PURDUE PHARMA L.P. Butrans · In completed Purdue-sponsored clinical studies involving adults, 7193 subjects (520 adults from phase 1 studies, 107 from nonchronic pain studies, and

Purdue Pharma L.P.

FDA Advisory Committee Briefing Package

September 14, 2017

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PURDUE PHARMA L.P.

Butrans® (buprenorphine) Transdermal System

NDA 021306/S-027

Advisory Committee Briefing Materials

For

Joint Meeting of the Anesthetic and Analgesic Drug Products Advisory Committee and Drug

Safety and Risk Management Advisory Committee

On

September 14, 2017

ADVISORY COMMITTEE BRIEFING MATERIALS:

AVAILABLE FOR PUBLIC RELEASE

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EXECUTIVE OVERVIEW

Butrans® (buprenorphine)Transdermal System, a Schedule III 7-day opioid analgesic, was

approved by the FDA in June 2010 and is currently marketed in the United States (US) for the

management of pain severe enough to require daily, around-the-clock, long-term opioid

treatment and for which alternative treatment options are inadequate. To satisfy the Pediatric

Research Equity Act (PREA) regulatory requirement upon approval of Butrans for adults, PMR

1655-1: Deferred pediatric study under PREA, a pharmacokinetic (PK) and safety study for the

treatment of moderate to severe chronic pain requiring continuous, around-the-clock opioid

treatment for an extended period of time in pediatric patients ages 7 through 16 was required.

Study BUP3031, ‘An Open-label, Multicenter Study of the Safety, Pharmacokinetics, and

Efficacy of Butrans® (buprenorphine) Transdermal System (BTDS) in Children From 7 to 16

Years of Age, Inclusive, Who Require Continuous Opioid Analgesia for Moderate to Severe

Pain’ was developed and conducted by Purdue to meet that requirement and to provide

information for prescribers making important decisions about the management of the small

population of children needing medicines like Butrans. The BUP3031 protocol was developed

and finalized through discussions with the FDA prior to initiation of the study. In study

BUP3031, Butrans had the expected safety profile and maintained or improved pain control in

combination with supplemental analgesics when administered to patients 7 to 16 years old who

required a continuous, around-the-clock opioid analgesic therapy for management of moderate to

severe persistent pain. No new or unexpected safety concerns were observed in the study.

Adverse events most frequently reported were consistent with those commonly associated with

the use of opioid analgesics or the transdermal route of administration. The small sample size in

the 7 to 11 year age group should be carefully considered when interpreting the data for this

population. The age distribution of enrolled patients in study BUP3031 is reflective of the age

distribution observed in prior pediatric opioid analgesic studies, prescreening data, and

epidemiologic data. The conduct and completion of study BUP3031 over a period of

approximately 5 years reflects extensive recruitment efforts by investigators and Purdue, despite

the small pediatric pain population and stringent protocol criteria.

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The number of pediatric patients for which alternative treatment options are inadequate and who

require the use of extended-release opioid analgesics for the management of pain severe enough

to require daily, around-the-clock, long-term opioid treatment is extremely small and the

duration of treatment in clinical practice tends to be less than 3 weeks. For example, in 2015, out

of almost 2 million children 7 to 16 years of age dispensed opioid analgesics, only 0.3% were

dispensed an extended-release opioid.27 The FDA publication CDER Conversation: Pediatric

pain management options regarding the 2015 approval of the pediatric labeling for OxyContin®

tablets states: “Children are not treated with opioids very often and usually it's only for a limited

period of time with close supervision by health care professionals,”

(http://www.fda.gov/Drugs/NewsEvents/ucm456973.htm).

Study BUP3031 fulfills the PREA requirement for the Butrans NDA 021306 with an adequate

number of pediatric patients exposed to buprenorphine to evaluate pharmacokinetics and safety.

The population is representative of the overall population of pediatric patients with persistent

pain requiring opioid analgesics for at least 2 weeks. We propose that the BUP3031 pediatric

patient experience should be described in Section 8.4 (ie, USE IN SPECIFIC

POPULATIONS, Pediatric Use) of the US Full Prescribing Information. Given the small

sample size and open label design of the study, a pediatric indication is not being requested.

Nevertheless, the pediatric study data on Butrans will be of value to prescribers as they make

challenging decisions about the care of the small number of children with pain severe enough to

require daily, around-the-clock, long-term opioid treatment and for which alternative treatment

options are inadequate.

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TABLE OF CONTENTS

EXECUTIVE OVERVIEW .............................................................................................................2

TABLE OF CONTENTS ..............................................................................................................4

LIST OF TABLES ...........................................................................................................................5

LIST OF FIGURES .........................................................................................................................6

LIST OF ABBREVIATIONS ..........................................................................................................7

1 Background ..............................................................................................................................9

1.1 Butrans Overview ........................................................................................................... 9

1.2 Study of Extended-Release Opioid Analgesics in Pediatric Patients ........................... 10

2 Butrans Pediatric Clinical Development Program .................................................................15

2.1 Pediatric Pharmacokinetics ........................................................................................... 18

2.2 Pediatric Safety ............................................................................................................. 19

2.3 Pediatric Efficacy .......................................................................................................... 32

2.4 Study conclusion ........................................................................................................... 35

3 Proposed Butrans Pediatric Labeling .....................................................................................35

4 Epidemiology of Opioid Utilization in the Pediatric Population and Relevence to Study

BUP3031 ........................................................................................................................................36

5 Pediatric Utilization Of Butrans.............................................................................................40

6 Conclusions ............................................................................................................................41

7 References ..............................................................................................................................43

8 Appendices .............................................................................................................................46

8.1 Appendix A ................................................................................................................... 46

8.2 Appendix B ......................................................................................................................... 48

8.3 Appendix C ......................................................................................................................... 49

8.4 Appendix D ......................................................................................................................... 50

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LIST OF TABLES

Table 1 Summary of Demographics and Baseline Characteristics (Safety Population)12,13 ........ 17 Table 2 Summary of Severe Treatment-Emergent Adverse Events (Safety Population) ............ 20

Table 3 Incidence of Treatment-Emergent Adverse Events by System Organ Class and Preferred

Term, Safety Population ............................................................................................................... 22 Table 4 Incidence of Treatment-Emergent Adverse Events Related to Study Drug by System

Organ Class and Preferred Term (Safety Population) .................................................................. 24 Table 5 Listing of Patients with AEs Leading to Study Discontinuation (Safety Population) ..... 26

Table 6 Listing of Serious Adverse Events (Safety Population) .................................................. 29 Table 7 Pain right now scores for patients aged 7 to 11 years (FPS-R ) .................................... 33 Table 8 Databases in the Epidemiologic Studies Evaluating the use of OxyContin in Actual

Clinical Practice ............................................................................................................................ 37 Table 9: National estimates of pediatric patients ages 7 to 16 years who received prescriptions

dispensed for transdermal buprenorphine .................................................................................... 40

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LIST OF FIGURES

Figure 1 BUP3031 Patient Recruitment Summary ....................................................................... 12 Figure 2 100-mm Visual Analog Scale from Baseline to Week 24 for patients aged 12 to 16

years ............................................................................................................................................. 34

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LIST OF ABBREVIATIONS

AE adverse event

AERS adverse event reporting system

AUC area under the plasma concentration-time curve

AUCss area under the concentration-time curve for a dosing interval at steady-state

BMI

BTDS

body mass index

buprenorphine transdermal system

CL/F apparent clearance after patch dosing

CSR clinical study report

ECG electrocardiogram

ER extended-release

FAP Full Analysis Population

FDA

FPS-R

Food and Drug Administration

Faces Pain Scale-Revised

h hour

IBW ideal body weight

mcg microgram

MedDRA Medical Dictionary for Regulatory Activities

mm

msec

millimeter

millisecond

NDA new drug application

PGIC Parent/Caregiver-assessed Global Impression of Change

PI Package Insert

PK

PMR

PREA

pharmacokinetic(s)

post-marketing requirements

Pediatric Research Equity Act

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q

QT

QTc

every

QT interval (ECG)

QT data corrected for heart rate

QTcB QT data corrected for heart rate using the Bazett formula

SAE serious adverse event

SD standard deviation

SE Standard error

TEAE treatment-emergent adverse event

US United States

VAS visual analog scale

WHO World Health Organization

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1 BACKGROUND

1.1 Butrans Overview

Butrans® (buprenorphine) Transdermal System was approved by the FDA in June 2010 and is

currently marketed as a Schedule III medicine for the management of pain severe enough to

require daily, around-the-clock, long-term opioid treatment and for which alternative treatment

options are inadequate. Butrans is a transdermal system providing systemic delivery of

buprenorphine. Butrans is currently available in 5 patch strengths delivering, on average 5, 7.5,

10, 15, and 20 mcg/h of buprenorphine, respectively, over 7 days.

Buprenorphine, a semisynthetic opioid pain medication derived from the opium alkaloid

thebaine, is an opioid pain medication with partial mu-opioid agonist and kappa-opioid

antagonist properties.1 Buprenorphine is available in the US in sublingual formulations, with or

without naloxone and as a subdermal implant, for addiction treatment only, as well as buccal

film, intravenous, transdermal forumulations for the treatment of pain. Pediatric indications for

buprenorphine In the US is currently limited to buprenorphine hydrochloride injection

(Buprenex®, not a Purdue product). Buprenex is indicated for the management of pain severe

enough to require an opioid analgesic and for which alternate treatments are inadequate,2 and has

been marketed since 1982 as an injectable for use in adults and children aged 6 years and older,

primarily for the management of postoperative pain. The US Package Insert (PI) for Buprenex

notes that use of Buprenex in children is supported by evidence from clinical trials in adults, as

well as data from studies of 960 pediatric patients (9 months to 18 years of age). The

information “provides reasonable evidence that Buprenex may be used safely in children from 2

to 12 years of age, and that effectiveness is similar in children as in adults,” however, study

results are not readily available in the medical literature. 2

Butrans provides dose-proportional total buprenorphine exposures (AUC) following 7-day

applications.1 In adults, plasma buprenorphine concentrations after titration showed no further

change over the 60-day period studied. After removal of Butrans, mean buprenorphine

concentrations decreased by approximately 50% within 10 to 24 hours, followed by decline with

an apparent terminal half-life of approximately 26 hours. 1

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In completed Purdue-sponsored clinical studies involving adults, 7193 subjects (520 adults from

phase 1 studies, 107 from nonchronic pain studies, and 6566 adults from chronic pain studies)

have been treated with Butrans.1 Among the 6566 subjects who were treated with Butrans in

chronic pain studies, 27.7%, 14.1%, and 3.4% were exposed to Butrans for a minimum of 3, 6,

and 12 months (28 days counted as 1 month), respectively. 1 The AEs which occurred in ≥5% of

subjects in the chronic pain studies were nausea, headache, application site pruritus, dizziness,

somnolence, constipation, vomiting, application site erythema, dry mouth, application site rash,

and fatigue.1 (See Appendix A for an excerpt from the Butrans US Full Prescribing Information)

Across all adult studies, 224 of 7193 Butrans-treated subjects (3.1%) experienced a total of 406

nonfatal SAEs. Eighteen (18) deaths occurred in the Butrans clinical program. No deaths

occurred in the clinical pharmacology studies. Two (2) of the 18 deaths occurred greater than 30

days after discontinuation of study drug and are included here for completeness; one (1) subject

died during the screening period and never received study drug.1 Seven (7) deaths (6 in Butrans-

treated subjects, 1 in a placebo-treated subject) occurred in study BUP3002 and its extension,

which were conducted in elderly subjects (median age, 80 years) in a supervised living

environment.1 Studies in adults showed that higher doses (40 mcg/h) of Butrans resulted in

prolongation of the QT data corrected for heart rate (QTc) interval. The safety and efficacy of

Butrans in patients under 18 years was not evaluated in these studies.1

In order to satisfy the Pediatric Research Equity Act (PREA) requirement upon approval of

Butrans, 3 approved patch strengths, Butrans 5, 10, and 20 mcg/h, were evaluated in pediatric

study BUP3031, as well as an investigational 2.5 mcg/h formulation. The 2.5 mcg/h dose was

included in the trial to facilitate the study of Butrans in young children. The 7.5 mcg/h and 15

mcg/h doses were not included because the doses were not approved at the time the study was

initiated.

1.2 Study of Extended-Release Opioid Analgesics in Pediatric Patients

Only a small number of extended-release opioid analgesics have been studied in the pediatric

population.3,4,5,7 The number of pediatric patients who require opioid analgesics to treat their

chronic pain, specifically extended-release formulations, is extremely limited.6 Data from the

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completed Purdue pediatric OxyContin program previously submitted to the FDA further support

that the population of pediatric patients requiring extended-release opioids is small, and the

duration of treatment in clinical practice tends to be less than 3 weeks.7

There are currently few FDA-approved extended-release opioid analgesic treatment options for

children. Two examples of extended-release opioid analgesics approved for pediatric use are

OxyContin® (oxycodone HCl extended-release tablets, Purdue Pharma L.P.) and Duragesic®

(transdermal fentanyl, Ortho-McNeil-Janssen Pharmaceuticals, Inc.). The Duragesic study

enrolled 199 pediatric patients, aged 2 to 16 years, with both malignant and nonmalignant

conditions who were receiving oral or parenteral opioids for moderate to severe chronic pain.4 In

that study, transdermal fentanyl was found to be a safe and well tolerated alternative to oral

opioid treatment for children who were previously exposed to opioid therapy. In the OxyContin

study, the safety, PK, and efficacy of OxyContin tablets were evaluated in 155 opioid-tolerant

pediatric patients aged 6 to 16 years with moderate to severe chronic pain. In that study, the

safety and efficacy of OxyContin tablets were established in opioid-tolerant pediatric patients

aged 11 to 16 years who were already receiving and tolerating a minimum daily opioid dose of at

least 20 mg oxycodone orally or its equivalent.7 Both the OxyContin and Duragesic pediatric

trials were conducted under the Best Pharmaceuticals for Children Act (BPCA).

Recruitment and enrollment for pediatric studies evaluating opioid analgesics are exceptionally

challenging because pediatric use of opioid analgesics is infrequent, only used for short periods

of time, and extended-release use is predominantly in older children (see Section 4). The

difficulties are documented in Purdue’s previous experience with conducting a clinical trial of

OxyContin tablets in pediatric patients, and in the published literature.7,8 The challenges of

conducting clinical trials with opioid analgesics in pediatric patients were recently highlighted in

the September 2016 Joint Meeting of the Anesthetic and Analgesic Drug Products Advisory

Committee, the Drug Safety and Risk Management Advisory Committee, and the Pediatric

Advisory Committee presentation, “The Challenges of Conducting Opioid Clinical Trials in

Pediatrics.” Population challenges and the lack of potential study patients contribute to the

difficulty of conducting such trials.9 In light of these multiple challenges, intensive efforts to

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locate appropriate investigative sites to achieve the desired age distribution and treatment

duration of patients in study BUP3031 were employed.

Sites participating in study BUP3031 were asked to submit, voluntarily and routinely,

documentation of patient recruitment activities. “Prescreening” data, were defined as information

from any child experiencing pain whom the site considered for enrollment. Prescreening data

had been utilized in previous Purdue pediatric clinical trials, and a Prescreen Data Analysis for

OxyContin pediatric study OTR3001was submitted to the FDA in 2012.10 Recognizing the

rarity of the pediatric population eligible for the BUP3031 trial, the same methodology was

applied to understand the appropriate patient population for this study in a concerted attempt to

improve recruitment and retention.

Over approximately 3 years, 3108 patients were prescreened for study BUP3031 at 29 study

sites.11 Of these prescreened patients, 3038 were deemed ineligible, 70 entered screening, 29

failed screening, and the remaining 41 were enrolled (Figure 1).11 These 41 enrolled represent

1.3% of those prescreened. Among the 41 patients enrolled, only 6 (15%) were in the 7 to 11-

year age group.

Figure 1 BUP3031 Patient Recruitment Summary

3108

70 41

0

500

1000

1500

2000

2500

3000

3500

Pat

ien

ts

Prescreened Screened Enrolled

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Prescreened patients were excluded due to age (31%), minimum expected duration of therapy of at

least 2 weeks (28%), and prohibited medicines (20%, eg, ondansetron, diphenhydramine, and

famotidine).11 Exclusions due to medical conditions (6%) included history of seizures, sleep apnea,

renal failure, and cardiac conditions. Other reasons for prescreen failure included patients or parents

declining to participate in the trial, and patients deemed unsuitable for study participation by the

investigator.11 Primary pain conditions of the prescreened patients included surgery, acute pain,

sickle cell disease, cancer, orthopedics/traumatic injuries, and conditions such as rheumatologic

disorders, neurologic conditions, burns, and chronic pain syndromes. The prescreen failure data

show that the most frequent reasons for ineligibility in the pediatric patients were related to the

protocol age requirement and the requirement for continuous opioid analgesic treatment over the

protocol-required period of at least 2 weeks. The most common pain etiologies for patients not

enrolled were surgery, acute pain, and pain related to underlying sickle cell disease.11

Based on the protocol criterion requiring at least 2 weeks of opioid therapy, potential patient

populations anticipated for enrollment included pediatric patients with cancer, orthopedic conditions,

sickle cell disease, traumatic injuries, and various uncommon disease conditions causing persistent

or chronic pain. A post hoc analysis of the primary pain conditions of patients actually enrolled

showed that this population had pain related to varied underlying medical conditions, including, by

prevalence: Crohns/irritable bowel syndrome, sickle cell disease, chronic migraines, systemic

rheumatologic/connective tissue disorders, general pain, traumatic injury, post-surgical pain, kidney

stones; neuroma, and congenital anomaly.

The protocol criteria for expected treatment duration, maximum opioid dose, and prohibited concomitant

medicines significantly limited the potential patient population for the trial. In previous pediatric opioid

analgesic trials, oncology patients made up a significant portion of the study population. For example, in

the Duragesic pediatric trial, over 60% of study patients had malignant disease; in Purdue’s OTR3001

pediatric trial of OxyContin, patients with cancer represented almost one-third of the study population.4,7

The potential for inclusion of a pediatric oncology population in study BUP3031 was significantly

limited due to protocol restrictions regarding concomitant medicines, such as those for prevention of

nausea and vomiting. These and many other commonly used medicines in pediatric patients, such as 5-

HT3 receptor antagonists and some selective serotonin reuptake inhibitors, were prohibited due to their


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potential to prolong the QT interval. This restriction excluded most pediatric oncology patients, as well

as a significant number of patients with pain due to underlying conditions other than cancer. Only 1

patient with underlying cancer was enrolled in study BUP3031.

The BUP3031 protocol limited the incoming opioid dose for patients already receiving high doses of an

opioid. Since Butrans may precipitate withdrawal in such patients, the protocol required tapering of

opioid for certain patients, based on age and incoming opioid dosing. The upper dosing limits and

required taper of current opioid therapy were additional medical barriers to enrollment.

The age distribution of enrolled patients in study BUP3031 is reflective of the age distribution

demonstrated in prior pediatric opioid analgesic studies, prescreening data, and epidemiologic data.7,

10,11,20 The conduct and completion of study BUP3031 reflects extensive recruitment efforts by

investigators and Purdue, despite the small pediatric pain population and stringent protocol criteria.



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2 BUTRANS PEDIATRIC CLINICAL DEVELOPMENT PROGRAM 12

In order to satisfy the PREA regulatory requirement upon approval of Butrans for adults, PMR 1655-1:

Deferred pediatric study under PREA, a pharmacokinetic and safety study for the treatment of moderate

to severe chronic pain requiring continuous, around-the-clock opioid treatment for an extended period of

time in pediatric patients ages 7 through 16 was required. Therefore, study BUP3031, ‘An Open-label,

Multicenter Study of the Safety, Pharmacokinetics, and Efficacy of Butrans® (buprenorphine)

Transdermal System (BTDS) in Children From 7 to 16 Years of Age, Inclusive, Who Require Continuous

Opioid Analgesia for Moderate to Severe Pain’ was developed and conducted by Purdue Pharma. The

study was designed to characterize the safety, PK, and efficacy of Butrans in a study population of

pediatric patients with moderate to severe chronic pain. The BUP3031 protocol was developed in

discussions with the FDA prior to initiation of the study.

The primary objectives of study BUP3031 were:

To characterize the safety of Butrans in patients aged 7 to 16 years, inclusive, who required

continuous around-the-clock opioid analgesia for moderate to severe pain.

To characterize the PK of Butrans in patients aged 7 to 16 years, inclusive, who required continuous

around-the-clock opioid analgesia for moderate to severe pain.

The secondary objective of this study was:

To assess the efficacy (analgesic activity) of Butrans in patients aged 7 to 16 years, inclusive, who

required continuous around-the-clock opioid analgesia for moderate to severe pain.

The BUP3031 study consisted of a Screening Period (up to 14 days), a Treatment Period (up to 24

weeks), and a Taper/Follow-up Period (up to 14 days). Patients were treated for up to 26 weeks (up to

and including the 14-day follow-up tapering period) with at least 1 of the following Butrans doses: 2.5,

5, 10, or 20 mcg/h. The starting dose for patients aged 7 to 11 years, inclusive, was Butrans 2.5 mcg/h

and the starting dose for patients aged 12 to 16 years, inclusive, was Butrans 5 mcg/h. Patients had

scheduled visits following Butrans treatment initiation to assess the safety, PK, and efficacy of Butrans.



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Target enrollment was 40 patients. There were 70 patients enrolled in the study, and 41 patients

received treatment. There were 29 screen failures (25 patients, 4 patients rescreened). Reasons for

screen failure included abnormal ECG findings, abnormal laboratory criteria, and other medical

exclusions.

A total of 41 patients were evaluated in study BUP3031. The safety population (N = 41) was defined as

patients who received at least 1 dose of the study drug during the study. The full analysis population

(FAP) (N = 40) was the group of patients who received at least 1 dose of the study drug during the

study. The data for one patient was excluded from the full analysis population due to protocol

compliance issues in multiple categories (eg, drug compliance and study procedure compliance issues).

The full analysis population for PK consisted of patients who received study drug and had at least 1

valid, quantifiable PK blood sample. A study completer (n=23) was defined in the protocol as a patient

who completed at least 2 weeks of study drug dosing, had not met any of the discontinuation reasons,

did not require additional treatment with an opioid analgesic for pain relief at the minimum study drug

dose or equivalent, or who had completed the entire 6 months (24 weeks) of study drug dosing.

A summary of key demographic and baseline characteristics for the overall safety population and by age

group is provided in Table 1. A summary of the patients’ primary pain etiology at study entry is

provided in Appendix B. The 7 to 11 year age group had diverse sources of pain (sickle cell anemia,

Epstein-Barr virus antibody positive, arthralgia, juvenile arthritis, osteonecrosis, hemipelvectomy). For

the 12 to 16 years age group, the most commonly reported sources for moderate to severe pain were

back pain (8 patients, 23%) and chronic migraine (6 patients, 17%).



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Table 1 Summary of Demographics and Baseline Characteristics (Safety Population)12,13

Age Group

Category

7 to 11 years

(N = 6)

n (%)

12 to 16 years

(N = 35)

n (%)

Total

(N = 41)

n (%)

Age (years)

N 6 35 41

Mean (SD) 10.3 (1.21) 14.6 (1.31) 14.0 (1.99)

Median 11.0 15.0 14.0

Min, Max 8, 11 12, 16 8, 16

Sex, n (%)

Male 3 (50) 12 (34) 15 (37)

Female 3 (50) 23 (66) 26 (63)

Race, n (%)

White 3 (50) 18 (51) 21 (51)

Black or African American 2 (33) 15 (43) 17 (41)

Native Hawaiian or Other Pacific Islander 0 0 0

Asian 0 0 0

American Indian or Alaskan Native 0 0 0

Other 1 (17) 2 (6) 3 (7)

Ethnicity, n (%)

Hispanic or Latino 1 (17) 6 (17) 7 (17)

Not Hispanic or Latino 5 (83) 29 (83) 34 (83)

Screening Body Mass Index (kg/m2)

N 5 34 39

Mean (SD) 16.66 (1.876) 24.48 (7.294) 23.48 (7.320)

Median 16.01 22.25 21.16

Min, Max 14.9, 19.9 15.0, 47.7 14.9, 47.7

Most Frequent Reason for Moderate to Severe

Pain at Study Entry n, (%)

Back Pain 0 8 (23) 8 (20)

Migraine 0 6 (17) 6 (15)

Sickle Cell Anemia 1 (17) 4 (11) 5 (12)

Abbreviations: cm = centimeter; max = maximum; min = minimum; N = number of patients in the population; n =

number of patients with data; SD = standard deviation.

Cross-reference: BUP3031 CSR, Table 14, Table 15

Notes: Body Mass Index (kg/m2) is calculated as screening weight (kg) / [screening height (cm)/100]2.

Screening value is defined as the last available value prior to the first dose of study drug.

Percentages are based on N.

Of the 41 patients enrolled, 23 completed the study, with treatment durations ranging from 2 to 26

weeks. Of the 23 patients who completed the study, 21 patients (51%) received > 8 weeks of treatment,

of which 13 received > 24 weeks of treatment. In the 7 to 11 year age group, 1 patient completed ≥ 12



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weeks (86 days), and in the 12 to 16 year age group, 13 patients completed ≥ 24 weeks. The mean (SD)

number of days on Butrans (100.8 [72.63] days) was higher in the 12 to 16 year age group compared

with the mean (25.8 [30.38] days) in the 7 to 11 year age group. The minimum and maximum

cumulative number of days on Butrans varied for both the 7 to 11 (3 to 86 days) and 12 to 16 (11 to 188

days) year age groups.

Both opioid naïve and opioid tolerant pediatric patients were eligible to participate if they required

continuous, around-the-clock, opioid treatment for at least 2 weeks for management of malignant and/or

nonmalignant moderate to severe pain. The majority of patients (39 patients, 95%) in the safety

population were receiving opioids to treat their pain at baseline before beginning treatment with Butrans.

2.1 Pediatric Pharmacokinetics

Blood samples for determining buprenorphine and its metabolite concentrations in plasma were

collected up to 5 times during the first 4 weeks of treatment:

18 to 24 hours after the application of the first Butrans patch

End of week 1

2 to 3 days after the end of week 1

End of week 2

End of week 4 or at discontinuation prior to week 4.

Population PK data from study BUP3031, including concentration observations, dosing histories, event

times, and covariate factors (age, weight, ideal body weight [IBW]) were assembled and formatted for

analysis.14 Population PK analyses for repeated-measures endpoints were conducted via nonlinear mixed

effects modeling with a qualified installation of the nonlinear mixed effects modeling (NONMEM)

software, Version 7.3 (ICON Development Solutions, Hanover, MD). Model selection was guided by

various goodness-of-fit criteria, and final model parameter estimates were reported with a measure of

estimation uncertainty. 14



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The buprenorphine pediatric PK data set comprised 38 patients contributing a total of 151

plasma buprenorphine concentrations. The study population consisted of 14 (37%) males and 24

(63%) females with ages ranging from 8 to 16 years and IBW ranging from 17.9 to 77.6 kg. Plasma

buprenorphine concentrations were sampled at sparse times throughout the dosing interval, including at

trough following approximately 4 weekly patch applications. 14

Butrans CL/F (apparent clearance after patch dosing) is expected to increase with increasing body size

based on the allometric relationship used to relate CL/F. Simulations of AUCss in typical pediatric

patients using fixed Butrans doses showed decreasing exposure with increasing age and increases in

weight due to this allometric relationship. To match the adult exposure following a Butrans 10 mcg/h

dose, the median dose for a 7-year-old patient is approximately one-half (4.6 mcg/h) that of a 16-year-

old patient (9.2 mcg/h). In the 12 to 16-year age group, systemic exposure (AUC) of buprenorphine is

similar to that for adults at any given adult dose of Butrans for 12 to 16 year olds that are at least 50kg.

This should be used as a guide, and doses will be individually titrated. 14

2.2 Pediatric Safety

The evaluation of safety of Butrans in this pediatric population was one of the two primary objectives of

the study. Safety assessments consisted of AEs, vital signs (ie, blood pressure, pulse rate, respiratory

rate, and temperature), weight, hemoglobin-oxygen saturation, clinical laboratory tests, somnolence

(assessed by University of Michigan Sedation Scale [UMSS]), conventional 12 lead ECGs, and 24-hour

digital 12-lead ECGs (Holter monitor).

Intensive electrocardiogram (ECG) monitoring was performed throughout the study, with particular

attention paid to QT interval measurements, as prior studies in adults showed that higher doses (40

mcg/h) of Butrans resulted in prolongation of the QT data corrected for heart rate (QTc) interval.

Patients receiving medicines that had known or possible associations with QTc prolongation within last

7 days prior to the start or anticipated during study drug treatment were excluded. Patients with

abnormal findings demonstrated on conventional 12-lead ECG were excluded from the study (eg,

prolonged QTc, ventricular arrhythmias, prolonged QRS, AV block). The criteria were revised during



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the study to align with standard medical practice in pediatric patients regarding cardiology parameters

(eg, definition of abnormal QRS changed from > 90 milliseconds to > 110 milliseconds).

The overall safety population consisted of a total of 41 patients, of which 6 (15%) were in the 7 to 11-

year age group and 35 (85%) in the 12 to 16-year age group. Treatment-emergent AEs (TEAEs) in the

overall safety population were reported for a total of 32 patients (78%) (see Table 3 for the Incidence of

Treatment-Emergent Adverse Events (Safety Population)). There were no deaths during the study, and 8

patients (20%) in the overall safety population experienced treatment-emergent serious AEs (SAEs).

See Table 6 for the listing of patients with SAEs.

In the 7-11 year and 12-16-year age groups, TEAEs were reported for 6 patients (100%) and 26 patients

(74%), respectively. Of the TEAEs reported for the 7 to 11-year age group, there were no mild AEs,

most TEAEs were moderate (4 patients, 67%) and 2 patients reported severe TEAEs. The severe

TEAEs were appendicitis and neutropenia; the neutropenia occurred in a patient with an underlying

condition of malignant neoplasm (Table 2). In the 12-16-year age group, 26 patients reported adverse

events, of which most were mild (12 patients, 34%) or moderate (9 patients, 26%,) and 5 were severe.

The severe TEAEs reported by the 5 patients in the 12-16-year age group included back pain (1 patient),

sickle anemia with crisis (2 patients) and migraine (2 patients); the sickle cell anemia was related to the

patient’s underlying condition (Table 2).

Table 2 Summary of Severe Treatment-Emergent Adverse Events (Safety Population)

Age Group

7 to 11 years

(N = 6)

n (%)

12 to 16 years

(N = 35)

n (%)

Total

(N = 41)

n (%)

Neutropenia 1 (17) 0 1 (2)

Sickle Cell Anaemia with

Crisis

0 2 (6) 2 (5)

Appendicitis 1 (17) 0 1 (2)

Back Pain 0 1 (3) 1 (2)

Migraine 0 2 (6) 2 (5)

Abbreviations: N = number of patients in the population; n = number of patients with event.

Cross-reference: BUP3031 CSR, Table 29.

Notes: MedDRA Version 15.0 was used to code adverse events.




Page 21 of 51

The most frequently reported AEs in the overall safety population (Table 3) were consistent with events

commonly associated with the use of opioid analgesics or with the transdermal route of administration

and were consistent with the established safety profile for adult patients. The most frequently reported

TEAEs related to study drug in the 12-16 years age group were similar to those in the overall

population. Due to the limited number of patients in the 7 to 11-year age group (6 patients), a similar

observation could not be made when analyzing safety data for that age group. See Table 3 below for the

incidence of TEAEs by System Organ Class and Preferred Term for the Safety Population.

TEAEs related to study drug (ie, unlikely, possibly, probably, or definitely related) were reported for 21

patients, including 5 of 6 patients in the 7 to 11-year age group and 16 of 35 patients in the 12 to 16-year

age group. See Table 4 for TEAEs that were considered by investigators to be related to the study drug.

The most frequently reported (≥ 10% of patients) TEAEs related to study drug in the overall safety

population involved events commonly associated with use of opioid analgesics or administration of

transdermal patches, including nausea (7 patients, 17%), application site pruritus (7 patients, 17%),

somnolence (6 patients, 15%), and application site irritation (5 patients, 12%).



Page 22 of 51


Term, Safety Population

Age Group

7 to 11 years 12 to 16 years Total

MedDRA System Organ Class

Preferred Term

(N=6)

n(%)

(N=35)

n(%)

(N=41)

n(%)

Any Adverse Event 6 (100) 26 ( 74) 32 ( 78)

BLOOD AND LYMPHATIC SYSTEM DISORDERS 3 ( 50) 1 ( 3) 4 ( 10)

ANAEMIA 1 ( 17) 1 ( 3) 2 ( 5) LEUKOCYTOSIS 1 ( 17) 0 1 ( 2)

NEUTROPENIA 1 ( 17) 0 1 ( 2)

CARDIAC DISORDERS 2 ( 33) 0 2 ( 5)

ATRIOVENTRICULAR BLOCK FIRST DEGREE 1 ( 17) 0 1 ( 2)

SINUS TACHYCARDIA 1 ( 17) 0 1 ( 2)

CONGENITAL, FAMILIAL AND GENETIC DISORDERS 0 4 ( 11) 4 ( 10)

SICKLE CELL ANAEMIA WITH CRISIS 0 4 ( 11) 4 ( 10)

EYE DISORDERS 0 1 ( 3) 1 ( 2) VISION BLURRED 0 1 ( 3) 1 ( 2)

GASTROINTESTINAL DISORDERS 2 ( 33) 12 ( 34) 14 ( 34) NAUSEA 1 ( 17) 7 ( 20) 8 ( 20)

VOMITING 1 ( 17) 3 ( 9) 4 ( 10)

CONSTIPATION 1 ( 17) 1 ( 3) 2 ( 5) CROHN'S DISEASE 1 ( 17) 1 ( 3) 2 ( 5)

DIARRHOEA 0 2 ( 6) 2 ( 5)

GASTROOESOPHAGEAL SPHINCTER INSUFFICIENCY 0 1 ( 3) 1 ( 2) GINGIVAL SWELLING 0 1 ( 3) 1 ( 2)

GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 2 ( 33) 12 ( 34) 14 ( 34) APPLICATION SITE PRURITUS 0 7 ( 20) 7 ( 17)

APPLICATION SITE IRRITATION 1 ( 17) 4 ( 11) 5 ( 12)

FATIGUE 1 ( 17) 1 ( 3) 2 ( 5) APPLICATION SITE EROSION 0 1 ( 3) 1 ( 2)

APPLICATION SITE PAIN 0 1 ( 3) 1 ( 2)

CHEST DISCOMFORT 0 1 ( 3) 1 ( 2) PAIN 0 1 ( 3) 1 ( 2)

SLUGGISHNESS 0 1 ( 3) 1 ( 2)

INFECTIONS AND INFESTATIONS 2 ( 33) 4 ( 11) 6 ( 15)

APPENDICITIS 1 ( 17) 0 1 ( 2)

CLOSTRIDIUM DIFFICILE COLITIS 1 ( 17) 0 1 ( 2) INFECTIOUS MONONUCLEOSIS 0 1 ( 3) 1 ( 2)

OSTEOMYELITIS CHRONIC 0 1 ( 3) 1 ( 2)

SINUSITIS 0 1 ( 3) 1 ( 2) UPPER RESPIRATORY TRACT INFECTION 0 1 ( 3) 1 ( 2)

INJURY, POISONING AND PROCEDURAL COMPLICATIONS 0 2 ( 6) 2 ( 5)

CONTUSION 0 1 ( 3) 1 ( 2)

LIGAMENT SPRAIN 0 1 ( 3) 1 ( 2)

INVESTIGATIONS 0 3 ( 9) 3 ( 7)

ELECTROCARDIOGRAM QT PROLONGED 0 2 ( 6) 2 ( 5)

ELECTROCARDIOGRAM QRS COMPLEX PROLONGED 0 1 ( 3) 1 ( 2) HEPATIC ENZYME INCREASED 0 1 ( 3) 1 ( 2)

METABOLISM AND NUTRITION DISORDERS 1 ( 17) 1 ( 3) 2 ( 5) DECREASED APPETITE 0 1 ( 3) 1 ( 2)

MALNUTRITION 1 ( 17) 0 1 ( 2)



Page 23 of 51


Term, Safety Population, continued

Cross Reference: BUP3031 CSR Table 14.3.1.1

Note: N = Number of patients in the population; n = Number of patients with event.

Multiple occurrences of the same adverse event in one individual are counted only once. Treatment-emergent adverse event is defined as any sign or symptom that emerges during treatment, having been absent at pretreatment; or re-emerges

during treatment, having been present at pretreatment but stopped prior to treatment; or worsens in severity during treatment relative to the pretreatment

state, when the AE is continuous. Adverse events that started after a patient’s last dose but within 7 days of dosing are considered treatment-emergent. MedDRA Version 15.0 was used to code adverse events. Percentages are based on N.

Age Group


MedDRA System Organ Class Preferred Term

(N=6) n(%)

(N=35) n(%)

(N=41) n(%)

MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 2 ( 33) 6 ( 17) 8 ( 20)

ARTHRALGIA 1 ( 17) 2 ( 6) 3 ( 7) BACK PAIN 0 3 ( 9) 3 ( 7)

PAIN IN EXTREMITY 0 2 ( 6) 2 ( 5)

JUVENILE ARTHRITIS 1 ( 17) 0 1 ( 2) MUSCULOSKELETAL PAIN 0 1 ( 3) 1 ( 2)

NERVOUS SYSTEM DISORDERS 3 ( 50) 13 ( 37) 16 ( 39) HEADACHE 1 ( 17) 5 ( 14) 6 ( 15)

SOMNOLENCE 1 ( 17) 5 ( 14) 6 ( 15)

DIZZINESS 1 ( 17) 2 ( 6) 3 ( 7) MIGRAINE 0 3 ( 9) 3 ( 7)

PARAESTHESIA 0 2 ( 6) 2 ( 5)

HYPERSOMNIA 1 ( 17) 0 1 ( 2) SEDATION 1 ( 17) 0 1 ( 2)

PSYCHIATRIC DISORDERS 0 3 ( 9) 3 ( 7) AGITATION 0 1 ( 3) 1 ( 2)

ANXIETY 0 1 ( 3) 1 ( 2)

INITIAL INSOMNIA 0 1 ( 3) 1 ( 2) INSOMNIA 0 1 ( 3) 1 ( 2)

TEARFULNESS 0 1 ( 3) 1 ( 2)

RENAL AND URINARY DISORDERS 0 2 ( 6) 2 ( 5)

BILIRUBINURIA 0 1 ( 3) 1 ( 2)

BLADDER SPASM 0 1 ( 3) 1 ( 2) PROTEINURIA 0 1 ( 3) 1 ( 2)

RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 1 ( 17) 3 ( 9) 4 ( 10)

COUGH 0 1 ( 3) 1 ( 2)

EPISTAXIS 1 ( 17) 0 1 ( 2) LUNG DISORDER 0 1 ( 3) 1 ( 2)

NASAL CONGESTION 0 1 ( 3) 1 ( 2)

OROPHARYNGEAL PAIN 0 1 ( 3) 1 ( 2) WHEEZING 0 1 ( 3) 1 ( 2)

SKIN AND SUBCUTANEOUS TISSUE DISORDERS 0 4 ( 11) 4 ( 10) ACNE 0 1 ( 3) 1 ( 2)

DERMATITIS CONTACT 0 1 ( 3) 1 ( 2)

PRURITUS 0 1 ( 3) 1 ( 2) RASH 0 1 ( 3) 1 ( 2)

VASCULAR DISORDERS 0 1 ( 3) 1 ( 2) HOT FLUSH 0 1 ( 3) 1 ( 2)



Page 24 of 51

Table 4 Incidence of Treatment-Emergent Adverse Events Related to Study Drug by System

Organ Class and Preferred Term (Safety Population)

Age Group


MedDRA System Organ Class

Preferred Term

(N = 6)

n (%)

(N = 35)

n (%)

(N = 41)

n (%)

Any Related Adverse Event 5 (83) 16 (46) 21 (51)

Blood and Lymphatic System Disorders 1 (17) 0 1 (2)

Neutropenia 1 (17) 0 1 (2)

Cardiac Disorders 2 (33) 0 2 (5)

Atrioventricular Block First Degree 1 (17) 0 1 (2)

Sinus Tachycardia 1 (17) 0 1 (2)

Eye Disorders 0 1 (3) 1 (2)

Vision Blurred 0 1 (3) 1 (2)

Gastrointestinal Disorders 2 (33) 6 (17) 8 (20)

Nausea 1 (17) 6 (17) 7 (17)

Constipation 1 (17) 1 (3) 2 (5)

Vomiting 1 (17) 1 (3) 2 (5)

General Disorders and Administration Site Conditions 1 (17) 10 (29) 11 (27)

Application Site Pruritus 0 7 (20) 7 (17)

Application Site Irritation 1 (17) 4 (11) 5 (12)

Application Site Erosion 0 1 (3) 1 (2)

Application Site Pain 0 1 (3) 1 (2)

Fatigue 0 1 (3) 1 (2)

Infections And Infestations 1 (17) 0 1 (2)

Clostridium Difficile Colitis 1 (17) 0 1 (2)

Investigations 0 3 (9) 3 (7)

Electrocardiogram QT Prolonged 0 2 (6) 2 (5)

Electrocardiogram QRS Complex Prolonged 0 1 (3) 1 (2)

Hepatic Enzyme Increased 0 1 (3) 1 (2)

Metabolism and Nutrition Disorders 0 1 (3) 1 (2)

Decreased Appetite 0 1 (3) 1 (2)

Musculoskeletal and Connective Tissue Disorders 0 3 (9) 3 (7)

Back Pain 0 2 (6) 2 (5)

Pain In Extremity 0 1 (3) 1 (2)

Nervous System Disorders 2 (33) 10 (29) 12 (29)

Somnolence 1 (17) 5 (14) 6 (15)

Dizziness 1 (17) 2 (6) 3 (7)

Headache 0 3 (9) 3 (7)

Paraesthesia 0 2 (6) 2 (5)

Migraine 0 1 (3) 1 (2)

Sedation 1 (17) 0 1 (2)

Psychiatric Disorders 0 3 (9) 3 (7)

Agitation 0 1 (3) 1 (2)

Anxiety 0 1 (3) 1 (2)

Initial Insomnia 0 1 (3) 1 (2)

Insomnia 0 1 (3) 1 (2)

Tearfulness 0 1 (3) 1 (2)



Page 25 of 51

Renal and Urinary Disorders 0 1 (3) 1 (2)

Bilirubinuria 0 1 (3) 1 (2)

Proteinuria 0 1 (3) 1 (2)

Respiratory, Thoracic And Mediastinal Disorders 1 (17) 0 1 (2)

Epistaxis 1 (17) 0 1 (2)

Skin And Subcutaneous Tissue Disorders 0 2 (6) 2 (5)

Dermatitis Contact 0 1 (3) 1 (2)

Pruritus 0 1 (3) 1 (2)

Vascular Disorders 0 1 (3) 1 (2)

Hot Flush 0 1 (3) 1 (2)

Abbreviations: N = number of patients in the population; n = number of patients with event.

Cross Reference: BUP3031 CSR Table 27

Related to study drug = unlikely, possibly, probably or definitely related categories of the adverse event CRF. If a

patient had more than 1 occurrence of the same system organ class/preferred term, the worst relationship was

summarized and counted only once. If a relationship was missing for an adverse event, it was assumed to be

related to study drug.



Of the 12 TEAEs leading to study discontinuation, 2 (application site irritation and somnolence)

were considered definitely related, 2 (prolonged QT) were considered probably and possibly

related to study drug; 4 (migraine, sinus tachycardia, prolonged QRS, and first degree AV

block) were considered unlikely to be related, and 4 (pain, sickle cell anemia with crisis,

hypersomnia, migraine) were considered not related. See Table 5 for a by-patient summary of

all AEs leading to permanent discontinuation.

Of the 5 TEAEs (in 3 patients) leading to to a dose reduction, 3 (somnolence [2 events] and

sedation) were considered probably related and 2 (chest discomfort and headache) were

considered not related. One patient experienced an event (dizziness) after a dose interruption (not

wearing a patch for 48 hours).



Page 26 of 51

Table 5 Listing of Patients with AEs Leading to Study Discontinuation (Safety Population)

Patient

Number

Age (yrs),

Sex, Race

Preferred Term/

Verbatim Term

AE Onset Date/

Study Period

(Study Day)

AE Stop Date/

Study Period

(Study Day) Severity

Relationship

to Study Drug

Study Drug

Action Taken/

Other Action

Taken

Outcome/

(duration) Serious

Treatment-emergent

2124A-

0008002

16/F/W Migraine/

Increased Migraine Pain

2014-03-01/

Open-Label

(4)

Severe Unlikely Stopped

Permanently/

Treatment Given

And Withdrawn

From Study

Ongoing/ N

2124A-

0008003

13/M/W Electrocardiogram QT Prolonged/

QTcB Prolonged (> 480 Msec)

2014-11-18/

Open-Label

(28)

2014-11-24/

Open-Label

(34)

Mild Probably Stopped

Permanently/

Withdrawn From

Study

Recovered/

(7)

N

1864A-

0030003

15/M/O Pain/

Worsening Pain due to Neuroma

2015-11-02/

Open-Label

(26)

Moderate Not Related Stopped

Permanently/

Treatment Given

And Withdrawn

From Study

Ongoing/ N

1864A-

0030004

12/F/W Application Site Irritation/

Skin Irritation on Patch Site

2016-03-08/

Open-Label

(127)

2016-05-23/

Follow-up/Taper

(203)

Mild Definitely Stopped

Permanently/

Withdrawn From

Study

Recovered/

(77)

N

2493A-

9009004

10/F/W Sinus Tachycardia/

Worsening Sinus Tachycardia

2013-01-15/

Open-Label

(9)

Mild Unlikely Stopped

Permanently/

Withdrawn From

Study

Ongoing/ N

2125A-

0024002

16/F/B Sickle Cell Anaemia With Crisis/

Vaso-occlusive Crisis

2014-10-29/

Open-Label

(23)

2014-11-04/

Open-Label

(29)


Permanently/

Treatment Given

Recovered/

(7)

Y

2125A-

0024003

11/F/B Hypersomnia/

Hypersomnolence

2015-02-19/

Open-Label

(3)

2015-02-20/

Open-Label

(4)


Permanently/

Withdrawn From

Study

Recovered/

(2)

Y



Page 27 of 51

Patient

Number

Age (yrs),

Sex, Race

Preferred Term/

Verbatim Term

AE Onset Date/

Study Period

(Study Day)

AE Stop Date/

Study Period


Relationship

to Study Drug

Study Drug

Action Taken/

Other Action

Taken

Outcome/

(duration) Serious

2527A-

0010005

11/F/W Atrioventricular Block First Degree/

First Degree Heart Block

2013-07-02/

Open-Label

(8)

2013-07-12/

Follow-up/Taper

(18)

Moderate Unlikely Stopped

Permanently/

Withdrawn From

Study

Recovered/

(11)

Y

2527A-

0010006

15/F/W Electrocardiogram QRS Complex

Prolonged/

QRS Complex Prolonged

2013-11-25/

Open-Label

(55)

2013-12-03/

Follow-up/Taper

(63)


Permanently/

Withdrawn From

Study

Recovered/

(9)

N

2527A-

0010010

13/M/W Migraine/

Exacerbation Of Migraine Pain

2015-07-20/

Open-Label

(27)

2015-07-23/

Open-Label

(30)

Severe Not Related Stopped

Permanently/

Treatment Given

Recovered/

(4)

Y

2527A-

0010011

16/F/W Electrocardiogram QT Prolonged/

Prolonged QT

2015-07-31/

Open-Label

(11)

2015-08-21/

Follow-up/Taper

(32)

Mild Possibly Stopped

Permanently/

Withdrawn From

Study

Recovered/

(22)

N

Somnolence/

Somnolence

2015-07-27/

Open-Label

(7)

2015-08-03/

Open-Label

(14)

Moderate Definitely Stopped

Permanently/

Withdrawn From

Study

Recovered/

(8)

N

Not Treatment-emergent

2815A-

0023001

11/M/B Osteonecrosis/

Worsening Bilateral Avascular

Necrosis Of The Hip

2014-11-16/

Open-Label

(59)

2014-11-19/

Follow-up/Taper

(62)


Permanently/

Withdrawn From

Study

Recovered/

(4)

Y

Abbreviations: Race: W = White; B = Black or African American; O = Other; Serious: Y = Yes; N = No. Sex: M = Male; F = Female. yrs = years.

Cross Reference: BUP3031 CSR, Table 32.

Note: MedDRA Version 15.0 was used to code adverse events.



Page 28 of 51

There were no deaths during the study. Eight (20%) patients (4 in each age group) experienced a

treatment-emergent serious adverse event (SAE) (See Table 6 for a by-patient listing of

treatment emergent SAEs). One SAE (atrioventricular block first degree/first degree heart block)

was reported by the investigator as unlikely related to study drug. All other SAEs (n=7) were

judged unrelated to study drug.



Page 29 of 51

Table 6 Listing of Serious Adverse Events (Safety Population)

Patient

Number

Age

(yrs),

Sex,

Race

Preferred Term/

Verbatim Term

SAE Onset Date/

Study Period

(Study Day)

SAE Stop Date/

Study Period


Relationship

to Study Drug

Study Drug

Action Taken/

Other Action

Taken

Outcome/

(duration) SAE Type

1864A-

0030002

11/M/O Appendicitis/

Appendicitis

2014-12-24/

Open-Label

(51)

2014-12-27/

Open-Label

(54)

Severe Not Related None/

Treatment Given

Recovered/

(4)

Hospitalization

2763A-

0028001

13/M/B Sickle Cell Anaemia with Crisis/

Vaso-Occlusive Crisis

2014-11-17/

Open-Label

(54)

2014-11-21/

Open-Label

(58)

Moderate Not Related None/

Treatment Given

Recovered/

(5)

Hospitalization

2015-02-20/

Open-Label

(149)

2015-02-27/

Open-Label

(156)


Treatment Given

Recovered/

(8)

Hospitalization

2015-03-20/

Open-Label

(177)

2015-03-25/

Follow-up/Taper

(182)


Treatment Given

Recovered/

(6)

Hospitalization

Sickle Cell Anaemia with Crisis/

Vaso-Occlusive Sickle Cell Pain

Crisis

2014-10-01/

Open-Label

(7)

2014-10-09/

Open-Label

(15)

Severe Not Related Dose Increased/

Treatment Given

Recovered/

(9)

Hospitalization

2493A-

9009004

10/F/W Anaemia/

Worsening Anemia

2013-01-21/

Follow-up/Taper

(15)

2013-01-31/

Follow-up/Taper

(25)


Treatment Given

Recovered/

(11)

Hospitalization

Crohn's Disease/

Crohn's Exacerbation

2013-01-21/

Follow-up/Taper

(15)

2013-01-31/

Follow-up/Taper

(25)


Treatment Given

Recovered/

(11)

Hospitalization

Malnutrition/

Malnutrition

2013-01-21/

Follow-up/Taper

(15)


Treatment Given

Ongoing/ Hospitalization



Page 30 of 51

Patient

Number

Age

(yrs),

Sex,

Race

Preferred Term/

Verbatim Term

SAE Onset Date/

Study Period

(Study Day)

SAE Stop Date/

Study Period


Relationship

to Study Drug

Study Drug

Action Taken/

Other Action

Taken

Outcome/

(duration) SAE Type

2125A-

0024002

16/F/B Sickle Cell Anaemia with Crisis/


2014-10-29/

Open-Label

(23)

2014-11-04/

Open-Label

(29)


Permanently/

Treatment Given

Recovered/

(7)

Hospitalization

Sickle Cell Anaemia with Crisis/


2014-11-10/

Open-Label

(35)

2014-11-18/

Open-Label

(43)


Treatment Given

Recovered/

(9)

Hospitalization

2125A-

0024003

11/F/B Hypersomnia/

Hypersomnolence

2015-02-19/

Open-Label

(3)

2015-02-20/

Open-Label

(4)


Permanently/

Withdrawn From

Study

Recovered/

(2)

Hospitalization

0746A-

0001003

16/F/W Osteomyelitis Chronic/

Suspected Worsening of Chronic

Osteomyelitis

2012-11-29/

Open-Label

(22)

2012-12-05/

Open-Label

(28)

Mild Not Related None/

Treatment Given

Recovered/

(7)

Hospitalization

2527A-

0010005

11/F/W Atrioventricular Block First Degree/

First Degree Heart Block

2013-07-02/

Open-Label

(8)

2013-07-12/

Follow-up/Taper

(18)


Permanently/

Withdrawn From

Study

Recovered/

(11)

Medically

Important

2527A-

0010010

13/M/W Migraine/

Exacerbation of Migraine Pain

2015-07-20/

Open-Label

(27)

2015-07-23/

Open-Label

(30)

Severe Not Related Stopped

Permanently/

Treatment Given

Recovered/

(4)

Hospitalization

Abbreviations: Race: W = White; B = Black or African American; O = Other. Sex: M = Male; F = Female. SAE = serious adverse event. yrs = years.

Cross Reference: BUP3031 CSR, Table 31




Page 31 of 51

Clinical laboratory tests and vital sign assessments did not reveal any apparent safety concerns in

the study population. There were no clinically significant changes from baseline in mean

respiratory rate or the degree of hemoglobin-oxygen saturation or desaturation. The analysis of

the BUP3031 pediatric clinical trial data did not reveal any specific, unique safety issue not

already established as part of the Butrans safety profile for adult patients. The adverse event

profile observed for the 12 to 16-year age group was consistent with the known safety profile of

Butrans in adult clinical trials and post marketing experience. Due to the limited number of

patients in the 7 to 11-year age group, a similar conclusion could not be made.



Page 32 of 51

2.3 Pediatric Efficacy

Assessment of efficacy was a secondary objective in this open-label study and included the

following:

Pain right now assessed by patients using Faces Pain Scale-Revised (FPS-R), for patients

aged 7 to 11 years, inclusive.

Pain right now assessed by patients using 100-mm Visual Analog Scale (VAS), for

patients aged 12 to 16 years, inclusive.

Parent/Caregiver-assessed Global Impression of Change (PGIC), aged 7 to 16 years,

inclusive.

The FPS-R is a horizontal row of 6 faces representing pain intensity, with “no hurt” at the far left

and “hurts worst” at the far right; the 6 intensities are scored as 0, 2, 4, 6, 8, or 10 (the patient

was not shown the numbers associated with the faces).15 The 100-mm VAS is a 100-mm line

with 1 end marked “no pain” and the opposite end marked as “pain as bad as it could be.” The

patient was asked to make a mark on that line indicating his or her level of pain.16 The pain right

now 100-mm VAS score was defined as the distance (in mm) from the “no pain” end to the

patient’s mark.16-19

The majority of patients (n=39, 95%) in the safety population were receiving opioid analgesics to

treat their pain at baseline before beginning treatment with Butrans. The baseline pain scores

indicated that most patients had acceptable pain control at study entry. In general, the patients’

pain right now scores (VAS and FPS-R) were maintained or improved in both age groups during

Butrans treatment, compared with baseline scores. The data were more variable for the younger

age group due, at least in part, to the small sample size.

Overall, the patient’s pain right now scores as assessed by FPS-R were maintained or improved

when compared to baseline scores in patients aged 7 to 11 years (Table 7). For patients ages 7 to

11 years, pain right now was assessed using FPS-R. At baseline, the mean (SE) FPS-R score

was 2.80 (1.497), with a range of 0 to 8 for the 5 patients assessed. At week 1, the mean score

was 3.49 (1.768), with a range of 0.4 to 9.6 for the 5 patients assessed, and at week 2, the mean

score was 2.98 (1.871) for the 3 patients assessed. At week 3, there were 2 patients assessed and



Page 33 of 51

the mean score was 0.29. After week 4, there was 1 patient on Butrans in this age group, and the

mean score was 0 for weeks 4 through 12.

Table 7 Pain right now scores for patients aged 7 to 11 years (FPS-R ) *

Time point Number of patients

assessed (n)

FPS-R score, mean (SE)

Baseline 5 2.80 (1.50)

Week 1 5 3.49 (1.77)

Week 2 3 2.98 (1.87)

Week 3 2 0.29

Week 4 2 0

Weeks 5-12 1 0

Abbreviations: FPS-R, Faces Pain Scale-Revised; SE, Standard Error.

* Score Range 0 to 10

For patients aged 12 to 16 years, pain right now was assessed using the 100-mm VAS and the

scores are provided by week in Figure 2. At baseline, the mean (SE) VAS score was 46.6 (4.55),

with a range of 0 to 85 for the 33 patients assessed. The mean VAS scores decreased weekly

through week 6, when the mean (SE) score was 28.0 (6.56) for the 19 patients assessed, with

scores ranging from 1 to 92. The scores continued to fluctuate slightly, with a low of 27.3 (5.83)

at week 9 and a peak of 42.5 (8.31) at week 12. At week 24, the mean (SE) VAS score was 36.5

(5.35), with a range of 9 to 59 for the 11 patients assessed.



Page 35 of 51

50% of the patients had PGIC scores of 1 or 2 assessed at the end of treatment or at the early

discontinuation visit, indicating a very much improved or much improved impression of change.

2.4 Study conclusion

Butrans transdermal system in this pediatric population demonstrated the safety expected from

adult studies, although TEAEs were more common in the 7 to 11-year age group than in the 12-

16 age group. The small sample size (6 patients) in the 7 to 11-year age group should be

carefully considered when interpreting the data and drawing conclusions for this population.

Butrans had the expected safety profile and maintained or improved pain control in combination

with supplemental analgesics when administered to patients 7 to 16 years old who required a

continuous, around-the-clock opioid analgesic therapy for management of moderate to severe

persistent pain.

For children aged 12-16 years of age, the PK data suggest that no dose modification is needed

from adult dosing. For children 7-11 years of age, half of the adult dose should be used.

3 PROPOSED BUTRANS PEDIATRIC LABELING

The sample size and study design of BUP3031 are adequate to fulfill the PREA requirement as

requested by the Agency. While the study data are meaningful and will be of value to

prescribers, the data are limited when considering the appropriateness for a pediatric indication.

In consideration of the small sample size and the open-label design of the study, Purdue is not

requesting a pediatric indication. Rather, we propose that the BUP3031 pediatric patient

experience should be described only in Section 8.4 (ie, USE IN SPECIFIC POPULATIONS,

Pediatric Use) of the US Full Prescribing Information (see Appendix C for proposed labeling

provided to the FDA).

The decision to include data in the Pediatric Use section of the package insert was informed by

the sample size and open-label design of the study, not due to safety concerns. The proposed

language describes the clinical study experience of Butrans in the pediatric population and the

provision of such data in the Pediatric Use section will provide useful clinical information to

health care providers regarding Butrans in a pediatric setting.



Page 36 of 51

4 EPIDEMIOLOGY OF OPIOID UTILIZATION IN THE PEDIATRIC

POPULATION AND RELEVENCE TO STUDY BUP3031

Study BUP3031 sought an appropriate population of pediatric patients with persistent or chronic

pain who required opioid analgesic therapy for at least 2 weeks. However, as there was little

information about the demographic and clinical characteristics of pediatric patients using opioid

analgesics in a real world clinical setting, and to better understand the prevalence and treatment

of pediatric pain, Purdue has also conducted a program of 4 epidemiologic studies to provide

real-world context for its pediatric clinical trials.20,21 Three of the epidemiology studies were

conducted for the OxyContin pediatric program, so the focus of these analyses is on pediatric use

of OxyContin.

Three US healthcare claims/medical utilization databases were used to perform retrospective

cohort studies in children (≤16 years of age) receiving 1 or more inpatient or outpatient

prescription for OxyContin tablets or a specified comparator opioid analgesic in regular clinical

practice.20 These databases were:

Henry Ford Health System electronic medical record (EMR) database (HFHS) (Study 1),

HealthCore Integrated Research Database (HIRD) (Study 2), and

Kaiser Permanente Northwest and Northern California EMR database (KP) (Study 3).

The HFHS database was used for a pilot study that incorporated EMR review in a small cohort

of OxyContin users along with database analyses, which informed analyses for the other two

databases. The HIRD and KP databases were used for the primary studies, to describe population

characteristics and utilization patterns in a larger sample of pediatric patients treated with opioid

analgesics (Table 8). A fourth descriptive, retrospective cohort study was conducted using data

from the MarketScan Commercial and Medicaid databases to describe the prevalence and

treatment of conditions associated with pain in pediatric patients (Table 8).



Page 37 of 51

Table 8 Databases in the Epidemiologic Studies Evaluating the use of OxyContin in Actual

Clinical Practice20,21

Data Source Approx. Base Population,

Duration of Observation*

Database Type Geographic

Coverage

Study 1

Henry Ford Health System

127,000, ~10 years (2000-

2010)

EMR + chart

review

Detroit Michigan

metro area

Study 2

HealthCore Integrated Research

Database

12.7 million, ~10 years (2001-

2010)

Healthcare

claims

Nationwide United

States

Study 3

Kaiser Permanente

(Note: study population

included some individuals with

Medicaid, Medicare, and dual

coverage)

3.5 million, ~10 years (1998-

2010)

EMR Northern California,

Northwest

Study 4

MarketScan Commercial and

Multi-State Medicaid Databases

30 million pediatric patients,

~4 years (2009-2012 (~25

million Commercially-insured;

~5 million insured through the

Medicaid program)

Healthcare

claims

United States

*Base population includes all patients in database, not just pediatric patients.

While these epidemiology studies did not document in all cases the underlying conditions for

which opioid analgesics were prescribed. Examination of diagnoses proximal to the prescription,

along with chart review performed in Study 1, provided some information about the indications

for the use of opioid analgesics. The data indicate that a large percentage of pediatric patients

received opioid analgesics for treatment of acute pain conditions (eg, postsurgical pain, trauma).

In Study 1, 22 patients age 0 to 16 years prescribed OxyContin were identified who had data

available for chart review (out of 26 total). Of those 22 patients, 86% were older adolescents

aged 12 to 16 years and 77% of patients received prescriptions for OxyContin for postsurgical

pain, 4.5% for cancer pain, 4.5% for sickle cell disease, and 4.5% for trauma. Most patients

(86%, n=19) received a low dose of OxyContin (defined as ≤80 mg/day) and 41% of patients



Page 38 of 51

(n=9) had prior use of other opioid analgesics. The mean treatment duration was 9.7 days

(standard deviation (SD)=9.2 days), the median treatment duration was 5 days, and the range was

2 to 30 days.

There were 35 patients in the OxyContin cohort identified in Study 1 for claims-based analyses.

Of the 35 patients, 71% (n=25) were older adolescents aged 12 to 16 years and 74% (n=26) were

male. The mean treatment duration was 11.0 days (SD=10.9 days), the median was 5 days, and

the range was 2 to 45 days. Twenty-three percent of patients in this cohort (n=8) had prior use of

other opioid analgesics and an additional 5 patients were taking OxyContin along with other

opioid analgesics.

In Study 2, the much larger HIRD study (n=347 patients under 16 years prescribed OxyContin)

based solely on healthcare claims data, with diagnosis determined based on proximity to the

prescription, 7% of pediatric patients received an OxyContin prescription for cancer, 52% for

orthopedic conditions (including orthopedic surgeries), 9% for trauma, 8% for scoliosis, 0.6% for

sickle cell disease, and 37% for other indications such as burns.

These data also indicate that prescriptions for opioid analgesics in pediatric patients were

generally of short duration and for low doses. The median prescription duration was relatively

short; 5 days in Study 1 compared with 11 days in both OxyContin treatment groups (with and

without another concomitant opioid) in Study 2, and ≤30 days in Study 3. Many patients

received a prescription for OxyContin after an inpatient discharge: 25.9% of those prescribed

OxyContin; 36.1% of those prescribed OxyContin and another opioid analgesic (Study 2). Prior

opioid analgesic use was common in these studies. The large majority of pediatric patients

(range: 80.8% to 91.8% in these 3 studies) who received OxyContin or oxycodone ER were

between the ages of 12 and 16.

Purdue also conducted a fourth epidemiologic study (Study 4) to describe the prevalence of

conditions associated with pain in pediatric patients and how these conditions are treated. 21

Study 4 was a descriptive, retrospective cohort study using data from the MarketScan

Commercial and Medicaid databases for 2009-2012, with demographic, prescription, diagnosis,

and procedure data for over 30 million pediatric patients. A list of conditions associated with

pain was developed in consultation with experts on pediatric pain. The prevalence of each of the



Page 39 of 51

conditions over 1 year, the patients’ medical and demographic characteristics, and the proportion

of patients receiving various medicines used to treat pain were analyzed. The prevalence of most

conditions associated with pain was low. Overall, among commercially-insured patients, surgery

was the most common pain-related condition (5.6% of the database’s pediatric population),

followed by orthopedic conditions (2.7%), malignancies (2.1%), trauma (1.6%), and genetic

conditions (0.7%). Among Medicaid patients, surgery was the most prevalent condition (9.7%)

associated with pain in patients aged 0 to 16 years, followed by trauma (2.0%), orthopedic

conditions (1.9%), malignancies (1.7%), and genetic conditions (0.6%). Appendix D shows the

prevalence of commercially insured and Medicaid insured pediatric patients with conditions

associated with pain, by age group.

Estimates of the prevalence of conditions in Study 4 varied by age, but many diagnoses showed

higher prevalence in older children, such as orthopedic conditions, malignancies, and genetic

conditions. The types of analgesic and nonanalgesic treatments used in pediatric patients with

pain-associated conditions varied substantially by condition and the age of the patient, with the

highest prevalence of pharmacologic treatment occurring in older children.

These pediatric epidemiology studies improve the understanding of the population of pediatric

patients treated for pain. Results of these studies underscore the rarity of pediatric patients being

treated with opioid analgesics, particularly for persistent pain. These data indicate that the use of

opioid analgesics in the treatment of pain in pediatric patients is infrequent and typically of short

duration. 20 This conclusion is further substantiated in the literature, with the observation that

only a limited number of pediatric patients are prescribed extended-release opioid analgesics and

usually only for very brief periods.6

Despite the limited availability of appropriate patients and the considerable constraints imposed

by protocol eligibility criteria, the conduct over approximately 5 years and completion of study

BUP3031 attest to extensive recruitment efforts by investigators and Purdue to achieve a

population with balanced distribution of younger and older patients who required at least 2

weeks of opioid analgesic therapy. Published literature, Purdue’s prior pediatric clinical research

experience with OxyContin, and Purdue’s epidemiologic research, summarized above, confirm

the low prevalence of chronic pain in older pediatric patients and the rarity of chronic pain in



Page 40 of 51

younger patients, limiting those patients who would be available and appropriate for enrollment

in the BUP3031 study.7,20, 22-26 The consistency of the BUP3031 age distribution with these data

sources supports that the actual enrollment reflects the real world need and utilization of chronic

opioid analgesics in children.

5 PEDIATRIC UTILIZATION OF BUTRANS

We do not expect significant use of Butrans in pediatric patients given the limited use of

extended-release opioid analgesics in children, the very limited use of Butrans in children today,

and the trend toward less opioid use in adults in the US. At the September 2016 Joint Meeting of

the Anesthetic and Analgesic Drug Products Advisory Committee, the Drug Safety and Risk

Management Advisory Committee, and the Pediatric Advisory Committee, the Agency presented

a Pediatric Drug Utilization Review.27 In this review, data were provided for 2011-2015 annual

pediatric use of transdermal buprenorphine. Based on national estimates of pediatric patients 16

years of age and younger who received opioid analgesic prescriptions from US outpatient retail

pharmacies, a very small number of pediatric patients were dispensed prescriptions for Butrans,

presented in Table 9 below.

Table 9: National estimates of pediatric patients ages 7 to 16 years who received

prescriptions dispensed for transdermal buprenorphine 27

Year

Total

pediatric

patients

dispensed

opioids

Pediatric

Patients 7 to

16 years

dispensed

opioids

Pediatric

patients 7 to 16

dispensed ER

opioids

Pediatric

Patients

Dispensed

Butrans

Butrans

pediatric

patients as %

of those

dispensed ER

opioids

2011 3,696,469 2,730,648 7,613 59 0.80%

2012 3,512,496 2,611,444 7,637 55 0.70%

2013 3,020,392 2,318,908 6,763 86 1.30%

2014 2,660,016 2,092,767 6,554 92 1.40%

2015 2,455,960 1,963,469 5,863 75 1.30%

Data Source: Symphony Health Solutions Integrated DataVerse (IDV) Years 2011-2015 (as

reported in DHHS, FDA CDER, & OSE, 2016).



Page 41 of 51

A review of prescription data before and after the 2015 label change for OxyContin indication

revealed that the pediatric indication did not expand the number of children 11 years and older

(labelled age group) dispensed oxycodone ER products, according to an analysis conducted by

the Office of Public Health Strategy and Analysis, FDA.28 The study was conducted to

understand the effect of the labeling on dispensing of all oxycodone extended-release (ER)

products (OxyContin and authorized generics). Data were analyzed from IMS Health, with a

comparison of the number of dispensed oxycodone prescriptions in the 12 months prior to and

the 9 months after the labeling changes, in the age groups of 0-10 and 11-17.28 The study found

that the label changes did not expand the number of children 11 years and older dispensed

oxycodone ER products. The total number of oxycodone ER prescriptions initially increased

from 493 to 586 in December 2014, but subsequently declined to 323 in April 2016. Also, the

mean number of children 11 years and older dispensed oxycodone ER fell from 470 in the 12

months prior to 389 in the 9 months following the label changes, accounting for a 17% drop (P =

0.01). It was also found that dispensing of the drug occurred at extremely low levels. The

percentage of patients 11 to 17 prescribed oxycodone ER decreased by 15% from an average of

0.13% to 0.11% (P = 0.01), while the percentage of patients 0 to 10 accounts for less than 0.01%

of all oxycodone ER prescriptions (P = 0.48). Thus, the study team concluded that the

OxyContin pediatric label change did not expand pediatric use of the drug. 28

6 CONCLUSIONS

The BUP3031 study population is representative of the overall population of non-oncologic

pediatric patients with persistent pain requiring opioid analgesics for at least 2 weeks. Study

BUP3031 fulfills the PREA requirement for the Butrans NDA 021306 with an adequate number

of pediatric patients exposed to buprenorphine to evaluate pharmacokinetics and safety. Butrans

had the expected safety profile and maintained or improved pain control in combination with

supplemental analgesics when administered to patients 7 to 16 years old who required a

continuous, around-the-clock opioid analgesic therapy for management of moderate to severe

persistent pain.

Both the feasibility and conduct of pediatric opioid analgesic safety and efficacy studies lasting

more than 2 weeks present significant challenges.8,9 The population of pediatric patients with



Page 42 of 51

persistent or chronic pain requiring opioid analgesics for more than 2 weeks is uncommon, as

shown in the literature and supported by Purdue’s epidemiologic studies, clinical trial

experience, and study-specific prescreening documentation.7,10,11,20 The FDA publication

CDER Conversation: Pediatric pain management options regarding the recent approval of

the pediatric labeling for OxyContin tablets states: “Children are not treated with opioids very

often and usually it’s only for a limited period of time with close supervision by health care

professionals,” (http://www.fda.gov/Drugs/NewsEvents/ucm456973.htm). Children in the

younger age range comprise an even smaller subset of the rare population of pediatric patients

requiring opioid analgesics for more than a few days.

Given the sample size and open-label design of study BUP3031, a pediatric indication is not

being requested. Purdue considers that the provision of labeling text in the Pediatric Use section

8.4 of the Butrans US Full Prescribing Information describes the clinical study experience of

Butrans in the pediatric population and the provision of such data in the Pediatric Use section

will provide useful clinical information to health care providers regarding Butrans, and will help

them care for the small population of children who may benefit from an extended- release opioid

analgesic such as Butrans.



Page 43 of 51

7 REFERENCES

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2. Reckitt Benckiser Pharmaceuticals Inc. (n.d.) Buprenrex (buprenorphine

hydrochloride injection) Full Prescribing Information, retrieved online at

https://dailymed.nlm.nih.gov/dailymed/getFile.cfm?setid=b086772e-d15a-4d13-

b1a2-38bfbde1f18c&type=pdf&name=b086772e-d15a-4d13-b1a2-38bfbde1f18c

3. Yang YT, Chen B, Bennett CL. FDA Approval of extended-release oxycodone for

children with severe pain Pediatrics. 2016;137 (5) e20160205.

4. Finkel JC, Finley A, Greco C, Weisman SJ, Zeltzer L. Transdermal fentanyl in the

management of children with chronic severe pain: results from an international study.

Cancer. 2005;104(12):2847-57.

5. Czarnecki ML, Jandrisevits MD, Theiler SC, Huth MM, Weisman SJ. Controlled-

release oxycodone for the management of pediatric postoperative pain. J Pain

Symptom Manage. 2004 Apr;27(4):379-86.

6. Zernikow B, Michel E, Craig F, Anderson BJ. Pediatric palliative care: use of opioids

for the management of pain. Pediatr Drugs 2009;11(2):129-151.

7. Purdue Pharma L.P. OTR3001: An Open-label, Multicenter Study of the Safety of

Twice Daily Oxycodone Hydrochloride Controlled-release Tablets in Opioid

Experienced Children from Ages 6 to 16 Years Old, Inclusive, with Moderate to

Severe Malignant and/or Nonmalignant Pain Requiring Opioid Analgesics; data on

file, 2014.

8. Berde CB, Walco GA, Krane EJ, Anand KJ, Aranda JV, Craig KD, et al. Pediatric

analgesic clinical trial designs, measures, and extrapolation: report of an FDA

scientific workshop. Pediatrics. 2012;129(2):354–364. doi: 10.1542/peds.2010-3591

9. Weisman, S, (2016). The Challenges of Conducting Opioid Clinical Trials In

Pediatrics. Guest Speaker Presentation for the September 15-16, 2016 Joint Meeting

of the Anesthetic and Analgesic Drug Products Advisory Committee, the Drug Safety

and Risk Management Advisory Committee, and the Pediatric Advisory Committee.



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10. Purdue Pharma L.P. (2012). Prescreen Data Analysis-OTR3001: An Open-label,

Multicenter Study of the Safety of Twice Daily Oxycodone Hydrochloride

Controlled-release Tablets in Opioid Experienced Children from Ages 6 to 16 Years

Old, Inclusive, with Moderate to Severe Malignant and/or Nonmalignant Pain

Requiring Opioid Analgesics.

11. Baldridge S, Wallace L, Folta T. (2016). Analysis of Prescreening Data from

Pediatric Pain Trials poster. PainWeek 2016, Las Vegas, NV

12. Purdue Pharma L.P. Full Clinical Study Report BUP3031, data on file, 2016, 2017.

13. Hussain S, Tomasovic J, Cucchiaro G, Gebhard R, Kanter J, Galinkin J, Berkenbosch

JW, He E, Baldridge S. (2016). An Open-label, Multicenter Study of the Safety,

Pharmacokinetics, and Effectiveness of Buprenorphine Transdermal System (BTDS)

in Children from 7 to 16 Years of Age, Inclusive, Who Required Continuous Opioid

Analgesia for Moderate to Severe Pain poster. American Pain Society 2016,

Pittsburgh, PA.

14. Metrum Research Group (2016). Pharmacokinetics and exposure of transdermal

buprenorphine in pediatric patients 7-16 years of age, data on file.

15. Hicks CL, von Baeyer CL, Spafford PA, van Korlaar I, Goodenough B. The Faces

Pain Scale – Revised: toward a common metric in pediatric pain measurement. Pain

2001;93:173-83.

16. Wewers ME, Lowe NK. A critical review of visual analogue scales in the

measurement of clinical phenomena. Res Nurs Health 1990; 13:227-236.

17. Price DD, McGrath PA, Rafii A, Buckingham B. The validation of visual analogue

scales as ratio scale measures for chronic and experimental pain. Pain 1983;17:45-56.

18. Huskisson EC. Measurement of Pain. Lancet 1974;2(7889):1127-31.

19. Scott J, Huskisson EC. Graphic representation of pain. Pain 1976;2:175-84.

20. Purdue Pharma L.P. (2013) Pediatric OxyContin Epidemiology Studies, data on file.

21. Wallace, L, Matsuno, R, Baldridge, S, (2014). The Epidemiology of Outpatient Pain

Treatment in Pediatrics poster, Society for Pediatric Anesthesia, Fort Lauderdale, FL.



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22. Perquin CW, Hazebroek-Kampschreur AA, Hunfeld JA, Bohnen AM, van Suijlekom-

Smit LW, Passchier J, van der Wouden JC. Pain in children and adolescents: a

common experience. Pain 2000;87:51– 8

23. King S, Chambers C, Huguet A, MacNevin RC, McGrath PJ, Parker L, et al. The

epidemiology of chronic pain in children and adolescents revisited: A systematic

review. Pain 2011;152:2729-2738.

24. Richter HD, Hays SR. Demographics of Chronic Pain in Children. Handbook of

Pediatric Chronic Pain: Current Science and Integrative Practice. Editors: McClain

BC, Suresh S. New York, New York, United States: Springer; 2011 Jun;45-61.

25. Vetter, TR. A clinical profile of a cohort of patients referred to an anesthesiology-

based pediatric chronic pain medicine program. Anesthesia and Analgesia 2008 Mar;

106(3): 786-94.

26. Purdue Pharma L.P. (2016). Study BUP3031 Clinical Overview: BUP3031 Patient

Population Rationale

27. Department of Health and Human Services, Food and Drug Administration Center for

Drug Evaluation, and Research Office of Surveillance and Epidemiology (2016).

Background Package Addendum: Pediatric Drug Utilization Review. Retrieved from

https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/

Drugs/AnestheticAndAnalgesicDrugProductsAdvisoryCommittee/UCM519724.pdf

28. Xu J, Gill R, Cruz M, Staffa J, Lurie P. Effect of US Food and Drug Administration-

approved pediatric labeling on dispensing of extended release oxycodone in the

outpatient retail setting. JAMA Pediatr. 2016;170(11):1103-1104.



Page 46 of 51

8 APPENDICES

8.1 Appendix A

Excerpt below is from the Butrans US Full Prescribing Information. The full Butrans US

Prescribing Information is available at http://app.purduepharma.com/xmlpublishing/pi.aspx?id=b

Section 6 – Adverse Reactions [note: tables are numbered as they appear in the Full Prescribing

Information]

The most common adverse reactions (≥ 5%) reported by patients in clinical trials comparing

BUTRANS 10 or 20 mcg/hour to placebo are shown in Table 2, and comparing BUTRANS 20

mcg/hour to BUTRANS 5 mcg/hour are shown in Table 3 below:

Table 2: Adverse Reactions Reported in ≥ 5% of Patients during the Open-Label

Titration Period and Double-Blind Treatment Period: Opioid-Naïve Patients

Open-Label

Titration Period

Double-Blind Treatment

Period

BUTRANS BUTRANS Placebo

MedDRA Preferred Term (N = 1024) (N = 256) (N = 283)

Nausea 23% 13% 10%

Dizziness 10% 4% 1%

Headache 9% 5% 5%

Application site pruritus 8% 4% 7%

Somnolence 8% 2% 2%

Vomiting 7% 4% 1%

Constipation 6% 4% 1%

Table 3: Adverse Reactions Reported in ≥ 5% of Patients during the Open-Label

Titration Period and Double-Blind Treatment Period: Opioid-Experienced Patients

Open-Label

Titration Period Double-Blind Treatment Period

BUTRANS BUTRANS 20 BUTRANS 5

MedDRA Preferred Term (N = 1160) (N = 219) (N = 221)

Nausea 14% 11% 6%

Application site pruritus 9% 13% 5%

Headache 9% 8% 3%



Page 47 of 51

Somnolence 6% 4% 2%

Dizziness 5% 4% 2%

Constipation 4% 6% 3%

Application site erythema 3% 10% 5%

Application site rash 3% 8% 6%

Application site irritation 2% 6% 2%

The following table lists adverse reactions that were reported in at least 2.0% of patients in four placebo/active-

controlled titration-to-effect trials.

Table 4: Adverse Reactions Reported in Titration-to-Effect Placebo/Active-Controlled

Clinical Trials with Incidence ≥ 2%

MedDRA Preferred Term BUTRANS

(N = 392)

Placebo

(N = 261)

Nausea 21% 6%

Application site pruritus 15% 12%

Dizziness 15% 7%

Headache 14% 9%

Somnolence 13% 4%

Constipation 13% 5%

Vomiting 9% 1%

Application site erythema 7% 2%

Application site rash 6% 6%

Dry mouth 6% 2%

Fatigue 5% 1%

Hyperhidrosis 4% 1%

Peripheral edema 3% 1%

Pruritus 3% 0%

Stomach discomfort 2% 0%



Page 48 of 51

8.2 Appendix B

Table B1: Summary of Reasons for Moderate to Severe Pain at BUP3031 Study Entry

(Safety Population)

Age Group

System Organ Class

Preferred Term

7 to 11 years

(N = 6)

n (%)

12 to 16 years

(N = 35)

n (%)

Total

(N = 41)

n (%)

Congenital, Familial And Genetic Disorders 1 (17) 6 (17) 7 (17)

Sickle Cell Anaemia 1 (17) 4 (11) 5 (12)

Amniotic Band Syndrome 0 1 (3) 1 (2)

Haemoglobin C Disease 0 1 (3) 1 (2)

Gastrointestinal Disorders 0 4 (11) 4 (10)

Abdominal Pain 0 2 (6) 2 (5)

Crohn's Disease 0 2 (6) 2 (5)

General Disorders And Administration Site

Conditions 0 1 (3) 1 (2)

Pain 0 1 (3) 1 (2)

Injury, Poisoning And Procedural

Complications 0 3 (9) 3 (7)

Gun Shot Wound 0 2 (6) 2 (5)

Limb Crushing Injury 0 1 (3) 1 (2)

Investigations 1 (17) 0 1 (2)

Epstein-Barr Virus Antibody Positive 1 (17) 0 1 (2)

Musculoskeletal And Connective Tissue

Disorders 3 (50) 13 (37) 16 (39)

Back Pain 0 8 (23) 8 (20)

Musculoskeletal Pain 0 2 (6) 2 (5)

Arthralgia 1 (17) 0 1 (2)

Arthritis 0 1 (3) 1 (2)

Juvenile Arthritis 1 (17) 0 1 (2)

Osteonecrosis 1 (17) 0 1 (2)

Pain In Extremity 0 1 (3) 1 (2)

Systemic Sclerosis 0 1 (3) 1 (2)

Nervous System Disorders 0 6 (17) 6 (15)

Migraine 0 6 (17) 6 (15)

Reproductive System And Breast Disorders 0 1 (3) 1 (2)

Pelvic Pain 0 1 (3) 1 (2)

Surgical And Medical Procedures 1 (17) 1 (3) 2 (5)

Chest Wall Operation 0 1 (3) 1 (2)

Hemipelvectomy 1 (17) 0 1 (2)

Abbreviations: N = number of patients in the population; n = number of patients with data.

Cross-reference: BUP3031 CSR Table 15

Notes: MedDRA Version 15.0 was used to code reasons for moderate to severe pain terms.




Page 49 of 51

8.3 Appendix C

Proposed Butrans Label Text

Butrans Full Prescribing Information, Section 8.4 Pediatric Use

BUTRANS has been evaluated in an open-label clinical trial of 41 opioid-naïve and opioid-

experienced pediatric patients with moderate to severe chronic pain. The most frequent

underlying reason for moderate to severe pain in patients enrolled in this study were back pain,

chronic migraine and pain due to underlying sickle cell disease.

Too few patients (n=6) less than 12 years of age were enrolled in the clinical trial to provide

meaningful efficacy or safety data in this age group.

In patients ages 12 to 16 years, 34 patients initiated treatment in this study at a starting dose of

BUTRANS 5 mcg/hour. Patients who were opioid naïve or were receiving less than or equal to

10 mg/day of oral morphine or equivalent for five consecutive days (prior to initiation with

BUTRANS) were initiated on BUTRANS 5 mcg/hour and required to be inpatients at the time of

treatment initiation and be hospitalized for the first 48 hours of treatment.

Patients receiving greater than 10 mg/day, but less than 30 mg/day, of oral morphine or

equivalent for five consecutive days were initiated with BUTRANS 5 mcg/hour. Patients

receiving 30 – 80 mg/day of oral morphine or equivalent around-the-clock opioids (prior to

starting treatment with BUTRANS), had their current opioids tapered for up to 7 days, to no

more than 30 mg of morphine or equivalent and were also initiated with BUTRANS 5 mcg/hour.

Patients were allowed to use short-acting analgesics as needed until analgesic efficacy with

BUTRANS was attained. Patients in this age group received doses up to 20 mcg/hour. The

median duration of therapy was 73 days. The cumulative number of days on treatment ranged

from 11 to 188 days. Thirteen patients in the 12 to 16 age group completed ≥ 24 weeks of

treatment. BUTRANS, alone or in combination with supplemental analgesics reduced or

maintained pain ‘right now’ scores from baseline to week 24 in the 12 to 16 age group.

A population PK analysis conducted during this study concluded that the systemic exposure of

buprenorphine in the pediatric age group of 12-16 years is expected to be similar to adults at

any given dose of BUTRANS.

Overall (i.e. inclusive of all 41 patients enrolled in the study), the most frequently reported (≥

10% of patients) adverse events related to treatment were nausea (7 patients 17%), application

site pruritus (7 patients, 17%), somnolence (6 patients, 15%), application site irritation (5

patients, 12%), consistent with the use of opioids or the transdermal route of administration.

Overall, 27% of patients discontinued treatment due to an adverse event and 7 % of patients

required dose reduction due to an adverse event. Serious adverse events (SAEs) occurred in 8

patients (20%) during the study and none were considered to be related to the study drug. No

deaths occurred during the study. No new or unexpected safety concerns were observed in the

study.

Documents

PURDUE PHARMA L.P. Butrans · In completed Purdue-sponsored clinical studies involving adults, 7193 subjects (520 adults from phase 1 studies, 107 from nonchronic pain studies, and