Transdermal Patch CVD 2000: The Effect of Heat on Fentanyl Release From Fentanyl TDSs in Healthy Adults

Determination of Serum Fentanyl Levels After Using Reference and Generic Transdermal Fentanyl TDSs With and Without Standardized Heat Application in Healthy Human Volunteers

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.

Study Overview

• Status: Completed
• Conditions: Peer Review, Research
• Intervention / Treatment: Drug: Duragesic reference fentanyl TDS; Drug: Apotex generic fentanyl TDS; Drug: Mylan generic fentanyl TDS

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.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland, Baltimore Center for Vaccine Development

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 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.
• 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.

Exclusion Criteria:

• 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 fentanyl TDS.
• 6. History of chronic obstructive pulmonary disease.
• 7. Active positive Hepatitis B, C, and HIV serologies.
• 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 TDS (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 TDS 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 TDS. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Health Services Research
• Allocation: Non-Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Duragesic Reference Fentanyl TDS; 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.	Drug: Duragesic reference fentanyl TDS; 25 µg/hour; Other Names: Brand name fentanyl TDS
Active Comparator: Apotex Generic Fentanyl TDS; 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.	Drug: Apotex generic fentanyl TDS; 25 µg/hour; Other Names: Generic fentanyl TDS
Active Comparator: Mylan Generic Fentanyl TDS; 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.	Drug: Mylan generic fentanyl TDS; 25 µg/hour; Other Names: Generic fentanyl TDS

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Partial Area Under the Curve (AUC) Attained With Early and Late Heat in Each of the Three Fentanyl TDSs (Reference and Generic)	Partial area under the flux-time curve of fentanyl calculated from 11 to 14 h for Early Heat and 18 to 21 h for Late Heat study designs Blood samples obtained at 15 min prior to patch application [baseline], and 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 h post-patch application	six procedure days for each participant

Collaborators and Investigators

• Sponsor: University of Maryland, Baltimore
• Collaborators: Food and Drug Administration (FDA)
• Investigators: Principal Investigator: Audra Stinchcomb, PhD, University of Maryland, Baltimore

Study record dates

Study Major Dates

• Study Start (Actual): July 9, 2015
• Primary Completion (Actual): August 8, 2017
• Study Completion (Actual): August 9, 2017

Study Registration Dates

• First Submitted: June 26, 2015
• First Submitted That Met QC Criteria: June 29, 2015
• First Posted (Estimate): June 30, 2015

Study Record Updates

• Last Update Posted (Actual): March 23, 2020
• Last Update Submitted That Met QC Criteria: March 10, 2020
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Keywords: Bioequivalence; Therapeutic Equivalency
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Analgesics, Opioid; Narcotics; Adjuvants, Anesthesia; Fentanyl
• Other Study ID Numbers: HP-00059884

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Study Data/Documents

1. AAPS presented poster
   Information comments: Shin SH, Yu M, Thomas S, Hammell DC, Ghosh, P, Raney SG, Hassan HH, Stinchcomb AL. Evaluation of level A in vitro/in vivo correlations (IVIVC) for nicotine and fentanyl transdermal delivery systems with transient heat exposure by using multiple approaches. Poster presentation at the 2017 AAPS Annual Meeting and Exposition; November 12-15, 2017; San Diego, CA