What is the elimination half‑life of venlafaxine extended‑release (Effexor ER) in typical adult patients without hepatic impairment?

Elimination Half-Life of Venlafaxine Extended-Release

The elimination half-life of venlafaxine extended-release (Effexor ER) is approximately 5 hours (±2 hours) for the parent compound and 11 hours (±2 hours) for its active metabolite O-desmethylvenlafaxine (ODV), allowing for once-daily dosing despite the relatively short half-life of the parent drug. 1

Pharmacokinetic Profile

Parent Compound (Venlafaxine)

• Venlafaxine itself has a short elimination half-life of 3-5 hours in typical adult patients without hepatic impairment 1, 2, 3
• Mean steady-state plasma clearance is 1.3 ± 0.6 L/h/kg 1
• Steady-state concentrations are achieved within 3 days of multiple-dose therapy 1

Active Metabolite (O-desmethylvenlafaxine)

• The active metabolite ODV has a longer elimination half-life of approximately 10-12 hours, which is clinically significant because ODV contributes substantially to the therapeutic effect 1, 2, 3
• Mean steady-state plasma clearance of ODV is 0.4 ± 0.2 L/h/kg 1
• The area under the curve for ODV is two to three times greater than that for venlafaxine, making the metabolite the predominant active moiety at steady state 4

Clinical Implications of the Half-Life

Dosing Frequency

• The extended-release formulation permits once-daily dosing despite venlafaxine's short half-life, due to the sustained-release mechanism and the longer half-life of the active metabolite 5, 1
• The immediate-release formulation requires twice- or thrice-daily dosing due to the short elimination half-life 5

Discontinuation Risk

• The relatively short half-life of venlafaxine ER increases the risk of discontinuation syndrome if doses are missed or the medication is abruptly stopped 5, 6
• A gradual taper over 10-14 days is recommended when discontinuing to minimize withdrawal symptoms 6
• Venlafaxine has been specifically associated with discontinuation symptoms compared to other antidepressants 5

Special Populations with Altered Half-Life

Renal Impairment

• In patients with renal impairment (GFR 10-70 mL/min), venlafaxine elimination half-life is prolonged by approximately 50% and clearance is reduced by about 24% 1
• In dialysis patients, venlafaxine half-life is prolonged by approximately 180% and clearance is reduced by about 57% 1, 7
• ODV elimination half-life is prolonged by about 40% in renal impairment and by 142% in dialysis patients 1, 7
• Dosage adjustment is necessary in patients with renal impairment 1

Hepatic Impairment

• In patients with hepatic cirrhosis, venlafaxine elimination half-life is prolonged by approximately 30% and clearance decreases by about 50% 1
• ODV elimination half-life is prolonged by about 60% in cirrhotic patients 1
• In Child-Pugh B patients (moderate impairment), oral elimination half-life is approximately twice as long as in normal subjects 1
• Dosage adjustment is necessary in hepatically impaired patients 1

Elderly Patients

• In elderly patients, the half-life extends to 11-13 hours due to age-related changes in drug metabolism and clearance 6
• However, dose-normalized trough plasma levels are generally unaltered by age alone in the absence of renal or hepatic impairment 1

Pharmacokinetic Considerations

• Venlafaxine is a high-clearance drug subject to extensive first-pass metabolism via CYP2D6 2, 3
• Both venlafaxine and ODV have low protein binding (27-30%), minimizing protein-binding drug interactions 1
• The extended-release formulation has lower maximum plasma concentrations (Cmax) and achieves these at a later time compared to immediate-release 8