TAPCLOB Oral suspension Ref.[50136] Active ingredients: Clobazam

Absorption

Absorption of clobazam is virtually complete after oral administration.

Approximately 85% is protein bound in man. It is metabolised by demethylation and hydroxylation. It is excreted unchanged and as metabolites in the urine (87%) and faeces.

The peak plasma level of clobazam after oral administration of Tapcloboral suspension 2 mg/ml was higher than that observed after administration of a reference 10 mg tablet in a single dose, randomised, crossover bioequivalence study (mean C_max 267.5 ± 64.5 ng/ml and 220.4 ± 49.9 ng/ml, respectively).

Concomitant intake of alcohol can increase the bioavailability of clobazam by 50%.

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 N-desmethylclobazam (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 metabolized 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, primarily mediated by CYP2C19.

CYP2C19 poor metabolizers exhibit a 5-fold higher plasma concentration of N-CLB compared to extensive metabolizers.

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.

Concomitant administration of 400 mg ketoconazole (CYP3A4 inhibitor) increased Clobazam AUC by 54% with no effect on C_max.

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.

Teratogenicity

Oral administration of clobazam to pregnant rats and rabbits throughout the period of organogenesis resulted in increased embryofetal mortality and increased incidences of fetal skeletal variations. In rabbits clobazam also decreased fetal body weights and increased the incidence of fetal malformations (visceral and skeletal). Additionally, oral administration of clobazam to rats throughout pregnancy and lactation resulted in decreased pup survival and alterations in offspring behaviour (locomotor activity). The observed embryo-fetal effects were associated with plasma exposures for clobazam and its major active metabolite N-desmethylclobazam less than those in humans at the maximum recommended dose.

Impairment of fertility

A study in rats in which clobazam was orally administered to male and female rats prior to and during mating and continuing in females to gestation day 6 had no effect on fertility and early embryonic development. The study was limited as the highest dose was associated with plasma exposures for clobazam and N-desmethylclobazam less than those in humans at the maximum recommended dose.