Conditions: Peer Review, Research
Keywords: Bioequivalence Therapeutic Equivalency
Allocation: NON_RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 10
Healthy volunteers: yes

Brief summary:
This is an Open-label, Non-Randomized, 3-way Crossover Bioequivalence Study to compare fentanyl release after heating of a brand name (Duragesic) and generic (Apotex and Mylan) fentanyl (transdermal delivery system)TDSs in healthy adults.

Detailed description:
This research study is intended to determine the effect of heat on FDA-approved fentanyl TDSs and whether the heat applied will result in more fentanyl being absorbed through the skin than without applying heat. This is important given that little is known about how the release of fentanyl is affected by heat, particularly for generic products. This study will use fentanyl TDSs (brand name and generic TDSs) that have been approved by the Food and Drug Administration (FDA) and are already prescribed to customers in the United States, and will not include any placebos.

Arms:
arm 1: Each volunteer participates in two procedure days using the Duragesic reference (RLD) fentanyl TDS with heating applied for one hour at hour 11 and hour 18, respectively. arm 2: Each volunteer participates in two procedure days using the Apotex generic fentanyl TDS with heating applied for one hour at hour 11 and hour 18, respectively. arm 3: Each volunteer participates in two procedure days using the Mylan generic fentanyl TDS with heating applied for one hour at hour 11 and hour 18, respectively.

Interventions: intervention 1: Duragesic reference fentanyl TDS intervention 2: Apotex generic fentanyl TDS intervention 3: Mylan generic fentanyl TDS
Intervention descriptions: intervention 1: 25 µg/hour intervention 2: 25 µg/hour intervention 3: 25 µg/hour

Protocol document:
Prot_SAP_000.pdf: 
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I 
 
DETERMINATION OF SERUM FENTANYL LEVELS AFTER USING REFERENCE 
AND GENERIC TRANSDERMAL FENTANYL PATCHES WITH AND WITHOUT 
STANDARDIZED HEAT APPLICATION IN HEALTHY HUMAN VOLUNTEERS 
 
Short title: The Effect of Heat on Fentanyl Release from Fentanyl Patches in Healthy 
Adults 
 
Clinical Protocol Principal Investigator: 
Wilbur H. Chen, MD, MS 
 
U01 Principal Investigator(s): 
Audra L. Stinchcomb (contact), PhD 
Hazem E. Hassan, PhD 
 
Sponsor: 
Food and Drug Administration 
 
Grant Number: 1U01FD004955-01 
 
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II 
 
STATEMENT OF COMPLIANCE 
This study will be conducted in compliance with the protocol, International Conference on 
Harmonisation Good Clinical Practice E6 (ICH-GCP) and the applicable Food and Drug 
Administration and other Department of Health and Human Services regulatory requirements. 
All key personnel (all individuals responsible for the design and conduct of this study) have 
completed Human Subjects Protection Training. 
 
 


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III 
 
PROTOCOL SUMMARY 
Title:  
Determination of Serum Fentanyl Levels after using Reference 
and Generic Transdermal Fentanyl Patches with and without 
Standardized Heat Application in Healthy Human Volunteers 
Population: 
Healthy adults age 18 – 45 years  
Number of Sites: 
Single site: University of Maryland School of Medicine 
Study Duration: 
Approximately 18 weeks including the screening period 
 
Subject Participation 
Duration: 
Approximately 12 weeks including the screening period 
 
Description of Study 
Product: 
Fentanyl (Duragesic®, matrix type, Janssen Pharmaceutics; 
Mylan (fentanyl) matrix type, Mylan Pharmaceuticals and Apotex 
(fentanyl) matrix type, Apotex Corp.) transdermal patches, and 
naltrexone hydrochloride tablet and naloxone hydrochloride 
injections 
Objective: 
 
To determine serum fentanyl levels after using reference 
(Duragesic®) and generic fentanyl (Mylan and Apotex) 
transdermal patches with and without standardized heat 
application in healthy adult volunteers 
Description of Study 
Design: 
The study will be an open-label, study with six procedure days 
(n=10 healthy subjects completing all 6 procedure days) with at 
least two weeks between each procedure day and the 
subsequent one.  
Each of the 10 subjects will be enrolled to complete all six 
procedure days. For each of the fentanyl products (n=3) there 
will be two procedure days, and on all procedure days the 
patches will be applied for 19 hours.  
The study will contain six procedure days: 
 
Procedure Day 1: The heating pad will be set to induce a 
skin temperature of 42.0 ± 2°C and applied for 1 hour, 11 
hours after application of the Apotex (fentanyl) transdermal 
patch (25 µg/h). 
 
Procedure Day 2: The heating pad will be set to induce a 


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IV 
 
skin temperature of 42.0 ± 2°C and applied for 1 hour, 18 
hours after application of the Apotex (fentanyl) transdermal 
patch (25 µg/h). 
 
Procedure Day 3: The heating pad will be set to induce a 
skin temperature of 42.0 ± 2°C and applied for 1 hour, 11 
hours after application of the Duragesic® transdermal patch 
(25 µg/h). 
 
Procedure Day 4: The heating pad will be set to induce a 
skin temperature of 42.0 ± 2°C and applied for 1 hour, 18 
hours after application of the Duragesic® transdermal patch 
(25 µg/h). 
 
Procedure Day 5: The heating pad will be set to induce a 
skin temperature of 42.0 ± 2°C and applied for 1 hour, 11 
hours after application of the Mylan (fentanyl) transdermal 
patch (25 µg/h). 
 
Procedure Day 6: The heating pad will be set to induce a 
skin temperature of 42.0 ± 2°C and applied for 1 hour, 18 
hours after application of the Mylan (fentanyl) transdermal 
patch (25 µg/h). 
 
 
 


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1 KEY ROLES 
U01 Principal 
Investigators: 
 
 
Audra L. Stinchcomb (contact), PhD 
Professor, Department of Pharmaceutical Sciences 
University of Maryland School of Pharmacy 
20 N Pine St, Room PHN521 
Baltimore, MD 21201 
Phone: 410-706-2646 
Fax: 410-706-0886 
Email: astinchc@rx.umaryland.edu  
 
Hazem E. Hassan, PhD, RPh 
Research Assistant Professor 
Department of Pharmaceutical Sciences 
University of Maryland School of Pharmacy 
20 N Pine Street, Rooms: N525 (Office), N406 (Lab) 
Baltimore, MD 21201 
Phone:  410-706-3257 
Fax: 410-706-0886 
E-mail: hhassan@rx.umaryland.edu  
 
 
 
 
 
 
Clinical Protocol PI: 
(Medically Accountable PI) 
Wilbur H. Chen, MD, MS 
Director, UMB Travelers' Health Clinic 
Chief, Adult Clinical Studies section 
Associate Professor, Department of Medicine 
University of Maryland School of Medicine 
Center for Vaccine Development 
685 W. Baltimore St., Suite 480 
Baltimore, MD 21201 
(410) 706-6156 phone 
(410) 706-6205 fax 
wchen@medicine.umaryland.edu   
 
Regulatory Affairs: 
Alyson Kwon, BA, CCRC 
Regulatory Affairs Specialist 
Center for Vaccine Development 
University of Maryland, Baltimore 


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6 
685 West Baltimore Street, Room 480 
Baltimore, Maryland 21201 
 
410-706-6056 
Fax:  410-706-0850 
akwon@medicine.umaryland.edu  
 
 


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2 BACKGROUND INFORMATION AND SCIENTIFIC 
RATIONALE 
2.1 
Background Information 
There are numerous transdermal drug delivery systems (TDDS) that are currently 
available in the United States, the first of which was approved by the Food and Drug 
Administration (FDA) in 1979 [1]. TDDS are very attractive, convenient and easy to use 
systems and are available in various forms including patches (matrix or reservoir), 
sprays, gels, and ointments. Drug release from these TDDS varies significantly and is 
dependent on a number of factors including system design, physicochemical properties 
of the drug, excipients, occlusion, sweat, skin condition, skin type and temperature. 
Investigating the influence of these factors on drug release from reference and generic 
products that are often available in different forms is important to ensure that generic 
products are not less safe than the reference product. In this proposal we will focus on 
investigating the influence of heat on drug release from reference and generic products 
that are available in matrix systems. Systemic absorption of drugs is dependent on 
cutaneous blood flow. Application of, or exposure to heat, allows gradual increase in 
cutaneous blood flow and an increase in the absorption rate.  Indeed, exposure to heat 
has been demonstrated to increase drug release from TDDS, which led to increased 
serum concentrations of numerous drugs (e.g., fentanyl and nicotine) and raised a 
number of safety concerns [2-8]. As a result, almost all TDDS that are currently available 
have warnings against heat exposure. The issue is, if a reference product has a warning 
against applying heat, the generic product will have the same warning regardless of the 
dissimilarity that may exist between them (i.e., differences in inactive ingredients or type 
of TDDS), and it is possible that release rate and absorption rate of the same drug 
differs from different TDDS in response to heat. 
2.2 
Rationale 
The objective of this proposal is to conduct in vivo studies to compare the influence of 
heat on fentanyl drug release from FDA approved TDDS products (reference e.g. 
Duragesic®, versus generic products e.g. Apotex and Mylan transdermal patches) that 
have different inactive ingredients. While there is data in the literature for heat effect on 
different active pharmaceutical ingredients (API’s), specifically reference listed drugs 
(RLD), from exposure to heating blankets, sauna, hot showers, exercising, there is no 
head to head comparisons for heat effect on RLD versus generic drugs. This study will 
help support policy development for characterization of heat effects for future generic 
applications. Furthermore, if in-vitro in-vivo correlation (IVIVC) can be established, then 
in vitro studies can be used for generic applications in the future, which would mitigate 


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exposure of human beings to out of label studies. This approach will help ensure that 
patients would not be subjected to additional risks if they use a generic TDDS rather 
than its respective reference product. 
Fentanyl was selected for this study because it is a drug with significant and well 
characterized heat effect studies in the literature, and for which an antidote exists. 
Fentanyl has the most variability available in terms of generic transdermal systems with 
different formulations that are approved and already on the market. This study will 
provide data that could potentially help us determine if one formulation/adhesive is more 
prone to heat effect/changes in delivery compared to another. Furthermore by 
demonstrating IVIVC then in vitro studies can be conducted on generic fentanyl 
transdermal patches in the future without the need to subject human volunteers to 
additional testing. To mitigate the potential risk of a higher absorption of fentanyl through 
the skin, the lowest strength patch is being used in this study (25 µg/hr). 
 
 
Duragesic® versus Apotex (fentanyl) and Mylan (fentanyl) transdermal patches 
 
Duragesic® 
Apotex (fentanyl) patch 
Mylan (fentanyl) patch 
Inactive 
ingredients 
Alcohol, ethylene vinyl 
acetate-copolymer 
membrane and 
hydroxyethyl cellulose, 
polyester film backing, 
silicone adhesive 
Isopropyl myristate, 
octyldodecanol, polybutene 
and polyisobutene adhesive 
Dimethicone NF, 
polyolefin film backing, 
silicon adhesive 
 
 
 
 
TDDS type 
Matrix 
Matrix 
Matrix 
 
 
 
 
Manufacturer 
Janssen 
Apotex 
Mylan 
 
 
 
 
 
 
 


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3 OBJECTIVES 
3.1 
Study Objectives 
Rate of drug release and kinetics of drug absorption could vary from patches with 
different dosage form designs. The influence of heat on reference vs. generic products 
that are formulated differently impose a critical safety issue for users of generic TDDS. 
As such, the main objective of this project is to determine serum fentanyl levels after 
using reference (Duragesic®, matrix type patch, Janssen Pharmaceutics) and generic 
fentanyl (Apotex and Mylan) transdermal patches with and without standardized heat 
application in healthy adult volunteers. 
 
3.2 
Study Outcome Measures 
The main outcome measure of the study is the measurement of maximum serum 
concentration (Cmax); time of maximum serum concentration (Tmax) of fentanyl and 
area under the curve (AUC) attained with and without heating in each of the three 
fentanyl patches (reference and generic). 
 
 


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4   STUDY DESIGN 
This is an open-label, non-placebo controlled pharmacokinetic (PK) assessment study. The 
study will consist of six-procedure days (10 subjects) with at least two weeks between 
procedure days. The half-life of fentanyl is approximately 24 hours. Hence, 7 days (i.e. 5 half-
lives) will be sufficient for >95% of fentanyl to be eliminated from the body. Each of the 10 
subjects will be enrolled to complete all six procedure days (Procedure Days 1 to 6). The study 
is open label and not blinded, because PK assessment is not subject to participant and/or 
observer bias. After each procedure session (procedure day) is completed, the available safety 
data will be reviewed by an Independent Safety Monitor (ISM) to determine whether or not to 
proceed to the next procedure day. 
 
The six procedures days are as follows: 
 
Procedure Day 1:  An Apotex (fentanyl) patch will be applied without heat for 11 hours, then a 
theratherm® heating pad will be applied over it (see details in Manual of Procedures) and set to 
induce a skin temperature of 42.0 ± 2°C for 1 hour then removed, and the patch will be kept on 
for another 7 hours (patch will be applied for a total of 19 hours), then it will be removed. Each 
subject will receive a naltrexone hydrochloride 50 mg oral tablet 12 ± 1 hour and shortly prior to 
patch application and then every 12 ± 1 hour for 8 additional doses, then one dose every 24 ± 2 
hours for two more doses. A total of twelve 50 mg oral doses of naltrexone will be administered. 
 
Procedure Day 2:  An Apotex (fentanyl) patch will be applied without heat for 18 hours, then a 
theratherm® heating pad will be applied over it and set to induce a skin temperature of 42.0 ± 
2°C for 1 hour, then the patch and the heating pad will both be removed (patch will be applied 
for a total of 19 hours). Each subject will receive a naltrexone hydrochloride 50 mg oral tablet 12 
± 1 hour and shortly prior to patch application and then every 12 ± 1 hour for 8 additional doses, 
then one dose every 24 ± 2 hours for two more doses. A total of twelve 50 mg oral doses of 
naltrexone will be administered. 
 
Procedure Day 3:  A Duragesic® patch will be applied without heat for 11 hours, then a 
theratherm® heating pad will be applied over it and set to induce a skin temperature of 42.0 ± 
2°C for 1 hour then removed, and the patch will be kept on for another 7 hours (patch will be 
applied for a total of 19 hours), then it will be removed. Each subject will receive a naltrexone 
hydrochloride 50 mg oral tablet 12 ± 1 hour and shortly prior to patch application and then every 
12 ± 1 hour for 8 additional doses, then one dose every 24 ± 2 hours for two more doses. A total 
of twelve 50 mg oral doses of naltrexone will be administered. 
 
Procedure Day 4:  A Duragesic® patch will be applied without heat for 18 hours, then a 
theratherm® heating pad will be applied over it and set to induce a skin temperature of 42.0 ± 
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for a total of 19 hours Each subject will receive a naltrexone hydrochloride 50 mg oral tablet 12 
± 1 hour and shortly prior to patch application and then every 12 ± 1 hour for 8 additional doses, 
then one dose every 24 ± 2 hours for two more doses. A total of twelve 50 mg oral doses of 
naltrexone will be administered. 
 
Procedure Day 5:  A Mylan (fentanyl) patch will be applied without heat for 11 hours, then a 
theratherm® heating pad will be applied over it and set to induce a skin temperature of 42.0 ± 
2°C for 1 hour then removed, and the patch will be kept on for another 7 hours (patch will be 
applied for a total of 19 hours), then it will be removed. Each subject will receive a naltrexone 
hydrochloride 50 mg oral tablet 12 ± 1 hour and shortly prior to patch application and then every 
12 ± 1 hour for 8 additional doses, then one dose every 24 ± 2 hours for two more doses. A total 
of twelve 50 mg oral doses of naltrexone will be administered.  
 
Procedure Day 6:  A Mylan (fentanyl) patch will be applied without heat for 18 hours, then a 
theratherm® heating pad will be applied over it and set to induce a skin temperature of 42.0 ± 
2°C for 1 hour, then the patch and the heating pad will both be removed (patch will be applied 
for a total of 19 hours). Each subject will receive a naltrexone hydrochloride 50 mg oral tablet 12 
± 1 hour and shortly prior to patch application and then every 12 ± 1 hour for 8 additional doses, 
then one dose every 24 ± 2 hours for two more doses. A total of twelve 50 mg oral doses of 
naltrexone will be administered.  
 


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5 STUDY ENROLLMENT AND WITHDRAWAL 
Only adult subjects who meet the inclusion/exclusion criteria will be eligible for enrollment into 
this study. Ten subjects will be recruited, and five alternates who could replace subjects who 
drop out from the study for any unforeseen reason. The study population selected for this study 
includes healthy adult men and women ages 18 to 45, inclusive.  The selection criteria are 
designed to exclude persons who might have medical conditions that could pose a safety risk 
and persons whose medical conditions might interfere with the objectives and results of the 
study. 
 
Subjects may be recruited from the databases at the Center for Vaccine Development (CVD), 
by referral from another healthcare professional, and by advertisements local to the study 
center.  Potential subjects who are interested in the study will be informed of the study and if 
they wish to participate, will receive additional study information, including an informed consent 
form.  Each of the 10 subjects enrolled will be expected to complete the 6 procedure day 
sessions.  
5.1 
Subject Inclusion Criteria 
Subjects are eligible for this study if they fulfill the inclusion criteria specified below: 
1. Men or non-pregnant women of any ethnic background between the age of 18 and 45 
years old. 
2. Subjects must be non-smokers (must have refrained from the use of nicotine-containing 
substances, including tobacco products (e.g., cigarettes, cigars, chewing tobacco, gum, 
patch or electronic cigarettes) over the previous 2 months and are not currently using 
tobacco products. 
3. Provide written informed consent before initiation of any study procedures. 
4. Available for follow-up for the planned duration of the study. 
5. Able to communicate well with the investigators.  
6. Able to adhere to the study protocol schedule.  
7. Subjects who are within their ideal body weight (BMI>17 and ≤ 28). 
8. Demonstrate comprehension of the protocol procedures and knowledge of study by 
passing (>70% correct responses) a written examination containing 20 multiple choice 
and true false questions covering all aspects of the study including the purpose, 
procedures, risks and benefits. 
9. Subjects deemed to be healthy as judged by the Medically Accountable Investigator 
(MAI) and determined by medical history, physical examination, and medication history. 


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10. Negative urine drug screening test.   
11. Have a normal blood pressure (systolic: 90-140 mmHg; diastolic: 50-90 mmHg) and 
heart rate (55-100 bpm).  
12. Have normal screening laboratories for WBC, Hgb, platelets, sodium, potassium, 
chloride, bicarbonate, BUN, creatinine, ALT, AST and total bilirubin. 
13. Have normal screening laboratories for urine protein and urine glucose.  
14. Female subjects must be of non-childbearing potential (as defined as surgically sterile 
[i.e. history of hysterectomy or tubal ligation] or postmenopausal for more than 1 year), 
or if of childbearing potential must be non-pregnant at the time of enrollment and on the 
morning of each procedure, and must agree to use hormonal or barrier birth control such 
as implants, injectables, combined oral contraceptives, some intrauterine devices 
(IUDs), sexual abstinence, or a vasectomized partner.  
15. Agrees not to participate in another clinical study during the study period. 
16. Agrees not to donate blood to a blood bank throughout participation in the study and for 
at least 3 months after last procedure day. 
17. Have a normal ECG.  
 
5.2 
Subject Exclusion Criteria 
Subjects will be excluded for any of the following conditions/reasons: 
1. Women who are pregnant, lactating breast feeding or have a positive serum pregnancy 
test at enrollment or on the morning of any procedure day.  
2. Smokers (current use or use over the previous 2 months of nicotine-containing 
substances, including tobacco products (e.g., cigarettes, cigars, chewing tobacco, gum, 
patch or electronic cigarettes). 
3. Participation in any ongoing investigational drug trial or clinical drug trial.   
4. Abnormal Vital signs, defined as:  
 
Hypertension (systolic blood pressure >140 mm Hg or diastolic blood pressure 
>90 mm Hg) at rest on 2 separate days) 
 
Heart rate <55 at rest on 2 separate days 
 
Respiratory rate >20 
5. Temperature > 38.0°C (100.4°F) or symptoms of an acute self-limited illness such as an 
upper respiratory infection or gastroenteritis within 7 days of application of the 
transdermal fentanyl patch. 
6. History of chronic obstructive pulmonary disease. 
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8. Positive urine drug screening test.  
9. Use of any prescription medication during the period 0 to 30 days or over-the counter 
medication (vitamin, herbal supplements and birth control medications not included) 
during the period 0 to 3 days before entry to the study.  
10. Donation or loss of greater than one pint of blood within 60 days of entry to the study.  
11. Any prior serious adverse reaction or hypersensitivity to fentanyl, naltrexone or naloxone 
or any of the inactive ingredients in the patch (alcohol, ethylene vinyl acetate-copolymer 
membrane and hydroxyethyl cellulose, polyester, silicone adhesive, isopropyl myristate, 
octyldodecanol, polybutene, polyisobutene, dimethicone NF, or polyolefin).  
12. Have a diagnosis of schizophrenia or other major psychiatric diagnosis or mental illness 
(e.g. major depression).  
13. Received an experimental agent (vaccine, drug, biologic, device, blood product or 
medication) within 1 month before enrollment in this study or expects to receive an 
experimental agent during the study.  
14. Any condition that would, in the opinion of the Medically Accountable Investigator (MAI), 
place the subject at an unacceptable risk of injury or render the subject unable to meet 
the requirements of the protocol.  
15. Inability to communicate or co-operate with the investigators.  
16. History of consumption of alcohol within 24 hours prior to dose administration.  
17. Within 72 hours prior to dosing, use of antihistamines or use of topical drugs at patch 
site.  
18. Subject has an obvious difference in skin color between arms or the presence of a skin 
condition, open sore, scar tissue, tattoo, or coloration that would interfere with placement 
of test articles, skin assessment, or reactions to drug.  
19. Use of monoamine oxidase inhibitors 21 days prior to study. 
20. Failure to pass opioid dependence challenge test on each procedure day before 
application of the fentanyl patch. Each subject will be injected subcutaneously with 
naloxone HCl (0.8 mg injection) and will be observed for 45 minutes for signs and 
symptoms of opioid withdrawal. 
 


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6 STUDY PRODUCT 
6.1 
Study Product Description 
6.1.1 Apotex (fentanyl) patch 25 µg/hour 
Apotex (fentanyl) is a prescription transdermal patch that contains fentanyl which is a 
federally controlled substance (CII). Apotex (fentanyl) patches deliver fentanyl at a 
rate of 25 µg/hour and are only for patients with chronic (around the clock) pain that 
is moderate to severe and expected to last for weeks or longer. 
6.1.2 Mylan (fentanyl) patch 25 µg/hour 
Mylan (fentanyl) is a prescription transdermal patch that contains fentanyl which is a 
federally controlled substance (CII). Mylan (fentanyl) patches deliver fentanyl at a 
rate of 25 µg/hour and are only for patients with chronic (around the clock) pain that 
is moderate to severe and expected to last for weeks or longer. 
6.1.3 Duragesic® (fentanyl) patch 25 µg/hour 
Duragesic® is a prescription patch that contains fentanyl which is a federally 
controlled substance (CII). Duragesic® patches deliver fentanyl at a rate of 25 
µg/hour and are only for patients with chronic (around the clock) pain that is 
moderate to severe and expected to last for weeks or longer. 
6.1.4 Naltrexone hydrochloride tablets, USP 50 mg 
Naltrexone hydrochloride is an opioid antagonist which attenuates or reversibly 
blocks the effects of opioids. It is available as a prescription medication and is used 
to treat opioid addiction.  
6.2 
Formulation, Packaging, and Labeling 
6.2.1 Apotex (fentanyl) patch 25 µg/h 
Active ingredient (in each patch): Fentanyl, 25 µg delivered per hour.  In addition to the 
active ingredient (fentanyl), the following inactive ingredients are present in the patch: 
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polyisobutene (adhesive matrix), and polyester protective release liner. This product should 
be stored below 25°C (77°F). 
 
 
6.2.2 Mylan (fentanyl) patch 25 µg/h 
Active ingredient (in each patch): Fentanyl, 25 µg delivered per hour.  In addition to the 
active ingredient (fentanyl), the following inactive ingredients are present in the patch: 
Dimethicone NF and silicon adhesive and polyolefin film backing. This is a matrix type patch, 
manufactured by Mylan Pharmaceuticals Inc. This product should be stored below 25°C 
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6.2.3 Duragesic® (fentanyl) patch 25 µg/h 
Active ingredient (in each patch): Fentanyl, 25 µg delivered per hour.  In addition to the 
active ingredient (fentanyl), the following inactive ingredients are present in the patch: 
alcohol, ethylene vinyl acetate-copolymer membrane and hydroxyethyl cellulose, polyester 
film backing, silicone adhesive. This is a matrix type patch, manufactured by ALZA and 
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6.2.4 Naltrexone hydrochloride tablets, USP 50 mg 
Active ingredient (in each tablet): Naltrexone hydrochloride, USP 50 mg.  In addition to the 
active ingredient (naltrexone hydrochloride), the following inactive ingredients are present in 
the patch: crospovidone, hypromelloses, lactose monohydrate, magnesium stearate, 
microcrystalline cellulose, polyethylene glycols, polysorbate 80, silicon dioxide, titanium 
dioxide, ferric oxide yellow and ferric oxide red. This is an oral tablet, manufactured by 
Covidien Ltd. and distributed by Mallinckrodt Pharmaceuticals. This product will be stored at 
room temperature, 20 to 25°C (68 to 77°F). 
 


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6.2.5 Naloxone hydrochloride injection, USP 0.4 mg/ml 
Active ingredient (in each injection): Naloxone hydrochloride, USP 0.4 mg/ml single dose 
ampoule for intravenous, intramuscular or subcutaneous use. This product will be stored at 
room temperature, 20 to 25°C (68 to 77°F). 


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7 
PHARMACOKINETICS AND STATISTICAL 
CONSIDERATIONS 
7.1 
Study Hypotheses 
Due to differences in inactive ingredients between reference and generic fentanyl 
transdermal patches the release rate of fentanyl may differ from these patches upon 
exposure to heat. As a result, in this study the influence of standardized heat 
application (two heat periods) on the pharmacokinetics (PK) parameters of fentanyl 
will be studied after using Duragesic® (reference), Apotex (fentanyl) (generic), and 
Mylan (fentanyl) (generic) transdermal patches.  
 
The primary analysis will be to determine whether heat differentially impacts fentanyl 
serum concentrations among Duragesic® (reference), Apotex (fentanyl), and Mylan 
(fentanyl) transdermal patches. We will test the null hypothesis (H0) that the 
coefficient for the patch-by-heat interaction equals zero, adjusting for time. 
7.2 
Pharmacokinetics (PK) Analyses 
Fentanyl concentrations will be measured in serum samples collected from each subject 
from the opposite arm to which the fentanyl system will be applied. Blood samples 
(approximately 5 mL) will be collected during each procedure day, 15 min before patch 
application and then at 1:00, 10:00, 10:55, 11:05, 11:15, 11:25, 11:35, 11:45, 12:00, 
13:00, 14:00, 16:00, 17:00, 17:55, 18:05, 18:15, 18:25, 18:35, 18:45, 19:00 20:00, 21:00 
and  22:00 hr post-patch application. The fentanyl PK parameters to be estimated using 
non-compartmental analysis (NCA) after each system application are: maximum serum 
concentration (Cmax) at different time intervals; 0-11, 0-19, 0-22, 11-12, 12-18, 18-19 
and 19-22 hr; apparent elimination rate constant (k); apparent half-life (t1/2), calculated 
as 0.693/k; AUC of the serum concentration–time at different time intervals; 0-11, 0-19, 
0-22, 11-12, 12-18, 18-19 and 19-22 hr determined by the linear trapezoidal method; 
and AUC value extrapolated to infinity (AUCinf), calculated as the sum of AUC22 and the 
area extrapolated to infinity: AUCinf = AUC22 + C22/k where C22 would be the last 
quantifiable concentration. All NCA analyses will be conducted using Phoenix® 
WinNonlin® 6.3 (Pharsight, a Certara Company, CA). 
 


The Effect of Heat on Fentanyl Release from Fentanyl Patches in Healthy Adults  
Version 8.0 
 
12 June 2017 
 
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21 
7.3 
Final Analysis Plan 
The main objective of this study is to investigate the influence of heat application on the 
PK parameters of fentanyl after using reference and generic patch products. The primary 
PK parameters to be compared are 1) Cmax, before and after heat application and 2) 
AUC before and after heat application consistent with similar PK studies [4, 5, 7, 8, 16-
22]. Analysis of variance (ANOVA) followed by post-hoc Bonferroni test will be used for 
comparing the differences in the means of the PK parameters and significant differences 
will be declared at p<0.05. The statistical comparisons will be conducted as follow: 
 
Three pair-wise comparisons between the patches (Apotex v Mylan; Apotex v 
Duragesic®; and Mylan v Duragesic®) will be performed using the results of a three-way 
repeated-measures ANOVA. The model will include time, type of patch (e.g., Apotex or 
Mylan), application of heat (yes or no), and interaction between patch and application of 
heat. The time term comprises multiple indicator variables for maximum model flexibility 
to perform the comparison at different time points specified above. We will test the null 
hypothesis that the coefficient for the patch-by-heat interaction equals zero, adjusting for 
time. 
 
If fentanyl concentrations are found to be non-normally distributed, then we will examine 
Box-Cox transformations (e.g., log, square-root, etc.) that can achieve normality. If no 
transformation can achieve normality, then we will use permutation tests to compute 
empirical p-values, and we will use the bootstrap to compute standard errors and 
confidence intervals that account for within-person correlation.  
 
A secondary analysis will assess the effects of heat and time on fentanyl within a patch. 
Specifically, the ANOVA will also include interaction terms of time with patch and heat, 
and a three-way interaction between time, heat, and patch. Inclusion of the three-way 
term allows the effects of heat on fentanyl to differ by patch. Testing the time-by-heat 
interaction, separately for each patch, using the same procedure outlined above 
produces estimates of intra-procedure effects.  

SAP_001.pdf: 
DETERMINATION OF SERUM FENTANYL LEVELS AFTER USING REFERENCE 
AND GENERIC TRANSDERMAL FENTANYL PATCHES WITH AND WITHOUT 
STANDARDIZED HEAT APPLICATION IN HEALTHY HUMAN VOLUNTEERS 
 
Short title: The Effect of Heat on Fentanyl Release from Fentanyl Patches in Healthy 
Adults 
 
Clinical Protocol Principal Investigator: 
Wilbur H. Chen, MD, MS 
 
U01 Principal Investigator(s): 
Audra L. Stinchcomb (contact), PhD 
Hazem E. Hassan, PhD 
 
Sponsor: 
Food and Drug Administration 
 
Grant Number: 1U01FD004955-01 
Protocol Number:  HP-00059884 
NCT02486016 
 
 
Version 8.0 
12 June 2017 
 
 
 


CLINICAL STUDY STATISTICS 
IVIVC 
For IVIVC, three correlation levels were examined.  Level A was selected to use for analysis of 
the data.  Three different (I, II & III) approaches were examined for Level A. 
Level A:  a point-to point correlation between in vitro and in vivo profiles. 
Level B:  comparison between in vitro dissolution time and in vivo residence time. 
Level C:  a single point correlation between in vitro and in vivo parameters (e.g. Jmax vs. 
Cmax). 
Approach I:  IVPT data, PK-based mathematical equations and in vitro heat effect coefficient 
(Hi) were used to predict in vivo concentrations. 
 
 
 
 
• Eq. 1 Prediction while TDS was worn: 
 
 
 
 
 
 
• Eq. 2 Prediction after TDS removal: 
 
 
Approach II and III: 
1.  Reconstruct baseline (32°C) profile by combining the non-heat (32°C) portion of each profile 
from the early and late heat study designs. 
2.  Deconvolute the in vivo baseline concentration vs time profile using Phoenix®. 
3.  Construct an IVIVC model by plotting the fraction permeated in vitro vs the fraction absorbed 
in vivo. 
4.   Predict the in vivo fraction absorbed using the IVIVC model and IVPT data. 


5. Convolute the predicted in vivo fraction absorbed data using Phoenix® to obtain 
concentration vs time profile 
6.  Apply in vitro heat effect coefficient Hi (Approach II) or the in vivo heat effect coefficient Hii 
(Approach III) to the predicted in vivo profile. 
 
Pharmacokinetic parameters of fentanyl used for Approach I, II and III were obtained from: 
 
Bower et al. Br J Anaesth 1982 
 
McClain et al. Clin Pharmacol Ther 1980 
 
Scott et al. J Pharmacol Exp Ther 1986 
 
Fung et al. J Clin Pharmacol 1980 
 
Study [NIPTE-U01-MD-2015-001:  Transdermal Drug Delivery Systems-Fentanyl] at 
University of Maryland, Baltimore; still in progress 
 
 
F [absolute bioavailability for TDS] for Duragesic® (0.36) and Mylan (0.42) were each 
determined from  study [NIPTE-U01-MD-2015-001: Transdermal Drug Delivery 
Systems-Fentanyl] at the University of Maryland, Baltimore 
 
F [absolute bioavailability for TDS] for Apotex was estimated (0.39) by the mean of 0.36 
and 0.42, due to lack of available data