Pharmacology: Pharmacodynamics: Venlafaxine and its active metabolite, ODV, are potent inhibitors of neuronal serotonin and norepinephrine reuptake and weak inhibitors of dopamine reuptake. The antidepressant activity of venlafaxine is thought to be associated with potentiation of neurotransmitter activity in the CNS. Venlafaxine and ODV have no significant affinity for muscarinic, histaminergic, or α1-adrenergic receptors in vitro. Activity at these receptors is potentially associated with various anticholinergic, sedative, and cardiovascular effects seen with other psychotropic drugs. In preclinical rodent models, venlafaxine demonstrated activity predictive of antidepressant and anxiolytic actions, and cognitive-enhancing properties.
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).
Clinical Efficacy: Depression: The efficacy of venlafaxine extended-release capsules as a treatment for depression, including depression with associated anxiety, was established in two placebo-controlled short-term studies. Populations in both trials consisted of outpatients meeting DSM III-R or DSM-IV criteria for major depression.
The first study compared extended-release venlafaxine 75 to 150 mg/day, immediate-release venlafaxine 75 to 150 mg/day, and placebo for 12 weeks. Extended-release venlafaxine showed significant advantage over placebo starting at Week 2 of treatment on the Hamilton Rating Scale for Depression (HAM-D) Score and HAM-D Depressed Mood Item, at Week 3 on the Montgomery-Asberg Depression Rating Scale (MADRS) total, and at Week 4 on the Clinical Global Impressions (CGI) Severity of Illness Scale. All advantages were maintained through the end of treatment. Extended-release venlafaxine also showed significant advantage over immediate-release venlafaxine at Weeks 8 and 12 on the HAM-D total and CGI Severity of Illness Scale and at Week 12 for all efficacy variables.
The second study compared treatment with extended-release venlafaxine 75 to 225 mg/day and placebo for up to 8 weeks. Sustained statistical improvement over placebo was seen beginning at Week 2 for the CGI Severity of Illness Scale, beginning at Week 4 for the HAM-D total and MADRS total, and beginning at Week 3 for the HAM-D Depressed Mood Item.
Generalized Anxiety Disorder: The efficacy of venlafaxine extended-release capsules as a treatment for GAD was established in two short-term (8-week), placebo-controlled, fixed-dose studies, one long-term (6-month), placebo-controlled, fixed-dose study, and one long-term (6-month), placebocontrolled, flexible-dose study in outpatients meeting DSM-IV criteria for GAD.
One short-term study evaluating extended-release venlafaxine doses of 75, 150 and 225 mg/day, and placebo showed that the 225 mg/day dose was more effective than placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score, both the HAM-A anxiety and tension items, and the CGI scale. While there was also evidence for superiority over placebo for the 75 and 150 mg/day doses, these doses were not as consistently effective as the highest dose.
A second short-term study evaluating extended-release venlafaxine doses of 75 and 150 mg/day and placebo showed that both doses were more effective than placebo on some of these same outcomes; however, the 75 mg/day dose was more consistently effective than the 150 mg/day dose. Two long-term (6-month) studies, one with extended-release venlafaxine doses of 37.5, 75, and 150 mg/day and the other evaluating doses of 75 to 225 mg/day, showed that doses of 75 mg or higher were more effective than placebo on the HAM-A total, both the HAM-A anxiety and tension items, and the CGI scale after short-term (Week 8) and long-term (Month 6) treatment.
Pharmacokinetics: Absorption: At least 92% of venlafaxine is absorbed following single oral doses of immediate-release venlafaxine. Absolute bioavailability is 40% to 45% due to presystemic metabolism. In single-dose studies with 25 mg to 150 mg of immediate-release venlafaxine, mean peak plasma concentrations (Cmax) range from 37 to 163 mg/mL respectively and are attained within 2.1 to 2.4 hours (tmax).
Following the administration of venlafaxine extended-release capsules, peak plasma concentrations of venlafaxine and ODV are attained within 5.5 and 9 hours, respectively. Following the administration of venlafaxine immediate-release, peak plasma concentrations of venlafaxine and ODV are attained in 2 and 3 hours, respectively. Venlafaxine extended-release capsules and venlafaxine immediate-release tablets are associated with a similar extent of absorption.
Distribution: Steady-state concentrations of both venlafaxine and ODV in plasma are attained within 3 days of multiple-dose therapy of immediate-release venlafaxine. Both show linear kinetics over a dose range of 75 to 450 mg/day when administered every 8 hours. Venlafaxine and ODV are approximately 27% and 30% bound to human plasma proteins, respectively. Since this binding is independent of respective drug concentrations up to 2,215 and 500 ng/mL, both venlafaxine and ODV have low potential for involvement in significant drug-drug interactions involving drug displacement from serum proteins. The volume of distribution for venlafaxine at steady-state is 4.4 ± 1.9 L/kg following intravenous administration.
Metabolism: Venlafaxine undergoes extensive hepatic metabolism. In vitro and in vivo studies indicate that venlafaxine is biotransformed to its major active metabolite, ODV, by the P450 isoenzyme CYP2D6. In vitro and in vivo studies indicate that venlafaxine is metabolized to a minor, less active metabolite, N-desmethylvenlafaxine, by CYP3A4. Although the relative activity of CYP2D6 may differ among patients, related modification of the venlafaxine dosage regimen is not required. Drug exposure (AUC) and fluctuation in plasma levels of venlafaxine and ODV were comparable following administration of equal daily doses of venlafaxine as twice daily or three times daily regimens of immediate-release venlafaxine.
Elimination: Venlafaxine and its metabolites are excreted primarily through the kidneys. Approximately 87% of venlafaxine dose is recovered in the urine within 48 hours as either unchanged venlafaxine (5%), unconjugated ODV (29%), conjugated ODV (26%), or other minor inactive metabolites (27%).
Effects of Food: Food has no significant effect on the absorption of venlafaxine or the formation of ODV.
Patients with Hepatic Impairment: The pharmacokinetic disposition of 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.
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: Venlafaxine and ODV elimination half-lives increase with the degree of impairment in renal function. Elimination half-life increased by approximately 1.5-fold in patients with moderate renal impairment and by approximately 2.5-fold and 3-fold in patients with end-stage renal disease.
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.
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.