A randomized, single-site, open-label, 2-way crossover, single-dose Phase I clinical trial to assess the bioequivalence of 2 tablets of a tapentadol 25 mg prolonged-release tablet formulation and 1 tablet of a tapentadol 50 mg prolonged-release tablet formulation in healthy male subjects under fed conditions

The drug tapentadol is already approved in many countries throughout the world,
including Australia, Canada, the European Union, and the USA. The currently
available pharmaceutical forms are prolonged release tablets (with dose
strengths from 25 to 250 mg) for the treatment of chronic pain in adults,
immediate release tablets (with dose strengths from 50 to 100 mg) and an oral
solution for the treatment of acute pain in adults.

Tapentadol is a centrally acting analgesic, meaning that it works on the
central nervous system (i.e. in the brain) to reduce pain. This analgesic is
characterized by a twofold mechanism of action:
1. Tapentadol works like a painkiller from the class of drugs called opiates
(e.g. morphine)
2. Tapentadol prolongs the action of the messenger substance norepinephrine,
which influences pain perception among other things.
Tapentadol has been included in List 1 (marketable and prescriptible narcotics)
of the Narcotics Act (Opiumwet) and is therefore subject to the provisions of
this act.

In this medical-scientific study, two different prolonged release formulations
will be compared, one formulation containing 25 mg and the other 50 mg of
tapentadol. Both formulations are already approved and are available on the
market.

The purpose of this study is to investigate how quickly and to what extent two
25 mg prolonged release tapentadol tablets are absorbed and eliminated from the
body (this is called pharmacokinetics) when compared to one 50 mg prolonged
release tapentadol tablet (this is called bioequivalence).

It will also be investigated how safe both tablets are when administered to
healthy volunteers. Tapentadol is no new compound; both tapentadol formulations
used in this medical-scientific research are already approved and are available
on the market.

The actual study will consist of 2 periods during which the volunteer will stay
in the research center location UMCG for 4 days (3 nights). Between the
periods, the volunteer will not be in the research center for 4 to 11 days.

Day 1 is the day of administration of the study compound during each period. In
both periods, the volunteer is expected at the research center at 14:00 h in
the afternoon prior to the day of administration of the study compound. The
volunteer will leave the research center on Day 3 of each period.

The volunteer will receive tapentadol as 1 tablet (50 mg, reference
formulation) and 2 tablets (25 mg each, test formulation) with 240 milliliter
(mL) of tap water.

The volunteer will receive the study compound after a standardized high-fat
breakfast. This high-fat breakfast is an extensive breakfast with a fixed
composition (2 fried eggs, a portion bacon, fried potatoes, bread and milk).
The breakfast has to be started exactly on time and has to be finished
completely within 30 minutes. One hour before and after administration of the
study compound, the volunteer is not allowed to eat or drink except for the
high fat breakfast and the water for intake of the study compound. From 1 hour
after administration the volunteer is allowed to drink. Lunch will be served
approximately 4.5 hours after administration of the study compound.

Whether the volunteer will receive the reference or the test formulation first
will be determined by chance. Half of the volunteers will start with the
reference formulation and half with the test formulation. The volunteer will
get the other formulation during the second period.

The planning of the study is as follows:

Period 1 (Day 1)
Sequence 1 - 2 x 25 mg Test tablets
Sequence 2 - 1 x 50 mg Reference tablet

7 to 14 days Washout period

Period 2 (Day 1)
Sequence 1 - 1 x 50 mg Reference tablet
Sequence 2 - 2 x 25 mg Test tablets

All drugs can potentially cause adverse reactions; the extent to which this
occurs differs. The study compound(s) may also have side effects that are still
unknown.

A great deal of knowledge has already been gained about tapentadol in humans
from experience in numerous clinical studies in healthy volunteers and in
patients and from spontaneous reports in patients treated after marketing
authorization. Single doses of up to 300 mg of tapentadol twice daily, and
doses of up to 250 mg of prolonged release tapentadol twice daily were found to
be safe and tolerable in healthy volunteers. The pharmaceutical formulations
used in this medical-scientific research have already been approved and hence,
the 50 mg dose of prolonged release tapentadol per treatment period is
considered safe for the volunteer.

The most common side effects (occurring in more than 10% of those treated) in
medical scientific research on tapentadol tablets with prolonged release of the
active substance in the dose range 50 mg to 250 mg twice a day were nausea,
dizziness, sleepiness, headaches, and constipation.

In rare cases, treatment with tapentadol can lead to a reduction in the
breathing rate, as is known to occur with other opiate class substances.

Tapentadol has not been tested in patients who suffer from seizures. Therefore,
the volunteer cannot take part in this study if he suffer from seizures or
epilepsy or if he has suffered from them in the past.

The addictiveness of tapentadol has been shown to be similar to other opiate
class substances. However, with individual doses of tapentadol given in this
study, the likelihood of developing an addiction or withdrawal symptoms is
extremely low.

For tapentadol, there have been isolated reports of *serotonin syndrome* when
it is taken together with a certain class of antidepressants (selective
serotonin reuptake inhibitors). This syndrome is characterized by confusion,
abnormal restlessness, fever, sweating, muscle cramps, and diarrhea, and it
constitutes a medical emergency. If the volunteer take this type of medication,
he cannot take part in this medical-scientific study.

Some drugs that influence messenger substances such as norepinephrine have been
reported to increase the risk of suicide in patients who suffer from
depression. Although tapentadol strengthens the effect of norepinephrine, as
yet, there is no evidence of an increased risk with tapentadol.

As with any medication, allergic reactions (hypersensitivity reactions) may
occur after taking tapentadol. These may take the form of redness of the skin,
itching, fever, shortness of breath or circulatory problems to the point of
life-threatening shock. Suitable medicines and medical treatment methods are
available to manage these problems. Medically qualified staff who have been
trained to treat medical emergencies will monitor the volunteer during his stay
at the research center. If the volunteer has a known drug allergy or if he
suffer from a severe allergic condition, the volunteer is excluded from taking
part in this medical-scientific study.

More information about tapentadol can be found in the package leaflet and in an
seperate appendix of the subject information document.

The study compound may also have side effects that are still unknown.

Blood draw
The insertion of the needle for drawing blood and/or insertion of the
indwelling cannula may cause pain, bleeding or mild infection where the needle
goes into your arm. Another possible reaction is feeling dizzy or light-headed.
Rare complications during or after a blood draw include fainting, blood clot,
infections, inflammation of the vein, scarring of the vein, nerve injuries, and
accidental puncture of an artery. The amount of blood sampled during this study
does not cause any problems in adults. To compare: a blood donation involves
500 mL of blood being taken each time. Additional blood draws may be necessary
for medical reasons.

ECG electrodes
To monitor the heart rate, electrodes (small, plastic patches) will be pasted
at specific locations on the chest and abdomen. Prolonged use of these
electrodes can cause skin irritation (rash and itching).

Procedures: pain, minor bleeding, bruising, possible infection.