VENLOR XR Capsule Ref.[50467] Active ingredients: Venlafaxine

Absorption

At least 92% of a single oral dose of venlafaxine is absorbed. The absolute bioavailability of venlafaxine is about 45%. Administration of venlafaxine extended-release (150 mg q24 hours) generally resulted in a lower C_max (150 ng/mL for venlafaxine and 260 ng/mL for ODV) and delayed T_max (5.5 hours for venlafaxine and 9 hours for ODV) than for venlafaxine immediate-release. When equal daily doses of venlafaxine were administered as either the immediate-release tablet or the modified/extended-release capsule, the exposure (area under the concentration curve [AUC]) to both venlafaxine and ODV was similar for the two treatments, and the fluctuation in plasma concentrations was slightly lower following treatment with the modified/extended-release capsules. Therefore, the modified/extended-release capsule provides a slower rate of absorption, but the same extent of absorption (i.e. AUC), as the immediate-release tablet. The rate of absorption of venlafaxine from the extended-release formulation capsule is slower than its rate of elimination.

Steady-state concentrations of venlafaxine and ODV in plasma are attained within 3 days of oral multiple-dose therapy. Venlafaxine and ODV exhibited linear kinetics over the dose range of 75 to 450 mg/day. Mean ± S.D. steady-state plasma clearance of venlafaxine and ODV is 1.3 ± 0.6 and 0.4 ± 0.2 L/h/kg, respectively.

Food did not affect the bioavailability of venlafaxine or its active metabolite, ODV. Time of administration (a.m. versus p.m.) did not affect the pharmacokinetics of venlafaxine and ODV from the 75 mg venlafaxine extended-release capsule.

Distribution

Apparent (steady state) volume of distribution of venlafaxine and ODV is 7.5 ± 3.7 and 5.7 ± 1.8 L/kg, respectively. Venlafaxine and ODV are minimally bound at therapeutic concentrations to plasma proteins (27% and 30%, respectively).

Metabolism

Following absorption, venlafaxine undergoes extensive pre-systemic metabolism in the liver, primarily to ODV. In vitro studies indicate that the formation of ODV is catalysed by cytochrome (CY) P2D6; this has been confirmed in a clinical study showing that patients with low CYP2D6 levels (“poor metabolizers”) had increased levels of venlafaxine and reduced levels of ODV compared to people with normal CYP2D6 (“extensive metabolizers”). The differences between the CYP2D6 poor and extensive metabolizers, however, are not expected to be clinically important because the sum of venlafaxine and ODV is similar in the two groups and venlafaxine and ODV are pharmacologically approximately equi-active and equipotent. Venlafaxine is also metabolized to Ndesmethylvenlafaxine, which is catalysed by CYP3A3/4, and to other minor metabolites.

Elimination

Approximately 87% of a venlafaxine dose is recovered in the urine within 48 hours as unchanged venlafaxine (5%), unconjugated ODV (29%), conjugated ODV (26%), or other minor inactive metabolites (27%). Renal elimination of venlafaxine and its metabolites is, thus, the primary route of excretion. The rate of absorption of venlafaxine from the extended-release formulation capsule is slower than its rate of elimination. Therefore, the apparent elimination half-life of venlafaxine is 5±2 hours.

Special Populations

Age and Gender

A population pharmacokinetic analysis of venlafaxine-treated patients showed that dose-normalized trough plasma levels of either venlafaxine or ODV were unaltered by age or gender differences. Dosage adjustment based on the age or gender of a patient is generally not necessary. As with any therapy, caution should be exercised in treating the elderly (e.g. due to the possibility of renal impairment; see also dosage recommendations for renal impairment). The lowest effective dose should always be used and patients should be carefully monitored when an increase in the dose is required.

Extensive/Poor Metabolizers

Plasma concentrations of venlafaxine were higher in CYP2D6 poor metabolizers than extensive metabolizers. Because the total exposure (AUC) of venlafaxine and ODV was similar in poor and extensive metabolizer groups, however, there is no need for different venlafaxine dosing regimens for these two groups.

Renal Impairment

The half-lives of venlafaxine and its active metabolite, ODV, are increased in patients with renal impairment. In a pharmacokinetic study, the venlafaxine elimination half-life after oral administration was prolonged by about 50% and the clearance was reduced by about 24% in renally impaired patients glomerular filtration rate [GFR] = 10 to 70 mL/min). In dialysis patients, the venlafaxine elimination half-life was prolonged by about 180% and the clearance was reduced by about 57%, compared to normal subjects. Similarly, the ODV elimination half-life was prolonged by about 40% although the clearance was unchanged in patients with renal impairment (GFR = 10 to 70 mL/min), compared to normal subjects. In dialysis patients, the ODV elimination half-life was prolonged by about 142% and the clearance was reduced by about 56%, compared to normal subjects. A large degree of intersubject variability was noted. Dosage adjustment is necessary in these patients.

Liver Disease

In patients with hepatic cirrhosis, the pharmacokinetic disposition of both venlafaxine and ODV was significantly altered after oral administration of venlafaxine. The venlafaxine elimination half-life was prolonged by about 30% and the clearance decreased by about 50% in cirrhotic subjects, compared to normal subjects. The ODV elimination half-life was prolonged by about 60% and the clearance decreased by about 30% in cirrhotic subjects, compared to normal subjects. A large degree of intersubject variability was noted. compared to normal subjects, 3 patients with severe cirrhosis had a more substantial decrease in venlafaxine clearance (about 90%).

Venlafaxine oral bioavailability was increased 2- to 3-fold; the oral elimination half-life was approximately twice as long and the oral clearance was reduced by more than half in patients with mild-to-moderate hepatic impairment compared to normal subjects. In hepatically impaired subjects, the ODV oral elimination half-life was prolonged by about 40% while the oral clearance for ODV was similar to that for normal subjects. A large degree of intersubjective variability was noted.