VOXRA Extended-release tablet Ref.[115265] Active ingredients: Bupropion

Absorption

Following oral administration of bupropion tablets to healthy volunteers, time to peak plasma concentrations for bupropion was approximately 5 hours.

The absorption of bupropion is not significantly affected when taken with food.

Bupropion and its metabolites exhibit linear kinetics following chronic administration of 150 to 300 mg per day.

Distribution

Bupropion is widely distributed with an apparent volume of distribution of approximately 2000 l. Bupropion and hydroxybupropion are moderately bound to plasma proteins (84% and 77%, respectively). The extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion.

Metabolism

Bupropion is extensively metabolised in humans. Three pharmacologically active metabolites have been identified in plasma: hydroxybupropion and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion. These have clinical importance, as their plasma concentrations are as high as or higher than those of bupropion.

Peak plasma concentrations of hydroxybupropion occur approximately 7 hours following administration of VOXRA XL.

Erythrohydrobupropion cannot be measured in the plasma after a single dose of bupropion. The active metabolites are further metabolised to inactive metabolites and excreted in the urine.

In vitro studies indicate that bupropion is metabolised to its major active metabolite hydroxybupropion primarily by CYP2B6, while cytochrome P450s are not involved in the formation of threohydrobupropion (see section 4.5).

Bupropion and hydroxybupropion are both relatively weak competitive inhibitors of the CYP2D6 isoenzyme with Ki values of 21 and 13,3 μM, respectively. In human volunteers known to be extensive metabolisers of the CYP2D6 isoenzyme, co-administration of bupropion and desipramine has resulted in 2- and 5-fold increases in the C_max and AUC, respectively, of desipramine. This effect was present for at least 7 days after the last dose of bupropion. Since bupropion is not metabolised by the CYP2D6 pathway, desipramine is not anticipated to affect the pharmacokinetics of bupropion. Caution is advised when bupropion is administered with substrates for the CYP2D6 pathway (see section 4.5.). In humans, there is no evidence of enzyme induction of bupropion or hydroxybupropion in volunteers or patients receiving recommended doses of bupropion for 10 to 45 days.

Elimination

Following oral administration of 200 mg of ¹⁴C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and faeces, respectively. The fraction of the dose of bupropion excreted unchanged was only 0,5%, a finding consistent with the extensive metabolism of bupropion. Less than 10% of this ¹⁴C dose was accounted for in the urine as active metabolites.

The mean apparent clearance following oral administration of bupropion is approximately 200 l/hr and the mean elimination half-life of bupropion is approximately 20 hours.

The elimination half-life of hydroxybupropion is approximately 20 hours and its area under the plasma drug concentration versus time curve (AUC) at steady state is approximately 17 times that of bupropion. The elimination half-lives for threohydrobupropion and erythrohydrobupropion are longer (37 and 33 hours, respectively) and steady-state AUC values are 8 and 1,6 times higher than that of bupropion, respectively. Steady state for bupropion and its metabolites is reached within 8 days.

Special patient populations

Elderly

Pharmacokinetic studies in the elderly have shown variable results. A single dose study showed that the pharmacokinetics of bupropion and its metabolites in the elderly do not differ from those in the younger adults. Another pharmacokinetic study, single and multiple doses, has suggested that accumulation of bupropion and its metabolites may occur to a greater extent in the elderly. Clinical experience has not identified differences in tolerability between elderly and younger patients, but greater sensitivity in older patients cannot be ruled out.

Patients with renal impairment

The elimination of bupropion and its major metabolites may be reduced by impaired renal function (see section 4.4).

Patients with hepatic impairment

The pharmacokinetics of bupropion and its active metabolites were not statistically significantly different in patients with mild cirrhosis (Child- Pugh grade A, range 5-6) when compared to healthy volunteers, although more variability was observed between individual patients. For patients with moderate to severe hepatic cirrhosis (Child Pugh grades B & C, range 7-13), a single dose of bupropion produced a C_max and AUC that were substantially increased (mean difference approximately 70% and 3-fold, respectively) and more variable when compared to the values in healthy volunteers; the mean half-life was also longer (by approximately 40%). For the metabolites, the mean C_max was lower (by approximately 30 to 70%), the mean AUC tended to be higher (by approximately 30 to 50%), the median T_max was later (by approximately 20 hrs), and the mean half-lives were longer (by approximately 2 to 4-fold) than in healthy volunteers (see section 4.3).