Conditions: Heat Effect
Allocation: NON_RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 13
Healthy volunteers: yes

Brief summary:
This research study is intended to determine the effect of heat and occlusion on oxybutynin products.

Detailed description:
This research study is intended to determine the effect of heat and occlusion on oxybutynin products. This study will use an oxybutynin patch and gel that have been approved by the Food and Drug Administration (FDA) and are already sold to customers in the United States; will not include any placebos.

Arms:
arm 1: patch arm 2: gel arm 3: patch arm 4: gel

Interventions: intervention 1: oxybutynin intervention 2: oxybutynin
Intervention descriptions: intervention 1: patch intervention 2: gel

Protocol document:
Prot_SAP_000.pdf: 
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Determination of Serum Oxybutynin Levels after Using Oxybutynin Transdermal 
Delivery System and Transdermal Gel with and without Standardized Heat 
Application in Healthy Human Volunteers 
Short title: Effect of Heat on Oxybutynin Release and Absorption from Oxybutynin 
Products 
UMB IRB #:  HP-00070850 
 
Principal Investigator(s):  
Audra L. Stinchcomb (contact), PhD, RPh 
 
Medically Accountable Investigator(s): 
Jeffrey Fink, MD, MS 
Lee-Ann Wagner, MD 
Sponsor: 
Food and Drug Administration 
Office of Generic Drugs 
 
Grant Number: 1U01FD004955 
NCT:  03205605 
Version 12.0 
March 17, 2020 
 


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STATEMENT OF COMPLIANCE 
This trial will be conducted in compliance with the protocol, International Conference on 
Harmonization 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:  
Determination of Serum Oxybutynin Levels after Using 
Transdermal Oxybutynin Patch and Gel 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 up to 1 year 
 
Subject Participation 
Duration: 
Approximately 12 weeks including the screening period 
 
Description of Study 
Product: 
Oxybutynin (Oxytrol® for Women, 36 mg patch), Actavis 
Pharma, Inc.; Oxybutynin (Gelnique®) 10% gel, Watson 
Pharmaceuticals, Inc 
Objective: 
 
The aim of the present study is to generate human 
pharmacokinetic (PK) data in healthy subjects for the purpose of 
establishing a reference for in vitro-in vivo correlation (IVIVC) 
with an in vitro model following the application of oxybutynin 
products: Oxytrol® for Women (oxybutynin patch) with and 
without heat application and Gelnique® (oxybutynin 10% gel)with 
and without occlusion.     
Description of Study 
Design: 
The study will be an open-label, crossover study (n=12 healthy 
subjects) over 12 weeks includes four study sessions with up to 
a 45 day screening period with one week washout period 
between study sessions. 
The study contains four study sessions: 
• 
Study Session 1:  Oxytrol® for Women patch containing 36 
mg each of oxybutynin to be worn for 30 h. 
 
• 
Study Session 2:  Gelnique® gel containing 10% oxybutynin 
(0.5 g of gel/200 cm2/upper arm) to be applied (and not 
wiped) for 12 h without occlusion.   
• 
Study Session 3: Oxytrol® for Women patch containing 36 
mg each of oxybutynin to be worn for 30 h.  The heating pad 
will be set to induce a skin temperature of 42.0 ± 4°C and 
applied for 1 hour 30 minutes at 24 h and at 30 h after 
application of the Oxytrol® for Women patch.  Patch to be 


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worn for 30 h. 
• 
Study Session 4: Gelnique® gel containing 10% oxybutynin 
(0.5 g of gel/200 cm2/upper arm) to be worn for 12 h with 
occlusion from 7 through 10 h.   
A)  Pharmacokinetics (PK) 
Each subject will be his/her own control (pre-dose blood 
sample) 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 subject’s skin in the area of application (upper arm) will be 
relatively free of hair before patch/gel application. Blood 
samples (approximately 4 mL each) will be drawn in BD 
vacutainer tubes. Blood samples will be obtained as follows: 
• 
Within 60 min pre-application and then up to 34 h 30 min 
after patch application.  Within 60 min pre-application and 
then up to 12 h after gel application.   
 
B)  Residual Drug Analysis of Oxytrol® for Women Patch  
In conjunction with the above described study, residual drug 
analysis will also be conducted for the previously worn Oxytrol® 
for Women patches from Study Session 1 and 3.    
• 
Prior to administration to the subject as described in Part A, 
patches will be weighed and the weight recorded. 
• 
The pouch, release liner and all items coming into contact 
with the patch (gloves, forceps, etc..) applied in Part A will be 
retained for analysis. 
• 
The used patch will be retained for drug content analysis. 
• 
All items coming into contact with the patch during removal 
from the subject will be stored in a separate labeled sealable 
foil pouch until analyzed for drug content. 


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1 KEY ROLES 
U01 Principal Investigator: 
 
 
Audra L. Stinchcomb (contact), Ph.D., R.Ph. (PI) 
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 
Investigator(s) 
 
 
Jeffrey C Fink M.D., M.S.(primary) 
Professor 
Department of Medicine and Epidemiology (secondary) 
University of Maryland School of Medicine 
UMMC, Room NN3E03 
Baltimore, MD 21201 
Phone: 410-328-4822 
Fax: 410-328-5685 
Email:  jfink@medicine.umaryland.edu 
 
 
Lee-Ann Wagner, M.D. (secondary) 
University of Maryland School of Medicine 
Department of Medicine  
Pediatrics 
North Hospital 
Baltimore, MD 21201 
Phone:   410-328-7605 or 410-328-3158 
Email : lwagner@som.umaryland.edu 
 
 


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2 BACKGROUND INFORMATION AND SCIENTIFIC 
RATIONALE 
2.1 
Background Information 
There are numerous transdermal delivery systems (TDS) that are currently available in 
the United States, the first of which was approved by the Food and Drug Administration 
(FDA) in 1979 [1]. TDS 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 TDS 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 products that are often 
available in different forms is important to ensure that one formulation is not less safe 
than other formulations. In this proposal we will focus on investigating the influence of 
heat and occlusion on drug release from oxybutynin products (patch and gel). 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 and hence can increase drug permeation from TDS.  Indeed, exposure to heat has 
been demonstrated to increase drug release from patches, which led to increased serum 
concentrations of numerous drugs (e.g., fentanyl and nicotine) and raised a number of 
safety concerns (2-7). As a result, almost all patches that are currently available have 
warnings against heat exposure.  Occlusion effect on semi-solid formulations has not 
been widely investigated.  Skin occlusion prevents water loss from skin surface thus 
increasing hydration of stratum corneum.  Increased stratum corneum hydrophilicity can 
alter the movement of drug molecules through skin resulting in increased drug 
permeation (15).  
2.2 
Rationale 
The goal of this study is to conduct in vivo studies to compare the influence of heat and 
occlusion on oxybutynin drug release from FDA approved products; Oxytrol® for 
Women patch versus Gelnique® gel.  While there is data in the literature for heat and 
occlusion effect on different active pharmaceutical ingredients (APIs), specifically RLD 
products, from exposure to external heating sources (heating pads, sauna, hot showers, 
exercising) and occlusion, there is a lack of data to demonstrate in vivo-in vitro correlation 
under heat exposure and occlusion.  Therefore, to help ensure that gels and TDS are 
safe for patients, an in vitro setup is being developed to characterize the heat and 
occlusion effect for these TDS and gel systems, respectively, by correlating the in vivo 
data with in vitro data using the IVPT model with excised human skin.  This necessitates 
that a small number of human subject heat effect and occlusion studies are performed 


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under controlled and monitored conditions with selected products, to serve as an in vivo 
reference for parallel IVPT heat effect and occlusion studies.  The oxybutynin heat and 
occlusion effect studies described in this protocol are the final set in this series of studies. 
The intent of this research is to establish an IVIVC for the IVPT model in the specific 
context of heat and occlusion effect studies, so that IVPT studies can be utilized to 
evaluate these effects so future generic products are similar in quality to the brand name.  
In addition, the residual drug content of the used Oxytrol® for Women patches will be 
analyzed for the purpose of estimating the amount of drug absorbed. 
  
Oxybutynin Products 
  
Oxytrol® for Women  
Gelnique® 10%  
 
Inactive 
ingredients 
acrylic adhesive, 
polyester/ethylene-vinyl 
acetate film; siliconized 
polyester film and triacetin 
alcohol USP, glycerin 
USP, hydroxypropyl 
cellulose NF, sodium 
hydroxide NF and 
purified water USP 
 
  
 
 
Product 
Patch 
Gel 
 
  
  
 
 
Manufacturer 
Actavis Pharma, Inc. 
Watson 
Pharmaceuticals, Inc. 
 
 
 
 


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3 OBJECTIVES 
3.1 
Study Objectives 
The present study aims to: 
 
1)  Generate human PK data for the purpose of establishing an IVIVC model by 
collecting data following the application of oxybutynin products: Oxytrol® for Women 
(oxybutynin patch) and Gelnique® (oxybutynin 10% gel). 
 
2)  Determine serum oxybutynin concentrations after using Oxytrol® for Women (matrix 
type patch, Actavis Pharma, Inc.) with and without standardized heat application in 
healthy adult subjects and Gelnique® (gel, Watson Pharmaceuticals, Inc.) with and 
without occlusive backing application in healthy adult subjects.. 
 
3)  Determine residual drug content of Oxytrol® for Women patch for the purpose of 
estimating amount of drug absorbed.  
3.2 
Study Outcome Measures 
For the PK study the main outcome measure is the maximum serum concentration 
(Cmax); time of maximum serum concentration (Tmax) of oxybutynin and area under the 
curve (AUC) attained with and without heating for Oxytrol® for Women patch and with 
and without occlusive backing for Gelnique® gel.  In addition, we will determine residual 
drug content from worn Oxytrol® for Women patch to estimate total amount of absorbed 
oxybutynin.     
 
 


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4 
  STUDY ENROLLMENT AND WITHDRAWAL 
4.1 
Subject Inclusion Criteria 
Subjects are eligible for this study if they fulfill the inclusion criteria specified below: 
1. Men or non-pregnant, non-lactating women who are of any ethnic background 
between the age of 18 and 45 years old. 
2. Subjects must be non-smokers/tobacco users (must have refrained from the use 
of nicotine-containing substances, including tobacco products (e.g., cigarettes, 
cigars, chewing tobacco, snuff, gum, patches or electronic cigarettes) over the 
previous two months and are not currently using tobacco products. 
3. Provide written informed consent before initiation of any of the study procedures. 
4. Agree not to participate in another clinical trial/study or to participate in an 
investigational drug study for at least one month after the last study session. 
5. Able to adhere to the study restrictions and protocol schedule. 
6. Able to participate in all study sessions. 
7. Subjects have upper arms large enough to allow for application of 200 cm2 [31 
in2] area of gel.  The arm distance from the greater tubercle to the olecranon 
process should be a minimum of 30 cm. The circumference of the upper arms 
should be a minimum of 30 cm. 
8. Subjects deemed to be healthy as judged by the MAI and determined by medical 
history, physical examination and medication history. 
9. Negative urine drug screening test (cannabinoids, amphetamines, barbiturates, 
benzodiazepine, cocaine, methadone, opiates, PCP). 
10. Have normal screening laboratories for white blood cells (WBC), hemoglobin 
(Hgb), platelets, sodium, potassium, chloride, bicarbonate, blood urea nitrogen 
(BUN), creatinine, alanine transaminase (ALT) and aspartate aminotransferase 
(AST). 
11. Have normal screening laboratories for urine protein and urine glucose.  
12. 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 


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enrollment and on the morning of each procedure day, 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.  
13. Agree not to donate blood to a blood bank throughout participation in the study 
and for at least three months after the last procedure day. 
14. 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). 
15. Have normal vital signs: 
• Temperature 35-37.9°C (95-100.3°F) 
• Systolic blood pressure 90-165 mmHg 
• Diastolic blood pressure 60-100 mmHg 
• Heart rate 55-100 beats per minute 
• Respiration rate 12-20 breaths per minute  
 
4.2 
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 positive urine pregnancy test on the morning of 
any study session. 
2. Smokers/tobacco users (current use or use over the previous two months of 
nicotine-containing substances, including tobacco products (e.g., cigarettes, 
cigars, chewing tobacco, snuff, gum, patch or electronic cigarettes). 
3. Participation in any ongoing investigational drug trial/study or clinical drug 
trial/study. 
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/or HIV serologies (see Appendix B). 
6. Positive urine drug screening test. 
7. Use of chronic prescription medications during the period 0 to 30 days; or over-
the-counter 
medications 
(e.g. 
bisphosphonates 
[to 
treat 
osteoporosis], 
anticholinergics 
[used 
to 
treat 
diseases 
like 
asthma, 
incontinence, 


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gastrointestinal cramps, and muscular spasms], 
antihistamines, topical 
corticosteroids) and short term (<30 days) prescription medications during the 
period 0-3 days before a study session [vitamin, herbal supplements and birth 
control medications not included)]. 
8. Donation or loss of greater than one pint of blood within 60 days of entry to the 
study. 
9. Any prior allergies to oxybutynin, other ingredients in the patch or gel tested, to 
medical tape products or other skin patches. 
10. Subject has problems with urinary retention, gastric retention or gastrointestinal 
obstruction.   
11. Subject has ulcerative colitis. 
12. Subject has gastric reflux disease or esophagitis. 
13. Subject has uncontrolled narrow-angle glaucoma. 
14. Subject has myasthenia gravis. 
15. Received an experimental agent (vaccine, drug, biologic, device, blood product 
or medication) within one month before enrollment in this study or expects to 
receive an experimental agent during the study. 
16. 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. 
17. Consumption (food or drink) of alcohol within 24 h prior to dose administration. 
18. History as either reported by the subject or evident to the investigator of 
infectious disease or skin infection or of chronic skin disease (e.g., psoriasis, 
atopic dermatitis). 
19. History of diabetes.  
20. Hereditary skin disorders or any skin inflammatory conditions as reported by the 
volunteer or evident to the MAI. 
21. History of significant dermatologic cancers (e.g., melanoma, squamous cell 
carcinoma) except basal cell carcinomas that were superficial and did not involve 
the investigative sites. 


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22. Subject has an obvious difference in skin color between arms or the presence of 
a skin condition, excessive hair at application site (upper arms), sunburn, raised 
moles and scars, open sores at application site (upper arms), scar tissue, tattoo 
or coloration that would interfere with placement of products, skin assessment or 
reactions to oxybutynin. 
23. BMI  30 kg/m2. 
 


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5 
PHARMACOKINETICS AND STATISTICAL 
CONSIDERATIONS 
5.1 
Study Hypothesis 
Heat exposure can enhance the systemic delivery of oxybutynin from the patch and 
occlusion can enhance systemic delivery from gel. In this study, the influence of 
standardized heat application on the pharmacokinetics (PK) parameters of oxybutynin 
will be studied after using Oxytrol® for Women patch. Heat will be applied when the 
serum levels from the patch reach steady state levels around 24 h indicating steady 
state skin concentration. A second heat application will determine the influence of 
heat application on drug reservoir in the skin from the patch. Gel application area will 
be occluded for three hours.  We will test the null hypothesis (H0) that the coefficient 
for the patch-by-heat or gel-by-occlusion interaction equals zero, adjusting for time. 
 
5.2 
Analyses 
Oxybutynin concentrations will be measured in serum samples collected from each 
subject. Blood samples (approximately 4 mL (0.8 tsp)) will be collected at pre-dosing and 
then at 24 h, 24 h 15 min, 24 h 30 min, 24 h 45 min, 25 h,  25 h 15 min, 25 h 30 min, 25 
h 45 min, 26 h, 27 h, 28 h, 29 h, 30 h, 30 h 15 min, 30 h 30 min, 30 h 45 min, 31 h, 31 h 
15 min, 31 h 30 min, 31 h 45 min, 33 h and 34 h 30 min post-patch application.  Blood 
samples (approximately 4 mL (0.8 tsp)) will be collected at pre-dosing and then at 1 h, 2 
h, 3 h, 4 h, 5 h, 6 h, 7 h, 7 h 15 min, 7 h 30 min, 7 h 45 min, 8 h, 8 h 15 min, 8 h 30 min, 
8 h 45 min, 9 h, 9 h 15 min, 9 h 30 min, 9 h 45 min, 10 h, 10 h 30 min, 11 h, 11 h 30 min 
and 12 h post-gel application.   
 
Non compartmental analyses (NCA) will be conducted to estimate the  PK parameters 
such as: maximum serum concentration (Cmax), apparent elimination rate constant (k); 
apparent half-life (t1/2), calculated as 0.693/k; AUC0-last of the serum concentration–time 
determined by the linear trapezoidal method (patch) and AUC value extrapolated to 
infinity (AUCinf), calculated as the sum of AUC0-last and the area extrapolated to infinity: 
AUCinf = AUC0-last + Clast/k where Clast would be the last quantifiable concentration. All 
NCA analyses will be conducted using Phoenix® WinNonlin® 6.4 (Pharsight, a Certara 
Company, CA). 


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5.3 
Final Analysis Plan 
An objective of this study is to investigate the influence of heat application and occlusion 
application on the PK parameters of oxybutynin after using patch and gel products.  The 
primary PK parameters to be compared are 1) Cmax, before and after heat application or 
occlusion; 2) AUC before and after heat application or occlusion consistent with similar 
PK studies. (6,7)  Determine PK parameters (Cmax, AUC) of oxybutynin in healthy adults 
after using Oxytrol® for Women and Gelnique® for the purpose of IVIVC by collecting 
data over two separate periods. Complimentary in vitro data will be collected using 
human skin. 
 
IVIVC will be conducted comparing PK parameters and profiles to predicted PK 
parameters and profiles using IVPT results.  Multiple methods will be implemented to 
develop an IVIVC.  The first method is to compare the steady state concentrations.  The 
predicted steady state concentration using our current IVPT data will employ the 
following formula: 
𝐶𝑠𝑠= 𝐽𝑠𝑠 ∗𝐴
𝐶𝐿
 
 
Css=steady state serum concentration; Jss=steady state flux; A=area; CL=clearance 
  
The second method will compare the PK profiles of the clinical and IVPT study by 
predicting oxybutynin concentrations at each time point in the IVPT study and comparing 
it to the clinical PK profile.  The third method will be to determine and compare residual 
patch analysis between in vitro and in vivo.