DIAZEPAM Rectal solution Ref.[6780] Active ingredients: Diazepam

Source: Medicines & Healthcare Products Regulatory Agency (GB)  Revision Year: 2017  Publisher: Wockhardt UK Ltd, Ash Road North, Wrexham, LL13 9UF, UK

Pharmacodynamic properties

Pharmacotherapeutic group: Diazepam
ATC code: N05BA01

Diazepam has anticonvulsant, sedative and muscle relaxant properties.

Diazepam binds to specific receptors in the central nervous system and particular peripheral organs. The benzodiazepine receptors in the CNS have a close functional connection with receptors of the GABA-ergic transmitter system. After binding to the benzodiazepine receptor, diazepam augments the inhibitory effect of GABA-ergic transmission.

Pharmacokinetic properties

After rectal administration of the solution, diazepam is absorbed rapidly and almost completely from the rectum.

The onset of the therapeutic effect occurs within a few minutes of rectal administration. The rapidity of the rise in the serum level following rectal administration corresponds approximately to that following an intravenous dose but peak plasma concentrations are lower after rectal tubes than after intravenous administration. In adults maximal plasma concentrations following the administration of 10 mg diazepam in rectal solution are reached after about 10-30 minutes (ca. 150-400 ng/ml).

Diazepam is extensively protein bound (95-99%). The volume of distribution is between 0.95 and 2 l/kg depending on age. Diazepam is lipophilic and rapidly enters the cerebrospinal fluid. 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. The time to reach steady state plasma levels is therefore 4-10 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.

Preclinical safety data

Chronic toxicity studies in animals 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.

© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.