Efexor XR Mechanism of Action

Pharmacology: Venlafaxine is a structurally novel antidepressant that is chemically unrelated to tricyclic, tetracyclic or other available antidepressant agents.
Mode of Action: The mechanism of venlafaxine's antidepressant action in humans is believed to be associated with its potentiation of neurotransmitter activity in the central nervous system. Preclinical studies have shown that venlafaxine and its major metabolite, ODV, are potent inhibitors of serotonin and norepinephrine reuptake. Venlafaxine also weakly inhibits dopamine reuptake. Studies in animals show that tricyclic antidepressants may reduce β-adrenergic receptor responsiveness following chronic administration. In contrast, venlafaxine and ODV reduce β-adrenergic responsiveness after both acute (single dose) and chronic administration. The latter results may predict a more rapid onset of activity for venlafaxine. Venlafaxine and ODV are very similar with respect to their overall action on neurotransmitter reuptake.
Venlafaxine and ODV have no significant affinity for muscarinic cholinergic, H₁-histaminergic, or α₁-adrenergic receptors in vitro. Pharmacologic activity at these receptors is potentially associated with various anticholinergic, sedative, and cardiovascular effects seen with other psychotropic drugs.
Venlafaxine does not possess monoamine oxidase (MAO) inhibitory activity.
Cardiac Electrophysiology: In a dedicated thorough QTc study in healthy subjects, venlafaxine did not prolong the QT interval to any clinically relevant extent at a dose of 450 mg/day (given as 225 mg twice a day).
Pharmacodynamics: Patients with Depression: The efficacy of Efexor XR (venlafaxine hydrochloride) extended-release capsules as a treatment for depression was established in two placebo-controlled, short-term, flexible-dose studies in adult outpatients meeting DSM-III-R or DSM-IV criteria for major depression or major depressive disorder.
A 12-week study utilizing Efexor XR doses in a range 75-150 mg/day (mean dose for completers was 136 mg/day) and an 8-week study utilizing Efexor XR doses in a range 75-225 mg/day (mean dose for completers was 177 mg/day) both demonstrated superiority of Efexor XR over placebo on the HAM-D total score, HAM-D Depressed Mood Item, the MADRS total score, the CGI Severity of Illness scale, and the CGI Global Improvement scale. In both studies, Efexor XR was also significantly better than placebo for certain factors of the HAM-D, including the anxiety/somatization factor, the cognitive disturbance factor, and the retardation factor, as well as the psychic anxiety score.
Depression Relapse/Recurrence: A study of depressed outpatients who had responded to Efexor XR during an initial 8-week open-label treatment phase and were randomly assigned to continuation on Efexor XR or placebo for 6 months demonstrated a significantly lower relapse rate for patients taking Efexor XR compared with those on placebo.
A study of depressed outpatients who had responded to Efexor (the immediate-release form of venlafaxine) during an initial 6-month open-label treatment phase and were randomly assigned to maintenance therapy on Efexor or placebo for 12 months demonstrated a significantly lower recurrence rate for patients taking Efexor compared with those on placebo.
Patients with Anxiety: The efficacy of Efexor XR capsules as a treatment for anxiety was established in four placebo-controlled studies. The studies were done in outpatients meeting DSM-IV criteria for generalized anxiety disorder, who were not depressed.
The short-term efficacy of Efexor XR was demonstrated in four studies. Two were 8-week studies, utilizing Efexor XR doses of 75, 150, and 225 mg/day and of 75 and 150 mg/day, and the others were the first 8-weeks of two long-term studies, utilizing Efexor XR doses of 75-225 mg/day and of 37.5, 75, and 150 mg/day. Each of the four studies demonstrated superiority of Efexor XR over placebo on at least five of the following efficacy scales: the HAM-A total score, the HAM-A psychic anxiety factor, the Hospital Anxiety and Depression anxiety subscale, and the CGI Severity of Illness scale, as well as the HAM-A anxious mood item and tension item.
Two of the four studies continued up to 6-months. These two studies, which utilized Efexor XR doses of 75-225 mg/day and of 37.5, 75, and 150 mg/day, demonstrated superiority of Efexor XR over placebo on the HAM-A total score, HAM-A psychic anxiety factor, the HAD anxiety factor, and the CGI Severity of Illness scale, as well as the HAM-A anxious mood item.
Social Anxiety Disorder (Social Phobia): The efficacy of Efexor XR capsules as a treatment for Social Anxiety Disorder (also known as Social Phobia) was established in four double-blind, parallel-group, 12-week, multicenter, placebo-controlled, flexible-dose studies and one double-blind, parallel-group, 6-month, placebo-controlled, fixed/flexible-dose study in adult outpatients meeting DSM-IV criteria for Social Anxiety Disorder. Patients received doses in a range of 75-225 mg/day. Efficacy was assessed with Liebowitz Social Anxiety Scale (LSAS). In these five trials, Efexor XR was significantly more effective than placebo on change from baseline to endpoint on the LSAS total score. There was no evidence for any greater effectiveness of the 150 to 225 mg/day group compared to the 75 mg/day group in the 6-month study.
Examination of subsets of the population studied did not reveal any differential responsiveness on the basis of gender. There was insufficient information to determine the effect of age or race on outcome in these studies.
Panic Disorder: The efficacy of Efexor XR in the treatment of panic disorder was established in two 12-week placebo-controlled trials in adult outpatients with panic disorder (DSM-IV). The efficacy of Efexor XR in maintaining a response in panic disorder for up to 6 months following 12 weeks of acute treatment was demonstrated in a placebo-controlled trial. Nevertheless, the physician who elects to use Efexor XR for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see Dosage & Administration).
Pharmacokinetics: Steady-state concentrations of venlafaxine and ODV 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 ± SD steady-state plasma clearance of venlafaxine and ODV is 1.3 ± 0.6 and 0.4 ± 0.2 L/h/kg, respectively; apparent elimination half-life is 5 ± 2 and 11 ± 2 hours, respectively; and apparent (steady-state) volume of distribution is 7.5 ± 3.7 and 5.7 ± 1.8 L/kg, respectively.
Absorption: On the basis of mass balance studies, at least 92% of a single oral dose of venlafaxine is absorbed, indicating that absorption of venlafaxine is nearly complete. However, the presystemic metabolism of venlafaxine (which primarily forms the active metabolite, ODV) reduces the absolute bioavailability of venlafaxine to 40% to 45%.
After administration of Efexor XR, the peak plasma concentrations of venlafaxine and ODV are attained within 6.0 ± 1.5 and 8.8 ± 2.2 hours, respectively. The rate of absorption of venlafaxine from the Efexor XR capsule is slower than its rate of elimination. Therefore, the apparent elimination half-life of venlafaxine following administration of Efexor XR (15 ± 6 hours) is actually the absorption half-life instead of the true disposition half-life (5 ± 2 hours) observed following administration of an immediate release tablet.
When equal daily doses of venlafaxine were administered as either an immediate release tablet or the extended-release capsule, the exposure (AUC, area under the concentration curve) to both venlafaxine and ODV was similar for the two treatments, and the fluctuation in plasma concentrations was slightly lower following treatment with the Efexor XR capsule. Therefore, the venlafaxine ER capsule provides a slower rate of absorption, but the same extent of absorption (i.e., AUC), as the venlafaxine immediate release tablet.
Distribution: The degree of binding of venlafaxine to human plasma proteins is 27% ± 2% at concentrations ranging from 2.5 to 2215 ng/mL, and the degree of ODV binding to human plasma proteins is 30% ± 12% at concentrations ranging from 100 to 500 ng/mL. Protein-binding-induced drug interactions with concomitantly administered venlafaxine are not expected. Following intravenous administration, the steady-state volume of distribution of venlafaxine is 4.4 ± 1.9 L/kg, indicating that venlafaxine distributes well beyond the total body water.
Metabolism: Following absorption, venlafaxine undergoes extensive presystemic metabolism in the liver. The primary metabolite of venlafaxine is ODV, but venlafaxine is also metabolized to N-desmethylvenlafaxine, N,O-didesmethylvenlafaxine, and other minor metabolites. In vitro studies indicate that the formation of ODV is catalyzed by CYP2D6 and that the formation of N-desmethylvenlafaxine is catalyzed by CYP3A3/4. The results of the in vitro studies have been confirmed in a clinical study with subjects who are CYP2D6 poor and extensive metabolizers. However, despite the metabolic differences between the CYP2D6 poor and extensive metabolizers, the total exposure to the sum of the two active species (venlafaxine and ODV) was similar in the two metabolizer groups. Therefore, CYP2D6 poor and extensive metabolizers can be treated with the same regimen of Efexor XR.
Excretion: Approximately 87% of a venlafaxine dose is recovered in the urine within 48 hours after a single radio-labelled dose as either unchanged venlafaxine (5%), unconjugated ODV (29%), conjugated ODV (26%), or other minor inactive metabolites (27%), and 92% of the radioactive dose is recovered within 72 hours. Therefore, renal elimination of venlafaxine and its metabolites is the primary route of excretion.
Effects of Food: Food has no significant effect on the absorption of venlafaxine or the formation of ODV.
Age and Gender Studies: A population pharmacokinetic analysis of 404 immediate-release venlafaxine-treated patients from two studies involving both twice daily and three times daily. Regimens showed that dose-normalized trough plasma levels of either venlafaxine or ODV were unaltered by age or gender differences.
Patients with Hepatic Impairment: The pharmacokinetic disposition of both venlafaxine and ODV are significantly altered in some patients with compensated hepatic cirrhosis (moderate hepatic impairment) following oral administration of single-dose venlafaxine. In patients with hepatic impairment, mean plasma clearance of venlafaxine and ODV are reduced by approximately 30% to 33% and mean elimination half-lives are prolonged by 2-fold or more compared to normal subjects. The reduction in both the metabolism of venlafaxine and elimination of ODV resulted in higher plasma concentrations of both venlafaxine and ODV.
In a second study, venlafaxine was administered orally and intravenously in normal subjects (n=21), and in Child-Pugh A (n=8) and Child-Pugh B (n=11) subjects mildly and moderately hepatically-impaired, respectively. Oral bioavailability approximately doubled in patients with hepatic impairment compared to normal subjects. In patients with hepatic impairment, venlafaxine oral elimination half-life was approximately twice as long and oral clearance was reduced by more than half compared to normal subjects. In patients with hepatic impairment, ODV oral elimination half-life was prolonged by about 40% while oral clearance for ODV was similar to that for normal subjects. A large degree of intersubject variability was noted.
Patients with Renal Impairment: In patients with moderate to severe impairment of renal function, the total clearance of both venlafaxine and ODV was reduced, and t_½ was prolonged. The reduction in total clearance was most pronounced in subjects with creatinine clearance less than 30 mL/min.
Venlafaxine and ODV elimination half-lives increase with the degree of impairment in renal function. Elimination half-life increased approximately by 1.5-fold in patients with moderate renal impairment and approximately by 2.5-fold and 3-fold in patients with end stage renal disease.
Toxicology: Preclinical Safety Data: Carcinogenicity: Venlafaxine was given by oral gavage to mice for 18 months at doses up to 120 mg/kg per day, which was 1.7 times the maximum recommended human dose, on a mg/m² basis. Venlafaxine was also given to rats by oral gavage for 24 months at doses up to 120 mg/kg per day. In rats receiving the 120 mg/kg dose, plasma concentrations of venlafaxine at necropsy were 6 times (female rats) and 1 times (male rats) the plasma concentrations of patients receiving the maximum recommended human dose. Plasma levels of ODV were lower in rats than in patients receiving the maximum recommended dose. Tumors were not increased by venlafaxine treatment in mice or rats.
Mutagenicity: Venlafaxine and ODV were not mutagenic in the Ames reverse mutation assay in Salmonella bacteria or the Chinese hamster ovary/hypoxanthine guanine phosphoribosyl transferase (HGPRT) mammalian cell forward gene mutation assay. Venlafaxine was also not mutagenic or clastogenic in the in vitro BALB/c-3T3 mouse cell transformation assay, the sister chromatid exchange assay in cultured Chinese hamster ovary cells, or in the in vivo chromosomal aberration assay in rat bone marrow. O-desmethylvenlafaxine was not clastogenic in the in vitro Chinese hamster ovary cell chromosomal aberration assay, or in the in vivo chromosomal aberration assay in rat bone marrow.
Impairment of Fertility: Reproduction and fertility studies in rats showed no effect on male or female fertility at oral doses of up to 8 times the maximum recommended human daily dose, on a mg/kg basis, or of up to 2 times, on a mg/m² basis.
Reduced fertility was observed in a study in which both male and female rats were exposed to the major metabolite of venlafaxine (ODV). This ODV exposure was approximately 2 to 3 times that of a human venlafaxine dose of 225 mg/day. The human relevance of this finding is unknown.
Teratogenicity: Venlafaxine did not cause malformations in offspring of rats or rabbits given doses up to 11 times (rat) or 12 times (rabbit) the human dose of 375 mg/day of venlafaxine on a mg/kg basis, or 2.5 times (rat) and 4 times (rabbit) the human dose of 375 mg/day of venlafaxine, on a mg/m² basis.