A SINGLE-CENTER, SINGLE-DOSE, OPEN-LABEL, RANDOMIZED, 4-WAY CROSSOVER STUDY TO EVALUATE THE PHARMACOKINETIC PROFILE OF FLURBIPROFEN FOLLOWING ADMINISTRATION OF 2 FLURBIPROFEN TRANSDERMAL FORMULATIONS COMPARED TO FROBEN® 50 MG AND YAKUBAN TAPE® IN HEALTHY SUBJECTS

The flurbiprofen transdermal system (FTS) is a new, investigational, not
registered as a drug, transdermal application form (transdermal means: patch
for administration via the skin) of the known drug flurbiprofen that may
eventually be used as an anti-inflammatory drug.
This is the first time that this particular formulation of flurbiprofen, FTS,
will be tested in humans. In addition to two formulations of the FTS applied
for 24 hours, you will receive a single dose of registered Froben®, a tablet
that contains flurbiprofen and 2 Yakuban Tape® transdermal patches that also
contain flurbiprofen and will be applied consecutively for 12 hours. These
Yakuban Tape® transdermal patches are not registered in the European Union.

The purpose of the study is to investigate how quickly and to what extent
flurbiprofen is absorbed and eliminated from the body (this is called
pharmacokinetics) when it is administered via a FTS. Furthermore, the
pharmacokinetics of FTS will be compared to oral administration of Froben® and
application of Yakuban Tape®. In addition, the safety and tolerability of FTS
will be investigated.

The study will consist of 4 periods during which the volunteer will stay in de
clinical research center in Zuidlaren for 5 days (4 nights) for each period.
The time interval between leaving the clinical research center and entering the
clinical research center for the next period will be at least 7 days. A
follow-up phone call will take place 7-10 days after discharge from the clinic
in Period 4.

For each period the volunteer is expected at the clinical research center at
14:00 h in the afternoon prior to the day of study medication administration.

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On Day 1 of each period a 50 mg Froben® tablet will be administered with 240 ml
of water in Period 1 after a fasting period (no food or drinks) of at least 10
hours. During 2 out of the 3 remaining periods a FTS will be applied on the
lower back for 24 hours after a fasting period of at least 10 hours. During 1
of the 3 remaining periods two Yakuban Tape® patches will be applied on the
lower back each for 12 hours after a fasting period of at least 10 hours for
the first patch. Study personel will press the patches firmly in place, using
the palm of the hand for at least 30 seconds to assure good adhesion.
For Period 1 no fluids will be allowed from 1 hour before drug administration
until 1 hour after drug administration. Thereafter, fluids are allowed freely.
For Periods 2, 3 and 4 fluids are allowed freely after patch application. In
all periods fasting will continue for 4 hours until lunch is provided.

Procedures: pain, light bleeding, heamatoma, possibly an infection.

Other transdermal formulations that contain flurbiprofen have been administered
in humans and were shown to be safe and tolerable. Some of the documented side
effects with Yakuban Tape® include: itching, redness, rash, and tingling at the
site of patch application.

This is the first time that this particular transdermal system of flurbiprofen,
FTS, will be tested in humans. Though local tolerability was good in animal
experiments, local skin irritation may be a side effect of FTS.

Flurbiprofen administered through a tablet has well-documented side effects of
which the most important are: edema, abdominal pain, constipation, diarrhea,
indigestion/heartburn, elevated liver enzymes, flatulence, gastrointestinal
bleeding, nausea, vomiting, body weight changes, headache, nervousness,
anxiety, insominia, increased reflexes, tremor, amnesia, fatigue, depression,
malaise (feeling sick), somnolence, rhinitis, rash, changes in vision,
dizziness, tendinitis and tinnitus.

With the doses used in this study, no serious adverse effects are expected. The
occurrence of known or other (unknown) effects cannot be excluded. All
potential drugs cause adverse events to some extent.