URBANOL Capsule / Tablet Ref.[50584] Active ingredients: Clobazam

Absorption

After oral administration, clobazam is well-absorbed. Relative bioavailability of clobazam capsules, tablets or solution (in propylene glycol) was not significantly different.

Time to peak plasma concentration (T_max) is achieved from 0,5–4 hours. The administration of URBANOL tablets with food slows the rate of absorption by approximately 1 hour but does not affect the overall extent of absorption.

Concomitant intake of alcohol can increase the bioavailability of clobazam by 50% (see section 4.5).

Distribution

After a single dose of 20 mg clobazam, marked interindividual variability in maximum plasma concentrations (222 to 709 ng/mL) was observed after 0,25 to 4 hours. Clobazam is lipophilic and distributes rapidly throughout the body. Based on a population pharmacokinetic analysis, the apparent volume of distribution at steady state was approximately 102 L and is concentration independent over the therapeutic range. Approximately 80–90% of clobazam is bound to plasma protein.

Clobazam accumulates approximately 2 – 3-fold to steady-state while the active metabolite Ndesmethylclobazam (N-CLB) accumulates approximately 20-fold following clobazam twice-daily administration. Steady-state concentrations are reached within approximately 2 weeks.

Metabolism

Clobazam is rapidly and extensively metabolised in the liver. Clobazam metabolism occurs primarily by hepatic demethylation to N-desmethylclobazam (N-CLB), mediated by CYP3A4 and to a lesser extent by CYP2C19. N-CLB is an active metabolite and the main circulating metabolite found in human plasma.

N-CLB undergoes further biotransformation in the liver to form 4-hydroxy-N-desmethylclobazam, primary mediated by CYP2C19.

CYP2C19 poor metabolisers exhibit a 5-fold higher plasma concentration of N-CLB compared to extensive metabolisers. Clobazam is a weak CYP2D6 inhibitor. Co-administration with dextromethorphan led to increases of 90% in AUC and 59% in C_max values for dextromethorphan.

Elimination

Based on a population pharmacokinetic analysis, plasma elimination half-lives of clobazam and N-CLB were estimated to be 36 hours and 79 hours, respectively.

Clobazam is cleared mainly by hepatic metabolism with subsequent renal elimination. In a mass balance study, approximately 80% of the administered dose was recovered in urine and about 11% in the faeces.

Less than 1% of unchanged clobazam and less than 10% of unchanged N-CLB are excreted through the kidneys.

Special populations

Clobazam crosses the placental barrier and appears in breast milk. Both in the fetal blood and in breast milk, effective concentrations may be reached.

Elderly patients

In the elderly, there is a tendency to a reduction in clearance following oral administration; terminal half-life is prolonged, and the distribution volume increased. This may lead to a more extensive accumulation of the medicine, when administered on a multiple-dose basis than in younger subjects. The effect of age on the clearance and accumulation profile of clobazam seems also to apply to the active metabolite.

Hepatic impairment

In patients with severe liver disease, the distribution volume of clobazam is increased and the terminal half-life is prolonged.