Mechanism of Action

Although the precise mechanism by which diazepam exerts its antiseizure effects is unknown, animal and in vitro studies suggest that diazepam acts to suppress seizures through an interaction with g-aminobutyric acid (GABA) receptors of the A-type (GABA_A). GABA, the major inhibitory neurotransmitter in the central nervous system, acts at this receptor to open the membrane channel allowing chloride ions to flow into neurons. Entry of chloride ions causes an inhibitory potential that reduces the ability of neurons to depolarize to the threshold potential necessary to produce action potentials. Excessive depolarization of neurons is implicated in the generation and spread of seizures. It is believed that diazepam enhances the actions of GABA by causing GABA to bind more tightly to the GABA_A receptor.

Pharmacokinetic information of diazepam following rectal administration was obtained from studies conducted in healthy adult subjects. No pharmacokinetic studies were conducted in pediatric patients. Therefore, information from the literature is used to define pharmacokinetic labeling in the pediatric population.

Diazepam rectal gel is well absorbed following rectal administration, reaching peak plasma concentrations in 1.5 hours. The absolute bioavailability of Diazepam rectal gel relative to Valium^γ' injectable is 90%. The volume of distribution of Diazepam rectal gel is calculated to be approximately 1 L/kg. The mean elimination half-life of diazepam and desmethyldiazepam following administration of a 15 mg dose of Diazepam rectal gel was found to be about 46 hours (CV=43%) and 71 hours (CV=37%), respectively.

Both diazepam and its major active metabolite desmethyldiazepam bind extensively to plasma proteins (95-98%).

FIGURE 1: Plasma Concentrations of Diazepam and Desmethyldiazepam Following Diastat or IV Diazepam

Metabolism and Elimination: It has been reported in the literature that diazepam is extensively metabolized to one major active metabolite (desmethyldiazepam) and two minor active metabolites, 3-hydroxydiazepam (temazepam) and 3-hydroxy-N-diazepam (oxazepam) in plasma. At therapeutic doses, desmethyldiazepam is found in plasma at concentrations equivalent to those of diazepam while oxazepam and temazepam are not usually detectable. The metabolism of diazepam is primarily hepatic and involves demethylation (involving primarily CYP2C19 and CYP3A4) and 3-hydroxylation (involving primarily CYP3A4), followed by glucuronidation. The marked inter-individual variability in the clearance of diazepam reported in the literature is probably attributable to variability of CYP2C19 (which is known to exhibit genetic polymorphism; about 3-5% of Caucasians have little or no activity and are "poor metabolizers") and CYP3A4. No inhibition was demonstrated in the presence of inhibitors selective for CYP2A6, CYP2C9, CYP2D6, CYP2E1, or CYP1A2, indicating that these enzymes are not significantly involved in metabolism of diazepam.

Hepatic Impairment: No pharmacokinetic studies were conducted with diazepam rectal gel in hepatically impaired subjects. Literature review indicates that following administration of 0.1 to 0.15 mg/kg of diazepam intravenously, the half-life of diazepam was prolonged by two- to five-fold in subjects with alcoholic cirrhosis (n=24) compared to age-matched control subjects (n=37) with a corresponding decrease in clearance by half; however, the exact degree of hepatic impairment in these subjects was not characterized in this literature (see PRECAUTIONS section).

Renal Impairment: The pharmacokinetics of diazepam have not been studied in renally impaired subjects (see PRECAUTIONS section).

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