Conditions: Peer Review, Research
Keywords: Bioequivalence Therapeutic Equivalency
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 24
Healthy volunteers: yes

Brief summary:
The study to be performed will utilize already FDA-approved marketed products in healthy adults for the purpose to generate data for establishing rate of drug delivery comparisons between RLD (reference listed drug) Duragesic ® TDDS (transdermal drug delivery system) and Generic Fentanyl TDDS in healthy adults and to ensure safety of individuals utilizing these types of products.

Detailed description:
Transdermal drug delivery systems (TDDS) available in the form of patches are convenient, attractive, and easy to use systems. Fentanyl patches are very popular TDDS available on the United States market today. Accurate determination of the rate and extent of drug release and absorption is crucial to ensure the safety of individuals using these and other types of patches. Delivery rate can be determined early in the development process by using in vitro skin flux permeation studies, and later in humans by accurately quantifying residual drug from patches post-wear and in pharmacokinetic studies. In this proposal, we will employ two types of evaluation to determine the rate and extent of drug release and absorption from RLD (reference listed drug) Duragesic ® TDDS (transdermal drug delivery system) and Generic Fentanyl TDDS, namely residual drug analysis post-wear and pharmacokinetic analysis in healthy adult volunteers. In addition, we will compare the plasma drug concentrations following patch and intravenous administration of Fentanyl, in order to determine the absolute bioavailability of these patches. We will conduct residual drug analysis of TDDS following in vivo wear using highly sensitive validated quantification methods. Positive outcome of this project will identify appropriate methods to determine the rate and extent of drug release and absorption from TDDS, and will help regulatory agencies in the development of Guidances for Industry regarding the characterization of drug release and absorption kinetics to ensure the safety of individuals utilizing these types of products

Arms:
arm 1: Volunteers received a single-dose of 100 µg fentanyl citrate infusion (Study Session I) and blood samples obtained 0-36 h, washout at least one week, then wore a Duragesic® fentanyl TDDS (25 µg/h) for 72 h (Study Session II) and blood samples obtained 0-192 h, washout at least one week, then wore a Mylan fentanyl TDDS (25 µg/h) for 72 h (Study Session III) and blood samples obtained 0-192 h arm 2: Volunteers received a single-dose of 100 µg fentanyl citrate infusion (Study Session I) and blood samples obtained 0-36 h, washout at least one week, then wore a Mylan fentanyl TDDS (25 µg/h) for 72 h (Study Session II) and blood samples obtained 0-192 h, washout at least one week, then wore a Duragesic® fentanyl TDDS (25 µg/h) for 72 h (Study Session III) and blood samples obtained for 0-192 h

Interventions: intervention 1: Intravenous fentanyl citrate intervention 2: Duragesic® intervention 3: Mylan generic fentanyl
Intervention descriptions: intervention 1: 100 micrograms (2 millilitres) via intravenous injection intervention 2: TDDS dosage is 25 micrograms/hour (worn for 72 h) intervention 3: TDDS dosage is 25 micrograms/hour (worn for 72 h)

Protocol document:
Prot_SAP_000.pdf: 
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ABSOLUTE BIOAVAILABILITY/PHARMACOKINETIC AND RESIDUAL DRUG 
ANALYSIS OF DURAGESIC® TRANSDERMAL SYSTEM AND GENERIC 
FENTANYL TRANSDERMAL SYSTEM IN HEALTHY ADULTS 
 
Short title: Fentanyl Patch Pharmacokinetics in Healthy Adults 
 
U01 Principal Investigator: 
Audra L. Stinchcomb (contact), PhD, RPh 
 
 
Medically Accountable Investigator: 
Jeffrey Fink, MD, MS 
 
Sponsor: 
Food and Drug Administration 
 
NCT02531971 
 
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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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 PROTOCOL SUMMARY 
Title:  
Absolute Bioavailability/Pharmacokinetic and Residual 
Drug Analysis of Duragesic® Transdermal System and 
Generic Fentanyl Transdermal System in Healthy 
Adults  
Population: 
Healthy, non-smoking adults age 18-45 years  
Number of Sites: 
Single site: University of Maryland School of 
Medicine/General Clinical Research Center (GCRC)  
Study Duration: 
Approximately up to 18 months 
 
Subject Participation Duration: 
Approximately 12-18 weeks including the screening 
Session 
 
Description of Study Products: 
 
Fentanyl citrate injection, Fentanyl Duragesic®, matrix 
type, Janssen Pharmaceuticals transdermal drug delivery 
system (TDDS); Mylan (fentanyl) matrix type, Mylan 
Pharmaceuticals TDDS; naltrexone hydrochloride oral 
tablets and naloxone hydrochloride injections 
Objective: 
 
 
Description of Study Design: 
To determine serum fentanyl levels after using reference 
(Duragesic®) and generic fentanyl (Mylan) TDDS, and 
comparing them to the serum levels of intravenous 
fentanyl citrate, in healthy adult subjects 
This will be a three treatment, open-label, randomized, 
crossover clinical study with a Run-In Study Session 
(Study Session I) of intravenous fentanyl citrate, 
followed by a transdermal administration of a single 
strength of the reference listed drug (RLD) Duragesic®, 
and a transdermal administration of a generic equivalent 
to the RLD, Mylan fentanyl TDDS.   A total of 24 
subjects will be enrolled to complete this study. 
A) 
Pharmacokinetic Determination of Strength 
The study will be a three treatment, open-label, 
randomized crossover study, with a Run-In Study 


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Session 
I 
of 
an 
intravenous 
fentanyl 
citrate 
administration, with at least a one week washout interval 
between Study Sessions. 
The study products are: 
- Single intravenous (100 µg) administration of fentanyl 
citrate (50 µg/mL) 
- Duragesic® TDDS containing fentanyl (25 µg/h) to be 
worn for 3 days (72h) 
- Mylan fentanyl TDDS (Generic) containing fentanyl 
(25 µg/h) to be worn for 3 days (72h) 
Each Subject will be his/her own control. 
Administration of naloxone injection will be used to test 
for withdrawal prior to using any study products, and to 
be used emergently in case of fentanyl toxicity. 
Naltrexone oral tablets will be used to block the opioid 
receptors to avoid any clinical effects or side-effects of 
fentanyl.  
Blood samples will be obtained as follows (based on 
administration route): 
 
60 min pre-IV administration and then up to 36 hr 
(1.5 days) post start of IV administration 
 
60 min pre-application and then up to 192 hr (8 
days), during 3 day wear and post removal of RLD 
 
60 min pre-application and then up to 192 hr (8 
days), during 3 day wear and post removal of 
Generic product 
B) 
Residual Drug 
Analysis 
determination 
of 
Strength  
In conjunction with the above described study residual 
drug analysis will also be conducted for the used RLD 
and Generic TDDS described in Part A.    


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 
Prior to administration to the Subject as described in 
Part A, the TDDS will be weighed and the weight 
recorded.  
 
The pouch, release liner and all items coming into 
contact with the TDDS (gloves, forceps, etc.) to be 
applied in Part A will be retained for analysis.    
 
The used TDDS will be retained for drug content 
analysis.  
 
Upon removal of the product after prescribed wear 
Session, the skin (at site of application) will be 
swabbed and the swab retained for drug content 
analysis. 
 
All items coming into contact with the TDDS during 
removal from the Subject and storage in a separate 
labeled sealable foil pouch for analytical retention 
will be analyzed for drug content.   
 
 
 
 


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1 KEY ROLES 
U01 Principal Investigator: 
 
Audra L. Stinchcomb (contact), PhD, RPh 
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  
  
 
 
Medically Accountable 
(Clinical) Investigator: 
  
Jeffrey C Fink M.D., M.S. 
Professor 
Department of Medicine  
Department of Epidemiology and Public Health 
University of Maryland School of Medicine 
UMMC, Room NN3E03 
Baltimore, MD 21201 
Phone: 410-328-4822 
Fax: 410-328-5685 
 
E-mail: jfink@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]. Transdermal drug delivery systems (TDDS) available in the form of 
patches are convenient, attractive, and easy to use systems. Fentanyl is a very popular TDDS 
available on the United States market today. 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. Accurate determination of the 
rate and extent of drug release and absorption is crucial to ensure the safety of individuals 
using this and other types of TDDS.  
 
Positive outcome of this project will identify appropriate methods to determine the rate and 
extent of drug release and absorption from TDDS, and will help regulatory agencies in the 
development of Guidances for Industry regarding the characterization of drug release and 
absorption kinetics to ensure the safety of individuals utilizing these types of products. 
2.2 
Rationale 
The rationale of this study is to determine the delivery rate and the extent of absorption of 
fentanyl drug release from FDA-approved TDDS products (reference e.g. Duragesic®, versus 
Mylan transdermal patches) that have different inactive ingredients. can be determined in 
humans by accurately quantifying residual drug from TDDS post-wear, and the delivery rate 
can be determined in pharmacokinetic studies. This study will compare fentanyl levels by 
using in vitro skin flux permeation studies, as a predictor of in-vivo bioequivalence and 
pharmacokinetics of Duragesic® and Mylan fentanyl TDDS. This will be done through 
development of an appropriately controlled and well-characterized in-vitro methodology to 
quantify the in-vivo exposure of healthy adults to fentanyl during TDDS wear, so that the rate 
of drug delivery can be defined in a manner that can help the regulatory agency (FDA) in 
developing Guidance for Industry regarding the characterization of drug release and 
absorption kinetics to ensure the safety of individuals utilizing these types of products. 
In the clinical study component, we will employ two types of evaluation to determine the rate 
and extent of drug release and absorption from fentanyl TDDS, namely residual drug analysis 
post-wear and pharmacokinetic analysis in healthy adult Subjects. In addition, we will 
compare the serum drug concentrations following TDDS and intravenous administration, in 


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order to explore bioequivalence of these TDDSs. We will conduct residual drug analysis of 
TDDS following in vivo wear using highly sensitive validated quantification methods. 
 
 
Duragesic® versus Mylan (fentanyl) TDDS 
 
Duragesic® 
Mylan (fentanyl) TDDS 
Inactive 
ingredients 
polyester/ethyl vinyl acetate, 
polyacrylate adhesive 
dimethicone NF, polyolefin 
film backing, silicone 
adhesive 
TDDS type 
Matrix 
Matrix 
Manufacturer 
Janssen 
Mylan 
 


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3 OBJECTIVES 
3.1 
Study Objectives 
The objectives of this open label, randomized, crossover study are to 
 
To explore bioequivalence of Duragesic® transdermal system and generic Mylan fentanyl 
TDDS, and compare bioavailability to direct IV infusion of fentanyl citrate. 
 
To conduct release rate analysis of generic fentanyl (Mylan) TDDS compared to Duragesic® 
TDDS. 
 
To determine the residual drug content of the Duragesic® and generic fentanyl TDDS. 
 
3.2 
Study Outcome Measures 
The main outcome measure of the study is the determination of the pharmacokinetic parameters 
of fentanyl in healthy adult Subjects (i.e., clearance (CL), volume of distribution (V), elimination 
rate constant (Kel), maximum serum concentration (Cmax); time of maximum serum 
concentration (Tmax) of fentanyl and area under the serum concentration-time curve (AUC).  In 
addition, we will determine residual drug content from worn Duragesic® and Mylan fentanyl 
TDDS to estimate total amount of absorbed fentanyl from each. 
 
 


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4   STUDY DESIGN 
This is a three treatment open-label, randomized cross-over clinical study with a Run-In Study Session I 
of intravenous fentanyl citrate, followed by randomization to Duragesic® and generic fentanyl in a 
sequential, 2-Session fashion with at least a one week wash-out Session between the sessions.  
 
The study design is shown below: 
 
Study Session I 
(Run-in) 
Randomization 
 
Study Session II 
Study Session III 
Intravenous -Fentanyl 
Study Arm 1 
Duragesic® 
Mylan Fentanyl 
Study Arm 2 
Mylan Fentanyl 
Duragesic® 
 
 
The study will consist of a total of twenty-five Study Days (24 Subjects) within three Study Sessions, 
with at least a one week washout Session between successive Study Sessions. The half-life of fentanyl is 
approximately 24 hours. Hence, 5 days (i.e. 5 half-lives) will be sufficient for >95% of fentanyl to be 
eliminated from the body. Each of the 24 Subjects will be enrolled to complete all twenty-five study days 
(Run-In Study Session I = 5 Study Days; Study Sessions II and III = 10 Study Days each). The study is 
open label and not blinded, because PK assessment is not subject to participant and/or observer bias. After 
each Study Session 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 Study Session. 
Considering the objective of the study to explore bioequivalence of Duragesic® and generic fentanyl and 
to conduct release rate analysis of generic fentanyl to Duragesic®, the above study design would 
adequately address both questions.  The randomization to sequences [Reference (R) –Test (T), T-R] 
would appropriately take into account the sequence and the Session effect for bioequivalence evaluations. 
Having all Subjects enter the intravenous Run-In Study Session I initially would also help in accurate 
determination of absolute bioavailability for Duragesic® and generic Mylan fentanyl in this study.   
Each Subject will be his/her own control and each Subject will sign an institutional review board–
approved consent form explaining the purpose, nature, risks, benefits, and duration of the study. The 
study will be conducted in accordance with good clinical practice guidelines and with the ethical 
principles originating in the Declaration of Helsinki.  
 
The three Study Sessions are as follows:  
 
Study Session I (Run-in):  


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Each of the 24 Subjects will start the study with the Run-In Session of intravenous fentanyl citrate 
infusion by giving a single-dose of 100 µg fentanyl citrate infusion (2 mL over 2 minutes) as described in 
the Manual of Procedures. Each Subject will receive a naltrexone hydrochloride 50 mg oral tablet 12-17 
hours ± 1 hour before and again shortly prior to intravenous administration and then as described below 
after intravenous administration for 7 additional doses, for a total of nine 50 mg oral doses of naltrexone 
hydrochloride tablets. 
 
Study Session II:  
Twelve Subjects will be randomized to Study Arm 1 which will receive the Duragesic® fentanyl TDDS 
(25 µg/h); and other 12 Subjects to Study Arm 2 which will receive the Mylan fentanyl TDDS (25 µg/h). 
The patches will be applied for 3 days on each Subject. The Subject’s skin in the area of application 
(upper arm region) will be relatively free of hair before TDDS application. Each Subject will receive a 
naltrexone hydrochloride 50 mg oral tablet 12-17 hours ± 1 hour before and again shortly prior to patch 
application and then as described below after patch application for 16 additional doses, for a total of 
eighteen 50 mg oral doses of naltrexone hydrochloride tablets. 
 
Study Session III:  
The 12 Subjects who were randomized to Study Arm 1 to receive the Duragesic® fentanyl TDDS (25 
µg/h) will cross-over to receive the Mylan fentanyl TDDS (25 µg/h) applied; and the other 12 Subjects 
who were randomized to Study Arm 2 to receive the Mylan fentanyl TDDS (25 µg/h) will now cross-over 
to receive the Duragesic® fentanyl TDDS (25 µg/h). The patches will be applied for 3 days on each 
Subject. Each Subject will receive a naltrexone hydrochloride 50 mg oral tablet 12-17 hours ± 1 hour 
before and again shortly prior to patch application and then as described below after patch application for 
16 additional doses, for a total of eighteen 50 mg oral doses of naltrexone tablets. 
 
 


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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. Twenty-four Subjects will be recruited and at least 10 alternates will be screened, as needed, to 
ensure that any dropouts will be replaced until a total of 24 Subjects complete all study procedures. The 
study population selected for this study includes healthy non-smoking 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. 
 
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, study restrictions and examination schedule.  
7. Subjects who are within their ideal body weight (BMI between >17 and ≤28 Kg/m2). 
8. Subjects deemed to be healthy as judged by the Medically Accountable Investigator (MAI) and 
determined by medical history, physical examination, and medication history. 
9. Subjects have no history of the following: ongoing acute or intermittent pain, postoperative pain, 
respiratory compromise, acute or severe asthma, or constipation (less than 1 bowel movement 
every 2 days). 
10. Negative urine drug screening test at time of screening.  
11. Have normal screening laboratories for WBC, Hgb, platelets, sodium, potassium, chloride, 
bicarbonate, BUN, creatinine, ALT, AST and bilirubin. 
12. Have normal screening laboratories for urine protein and urine glucose.  
13. 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[no bleeding for 


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12 consecutive months), or if of childbearing potential must be non-pregnant at the time of 
enrollment and on the morning of the first day of each Study Session, 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.  
14. Agrees not to participate in another clinical study or to participate in an investigational drug study 
for at least 1 month after last Study Session. 
15. Agrees not to donate blood to a blood bank throughout participation in the study and for at least 3 
months after last Study Day. 
16. Have a normal ECG; must not have the following to be acceptable: pathologic Q wave 
abnormalities, significant ST–T wave changes, left ventricular hypertrophy, right bundle branch 
block, left bundle branch block. (sinus rhythm is between 55–100 beats per minute). 
17. Have normal vital signs: 
 Temperature 35-37.9°C (95-100.3°F) 
 Systolic blood pressure 90-140 mmHg 
 Diastolic blood pressure 60-90 mmHg 
 Heart rate 55-100 beats per minute 
 Respiration rate 12-18 breaths per minute 
5.2 
Subject Exclusion Criteria 
Subjects will be excluded for any of the following conditions/reasons: 
1. Women who are pregnant, lactating or breast feeding or have a positive serum pregnancy test at 
enrollment or positive urine pregnancy test on the morning of the first day of any Study Session.  
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. History of chronic obstructive pulmonary disease or cor pulmonale, or substantially decreased 
respiratory reserve, hypoxia, hypercapnia or pre-existing respiratory depression. 
5. Active positive Hepatitis B, C, and HIV serologies. 
6. Positive urine drug screening test. 
7. Use of any prescription medication during the Session 0 to 30 days or over-the counter 
medication e.g. antihistamines or topical corticosteroids (vitamin, herbal supplements and birth 
control medications not included) during the Session 0 to 3 days before entry to the study. 
8. Use of medications or treatments that would significantly influence or exaggerate responses to the 
test product or that would alter inflammatory or immune response to the product or agents 
deemed to be immunosuppressive as determined by physician investigator within 72 hours prior 
to dosing (e.g. antihistamines, systemic or topical corticosteroids (within 3 weeks prior to dosing), 
cyclosporine, tacrolimus, cytotoxic drugs, immune globulin, Bacillus Calmette-Guerin (BCG), 
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9. Use of monoamine oxidase inhibitors 21 days prior to study. 
10. Current use of mixed agonist/antagonist (such as pentazocine, nalbuphine or butorphanol) and 
partial agonist (buprenorphine) analgesics. 
11. Current use of anticholinergics or other medications with anticholinergic activity. 
12. Consumption of beverages containing alcohol, grapefruit juice, Seville oranges, or quinine (e.g. 
tonic water) or foods containing poppy seeds in the last 72 hours. 
13. Donation or loss of greater than one pint of blood within 60 days of entry to the study.  
14. Any prior serious adverse reaction or hypersensitivity to fentanyl, morphine, codeine, 
hydrocodone, hydromorphone, oxycodone,  oxymorphone, naltrexone or naloxone or any of the 
inactive ingredients in the TDDS (polyester/ethyl vinyl acetate, polyacrylate adhesive, silicone 
adhesive, dimethicone NF, or polyolefin).  
15. Have a diagnosis of schizophrenia or other major psychiatric diagnosis or mental illness (e.g., 
major depression).  
16. Medical history of personal drug or alcohol addiction or abuse). 
17. 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.  
18. Inability to communicate or co-operate with the investigators.  
19. Subject has an obvious difference in skin color between arms or the presence of a skin condition, 
excessive hair at the application site (upper arm), sunburn, raised moles and scars, open sores at 
application site (upper arm), scar tissue, tattoo, or coloration that would interfere with placement 
of test articles, skin assessment, or reactions to drug.  
20. Failure to pass opioid dependence challenge test on the first Study Day of any Study Session (i.e., 
before taking the first dose of naltrexone hydrochloride). Each Subject will be injected 
subcutaneously with naloxone hydrochloride (0.8 mg injection) and will be observed for 45 
minutes for signs and symptoms of opioid withdrawal. 
21. Within 4 weeks prior to dosing, use of medications or treatments that would significantly 
influence or exaggerate responses to the test product or that would alter inflammatory or immune 
response to the product or agents deemed to be immunosuppressive as determined by physician 
investigator. 
 


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6 STUDY PRODUCT 
6.1 Study Product Description 
6.1.1 Duragesic® (fentanyl) TDDS 25 µg/h 
Duragesic® is a prescription TDDS that contains fentanyl which is a federally controlled 
substance (CII). Duragesic® TDDSs deliver fentanyl at a rate of 25 µg/h 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) TDDS 25 µg/h 
Mylan (fentanyl) is a prescription TDDS that contains fentanyl which is a federally controlled 
substance (CII). Mylan (fentanyl) TDDS deliver fentanyl at a rate of 25 µg/h 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 Fentanyl citrate injection, USP 0.05 mg/mL 
Fentanyl citrate injection is a prescription that contains fentanyl which is a federally 
controlled substance (CII). Fentanyl citrate (100 µL, 2 mL) will be administered with a 
syringe over 2 min through the catheter into the vein.  Fentanyl citrate is for patients for short 
duration analgesic action during anesthetic Sessions (premedication, induction, maintenance, 
and immediate postoperative), analgesic supplement with anesthesia, administration of 
anesthetic agent with oxygen in selected high risk patients.  
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 and alcoholism.  
6.1.5 Naloxone hydrochloride injection, USP 0.4 mg/mL 
Naloxone hydrochloride is an opioid antagonist which attenuates or reversibly blocks the 
effects of opioids. It is available as a prescription medication and is used for the complete or 
partial reversal of opioid respiratory and/or central nervous system depression.  
  


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6.2 
Formulation, Packaging, and Labeling 
6.2.1 Duragesic® (fentanyl) TDDS 25 µg/h 
Active ingredient (in each TDDS): Fentanyl, 25 µg delivered per hour.  In addition to the active 
ingredient (fentanyl), the following inactive ingredients are present in the TDDS: polyester/ethyl 
vinyl acetate and a polyacrylate adhesive. This is a matrix type TDDS, manufactured by ALZA 
Corporation and distributed by Janssen Pharmaceuticals, Inc. This product should be stored below 
25°C (77°F). Excursions permitted at 15-30°C. 
 
6.2.2 Mylan (fentanyl) TDDS 25 µg/h 
Active ingredient (in each TDDS): Fentanyl, 25 µg delivered per hour.  In addition to the active 
ingredient (fentanyl), the following inactive ingredients are present in the TDDS: dimethicone NF and 
silicone adhesive and polyolefin film backing. This is a matrix type TDDS, manufactured by Mylan 
Pharmaceuticals Inc. This product should be stored between 20°-25°C (68°-77°F). 


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6.2.3 
Fentanyl citrate, preservative free, injection 0.05 mg/mL 
Active ingredient: Fentanyl, each mL contains fentanyl citrate equivalent to 50 µg (0.05 mg) fentanyl 
base.  In addition to the active ingredient (fentanyl), the following inactive ingredients are present in 
the injectable:  water for injection, pH 4.0-7.5:  sodium hydroxide and/or hydrochloric acid, if needed, 
for pH adjustment.  This injectable is manufactured by West-Ward Pharmaceuticals. This product 
should be stored between 20°-25°C (68°-77°F). 
 


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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 tablet: 
crospovidone, hypromelloses, lactose monohydrate, magnesium stearate, microcrystalline cellulose, 
polyethylene glycols, polysorbate 80, silicon dioxide, titanium dioxide, ferric oxide yellow and ferric 
oxide red. This oral tablet manufactured by Covidien Ltd., or a comparable generic equivalent, will be 
procured by the investigational drug pharmacy at the University of Maryland Medical Center from 
the appropriate distributor (e.g. Mallinckrodt Pharmaceuticals). This product will be stored at room 
temperature, 20 to 25°C (68 to 77°F). 
 
6.2.5 Naloxone hydrochloride injection, USP 0.4 mg/mL 


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Active ingredient (in each injection): Naloxone hydrochloride, USP 0.4 mg/mL is a sterile, 
nonpyrogenic solution of naloxone hydrochloride in water for injection from Hospira (Lake Forest, 
Illinois), or a comparable generic equivalent, will be procured by the investigational drug pharmacy at 
the University of Maryland Medical Center from the appropriate distributor.  Each mL contains 
naloxone hydrochloride and sodium chloride to adjust tonicity in water for injection.  May contain 
hydrochloric acid for pH adjustment; pH 4.0 (3.0 to 6.5).  The single dose ampoule is 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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8 
PHARMACOKINETICS AND STATISTICAL 
CONSIDERATIONS 
8.1 
Study Hypotheses 
Given the fact that there are formulation differences between Duragesic® and Mylan fentanyl 
TDDS, we hypothesize that: 
a. Bioequivalence exploration. 
b. Release rate analysis.  
These hypotheses will be tested by comparing the residual drug amounts in Duragesic® and 
Mylan fentanyl TDDS and by assessing the pharmacokinetic parameters following their 
application, and comparing them to the pharmacokinetic parameters estimated after direct IV 
infusion of fentanyl citrate. 
8.2 
Pharmacokinetics (PK) Analyses 
8.2.1 Pharmacokinetic endpoints 
 
Area under the time curve from dosing time to last measurement time (AUC0-t) and peak drug 
activity (Cmax) for Duragesic® TDDS and Mylan fentanyl TDDS will be used as the primary 
endpoint.  For intravenous fentanyl, AUC0-∞ will be determined. 
 
The time to maximum concentrations (Tmax) and AUC0-∞ for fentanyl from Duragesic® TDDS 
and Mylan fentanyl TDDS will also be determined.   
8.3 
Final Analysis Plan 
The primary statistical analysis will be performed on the natural log transformed AUC0-t, AUC0-A and 
Cmax of Fentanyl from the three Study Sessions using SAS V 9.3.  A linear mixed effects model will 
be used to assess the effects of treatment, Session, sequence and Subject within sequence on natural 
log transformed AUC0-t, AUC0-C and Cmax.  The treatment, Session, sequence effect will be treated as 
fixed effects and assessed at a significance level of 0.05.  The Subject within sequence will be treated 
as a random effect.  Intra and inter individual variabilities will be obtained.  The least square mean 
estimates for the adjusted differences between treatment means (the log transformed AUC0-t, AUC0-C 
and Cmax) and the standard error associated with these differences will be obtained.  The geometric 
means for AUC0-a will be obtained by exponentiating the log transformed AUC0-i for all the three 
treatments to determine the absolute bioavailability.       
The absolute bioavailability for Duragesic® TDDS and Mylan fentanyl TDDS will be calculated.  


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The analyses for IV administration of fentanyl citrate will be as follows:  
Non compartmental and compartmental analyses will be conducted to estimate the PK parameters 
such as clearance, volume of distribution, elimination rate constant, maximum serum concentration; 
time of maximum serum concentration and area under the serum concentration-time curve. All 
analyses will be conducted using Phoenix® WinNonlin® 6.3 (Pharsight, a Certara Company, CA). 
Absolute bioavailability will be calculated.   
The analyses for both TDDS applications (Duragesic® and Mylan fentanyl) will be as follows:   
The serum fentanyl concentrations will be determined and the PK parameters such as Cmax, Tmax, 
AUC, steady concentrations (Css) of fentanyl in each Subject will be elucidated. The rate of fentanyl 
absorption in each Subject is calculated by dividing the Css by the clearance predicted from the IV 
bolus data. 
Cumulative amount of fentanyl released by Duragesic® at the end of study Session will be obtained 
by subtracting residual fentanyl still remaining in the TDDS at the end of the study Session from the 
total amount of the drug present in an unused TDDS. 
 
Similarly, cumulative amount of the drug released by the Mylan TDDS at the end of study Session is 
computed. 
 
The rate of drug release from Duragesic® and Mylan TDDS will be determined.    
The means of fentanyl release rates from Duragesic® TDDS, standard deviations from their mean, and 
95% confidence intervals will be determined and tabulated. The statistical significance of difference 
between the means will be evaluated by two-tailed Student’s t-test.