Extended-Release Venlafaxine: Is More Better?

Sarah T. Melton, PharmD

Disclosures

July 13, 2010

Question

Is there any benefit to using venlafaxine extended-release, 75 mg twice daily, vs venlafaxine extended-release, 150 mg once daily? Would the drug level, once at steady state, be higher given the daily dosing or about the same?

Response from Sarah T. Melton, PharmD
Director of Addiction Outreach, Associate Professor, Appalachian College of Pharmacy, Oakwood, Virginia; Clinical Pharmacist, C-Health, PC, Lebanon, Virginia

Venlafaxine HCl extended-release is a serotonin-norepinephrine reuptake inhibitor available in capsule and tablet formulations. The capsule is marketed under the brand name Effexor XR® and is approved for the treatment of major depressive disorder, panic disorder, generalized anxiety disorder, and social anxiety disorder.[1] This formulation is indicated to be taken once daily and is available in strengths of 37.5 mg, 75 mg, and 150 mg.

The tablet formulation (venlafaxine ER) is approved for major depressive disorder and social anxiety disorder.[2] The tablet formulation is available in the same strengths as the capsule formulation but is also available in the 225-mg strength.

Venlafaxine ER is not AB-rated to Effexor XR® by the US Food and Drug Administration, and venlafaxine ER tablets are not a therapeutic equivalent to Effexor XR®.[2] Pharmacists in most states cannot automatically substitute one for another and must contact a physician to make the switch.

A prescription for Effexor XR® 75-mg capsules dosed twice daily would cost about $279.98 for a 30-day supply, compared with a cost of $149.99 for a 30-day supply of Effexor XR® 150-mg capsules dosed once daily.[3]

Pharmacokinetics

Venlafaxine is metabolized to its active metabolite, O-desmethylvenlafaxine (ODV). After administration of extended-release capsules, the peak plasma concentrations of venlafaxine and ODV are attained within 5.5 and 9 hours, respectively.[1] The absorption rate of capsule venlafaxine is slower than its rate of elimination. Thus, the elimination half-life of venlafaxine after administration of the extended-release capsule (15 ± 6 hours) is the absorption half-life instead of the true disposition half-life (5 ± 2) hours observed after administration of an immediate-release tablet.

After administration of multiple doses, the steady-state concentrations of both venlafaxine and ODV in plasma are attained within 3 days of oral multiple-dose therapy. The clearance of venlafaxine is slightly lower (15%) after multiple doses than after a single dose. Venlafaxine and ODV exhibited linear kinetics in ranges of 75-450 mg/d.[1] Steady-state concentrations of venlafaxine would expected to be similar regardless of whether the extended-release dosage is given once or twice daily.

When equal daily doses of venlafaxine were administered as either an immediate-release tablet or the extended-release capsule, exposure to venlafaxine and ODV was similar for the 2 treatments, and the fluctuation in plasma concentrations was slightly lower with the extended-release capsule. Therefore, venlafaxine extended-release provides a slower rate of absorption but the same extent of absorption compared with the immediate-release.[1]

Food did not affect the bioavailability of venlafaxine or its active metabolite, ODV. Time of administration (morning vs evening) did not affect the pharmacokinetics of venlafaxine and ODV from the 75-mg extended-release capsule. No accumulation of venlafaxine has been observed during long-term administration in healthy persons.[1]

Consistent with the pharmacokinetic properties, the use of the extended-release formulation is associated with less nausea and dizziness at the initiation of therapy when compared with immediate-release venlafaxine.[4]

Plasma concentrations of venlafaxine were higher in poor metabolizers of cytochrome P450 2D6 than in extensive metabolizers. Because the total exposure (area under the curve) of venlafaxine and ODV was similar in poor and extensive metabolizer groups, different venlafaxine dosing regimens are not needed for these 2 groups.[1]

Review of Literature

It is recommended that Effexor XR® be administered in a single daily dose with food either in the morning or in the evening at about the same time each day. Effexor XR® was administered once daily in all of the clinical studies that established its safety and efficacy in major depressive disorder, generalized anxiety disorder, social anxiety disorder, and panic disorder.[1]

A comprehensive search of the medical literature on extended-release venlafaxine and twice-daily dosing, conducted on May 15, 2010, failed to identify any relevant references. To my knowledge, no studies have evaluated the safety, efficacy, or pharmacokinetic profiles of a twice-daily dosing regimen for extended-release venlafaxine.

Of note, a study that evaluated the administration of immediate-release venlafaxine once daily vs a twice-daily formulation produced similar improvement in depressive symptoms at 6 weeks.[5] The rates of adverse effects were similar between the groups, with transient nausea and headaches being most common. The authors concluded that the immediate-release formulation may be safe and effective in some patients when used once daily. Further, the antidepressant activity of venlafaxine may be more influenced by the pharmacodynamic half-life than by the pharmacokinetic half-life.[5]

There is no rationale for twice-daily off-label administration of venlafaxine extended-release with regard to available evidence in the literature or based on the pharmacokinetic and pharmacodynamic profile of the medication. To increase benefit to patients in terms of ease of use and increased rates of adherence, venlafaxine extended-release formulations should be prescribed and administered in one daily dose.

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