An Evaluation of the Safety and Pharmacokinetics of Posaconazole (POS, SCH 56592) IV Solution via Peripheral Administration in Healthy Volunteers (P06356)

Posaconazole is a medicine currently only registered for oral intake.
Posaconazole IV Solution is a drug that is being developed for the treatment of
fungal infections through intravenous infusion.

- To investigate the safety and tolerability of posaconazole IV Solution (the
test medication).
- To study how the test compound posaconazole (the test medication) is
absorbed, broken-down and excreted by the body.
- To study the effect of the test compound posaconazole (the test medication)
on the adrenal function.

This trial is a double-blind, randomized, placebo controlled study.

The study will start with a screening. At the screening a physical examination
will take place and a few other standard medical assessments will be performed
(ECG, vital signs). Furthermore a blood and urine sample will be taken for
laboratory tests and an alcohol breath test and drug screen will be done.

During the stay in the clinic the subject will receive the study medication and
on several time points blood will be taken and urine will be collected. The
subjects will be asked for possible side effects on regular basis. Furthermore
ECGs will be taken frequently and the vital signs will be checked frequently.
Furthermore echocardiography will be done.

Finally, a follow-up visit will take place.

Posaconazole has been previously tested in total of 4154 subjects. The most
commonly observed side effects related to the drug were nausea (6%), headache
(5%), diarrhea (5%), vomiting (4%), abdominal pain (2%), dry mouth (2%),
dizziness (2%), increased liver enzyme (2%), fatigue (2%) and rash (2%). During
a previous study of the same drug form by intravenous infusion, 6 out of 9
healthy subjects receiving 200 mg Posaconazole IV Solution developed local
reactions (so called peripheral phlebitis) within hours after the 90 min
peripheral infusion was completed. Peripheral phlebitis is an inflammation of
the cannulated blood vessel and surrounding skin. The symptoms are: redness and
warmth of the skin surrounding the cannula, pain or burning along the length of
the vein, swelling of the skin and the inserted vein being hard, and cordlike.
The local reaction was severe in one subject. There were no other systemic
reactions reported during the infusion. The adverse events resolved in the
subjects over 3-20 days. The precise cause of this local intolerance is not
understood.

Peripheral phlebitis was also seen in this study. When placebo or vehicle (the
infusion solution without Posaconazole) was given, 1 subject (out of 12)
developed thrombophlebitis. When placebo or 100 mg Posaconazole was given daily
for several days, 3 subjects (out of 6 dosed) developed thrombophlebitis. Due
to the number of thrombophlebitis events, it was decided to stop the multiple
dose part of this study. Apparently giving multiple infusions into a vein
increases the chance of developing a local reaction. In the single dose groups
through 100 mg no thrombophlebitis was seen. In subjects receiving placebo or
200 mg Posaconazole as a single dose, one subject (out of 12) showed signs of
thrombophlebitis several hours after the completion of the infusion. The
subject*s condition resolved in 5 days after the date of infusion. The single
dose part of this study will be continued to investigate if a single dose can
be given safely in a peripheral vein at a dose level (250 to 300 mg) which is
needed for the treatment of patients with fungal infections