KRATIUM Solution for injection/infusion Ref.[27829] Active ingredients: Diazepam

Distribution

Following IV administration of diazepam, plasma levels decrease in 2 phases: a fast distribution phase (30 to 60 minutes) where concentrations reach values equal to those obtained after oral administration, then a slower elimination phase. By IM route, bioavailability is poor (partial and delayed adsorption).

The volume of distribution is between 1 to 2l/kg. The total plasma clearance of diazepam, calculated after intravenous administration is 30 ml/min. It tends to decrease after multiple administrations. Diazepam is intensively protein bound 95 to 98% on average.

The plasma elimination half-life of diazepam is between 32 and 47 hours.

The equilibrium of plasma concentrations is reached in one week at least.

Νο concentration-effect relation could be established for this class of products due to their metabolism intensity and the development of tolerance.
Benzodiazepines cross the hematoencephalic barrier and the placenta and are secreted in breastmilk.

For diazepam the plasma ratio is 2.

Biotransformation and Elimination

The liver plays a major role in the metabolism of benzodiazepines, and this explains the negligible percentage (<0,1 %) of unchanged product found in the urine.

The main metabolite of diazepam is desmethyldiazepam, which is also active; its half-life is longer than that of the mother molecule (between 30 and 150 hours). Hydroxylation of this molecule gives another active metabolite, oxazepam. Inactivation by glucure-conjugation provides hydrosoluble substances which are eliminated by the urinary route.

Special risk populations

• Elderly patients: The hepatic metabolism and total clearance decrease, thereby increasing equilibrium concentrations, free fractions and half-lives. Doses should therefore be reduced.
• Patients with kidney failure: An increase in the free fraction is observed (and thus of the distribution volume) as well as in half-life.
• Pregnant women: The distribution and half-life volume of diazepam are increased.

Not applicable.