Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2021 Publisher: Bristol Laboratories Limited, Unit 3, Canalside, Northbridge Road, Berkhamsted, Hertfordshire, HP4 1EG, United Kingdom
Pharmacotherapeutic group: Other antidepressants
ATC code: N06AX16
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, O-desmethylvenlafaxine (ODV), are inhibitors of serotonin and noradrenaline reuptake. Venlafaxine also weakly inhibits dopamine uptake. Venlafaxine and its active metabolite reduce β-adrenergic responsiveness after both acute (single dose) and chronic administration. Venlafaxine and ODV are very similar with respect to their overall action on neurotransmitter reuptake and receptor binding.
Venlafaxine has virtually no affinity for rat brain muscarinic, cholinergic, H1 histaminergic or α1-adrenergic receptors in vitro. Pharmacological activity at these receptors may be related to various side effects seen with other antidepressant medicinal products, such as anticholinergic, sedative and cardiovascular side effects.
Venlafaxine does not possess monoamine oxidase (MAO) inhibitory activity.
In vitro studies revealed that venlafaxine has virtually no affinity for opiate or benzodiazepine sensitive receptors.
The efficacy of venlafaxine immediate-release as a treatment for major depressive episodes was demonstrated in five randomised, double-blind, placebo-controlled, short-term trials ranging from 4 to 6 weeks duration, for doses up to 375 mg/day. The efficacy of venlafaxine prolonged-release as a treatment for major depressive episodes was established in two placebo-controlled, short-term studies for 8 and 12 weeks duration, which included a dose range of 75 to 225 mg/day.
In one longer-term study, adult outpatients who had responded during an 8-week open trial on venlafaxine prolonged-release (75, 150, or 225 mg) were randomised to continuation of their same venlafaxine prolonged-release dose or to placebo, for up to 26 weeks of observation for relapse.
In a second longer-term study, the efficacy of venlafaxine in prevention of recurrent depressive episodes for a 12-month period was established in a placebo-controlled double-blind clinical trial in adult outpatients with recurrent major depressive episodes who had responded to venlafaxine treatment (100 to 200 mg/day, on a twice daily schedule) on the last episode of depression.
The efficacy of venlafaxine prolonged-release capsules as a treatment for generalised anxiety disorder (GAD) was established in two 8-week, placebo-controlled, fixed-dose studies (75 to 225 mg/day), one 6-month, placebo-controlled, fixed-dose study (75 to 225 mg/day), and one 6-month, placebo-controlled, flexible-dose study (37.5, 75, and 150 mg/day) in adult outpatients.
While there was also evidence for superiority over placebo for the 37.5 mg/day dose, this dose was not as consistently effective as the higher doses.
The efficacy of venlafaxine prolonged-release capsules as a treatment for social anxiety disorder was established in four double-blind, parallel-group, 12-week, multi-center, placebo-controlled, flexible-dose studies and one double-blind, parallel-group, 6-month, placebo-controlled, fixed/flexible-dose study in adult outpatients. Patients received doses in a range of 75 to 225 mg/day. 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.
The efficacy of venlafaxine prolonged-release capsules as a treatment for panic disorder was established in two double-blind, 12-week, multi-center, placebo-controlled studies in adult outpatients with panic disorder, with or without agoraphobia. The initial dose in panic disorder studies was 37.5 mg/day for 7 days. Patients then received fixed doses of 75 or 150 mg/day in one study and 75 or 225 mg/day in the other study.
Efficacy was also established in one long-term double-blind, placebo-controlled, parallel-group study of the long-term safety, efficacy, and prevention of relapse in adult outpatients who responded to open-label treatment. Patients continued to receive the same dose of venlafaxine prolonged-release that they had taken at the end of the open-label phase (75, 150, or 225 mg).
In a dedicated thorough QTc study in healthy subjects, venlafaxine did not prolong the QT interval to any clinically relevant extent at a supra-therapeutic dose of 450 mg/day (given as 225 mg twice daily). However, post-marketing cases of QTc prolongation/TdP and ventricular arrhythmia have been reported, especially in overdose or in patients with other risk factors for QTc prolongation/TdP (see sections 4.4, 4.8 and 4.9).
Venlafaxine is extensively metabolised, primarily to the active metabolite, O-desmethylvenlafaxine (ODV). Mean ± SD plasma half-lives of venlafaxine and ODV are 5±2 hours and 11±2 hours, respectively. Steady-state concentrations of venlafaxine and ODV are attained within 3 days of oral multiple-dose therapy. Venlafaxine and ODV exhibit linear kinetics over the dose range of 75 mg to 450 mg/day.
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. After immediate-release venlafaxine administration, the peak plasma concentrations of venlafaxine and ODV occur in 2 and 3 hours, respectively. Following the administration of venlafaxine prolonged-release capsules, peak plasma concentrations of venlafaxine and ODV are attained within 5.5 hours and 9 hours, respectively. When equal daily doses of venlafaxine are administered as either an immediate-release tablet or prolonged-release capsule, the prolonged-release capsule provides a slower rate of absorption, but the same extent of absorption compared with the immediate-release tablet. Food does not affect the bioavailability of venlafaxine and ODV.
Venlafaxine and ODV are minimally bound at therapeutic concentrations to human plasma proteins (27% and 30%, respectively). The volume of distribution for venlafaxine at steady-state is 4.4±1.6 L/kg following intravenous administration.
Venlafaxine undergoes extensive hepatic metabolism. In vitro and in vivo studies indicate that venlafaxine is biotransformed to its major active metabolite, ODV, by CYP2D6. In vitro and in vivo studies indicate that venlafaxine is metabolised to a minor, less active metabolite, N-desmethylvenlafaxine, by CYP3A4. In vitro and in vivo studies indicate that venlafaxine is a weak inhibitor of CYP2D6. Venlafaxine did not inhibit CYP1A2, CYP2C9, or CYP3A4.
Venlafaxine and its metabolites are excreted primarily through the kidneys. Approximately 87% of a 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%). Mean ± SD plasma steady-state clearances of venlafaxine and ODV are 1.3±0.6 L/h/kg and 0.4±0.2 L/h/kg, respectively.
Subject age and gender do not significantly affect the pharmacokinetics of venlafaxine and ODV.
Plasma concentrations of venlafaxine are higher in CYP2D6 poor metabolisers than extensive metabolisers. Because the total exposure (AUC) of venlafaxine and ODV is similar in poor and extensive metabolisers, there is no need for different venlafaxine dosing regimens for these two groups.
In Child-Pugh A (mildly hepatically impaired) and Child-Pugh B (moderately hepatically impaired) subjects, venlafaxine and ODV half-lives were prolonged compared to normal subjects. The oral clearance of both venlafaxine and ODV was reduced. A large degree of intersubject variability was noted. There are limited data in patients with severe hepatic impairment (see section 4.2).
In dialysis patients, venlafaxine elimination half-life was prolonged by about 180% and clearance reduced by about 57% compared to normal subjects, while ODV elimination half-life was prolonged by about 142% and clearance reduced by about 56%. Dosage adjustment is necessary in patients with severe renal impairment and in patients that require haemodialysis (see section 4.2).
Studies with venlafaxine in rats and mice revealed no evidence of carcinogenesis. Venlafaxine was not mutagenic in a wide range of in vitro and in vivo tests.
Animal studies regarding reproductive toxicity have found in rats a decrease in pup weight, an increase in stillborn pups, and an increase in pup deaths during the first 5 days of lactation. The cause of these deaths is unknown. These effects occurred at 30 mg/kg/day, 4 times the human daily dose of 375 mg of venlafaxine (on an mg/kg basis). The no-effect dose for these findings was 1.3 times the human dose. The potential risk for humans is unknown.
Reduced fertility was observed in a study in which both male and female rats were exposed to ODV. This exposure was approximately 1 to 2 times that of a human venlafaxine dose of 375 mg/day. The human relevance of this finding is unknown.
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