DIAZEPAM Solution for injection Ref.[6779] Active ingredients: Diazepam

Diazepam is highly lipid soluble and crosses the blood brain barrier. These properties qualify it for intravenous use in short term anaesthetic procedures since it acts promptly on the brain, and its initial effects decrease rapidly as it is distributed into fat deposits and tissues. Following the administration of an adequate intravenous dose of diazepam, effective plasma concentrations are usually reached within 5 minutes (ca. 150-400 ng/ml).

Absorption is erratic following intramuscular administration and lower peak plasma concentrations may be obtained than those following oral administration.

Diazepam is extensively protein bound (95-99%). The volume of distribution is between 0.95 and 2 l/kg depending on age. Diazepam and its main metabolite, N-desmethyldiazepam, cross the placenta and are secreted in breast milk.

Diazepam is metabolised predominantly in the liver. Its metabolites, N-desmethyldiazepam (nordiazepam), temazepam and oxazepam, which appear in the urine as glucuronides, are also pharmacologically active substances. Only 20% of the metabolites are detected in the urine in the first 72 hours.

Diazepam has a biphasic half life with an initial rapid distribution phase followed by a prolonged terminal elimination phase of 1-2 days. For the active metabolites N-desmethyldiazepam, temazepam and oxazepam, the half lives are 30-100 hours, 10-20 hours and 5-15 hours, respectively.

Excretion is mainly renal and also partly biliary. It is dependent on age as well as hepatic and renal function.

Metabolism and elimination in the neonate are markedly slower than in children and adults. In the elderly, elimination is prolonged by a factor of 2 to 4. In patients with impaired renal function, elimination is also prolonged. In patients with hepatic disorders (liver cirrhosis, hepatitis), elimination is prolonged by a factor of 2.

Chronic toxicity studies have demonstrated no evidence of drug induced changes. There are no long term animal studies to investigate the carcinogenic potential of diazepam. Several investigations pointed to a weakly mutagenic potential at doses far above the human therapeutic dose.

Local tolerability has been studied following single and repeat dose applications into the conjunctival sac of rabbits and the rectum of dogs. Only minimal irritation was observed. There were no systemic changes.

In humans it would appear that the risk of congenital abnormalities from the ingestion of therapeutic doses of benzodiazepines is slight, although a few epidemiological studies have pointed to an increased risk of cleft palate. There are case reports of congenital abnormalities and mental retardation in prenatally exposed children following overdosage and intoxication with benzodiazepines.