Surgery – All Subjects 
Listing 16.2-9.3.1.1: Bupivacaine Pharmacokinetic Concentrations (Raw) (Group 1: 12 to <17 years) – All 
Subjects 
 
 


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Protocol: 402-C-319 
Listing 16.2-9.5.1.1: EXPAREL Pharmacokinetic Parameters (Group 1: 12 to <17 years) – PK Population 
Site Subject 
AUC(0-inf) 
(ng*hr/mL) 
AUC(0-last) 
(ng*hr/mL) 
Cmax 
(ng/mL) 
Tmax 
t1/2el 
(hr) 
CL/F 
(L/hr) 
Vd 
(L) 
 
 
 
 
 
 
 
 
 
xxx 
yyyy 
xxxx.xx 
xxxx.xx 
xxx.x 
x.xx 
x.xx 
xx.xx 
xx.xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ND = Not determined. 
Source: list SAS datasets used to create table 
 
ddmmmyyyyThh:mm 
SAS X.Y 
 
program_name 
 
Note to programmer: Sort by site and subject. Use this template also for listings: 
Listing 16.2-9.5.1.2: EXPAREL Pharmacokinetic Parameters (Group 2: 6 to < 12 years) – Spine Surgery – PK 
Population 
Listing 16.2-9.5.1.3: EXPAREL Pharmacokinetic Parameters (Group 2: 6 to < 12 years) – Cardiac Surgery – PK 
Population 
Listing 16.2-9.6.1.1: Bupivacaine Pharmacokinetic Parameters (Group 1: 12 to <17 years) – PK Population 
 
 


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402-C-319 
EXPAREL® 
Statistical Analysis Plan 
 
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Protocol: 402-C-319 
Listing 16.2-10.1.1: Hematology (Group 1: 12 to <17 years) – All Subjects 
TREATMENT: treatment-name 
 
 
 
 
 
 
 
Normal Range 
 
 
 
Subject Visit 
Date and Time 
Analyte (units) 
Low 
High 
Result Change Flag 
yyyy 
Screening 
ddmmmyyyyThh:mm 
xxxxxxxxxxxx (units) 
xxx.xx xxx.xx xxx.xx 
- 
H 
 
 
 
 
xxxxxxxxxxxx (units) 
xxx.xx xxx.xx xxx.xx 
- 
 
 
 
 
 
Xxxxxxxxxxxx (units) 
xxx.xx xxx.xx xxx.xx 
- 
L 
 
 
 
 
Xxxxxxxxxxxx (units) 
xxx.xx xxx.xx xxx.xx 
- 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline 
ddmmmyyyyThh:mm 
Xxxxxxxxxxxx (units) 
xxx.xx xxx.xx xxx.xx 
- 
 
 
 
 
 
Xxxxxxxxxxxx (units) 
xxx.xx xxx.xx xxx.xx 
- 
 
 
 
 
 
Xxxxxxxxxxxx (units) 
xxx.xx xxx.xx xxx.xx 
- 
L 
 
 
 
 
Xxxxxxxxxxxx (units) 
xxx.xx xxx.xx xxx.xx 
- 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
96 Hours 
ddmmmyyyyThh:mm 
xxxxxxxxxxxx (units) 
xxx.xx xxx.xx xxx.xx 
xx.X 
 
 
 
 
 
xxxxxxxxxxxx (units) 
xxx.xx xxx.xx xxx.xx 
xx.X 
 
 
 
 
 
xxxxxxxxxxxx (units) 
xxx.xx xxx.xx xxx.xx 
xx.X 
L 
 
 
 
 
xxxxxxxxxxxx (units) 
xxx.xx xxx.xx xxx.xx 
xx.X 
 
 
 
 
 
 
 
 
 
 
 
Flag: L=below normal range; H=above normal range. 
Source: list SAS datasets used to create table 
 
ddmmmyyyyThh:mm 
SAS X.Y 
 
program_name 
Note to programmer: Sort by date and time within subject and analyte alphabetically within date.  Change is 
only calculated for Day 10 visit. Use this template also for listings: 
Listing 16.2-10.1.2: Hematology (Group 2: 6 to < 12 years) – All Subjects  
Note to programmer: Replace “TREATMENT” with “SURGERY TYPE”, followed by “Spine Surgery” or “Cardiac 
Surgery”. 
Listing 16.2-11.1.1: Chemistry (Group 1: 12 to <17 years) – All Subjects  
Listing 16.2-11.1.2: Chemistry (Group 2: 6 to < 12 years) – All Subjects  
Note to programmer: Replace “TREATMENT” with “SURGERY TYPE”, followed by “Spine Surgery” or “Cardiac 
Surgery”. 
Listing 16.2-12.1.1: Urinalysis – Numeric Results (Group 1: 12 to <17 years)– All Subjects   


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EXPAREL® 
Statistical Analysis Plan 
 
CONFIDENTIAL 
80 of 111 
30 October 2019 
Listing 16.2-12.1.2: Urinalysis – Numeric Results (Group 2: 6 to < 12 years)– All Subjects  
Note to programmer: Replace “TREATMENT” with “SURGERY TYPE”, followed by “Spine Surgery” or “Cardiac 
Surgery”. 
 
 


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402-C-319 
EXPAREL® 
Statistical Analysis Plan 
 
CONFIDENTIAL 
81 of 111 
30 October 2019 
Pacira Pharmaceuticals 
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Protocol: 402-C-319 
Listing 16.2-13.1.1: Urinalysis – Character Results (Group 1: 12 to <17 years) – All Subjects 
TREATMENT: treatment-name 
 
Site 
Subject 
Visit 
Date and Time 
Analyte  
Normal Criteria 
Result 
Flag 
 
 
 
 
 
 
 
xxx 
yyyy 
Screening 
ddmmmyyyyThh:mm 
xxxxxxxxxxxxxxxX  
xxxxxxxx 
xxxxxxxx 
A 
 
 
 
 
xxxxxxxxxxxxxxxX  
xxxxxxxx 
xxxxxxxx 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline 
ddmmmyyyyThh:mm 
xxxxxxxxxxxxxxxX  
xxxxxxxx 
xxxxxxxx 
A 
 
 
 
 
xxxxxxxxxxxxxxxX  
xxxxxxxx 
xxxxxxxx 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 10 
ddmmmyyyyThh:mm 
xxxxxxxxxxxxxxxX  
xxxxxxxx 
xxxxxxxx 
 
 
 
 
 
xxxxxxxxxxxxxxxX  
xxxxxxxx 
xxxxxxxx 
 
 
 
 
 
 
 
 
 
Flag: A = abnormal. 
Source: list SAS datasets used to create table 
 
ddmmmyyyyThh:mm 
SAS X.Y 
 
program_name 
 
Note to programmer: Sort by date and time within subject and analyte alphabetically within date. Use this 
template also for listing: 
Listing 16.2-13.1.2: Urinalysis – Character Results (Group 2: 6 to < 12 years) – All Subjects 
Note to programmer: Replace “TREATMENT” with “SURGERY TYPE”, followed by “Spine Surgery” or “Cardiac 
Surgery”. 
 
 
 


Pacira Pharmaceuticals, Inc. 
402-C-319 
EXPAREL® 
Statistical Analysis Plan 
 
CONFIDENTIAL 
82 of 111 
30 October 2019 
Pacira Pharmaceuticals 
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Protocol: 402-C-319 
Listing 16.2-14.1.1: Vital Signs Assessment (Group 1: 12 to <17 years) – All Subjects 
TREATMENT: treatment-name 
 
 
 
 
Assessment 
 
 
Heart 
Rate 
(bpm) 
  Temp. 
  (ºC) 
SBP 
(mmHg) 
DBP 
(mmHg) 
  
Respirat
ory rate 
(breaths
/min) 
Oxygen 
Sat. (%) 
Site 
Subject 
Date and Time 
Schedule 
(hrs) 
Actual 
(hrs) 
Dev. 
(hrs) 
Actual 
(Change) 
 Actual 
(Change) 
Actual 
(Change) 
Actual 
(Change) 
 Actual 
(Change) 
Actual 
(Change) 
xxx 
yyyy 
ddmmmyyyyThh:mm 
Screening 
- 
- 
xx 
xx 
xxx 
xx 
xx 
xx 
 
 
ddmmmyyyyThh:mm 
Baseline 
- 
- 
xx 
xx 
xxx 
xx 
xx 
xx 
 
 
ddmmmyyyyThh:mm 
 
2 
 
xxx.xx 
 
xxx 
 
xx  
(-xx) 
xx  
(-xx) 
xxx 
(-xx) 
xx 
(-xx) 
xx 
(-xx) 
xx 
(-xx) 
 
 
ddmmmyyyyThh:mm 
 
4 
 
xxx.xx 
 
xxx 
 
xx  
(xx) 
xx  
(xx) 
xxx 
(xx) 
xx 
(xx) 
xx 
(xx) 
xx 
(xx) 
 
 
ddmmmyyyyThh:mm 
 
8 
 
xxx.xx 
 
xxx 
 
xx  
(xx) 
xx  
(xx) 
xxx 
(xx) 
xx 
(xx) 
xx 
(xx) 
xx 
(xx) 
 
 
ddmmmyyyyThh:mm 
 
12 
 
xxx.xx 
 
xxx 
 
xx H 
(xx) 
xx H 
(xx) 
xxx 
(xx) 
xx 
(xx) 
xx 
(xx) 
xx 
(xx) 
 
 
ddmmmyyyyThh:mm 
 
24 
 
xxx.xx 
 
xxx 
 
xx LI 
(xx) 
xx LI 
(xx) 
xxx 
(xx) 
xx 
(xx) 
xx 
(xx) 
xx 
(xx) 
 
 
ddmmmyyyyThh:mm 
 
36 
 
xxx.xx 
 
xxx 
 
xx  
(xx) 
xx  
(xx) 
xxx 
(xx) 
xx 
(xx) 
xx 
(xx) 
xx 
(xx) 
 
 
ddmmmyyyyThh:mm 
 
48 
 
xxx.xx 
 
xxx 
 
xx  
(xx) 
xx  
(xx) 
xxx 
(xx) 
xx 
(xx) 
xx 
(xx) 
xx 
(xx) 
 
 
ddmmmyyyyThh:mm 
 
60 
 
xxx.xx 
 
xxx 
 
xx  
(xx) 
xx  
(xx) 
xxx 
(xx) 
xx 
(xx) 
xx 
(xx) 
xx 
(xx) 
 
 
ddmmmyyyyThh:mm 
 
72 
 
xxx.xx 
 
xxx 
 
xx  
(xx) 
xx  
(xx) 
xxx 
(xx) 
xx 
(xx) 
xx 
(xx) 
xx 
(xx) 
 
 
ddmmmyyyyThh:mm 
 
96 
 
xxx.xx 
 
xxx 
 
xx  
(xx) 
xx  
(xx) 
xxx 
(xx) 
xx 
(xx) 
xx 
(xx) 
xx 
(xx) 
 
 
ddmmmyyyyThh:mm 
 
Hospital 
Discharge 
 
xxx.xx 
 
xxx 
 
xx  
(xx) 
xx  
(xx) 
xxx 
(xx) 
xx 
(xx) 
xx 
(xx) 
xx 
(xx) 
 
 
ddmmmyyyyThh:mm 
 
Day 30 
 
xxx.xx 
 
xxx 
 
xx  
(xx) 
xx  
(xx) 
xxx 
(xx) 
xx 
(xx) 
xx 
(xx) 
xx 
(xx) 
 
 
 
 
 
 
 
 
 
 
 
 
*=out of window; Change is change from baseline. 
Source: list SAS datasets used to create table 
 
ddmmmyyyyThh:mm 
SAS X.Y 
 
program_name 
 


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Statistical Analysis Plan 
 
CONFIDENTIAL 
83 of 111 
30 October 2019 
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. Use this template 
also for listing: 
Listing 16.2-14.1.2: Vital Signs Assessment (Group 2: 6 to < 12 years) – All Subjects 
Note to programmer: Replace “TREATMENT” with “SURGERY TYPE”, followed by “Spine Surgery” or “Cardiac 
Surgery”. 
 
 


Pacira Pharmaceuticals, Inc. 
402-C-319 
EXPAREL® 
Statistical Analysis Plan 
 
CONFIDENTIAL 
84 of 111 
30 October 2019 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-319 
Listing 16.2-15-1.1: Electrocardiogram Findings – Investigator Assessment (Group 1: 12 to <17 years) – All 
Subjects 
TREATMENT: treatment-name 
 
 
Assessment 
 
Site Subject 
Date and Time 
Schedule 
(hrs) 
 
 
Finding 
 
 
 
 
 
 
xxx 
yyyy 
ddmmmyyyyThh:mm 
Screening 
 
 
Normal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*=out of window 
 
Source: list SAS datasets used to create table 
 
ddmmmyyyyThh:mm 
SAS X.Y 
 
program_name 
 
Note to programmer: Sort by date and time within subject. Use this template also for listing: 
 
Listing 16.2-15-1.2: Electrocardiogram Findings – Investigator Assessment (Group 2: 6 to < 12 years) – All 
Subjects 
Note to programmer: Replace “TREATMENT” with “SURGERY TYPE”, followed by “Spine Surgery” or “Cardiac 
Surgery”. 
 
 


Pacira Pharmaceuticals, Inc. 
402-C-319 
EXPAREL® 
Statistical Analysis Plan 
 
CONFIDENTIAL 
85 of 111 
30 October 2019 
Pacira Pharmaceuticals 
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Protocol: 402-C-319 
Listing 16.2-16.1.1: Neurological Assessment (Group 1: 12 to <17 years) – All Subjects 
TREATMENT: treatment-name 
 
 
Assessment 
Question 
Site 
Subject 
Date and Time 
Schedule 
(hrs) 
Actual 
(hrs) 
Deviation 
(hrs) 
1 
2 
3 
4 
5 
6 
 
 
 
 
 
 
xxx 
yyyy 
ddmmmyyyyThh:mm 
Screening 
- 
- 
X 
X 
X 
X 
X 
X 
 
 
ddmmmyyyyThh:mm 
2 
xxx.xx 
xxx 
NA 
X 
X 
X 
X 
X 
 
 
ddmmmyyyyThh:mm 
4 
xxx.xx 
xxx 
X 
X 
X 
X 
X 
X 
 
 
ddmmmyyyyThh:mm 
8 
xxx.xx 
xxx 
X 
X 
X 
X 
X 
X 
 
 
ddmmmyyyyThh:mm 
12 
xxx.xx 
xxx 
NA 
X 
X 
X 
X 
X 
 
 
ddmmmyyyyThh:mm 
24 
xxx.xx 
xxx 
X 
X 
X 
X 
X 
X 
 
 
ddmmmyyyyThh:mm 
36 
xxx.xx 
xxx 
X 
X 
X 
X 
X 
X 
 
 
ddmmmyyyyThh:mm 
48 
xxx.xx 
xxx 
X 
X 
X 
X 
X 
X 
 
 
ddmmmyyyyThh:mm 
60 
xxx.xx 
xxx 
X 
X 
X 
X 
X 
X 
 
 
ddmmmyyyyThh:mm 
72 
xxx.xx 
xxx 
X 
X 
X 
X 
X 
X 
 
 
ddmmmyyyyThh:mm 
96 
xxx.xx 
xxx 
X 
X 
X 
X 
X 
X 
 
 
ddmmmyyyyThh:mm 
Hospital 
Discharge 
xxx.xx 
- 
X 
X 
X 
X 
X 
X 
 
 
ddmmmyyyyThh:mm 
Day 30 
xxx.xx 
xxx 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
*=out of window; NA=Not Assessable 
1) Is subject oriented? 
2) Do you have numbness of the lips, the tongue or around the mouth? 
3) Do you have a metallic taste in your mouth? 
4) Are you having problems with your hearing not related to the use of a hearing aid? 
5) Are you having problems with your vision not related to the use of eye glasses? 
6) Are your muscles twitching? 
Source: list SAS datasets used to create table 
 
ddmmmyyyyThh:mm 
SAS X.Y 
 
program_name 
 
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. Use this template 
also for listing: 
Listing 16.2-16.1.2: Neurological Assessment (Group 2: 6 to < 12 years) – All Subjects 
Note to programmer: Replace “TREATMENT” with “SURGERY TYPE”, followed by “Spine Surgery” or “Cardiac 
Surgery”. 


Pacira Pharmaceuticals, Inc. 
402-C-319 
EXPAREL® 
Statistical Analysis Plan 
 
CONFIDENTIAL 
86 of 111 
30 October 2019 
 
Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-319 
Listing 16.2-17.1.1.1: All Adverse Events (Group 1: 12 to <17 years) – All Subjects 
Treatment: treatment-name 
Site Subject 
TEAE Data Type 
Data 
xxx 
yyyy 
N 
Start (Day) 
ddmmmyyyyThh:mm (XX) 
 
 
 
Stop (Day) 
ddmmmyyyyThh:mm (XX) 
 
 
 
AE Number 
X 
 
 
 
System Organ Class 
xxxxxxxxxxxxxxxxxx 
 
 
 
  Preferred 
  xxxxxxxxxxxxxxxxxxxx 
 
 
 
    Verbatim 
    xxxxxxxxxxxxxxxxxxxxxX 
 
 
 
Severity 
xxxxxxxx 
 
 
 
Relationship to Study 
Drug 
xxxxxxxx 
 
 
 
Action Taken 
xxxxxxxxxxxxxxxxxxxxx 
 
 
 
Outcome 
xxxxxxxxxxxxxx 
 
 
 
Serious 
xxx 
 
 
 
  Serious Cause(s) 
  xxxxxxxxxxxxX 
 
 
 
 
  xxxxxxxxxxxxxxxxxxxxxX 
 
 
 
 
 
TEAE: Treatment-emergent AE (Y=TEAE/N=Not TEAE) 
Source: list SAS datasets used to create listing 
 
ddmmmyyyyThh:mm 
SAS X.Y 
 
program_name 
 
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 template also for listings: 
Listing 16.2-17.1.1.2: All Adverse Events (Group 2: 6 to < 12 years) – All Subjects 
Note to programmer: Replace “TREATMENT” with “SURGERY TYPE”, followed by “Spine Surgery” or “Cardiac 
Surgery”. 
Listing 16.2-17.2.1.1.1: Treatment-emergent Adverse Events (Group 1: 12 to <17 years) – All Subjects  
Listing 16.2-17.2.1.1.2: Treatment-emergent Adverse Events (Group 2: 6 to < 12 years) – All Subjects  
Note to programmer: Replace “TREATMENT” with “SURGERY TYPE”, followed by “Spine Surgery” or “Cardiac 
Surgery”. 


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Listing 16.2-17.2.2.1.1: Treatment-emergent Study Drug Related Adverse Events (Group 1: 12 to <17 years) – 
All Subjects  
Listing 16.2-17.2.2.1.2: Treatment-emergent Study Drug Related Adverse Events (Group 2: 6 to < 12 years) – 
All Subjects  
Note to programmer: Replace “TREATMENT” with “SURGERY TYPE”, followed by “Spine Surgery” or “Cardiac 
Surgery”. 
Listing 16.2-17.3.1.1: All Serious Adverse Events (Group 1: 12 to <17 years) – All Subjects  
Listing 16.2-17.3.1.2: All Serious Adverse Events (Group 2: 6 to < 12 years) – All Subjects  
Note to programmer: Replace “TREATMENT” with “SURGERY TYPE”, followed by “Spine Surgery” or “Cardiac 
Surgery”. 
Listing 16.2-17.4.1.1.1: Treatment-emergent Serious Adverse Events (Group 1: 12 to <17 years) – All 
Subjects  
Listing 16.2-17.4.1.1.2: Treatment-emergent Serious Adverse Events (Group 2: 6 to < 12 years) – All 
Subjects  
Note to programmer: Replace “TREATMENT” with “SURGERY TYPE”, followed by “Spine Surgery” or “Cardiac 
Surgery”. 
Listing 16.2-17.4.2.1.1: Treatment-emergent Study Drug Related Serious Adverse Events (Group 1: 12 to <17 
years) – All Subjects  
Listing 16.2-17.4.2.1.2: Treatment-emergent Study Drug Related Serious Adverse Events (Group 2: 6 to < 12 
years) – All Subjects  
Note to programmer: Replace “TREATMENT” with “SURGERY TYPE”, followed by “Spine Surgery” or “Cardiac 
Surgery”. 
Listing 16.2-17.5.1.1.1: Treatment-emergent Adverse Events of Special Interest, as Reported by 
Investigators (Group 1: 12 to <17 years) – All Subjects  
Listing 16.2-17.5.1.1.2: Treatment-emergent Adverse Events of Special Interest, as Reported by 
Investigators (Group 2: 6 to < 12 years) – All Subjects  
Note to programmer: Replace “TREATMENT” with “SURGERY TYPE”, followed by “Spine Surgery” or “Cardiac 
Surgery”.  For these tables, use the CRF checkbox to identify AEs of Special Interest. 
Listing 16.2-17.5.2.1.1: Treatment-emergent Study Drug Related Adverse Events of Special Interest (Group 1: 
12 to <17 years) – All Subjects 
Listing 16.2-17.5.2.1.2: Treatment-emergent Study Drug Related Adverse Events of Special Interest (Group 2: 
6 to < 12 years) – All Subjects 


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CONFIDENTIAL 
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Note to programmer: Replace “TREATMENT” with “SURGERY TYPE”, followed by “Spine Surgery” or “Cardiac 
Surgery”. 
 


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Statistical Analysis Plan 
 
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Protocol: 402-C-319 
Listing 16.2-17.5.3.1.1: Adverse Events of Special Interest, as Defined in the Protocol (Group 1: 12 to <17 
years) – All Subjects 
Treatment: treatment-name 
 
Site Subject 
Preferred Term 
Start Time (Day) 
End Time (Day) 
xxx 
yyyy 
Chest Pain 
 
 
 
 
Heart Rate Irregular 
 
 
 
 
… 
 
 
 
 
 
 
 
xxx 
yyyy 
… 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: list SAS datasets used to create listing 
 
ddmmmyyyyThh:mm 
 
Note to programmer: Refer to Table 5 for list of AESI’s defined in the protocol.  Use this template also 
for listings: 
Listing 16.2-17.5.3.1.2: Adverse Events of Special Interest, as Defined in the Protocol (Group 2: 6 to < 12 
years) – All Subjects 
 
 


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Protocol: 402-C-319 
Listing 16.2-18.1.1.1: Prior Medications (Group 1: 12 to <17 years) – All Subjects 
Treatment: treatment-name 
 
 
Site Subject 
Data Type 
Date 
xxx 
yyyy 
Start (Day) 
ddmmmyyyyThh:mm (XX) 
 
 
Stop (Day) 
ddmmmyyyyThh:mm (XX) 
 
 
Medication Number 
X 
 
 
ATC Level 1 
xxxxxxxxxxxxxxxxxx 
 
 
  ATC Level 2 
  xxxxxxxxxxxxxxxxxxxx 
 
 
    ATC Level 3 
    xxxxxxxxxxxxxxxxxxxxxX 
 
 
      ATC Level 4 
      xxxxxxxxxxxxxxxxxxxx 
 
 
  Preferred Name 
xxxxxxxxxxxxxxxxxxxxx 
 
 
    Verbatim 
  xxxxxxxxxxxxxxxxxxxx 
 
 
Dose (Unit) 
X (XX) 
 
 
Route 
xxxxxxxx 
 
 
Frequency 
xxxxxxxx 
 
 
Given for AE or MH? 
xxxxxxxxxxxxxxxxxxxxx AE # xx (or MH # xx) 
 
 
 
 
 
 
 
 
ATC=Anatomical therapeutic class 
Source: list SAS datasets used to create listing 
 
ddmmmyyyyThh:mm 
SAS X.Y 
 
program_name 
 
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.  For SURGICAL/ANESTHESIA, Frequency is not collected. Use this 
template also for listings: 
 
Listing 16.2-18.1.1.2: Prior Medications (Group 2: 6 to < 12 years) – All Subjects 
Listing 16.2-18.2.1.1: Concomitant Medications (Group 1: 12 to <17 years) – All Subjects  
Listing 16.2-18.2.1.2: Concomitant Medications (Group 2: 6 to < 12 years) – All Subjects  
 
 
 


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Protocol: 402-C-319 
Listing 16.2-19.1.1: Medical/Surgical History (Group 1: 12 to <17 years) – All Subjects 
Treatment: treatment-name 
Site 
Subject 
Data Type 
Data 
xxx 
yyyy 
Start 
ddmmmyyyy 
 
 
Stop 
ddmmmyyyy 
 
 
System Organ Class 
xxxxxxxxxxxxxxxxxx 
 
 
  Preferred 
  xxxxxxxxxxxxxxxxxxxx 
 
 
    History Verbatim 
    xxxxxxxxxxxxxxxxxxxxxX 
 
 
Start 
ddmmmyyyy 
 
 
Stop 
ddmmmyyyy 
 
 
System Organ Class 
xxxxxxxxxxxxxxxxxx 
 
 
  Preferred 
  xxxxxxxxxxxxxxxxxxxx 
 
 
    History Verbatim 
    xxxxxxxxxxxxxxxxxxxxxX 
 
 
 
 
Source: list SAS datasets used to create listing 
 
ddmmmyyyyThh:mm 
SAS X.Y 
 
program_name 
 
Note to programmer: Use this template also for the following listing, Replace “TREATMENT” with “SURGERY 
TYPE”, followed by “Spine Surgery” or “Cardiac Surgery”. 
Listing 16.2-19.1.2: Medical/Surgical History (Group 2: 6 to < 12 years) – All Subjects 
 
 


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CONFIDENTIAL 
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Protocol: 402-C-319 
Listing 16.2-20.1.1: Intraoperative Medications (Group 1: 12 to <17 years) – All Subjects 
TREATMENT: treatment-name 
Site 
Subject 
 
Medication Name 
Dose 
Unit 
Route 
 
  
 
 
 
 
 
 
xxx 
yyyy 
 
xxx 
xxx.xx 
(UNITS) 
xxxx 
 
  
xxx 
yyyy 
 
xxx 
xxx.xx 
(UNITS) 
xxxx 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
Source: list SAS datasets used to create table 
 
ddmmmyyyyThh:mm 
SAS X.Y 
 
program_name 
 
Note to programmer: Use this template also for listing: 
Listing 16.2-20.1.2: Intraoperative Medications (Group 2: 6 to < 12 years) – All Subjects 
Note to programmer: Replace “TREATMENT” with “SURGERY TYPE”, followed by “Spine Surgery” or “Cardiac 
Surgery”. 
 


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402-C-319 
EXPAREL® 
Statistical Analysis Plan 
 
CONFIDENTIAL 
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Pacira Pharmaceuticals 
(Page X of Y) 
Protocol: 402-C-319 
Listing 16.2-21.1.1: Study Drug Administration (Group 1: 12 to <17 years) – All Subjects 
TREATMENT: treatment-name 
Site 
Subject 
Date 
Start Time 
Stop Time 
Incision Length 
(cm) 
Dose 
(mg) 
Total Volume 
(mL) 
 
 
 
 
 
 
 
xxx 
yyyy 
ddmmmyyyy 
HH:MM 
HH:MM 
xx.x 
xx.x 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: list SAS datasets used to create table 
 
ddmmmyyyyThh:mm 
SAS X.Y 
 
program_name 
 
Note to programmer: Use this template for the following listing. Replace “TREATMENT” with “SURGERY TYPE”, 
followed by “Spine Surgery” or “Cardiac Surgery”. 
Listing 16.2-21.1.2: Study Drug Administration (Group 2: 6 to < 12 years) – All Subjects 
 
 


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Protocol: 402-C-319 
Listing 16.2-22.1.1: Urine Drug Screen, Alcohol Blood Test and Pregnancy Test (Group 1: 12 to <17 years) – 
All Subjects 
TREATMENT: treatment-name 
Site 
Subject 
Visit 
Urine Drug 
Blood 
Alcohol 
Pregnancy 
 
 
 
 
 
 
 
 
xxx 
yyyy 
Screening 
xxxxxxxx 
xxxxxxxx 
xxxxxxxx 
 
 
 
Day 1 (Preop) 
xxxxxxxx 
xxxxxxxx 
xxxxxxxx 
 
 
 
 
 
 
 
 
xxx 
yyyy 
Screening 
xxxxxxxx 
xxxxxxxx 
xxxxxxxx 
 
 
 
Day 1 (Preop) 
xxxxxxxx 
xxxxxxxx 
xxxxxxxx 
 
 
 
 
 
 
 
 
xxx 
yyyy 
Screening 
xxxxxxxx 
xxxxxxxx 
xxxxxxxx 
 
 
 
Day 1 (Preop) 
xxxxxxxx 
xxxxxxxx 
xxxxxxxx 
 
 
 
 
 
 
 
 
xxx 
yyyy 
Screening 
xxxxxxxx 
xxxxxxxx 
xxxxxxxx 
 
 
 
Day 1 (Preop) 
xxxxxxxx 
xxxxxxxx 
xxxxxxxx 
 
 
 
 
 
 
 
 
Source: list SAS datasets used to create table 
 
ddmmmyyyyThh:mm 
SAS X.Y 
 
program_name 
 
Note to programmer: Use this template also for listing: 
 
Listing 16.2-22.1.2: Urine Drug Screen, Alcohol Blood Test and Pregnancy Test (Group 2: 6 to < 12 years) – 
All Subjects 
Note to programmer: Replace “TREATMENT” with “SURGERY TYPE”, followed by “Spine Surgery” or “Cardiac 
Surgery”. 
 
 


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402-C-319 
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Statistical Analysis Plan 
 
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Protocol: 402-C-319 
Listing 16.2-23.1.1: Admission and Discharge (Group 1: 12 to <17 years) – All Subjects 
TREATMENT: treatment-name 
 
 
Date and Time 
 
 
Surgical Facility 
 
PACU 
Site 
Subject 
Admission 
Discharge 
 
Admission 
Discharge 
 
 
 
 
 
 
xxx 
yyyy 
ddmmmyyyyThh:mm 
ddmmmyyyyThh:mm 
  
ddmmmyyyyThh:mm 
ddmmmyyyyThh:mm 
xxx 
yyyy 
ddmmmyyyyThh:mm 
ddmmmyyyyThh:mm 
 
ddmmmyyyyThh:mm 
ddmmmyyyyThh:mm 
xxx 
yyyy 
ddmmmyyyyThh:mm 
ddmmmyyyyThh:mm 
 
ddmmmyyyyThh:mm 
ddmmmyyyyThh:mm 
 
 
 
 
 
 
 
Source: list SAS datasets used to create table 
 
ddmmmyyyyThh:mm 
SAS X.Y 
 
program_name 
 
Note to programmer: Use this template also for listing: 
Listing 16.2-23.1.2: Admission and Discharge (Group 2: 6 to < 12 years) – All Subjects 
Note to programmer: Replace “TREATMENT” with “SURGERY TYPE”, followed by “Spine Surgery” or “Cardiac 
Surgery”. 
 
 
 


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Protocol: 402-C-319 
Listing 16.2-24.1.1: Informed Consent (Group 1: 12 to <17 years) – All Subjects 
TREATMENT: treatment-name 
 
 
 
Met Criteria 
Site 
Subject 
Screening 
Visit 
Signed 
Consent 
Protocol 
Version 
 
Inclusion 
 
Exclusion 
 
 
 
 
 
 
 
xxx 
yyyy 
ddmmmyyyy 
ddmmmyyyy 
ORIGINAL 
YES 
YES 
xxx 
yyyy 
ddmmmyyyy 
ddmmmyyyy 
AMENDMENT 1 
NO 
YES 
xxx 
yyyy 
ddmmmyyyy 
ddmmmyyyy 
ORIGINAL 
YES 
NO 
 
Source: list SAS datasets used to create table 
 
ddmmmyyyyThh:mm 
SAS X.Y 
 
program_name 
 
Note to programmer: Use this template for the following listing. Replace “TREATMENT” with “SURGERY TYPE”, 
followed by “Spine Surgery” or “Cardiac Surgery”. 
 
Listing 16.2-24.1.2: Informed Consent (Group 2: 6 to < 12 years) – All Subjects 
 
 


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Listing 16.2-25.1.1: Subject Eligibility (Group 1: 12 to <17 years) – All Subjects 
TREATMENT: treatment-name 
 
 
Date of 
 
Site 
Subject 
Informed Consent 
Eligibility 
Assessment 
Criteria Failed 
xxx 
yyyy 
ddmmmyyyy 
ddmmmyyyy 
 
xxx 
yyyy 
ddmmmyyyy 
ddmmmyyyy 
 
xxx 
yyyy 
ddmmmyyyy 
ddmmmyyyy 
Inclusion:  1, 4 
xxx 
yyyy 
ddmmmyyyy 
ddmmmyyyy 
Exclusion: 8, 10, 12 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: list SAS datasets used to create listing  
  
ddmmmyyyyThh:mm  
SAS X.Y  
  
program_name  
 
Note to programmer: Include screen failures in this listing. 
  
Note to programmer: Use this template also for listing: 
Listing 16.2-25.1.2: Subject Eligibility (Group 2: 6 to < 12 years) – All Subjects 
Note to programmer: Replace “TREATMENT” with “SURGERY TYPE”, followed by “Spine Surgery” or “Cardiac 
Surgery”. 
 
 
 


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Protocol: 402-C-319 
Listing 16.2-25a: Subject Eligibility Inclusion Criteria – All Subjects 
Inclusion Criteria 
xxxxxxxxxxxxxxxxxxxxxxxxxxx 
Xxxxxxxxxxxxxxxxxxxxxxxxxxx 
Xxxxxxxxxxxxxxxxxxxxxxxxxxx 
Xxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
Source: list SAS datasets used to create listing  
  
ddmmmyyyyThh:mm  
SAS X.Y  
  
program_name  
 
Note to programmer: List inclusion criteria from protocol. 
 
 
 
 
 


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Listing 16.2-25b: Subject Eligibility Exclusion Criteria – All Subjects 
Exclusion Criteria 
Xxxxxxxxxxxxxxxxxxxxxxxxxxx 
Xxxxxxxxxxxxxxxxxxxxxxxxxxx 
Xxxxxxxxxxxxxxxxxxxxxxxxxxx 
Xxxxxxxxxxxxxxxxxxxxxxxxxxx 
Xxxxxxxxxxxxxxxxxxxxxxxxxxx 
Xxxxxxxxxxxxxxxxxxxxxxxxxxx 
Xxxxxxxxxxxxxxxxxxxxxxxxxxx 
Xxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
Source: list SAS datasets used to create listing  
  
ddmmmyyyyThh:mm  
SAS X.Y  
  
program_name  
 
Note to programmer: List exclusion criteria from protocol. 
 
 
 


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Listing 16.2-26: Unique Adverse Event 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 
Source: list SAS datasets used to create listing 
 
ddmmmyyyyThh:mm  
SAS X.Y 
 
program_name 
 
Note to programmer: Sort by SOC and preferred term in alphabetical order.  
 
 
 
 


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Protocol: 402-C-319 
Listing 16.2-27: 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 
Source: list SAS datasets used to create listing 
 
ddmmmyyyyThh:mm  
SAS X.Y 
 
program_name 
 
Note to programmer: Sort by ATC1, ATC2, ATC3, ATC4 and preferred name in alphabetical order.  
 
 
 
 


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Listing 16.2-28.1.1: Protocol Deviations (Group 1: 12 to <17 years) – All Subjects 
TREATMENT: treatment-name 
Site 
Subject 
Importance 
Date 
Description 
 
 
 
 
 
xxx 
yyyy 
Important ddmmmyyyyThh:mm 
xxxxxxxxxxxxxxxxxx 
 
 
Minor 
ddmmmyyyyThh:mm 
xxxxxxxxxxxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: list SAS datasets used to create listing 
 
ddmmmyyyyThh:mm  
SAS X.Y 
 
program_name 
 
Note to programmer: Subjects may have multiple deviations.  Sort deviations by importance, then by 
treatment, site, and subject.  Date may or may not include time. Use this template also for listing: 
Listing 16.2-28.1.2: Protocol Deviations (Group 2: 6 to < 12 years) – All Subjects 
Note to programmer: Replace “TREATMENT” with “SURGERY TYPE”, followed by “Spine Surgery” or “Cardiac 
Surgery”. 
 
 
 
 
 


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Listing 16.2-29-1.1: Physical Exam (Group 1: 12 to <17 years) – All Subjects 
TREATMENT: treatment-name 
Site Subject 
Not Done 
If Not Done, Provide 
Reason 
Date and Time 
 
 
 
 
 
 
 
xxx 
yyyy 
 
 
ddmmmyyyyThh:mm 
 
 
 
 
 
 
 
Source: list SAS datasets used to create table 
 
ddmmmyyyyThh:mm 
SAS X.Y 
 
program_name 
 
Note to programmer: Sort by date and time within subject. Use this template also for listing: 
 
Listing 16.2-29-1.2: Physical Exam (Group 2: 6 to < 12 years) – All Subjects 
Note to programmer: Replace “TREATMENT” with “SURGERY TYPE”, followed by “Spine Surgery” or “Cardiac 
Surgery”. 
 
 


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13. TABLE OF CONTENTS FOR FIGURE MOCK-UPS
Figure 1.1.1 Plot of Time to First Rescue Medication Use (Group 1: 12 to <17 years) – Safety 
Population ......................................................................................................................................... 105 
Figure 1.1.2 Plot of Time to First Rescue Medication Use (Group 2: 6 to < 12 years) – Safety 
Population ......................................................................................................................................... 105 
Figure 2.1.1 Plot of Mean (± SD) Bupivacaine Concentrations (ng/mL) over Time (Group 1: 12 to 
<17 years) – PK Population – Linear Scale ...................................................................................... 106 
Figure 2.1.2 Plot of Mean (± SD) Bupivacaine Concentrations (ng/mL) over Time (Group 2: 6 to < 12 
years) – Spine Surgery - PK Population – Linear Scale ................................................................... 107 
Figure 2.1.3 Plot of Mean (± SD) Bupivacaine Concentrations (ng/mL) over Time (Group 2: 6 to < 12 
years) – Cardiac Surgery - PK Population – Linear Scale ................................................................ 107 
Figure 2.1.4 Plot of Mean (± SD) Bupivacaine Concentrations (ng/mL) over Time (Both Groups: 6 to 
< 17 years) – Spine Surgery - PK Population – Linear Scale ........................................................... 107 
Figure 3.1.1 Plot of Mean (± SD) Bupivacaine Concentrations (ng/mL) over Time (Group 1: 12 to 
<17 years) – PK Population – Semi-logarithmic Scale..................................................................... 108 
Figure 3.1.2 Plot of Mean (± SD) Bupivacaine Concentrations (ng/mL) over Time (Group 2: 6 to < 12 
years) – Spine Surgery - PK Population – Semi-logarithmic Scale.................................................. 108 
Figure 3.1.3 Plot of Mean (± SD) Bupivacaine Concentrations (ng/mL) over Time (Group 2: 6 to < 12 
years) – Cardiac Surgery - PK Population – Semi-logarithmic Scale............................................... 109 
Figure 3.1.4 Plot of Mean (± SD) Bupivacaine Concentrations (ng/mL) over Time (Both Groups: 6 to 
< 17 years) – Spine Surgery - PK Population – Semi-logarithmic Scale.......................................... 109 
Figure 4.1.1 Plot of Individual Bupivacaine Concentrations (ng/mL) over Time (Group 1: 12 to <17 
years) – PK Population – Linear-Linear and Log-Linear ................................................................. 110 
Figure 4.1.2 Plot of Individual Bupivacaine Concentrations (ng/mL) over Time (Group 2: 6 to < 12 
years) – PK Population – Cardiac Surgery – Linear-Linear and Log-Linear.................................... 111 
Figure 4.1.3 Plot of Individual Bupivacaine Concentrations (ng/mL) over Time (Group 2: 6 to < 12 
years) – PK Population – Spine Surgery – Linear-Linear and Log-Linear....................................... 111 
Figure 4.1.4 Plot of Individual Bupivacaine Concentrations (ng/mL) over Time (Group 1: 12 to <17 
years) – PK Population – Linear-Linear and Log-Linear ................................................................. 111 
Figure 5.1.1 Plot of Mean (± SD) Numeric Rating Scale at Rest Pain Intensity Scores over Time 
(Group 1: 12 to <17 years) – Safety Population................................................................................ 111 
Figure 5.1.2 Plot of Mean (± SD) Color Analog Scale Pain Intensity Scores over Time (Group 2: 6 to 
< 12 years) – Safety Population ........................................................................................................ 111 


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Figure 1.1.1 Plot of Time to First Rescue Medication Use (Group 1: 12 to <17 years) – Safety Population 
 
Note to programmer: Time to first rescue on x-axis 0-72 Hours by 12. Overlay both treatments for Group 1. For table underneath plot, provide 
for each treatment in Group 1 with a header for treatment.  Add footnote: “Subjects who are not administered an opioid rescue medication by 72 
hours are censored at 72 hours after surgery or at the time of last follow-up, whichever is earliest.” 
Use this template for the following figure: 
Figure 1.1.2 Plot of Time to First Rescue Medication Use (Group 2: 6 to < 12 years) – Safety Population 
Note to programmer: Time to first rescue on x-axis 0-72 Hours by 12. Overlay both surgery types for Group 2. For table underneath plot, provide 
for each surgery type in Group 2 with a header for surgery type.  Add footnote: “Subjects who are not administered an opioid rescue medication 
by 72 hours are censored at 72 hours after surgery or at the time of last follow-up, whichever is earliest.” 
 


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Figure 2.1.1 Plot of Mean (± SD) Bupivacaine Concentrations (ng/mL) over Time (Group 1: 12 to <17 years) – 
PK Population – Linear Scale 
 
Note to programmer: Overlay both treatments for Group 1. For Samples 4-8, use the midpoint of the collection window for the tick mark (i.e. 
1.125 for 1-1.25 window).  Label the tick mark with the time window (i.e. “1-1.25 hr”).  Change the y-axis label to “Bupivacaine Concentration 
(mg/mL)”. 
Add footnotes: “For concentrations below the limit of quantification (BLOQ), pre-dose values are set to zero, BLOQ values between the dosing 
time and the first time point above lower limit of quantification (LLOQ) are set to 0, BLOQ values at time points between two measurable 
concentration values are set to ½ of LLOQ (lower limit of quantification), and all remaining BLOQ values are set to missing.  For Samples 4-8, 
the midpoint of the collection window is used for the tick mark. ”   


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Use this template for the following figures: 
Figure 2.1.2 Plot of Mean (± SD) Bupivacaine Concentrations (ng/mL) over Time (Group 2: 6 to < 12 years) – 
Spine Surgery - PK Population – Linear Scale 
Figure 2.1.3 Plot of Mean (± SD) Bupivacaine Concentrations (ng/mL) over Time (Group 2: 6 to < 12 years) – 
Cardiac Surgery - PK Population – Linear Scale 
Figure 2.1.4 Plot of Mean (± SD) Bupivacaine Concentrations (ng/mL) over Time (Both Groups: 6 to < 17 
years) – Spine Surgery - PK Population – Linear Scale 
 
 


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Figure 3.1.1 Plot of Mean (± SD) Bupivacaine Concentrations (ng/mL) over Time (Group 1: 12 to <17 years) – 
PK Population – Semi-logarithmic Scale 
 
 
Note to programmer: Overlay both treatments for Group 1. Change the y-axis label to “Log(Bupivacaine Concentration (mg/mL))”.Use this 
template for the following figure: 
Figure 3.1.2 Plot of Mean (± SD) Bupivacaine Concentrations (ng/mL) over Time (Group 2: 6 to < 12 years) – 
Spine Surgery - PK Population – Semi-logarithmic Scale 


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Figure 3.1.3 Plot of Mean (± SD) Bupivacaine Concentrations (ng/mL) over Time (Group 2: 6 to < 12 years) – 
Cardiac Surgery - PK Population – Semi-logarithmic Scale 
Figure 3.1.4 Plot of Mean (± SD) Bupivacaine Concentrations (ng/mL) over Time (Both Groups: 6 to < 17 
years) – Spine Surgery - PK Population – Semi-logarithmic Scale 
 
 


Pacira Pharmaceuticals, Inc. 
402-C-319 
EXPAREL® 
Statistical Analysis Plan 
 
CONFIDENTIAL 
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Figure 4.1.1 Plot of Individual Bupivacaine Concentrations (ng/mL) over Time (Group 1: 12 to <17 years) – 
PK Population – Linear-Linear and Log-Linear 
 
Note to programmer: Modify the figures below as follows:  Combine each pair of figures for individual subjects into one figure.  Put log-linear 
scale on right hand side x-axis.  Overlay two lines on one figure. 
 
 


Pacira Pharmaceuticals, Inc. 
402-C-319 
EXPAREL® 
Statistical Analysis Plan 
 
CONFIDENTIAL 
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Note to programmer: Use this template for the following figures: 
Figure 4.1.2 Plot of Individual Bupivacaine Concentrations (ng/mL) over Time (Group 2: 6 to < 12 years) – 
PK Population – Cardiac Surgery – Linear-Linear and Log-Linear 
 
Figure 4.1.3 Plot of Individual Bupivacaine Concentrations (ng/mL) over Time (Group 2: 6 to < 12 years) – 
PK Population – Spine Surgery – Linear-Linear and Log-Linear 
 
Figure 4.1.4 Plot of Individual Bupivacaine Concentrations (ng/mL) over Time (Group 1: 12 to <17 years) – 
PK Population – Linear-Linear and Log-Linear 
 
Note to Programmer:  If there is a lot of dose variation (i.e. a lot of departure from 4 mg/kg EXPAREL or Bupivacaine HCl 2 mg/kg), add figures 
for dose normalized concentration.   
 
Note to programmer: Use Figure 2.1.1 for the figures below.   
 
Figure 5.1.1 Plot of Mean (± SD) Numeric Rating Scale at Rest Pain Intensity Scores over Time (Group 1: 12 
to <17 years) – Safety Population 
Note to programmer: Replace label on y-axis with “NRS-R”.  Overlay both treatments for Group 1.  
 
Figure 5.1.2 Plot of Mean (± SD) Color Analog Scale Pain Intensity Scores over Time (Group 2: 6 to < 12 
years) – Safety Population 
Note to programmer: Replace label on y-axis with “CAS”.  Overlay lines for Spine Surgery and Cardiac Surgery for Group 2.