CLINICAL PHARMACOLOGY
Pharmacodynamics
The mechanism of the antidepressant action of venlafaxine
in humans is believed to be associated with its potentiation
of neurotransmitter activity in the CNS. Preclinical studies
have shown that venlafaxine and its active metabolite,
O-desmethylvenlafaxine (ODV), are potent inhibitors of
neuronal serotonin and norepinephrine reuptake and weak
inhibitors of dopamine reuptake.
Venlafaxine and ODV have no significant affinity for
muscarinic, cholinergic, H-histaminergic, or a-1 adrenergic
receptors in vitro. Pharmacologic activity at these receptors
is hypothesized to be associated with the various anticholinergic,
sedative, and cardiovascular effects seen with other psychotropic
drugs. Venlafaxine and ODV do not possess monoamine oxidase
(MAO) inhibitory activity.
Pharmacokinetics
Steady-state concentrations of venlafaxine and ODV in
plasma were attained within 3 days of multiple-dose therapy.
Venlafaxine and ODV exhibited linear kinetics over the
dose range of 75 to 450 mg total dose per day (administered
on a q8h schedule). 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 L/kg and 5.7±1.8 L/kg, respectively.
Venlafaxine and ODV are minimally bound at therapeutic
concentrations to plasma proteins (27 and 30%, respectively).
Absorption
Venlafaxine is well absorbed and extensively metabolized
in the liver. O-desmethylvenlafaxine (ODV) is the only
major active metabolite. On the basis of mass balance
studies, at least 92% of a single dose of venlafaxine
is absorbed. The absolute bioavailability of venlafaxine
is about 45%.
Administration of venlafaxine HCl (extended release)
(150 mg q24 hours) generally resulted in lower Cmax (150
ng/ml for venlafaxine and 260 ng/ml for ODV) and later
Tmax (5.5 hours for venlafaxine and 9 hours for ODV) than
for immediate release venlafaxine tablets (Cmax's for
immediate release 75 mg q12 hours were 225 ng/ml for venlafaxine
and 290 ng/ml for ODV; Tmax's were 2 hours for venlafaxine
and 3 hours for ODV). When equal daily doses of venlafaxine
were administered as either an immediate release tablet
or the extended release capsule, the exposure to both
venlafaxine and ODV was similar for the two treatments,
and the fluctuation in plasma concentrations was slightly
lower with the venlafaxine HCl (extended release) capsule.
Venlafaxine HCl (extended release), therefore, provides
a slower rate of absorption but the same extent of absorption
compared with the immediate release tablet.
Food did not affect the bioavailability of venlafaxine
or its active metabolite, ODV. Time of administration
(AM vs PM) did not affect the pharmacokinetics of venlafaxine
and ODV from the 75 mg venlafaxine HCl extended release
capsule.
Metabolism and Excretion
Extended Release Tablets: Following
absorption, venlafaxine undergoes extensive presystemic
metabolism in the liver, primarily to ODV, but also to
N-desmethylvenlafaxine, N.O-didesmethylvenlafaxine, and
other minor metabolites. In vitro studies indicate that
the formation of ODV is catalyzed by CYP2D6; this has
been confirmed in a clinical study showing that patients
with low CYP2D6 levels (“poor metabolizers”)
had increased levels of venlafaxine and reduced levels
of ODV compared to people with normal CYP2D6 (“extensive
metabolizers”). The differences between the CYP2D6
poor and extensive metabolizers, however, is not expected
to be clinically important because the sum of venlafaxine
and ODV is similar in the two groups and venlafaxine and
ODV are pharmacologically approximately equiactive and
equipotent.
Approximately 87% of a venlafaxine dose is recovered
in the urine within 48 hours as unchanged venlafaxine
(5%), unconjugated ODV (29%), conjugated ODV (26%), or
other minor inactive metabolites (27%). Renal elimination
of venlafaxine and its metabolites is thus the primary
route of excretion.
Special Populations
Age and Gender
A pharmacokinetic analysis of 404 venlafaxine treated
patients from two studies involving both b.i.d. and t.i.d.
regimens showed that dose normalized trough plasma levels
of either venlafaxine or ODV were unaltered due to age
or gender differences. Dosage adjustment based upon the
age or gender of a patient is generally not necessary
(see DOSAGE AND ADMINISTRATION).
Extensive/Poor Metabolizers
Plasma concentrations of venlafaxine were higher in CYP2D6
poor metabolizers than extensive metabolizers. Because
the total exposure (AUC) of venlafaxine and ODV was similar
in poor and extensive metabolizer groups, however, there
is no need for different venlafaxine dosing regimens for
these two groups.
Liver Disease
In 9 patients with hepatic cirrhosis, the pharmacokinetic
disposition of both venlafaxine and ODV was significantly
altered after oral administration of venlafaxine. Venlafaxine
elimination half-life was prolonged by about 30%, and
clearance decreased by about 50% in cirrhotic patients
compared to normal subjects. ODV elimination half-life
was prolonged by about 60% and clearance decreased by
about 30% in cirrhotic patients compared to normal subjects.
A large degree of intersubject variability was noted.
Three patients with more severe cirrhosis had a more substantial
decrease in venlafaxine clearance (about 90%) compared
to normal subjects. Dosage adjustment is necessary in
these patients (see DOSAGE AND ADMINISTRATION).
Renal Disease
In a renal impairment study, venlafaxine elimination
half-life after oral administration was prolonged by about
50% and clearance was reduced by about 24% in renally
impaired patients (GFR=10-70 ml/min), compared to normal
subjects. In dialysis patients, venlafaxine elimination
half-life was prolonged by about 180% and clearance was
reduced by about 57% compared to normal subjects. Similarly,
ODV elimination half-life was prolonged by about 40% although
clearance was unchanged in patients with renal impairment
(GFR=10-70 ml/min) compared to normal subjects. In dialysis
patients, ODV elimination half-life was prolonged by about
142% and clearance was reduced by about 56%, compared
to normal subjects. A large degree of intersubject variability
was noted.
Dosage adjustment is necessary in these patients (see
DOSAGE AND ADMINISTRATION).
CLINICAL STUDIES
Immediate Release Tablets
The efficacy of venlafaxine hydrochloride as a treatment
for depression was established in 5 placebo-controlled,
short-term trials. Four of these were 6-week trials in
outpatients meeting DSM III or DSM-III-R criteria for
major depression: two involving dose titration with venlafaxine
HCl in a range of 75 to 225 mg/day (t.i.d. schedule),
the third involving fixed venlafaxine HCl doses of 75,
225, and 375 mg/day (t.i.d. schedule), and the fourth
involving doses of 25, 75, and 200 mg/day (b.i.d. schedule).
The fifth was a 4-week study of inpatients meeting DSM-III-R
criteria for major depression with melancholia whose venlafaxine
HCl doses were titrated in a range of 150 to 375 mg/day
(t.i.d. schedule). In these 5 studies, venlafaxine HCl
was shown to be significantly superior to placebo on at
least 2 of the following 3 measures: Hamilton Depression
Rating Scale (total score), Hamilton depressed mood item,
and Clinical Global Impression¾Severity of Illness
rating. Doses from 75 to 225 mg/day were superior to placebo
in outpatient studies and a mean dose of about 350 mg/day
was effective in inpatients. Data from the 2 fixed-dose
outpatient studies were suggestive of a dose-response
relationship in the range of 75 to 225 mg/day. There was
no suggestion of increased response with doses greater
than 225 mg/day.
While there were no efficacy studies focusing specifically
on an elderly population, elderly patients were included
among the patients studied. Overall, approximately 2/3
of all patients in these trials were women. Exploratory
analyses for age and gender effects on outcome did not
suggest any differential responsiveness on the basis of
age or sex.
Extended Release Tablets
Depression
The efficacy of 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.
A 12-week study utilizing venlafaxine HCl (extended release)
doses in a range 75-150 mg/day (mean dose for completers
was 136 mg/day) and an 8-week study utilizing venlafaxine
HCl (extended release) doses in a range 75-225 mg/day
(mean dose for completers was 177 mg/day) both demonstrated
superiority of venlafaxine HCl (extended release) 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,
venlafaxine HCl (extended release) 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 for the psychic anxiety score.
A 4-week study of inpatients meeting DSM-III-R criteria
for major depression with melancholia utilizing venlafaxine
HCl (the immediate release form of venlafaxine) in a range
of 150 to 375 mg/day (t.i.d. schedule) demonstrated superiority
of venlafaxine HCl over placebo. The mean dose in completers
was 350 mg/day.
Examination of gender subsets of the population studied
did not reveal any differential responsiveness on the
basis of gender.
Generalized Anxiety Disorder
The efficacy of venlafaxine HCl extended-release capsules
as a treatment for Generalized Anxiety Disorder (GAD) was
established in two 8-week, placebo-controlled, fixed-dose
studies in outpatients meeting DSM-IV criteria for GAD.
One study evaluating venlafaxine HCl extended-release 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 Clinical Global Impressions
(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 study evaluating venlafaxine HCl extended-release
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. A dose-response relationship
for effectiveness in GAD was not clearly established in
the 75-225 mg/day dose range utilized in these two studies.
Examination of gender subsets of the population studied
did not reveal any differential responsiveness on the basis
of gender.
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