Evaluation of Bioavailability of Diclofenac Dermal Products

The study will utilize already FDA-approved marketed diclofenac products in healthy adults to
generate data for establishing rate of drug delivery comparisons between diclofenac epolamine
patches and diclofenac sodium solution in healthy adults and to determine skin
concentrations. This study supports FDA's continuing effort to identify the most accurate,
sensitive, reproducible and efficient methods to evaluate topical dermatological drug
products.

Inclusion Criteria:

1. Men or non-pregnant, women who are of any ethnic background between the age of 18 to
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,
snuff, gum, patches or electronic cigarettes) over the previous 2 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 during the study period or to
participate in an investigational drug study for at least 1 month after the last study
session

5. Able to adhere to the study protocol and study restrictions

6. Able to participate in all study sessions

7. Has a volar forearm of either at least 24 cm (9.45 inches) in length or of sufficient
size that can accommodate the products to be tested in a study area that begins at
least 5 cm (1.97 inches) above the wrist and ends a minimum of 0.5 cm (0.197 inches)
below the antecubital fossa (i.e., the bend in the arm at the elbow).

8. Subjects have upper arms large enough to allow for placement of two 140 cm2 [21.7 in2]
patches (distance from acromion process of the scapula to olecranon process should be
a minimum of 35 cm [13.8 inches]; circumference of upper arms should be a minimum of
30 cm [11.8 inches] and 200 cm2 [31 in2] area for application of solution

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 (cannabinoids, amphetamines, barbiturates,
benzodiazepine, cocaine, methadone, opiates, PCP)

11. 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)

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), or if of childbearing potential must be non-pregnant at the time of
enrollment and on the morning 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 donate blood to a blood bank throughout participation in the study and
for at least 3 months after last study session

15. 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)

16. 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

Exclusion Criteria:

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 the first day of
each 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,
snuff, gum, patch or electronic cigarettes)

3. Participation in any ongoing investigational drug trial/study or clinical drug
trial/study

4. History as either reported by the subject or evident to the Medically Accountable
Investigator (MAI) of infectious disease or skin infection or of chronic skin disease
(e.g., psoriasis, atopic dermatitis)

5. History of diabetes

6. History of significant skin cancers (e.g., melanoma, squamous cell carcinoma) except
basal cell carcinomas that were superficial and did not involve the investigative
sites

7. Body Mass Index (BMI) ≥30 kg/m2

8. History of chronic obstructive pulmonary disease or cor pulmonale, or substantially
decreased respiratory reserve, hypoxia, hypercapnia or pre-existing respiratory
depression

9. Active positive Hepatitis B, C and/or HIV serologies

10. Positive urine drug screening test

11. Use of any prescription medication during the period 0 to 30 days or over-the-counter
medication e.g. antihistamines, topical corticosteroids during the period 0-5 days
before entry to the study (vitamins, herbal supplements and birth control medications
not included)

12. Currently taking daily oral nonsteroidal anti-inflammatory drug [NSAIDs] (aspirin,
ibuprofen, naproxen, etc…)

13. Currently taking daily anticoagulants or within the past month prior to entry into the
study (warfarin, heparin, rivaroxaban, dabigatran, etc…), ACE-inhibitors,
cyclosporine, diuretics, lithium or methotrexate

14. Donation or loss of greater than one pint of blood within 60 days of entry to the
study

15. Any prior adverse reaction or hypersensitivity to diclofenac, aspirin, ibuprofen,
naproxen or other nonsteroidal anti-inflammatory drug (NSAID), other inactive
ingredients in the patch or topical solution or to adhesives or tapes used to cover or
tape strip the treatment sites

16. 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

17. Eat or drink anything containing alcohol within 24 hours prior to dose administration

18. 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

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 arms/volar forearms),
sunburn, raised moles or scars, open sores at application site (upper arms/volar
forearms), scar tissue, tattoo, or coloration that would interfere with placement of
diclofenac products, skin assessment, or reactions to diclofenac

20. History of asthma or urticaria,, hypertension, myocardial infarction, thrombotic
events, stroke, congestive heart failure, impaired renal function or liver disease

21. History of gastrointestinal bleeding or peptic ulcer disease