REMEDIUM Tablet Ref.[51162] Active ingredients: Diazepam

Absorption

After a single oral dose, diazepam is rapidly and almost completely (>90%) absorbed from the gastrointestinal tract, reaching peak plasma concentrations within 30-90 minutes after dosing.

It takes approximately 5 days for diazepam to reach steady state and roughly twice as long for desmethyldiazepam. Mean steady-state diazepam levels after daily dosing are approximately twice as high as peak levels after the first dose.

Distribution

Diazepam and its metabolites are widely distributed in tissues, despite their high binding to plasma proteins (98-99%), mainly albumin and, to a lesser extent, to α1-acid glycoprotein. Diazepam and its metabolites cross the blood-brain barrier. The mean volume of distribution at steady-state ranges from 0.88 to 1.1 L/kg based on plasma concentration measurements. Both the binding to both proteins and the volume of distribution of desmethyldiazepam are similar to those of diazepam.

The extent of cerebrospinal fluid (CSF) transfer of diazepam is limited by plasma protein binding. Unlike diazepam, after repeated doses, desmethyldiazepam can accumulate in the CSF to a significant extent. Diazepam is very rapidly taken up in the brain where it also very rapidly reaches steady state, with steady state concentrations in the brain exceeding those in plasma. The overall receptor occupancy profile was consistent with the action profile of the sum of brain concentrations of diazepam and its metabolites.

Metabolism or biotransformation

Diazepam is metabolised in the liver to pharmacologically active metabolites, mainly desmethyldiazepam, which accounts for 50-60% of the total clearance of diazepam; in addition 3-hydroxylation which accounts for 27% of total diazepam clearance, gives rise to the hydroxylated metabolites temazepam and oxazepam. Oxazepam and temazepam subsequently undergo glucuronide conjugation.

After multiple doses of diazepam, the plasma concentration ratio of desmethyldiazepam/diazepam was 1.1 ± 0.2, that of temazepam/diazepam 0.11 ± 0.05 and that of oxazepam/diazepam 0.09 ± 0.03.

The metabolism of diazepam is mediated by cytochrome P450; metabolism to desmethyldiazepam is mediated mainly by isoenzymes CYP2C19 and CYP3A, and metabolism to temazepam and oxazepam by CYP3A.

Because CYP2C19 is polymorphic, a distinction is made between extensive and poor metabolisers of diazepam. Poor metabolisers showed a significantly lower clearance (12 vs 26 mL/min) and longer elimination half-life (88 vs. 41 hrs) of diazepam than extensive metabolisers after a single oral dose. In addition, poor metabolisers had a lower clearance, higher AUC and longer elimination half-life for desmethyldiazepam.

There appear to be differences in this polymorphism between different ethnicities.

Elimination

The decline in the plasma concentration time profile of diazepam after oral administration is biphasic, with an initial rapid and extensive distribution phase followed by a prolonged terminal elimination phase. The elimination half-life is in the range of 24-48 hours for diazepam and 40-

100 hours for the active metabolite desmethyldiazepam. The clearance of diazepam is 20-40 mL/min.

Diazepam is almost completely metabolised, with only negligible amounts excreted unchanged in the urine. The main metabolite in urine is oxazepam-glucuronide.

Pharmacokinetics in special situations

Elderly patients

As plasma protein levels decrease with age, the free fraction of diazepam is higher than in younger patients. In older age, the metabolism slows and free drug clearance is reduced. This results in a 2-4 fold increase in the elimination half-life (more noticeable in males than in females). Therefore, the degree of accumulation of free diazepam after multiple dosing is greater in the elderly than in younger adults (see section 4.2).

Hepatic impairment

In patients with hepatic impairment, the bioavailability of diazepam and desmethyldiazepam, its major metabolite, is altered. These changes are mainly due to altered hepatic metabolism; along with changes in plasma protein binding.

In acute viral hepatitis, the half-life of diazepam is increased approximately 2-fold, but slowly returns to normal on recovery. In patients with alcoholic cirrhosis, a more marked increase (2-5-fold) in the elimination half-life is observed. The reduced clearance of diazepam and desmethyldiazepam causes them to accumulate with long-term use, which is associated with increased pharmacological effects (see section 4.2).

Renal impairment

In chronic kidney disease, the elimination of diazepam, as indicated by clearance of unbound drug, was similar to that in healthy volunteers; therefore, average steady-state concentrations of unbound diazepam at any daily dose should not differ between patients with renal insufficiency and healthy individuals. Due to changes in the plasma protein binding and tissue distribution of diazepam, in CKD its elimination half-life was shortened from (mean ± SD) 92 ± 23 hours in controls to 37 ± 7 hours in subjects with renal insufficiency.

Pregnancy and breast-feeding

Diazepam and desmethyldiazepam readily cross the placental barrier. N-demethylation of diazepam also occurs in the fetus. Long-term treatment leads to accumulation of both compounds in the fetus with high levels in fetal heart, lung and brain tissue.

Plasma protein binding of diazepam is decreased during pregnancy, particularly during the third trimester, in part due to decreased levels of serum albumin. As a result, pharmacological effects after a single dose may be increased (see section 4.6).

Term and preterm neonates metabolise diazepam more slowly than older infants (>5 months old) and adults, leading to prolongation of its half-life (much more pronounced in preterm infants).

Diazepam and its metabolites are excreted in human milk. Levels of diazepam in breast milk are only 10% of those in maternal blood. Normalised for body weight, approximately 5% of the maternal dose is transferred to the nursing infant. After multiple daily doses of more than 10 mg, the amounts transferred may be large enough for effects to show in the infant (see section 4.6).

Carcinogenicity

The carcinogenic potential of oral diazepam has been studied in several rodent species. An increased incidence of liver tumours was found in male mice given diazepam in the diet. No significant increase in the of tumours was observed in female mice, rats, hamsters, or gerbils.

Mutagenicity studies have yielded contradictory results. Other studies have shown no carcinogenic effect.

Genotoxicity

Various studies have shown little evidence of a mutagenic potential of diazepam even at concentrations considered much higher than those reached with the human dosage.

Effect on fertility

Fertility studies conducted in rats given diazepam orally at doses of 100 mg/kg/day before and during mating and during pregnancy and lactation showed a decrease in the number of pregnancies and in the number of live offspring.

Reproductive toxicity

Studies conducted in rats and rabbits given 80-300 mg/kg/day and 20-50 mg/kg/day, respectively, revealed no teratogenic effects in the offspring (see section 4.6). In contrast, diazepam is teratogenic in mice at doses of 45-50 mg/kg, 100 mg/kg and 140 mg/kg/day, as well as in hamsters at 280 mg/kg.