Description
Diazepam
diazepam 15 mg dose is available for oral administration as tablets containing 2 mg, 5 mg or 10 mg diazepam. In addition to the active ingredient diazepam, each tablet contains the following inactive ingredients: anhydrous lactose, magnesium stearate and microcrystalline cellulose.
Diazepam Tablets USP 5 mg also contain D&C Yellow No. 10.
Diazepam Tablets USP 10 mg also contain FD&C Blue No. 1.
CLINICAL PHARMACOLOGY
Diazepam is a benzodiazepine that exerts anxiolytic, sedative, muscle-relaxant, anticonvulsant and amnestic effects.
Pharmacokinetics
Absorption
After oral administration >90% of diazepam 15 mg dose is absorbed and the average time to achieve peak plasma concentrations is 1 – 1.5 hours with a range of 0.25 to 2.5 hours. Absorption is delayed and decreased when administered with a moderate fat meal. In the presence of food mean lag times are approximately 45 minutes as compared with 15 minutes when fasting. There is also an increase in the average time to achieve peak concentrations to about 2.5 hours in the presence of food as compared with 1.25 hours when fasting. This results in an average decrease in Cmax of 20% in addition to a 27% decrease in AUC (range 15% to 50%) when administered with food.
Distribution
Diazepam and its metabolites are highly bind to plasma proteins (diazepam 98%). Diazepam and its metabolites cross the blood-brain and placental barriers and are also in breast milk in concentrations approximately one tenth of those in maternal plasma (days 3 to 9 post-partum). In young healthy males, the volume of distribution at steady-state is 0.8 to 1.0 L/kg. The decline in the plasma concentration-time profile after oral administration is biphasic. The initial distribution phase has a half-life of approximately 1 hour, although it may range up to >3 hours.
Elimination
The initial distribution phase is followed by a prolonged terminal elimination phase (half-life up to 48 hours). The terminal elimination half-life of the active metabolite N-desmethyldiazepam is up to 100 hours. Diazepam and its metabolites are excreted mainly in the urine, predominantly as their glucuronide conjugates. The clearance of diazepam is 20 to 30 mL/min in young adults.
Pharmacokinetics in Special Populations
Children
In children 3 – 8 years old the mean half-life of diazepam is 18 hours.
Newborns
In full term infants, elimination half-lives around 30 hours, with a longer average half-life of 54 hours in premature infants of 28 – 34 weeks gestational age and 8 – 81 days post-partum. In both premature and full term infants the active metabolite desmethyldiazepam shows evidence of continued accumulation compared to children. Longer half-lives in infants may be due to incomplete maturation of metabolic pathways.
Geriatric
Elimination half-life increases by approximately 1 hour for each year of age beginning with a half-life of 20 hours at 20 years of age. This appears to be due to an increase in volume of distribution with age and a decrease in clearance. Consequently, the elderly may have lower peak concentrations, and on multiple dosing higher trough concentrations. It will also take longer to reach steady-state. Reported changes in free drug may be due to significant decreases in plasma proteins due to causes other than simply aging.
Hepatic Insufficiency
In mild and moderate cirrhosis, average half-life increases. Reports for the average increase is from 2-fold to 5-fold, with individual half-lives over 500 hours reported. There is also an increase in volume of distribution, and average clearance decreases by almost half. Mean half-life is also an extension of the hepatic fibrosis to 90 hours (range 66 – 104 hours), with chronic active hepatitis to 60 hours (range 26 – 76 hours), and with acute viral hepatitis to 74 hours (range 49 – 129). In chronic active hepatitis, there is a decrease in clearance by almost half.
Reviews
There are no reviews yet.