Effexor® XR
Venlafaxine HCl
Antidepressant--Anxiolytic
Wyeth Canada
http://www.wyeth.com/
Effexor Monograph PDF download here.
CPS:PIS_m191600
Date of Preparation: July 18, 1994
Date of Revision: May 27, 2004
Pharmacology
Venlafaxine is a phenethylamine bicyclic
derivative, chemically unrelated to tricyclic, tetracyclic or other available
antidepressant or anxiolytic agents.
Pharmacodynamics: The
mechanism of venlafaxine's antidepressant action 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, histaminergic, or α1-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
MAO inhibitory activity.
Pharmacokinetics
Effexor: Venlafaxine is well absorbed, with peak
plasma concentrations with Effexor tablets occurring approximately 2 hours
after dosing. Venlafaxine is extensively metabolized, with
O-desmethylvenlafaxine, (ODV, the only major active metabolite) peak plasma
levels occurring approximately 4 hours after dosing. Following single
doses of 25 to 75 mg, mean (±SD) peak plasma concentrations of venlafaxine
range from 37±14 to 102±41 ng/mL, respectively, and are reached in
2±1 hours, and mean peak ODV plasma concentrations range from 61±13 to
168±37 ng/mL and are reached in 4±2 hours. Approximately 87% of a
single dose of venlafaxine 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%), 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.
Effexor XR: After administration of
Effexor XR (extended release capsules), 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 Effexor XR
capsule is slower than its rate of elimination. Therefore, the apparent
elimination half-life of venlafaxine following administration of
Effexor 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 Effexor immediate release tablet.
Multiple-Dose Pharmacokinetic Profile (Tablets
and Extended Release Capsules): 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 (15%) lower following
multiple doses than following a single dose.
Venlafaxine and ODV
exhibited approximately linear kinetics over the dose range of 75 to
450 mg/day.
The mean±SD
steady-state plasma clearances of venlafaxine and ODV are 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.
Venlafaxine and ODV
renal clearances are 49±27 and 94±56 mL/h/kg, respectively, which
correspond to 5±3.0% and 25±13% of an administered venlafaxine dose recovered
in urine as venlafaxine and ODV, respectively.
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 2 treatments, and
the fluctuation in plasma concentrations was slightly lower following treatment
with the extended release capsule. Therefore, the Effexor XR capsules
provide a slower rate of absorption, but the same extent of absorption (i.e.,
AUC), as the venlafaxine immediate release tablet.
Venlafaxine and ODV are
27 and 30% bound to human plasma proteins, respectively. Therefore,
administration of venlafaxine to a patient taking another drug that is highly
protein-bound should not cause increased free concentrations of the other drug.
Following i.v. 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.
Following absorption,
venlafaxine undergoes extensive presystemic metabolism in the liver. On the
basis of mass balance studies, at least 92% of a single dose of venlafaxine is
absorbed. The absolute bioavailability of venlafaxine is approximately 45%. The
primary metabolite of venlafaxine is ODV, which is an active metabolite.
Venlafaxine is also metabolized to N-desmethylvenlafaxine,
N,O-didesmethylvenlafaxine, and other minor metabolites. In vitro studies
indicate that the formation of ODV is catalysed by CYP2D6 and that the
formation of N-desmethylvenlafaxine is catalysed 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 2 active species (venlafaxine and ODV, which
have comparable activity) was similar in the 2 metabolizer groups.
Food has no significant
effect on the absorption of venlafaxine or on the subsequent formation of ODV.
Age and Gender: Population pharmacokinetic
analyses of 547 venlafaxine-treated patients from 3 studies involving both
venlafaxine immediate release tablets and venlafaxine extended release
capsules showed that age and sex do not significantly affect the
pharmacokinetics of venlafaxine. A 20% reduction in clearance was noted for ODV
in subjects over 60 years old; this was possibly caused by the decrease in
renal function that typically occurs with aging. Dosage adjustment based upon
age or gender is generally not necessary (see Dosage).
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, there is no need for
different venlafaxine dosing regimens for these 2 groups.
Hepatic Disease: In 9 patients with hepatic
cirrhosis, the pharmacokinetic disposition of both venlafaxine and ODV were
significantly altered. Venlafaxine elimination half-life was prolonged by about
30%, and clearance was 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 patients with liver
disease (see Dosage).
Renal Disease: In patients with moderate to
severe impairment of renal function (GFR=10 to 70 mL/min), venlafaxine
elimination half-life was prolonged by 50%, and clearance was decreased by
about 24% compared to normal subjects. ODV elimination half-life was prolonged
by about 40%, but clearance was unchanged.
In dialysis patients,
venlafaxine elimination half-life was prolonged by about 180% and clearance was
decreased by about 57%. 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 patients with renal disease (see Dosage).
Clinical Trials
Depression: Venlafaxine tablets (immediate
release): The efficacy of venlafaxine tablets in the treatment of depression
was established in 6-week controlled trials of outpatients whose diagnoses
corresponded most closely to the DSM-II or DSM-III-R category of major
depressive disorder and in a 4-week controlled trial of inpatients meeting
diagnostic criteria for major depressive disorder with melancholia.
In one longer term
study, outpatients meeting DSM-III-R criteria for major depressive disorder,
recurrent type, who had “responded”{*For the purposes of this study: “Responded”
was defined as HAM-D-21 total score ≤ 12 at the day 56 evaluation). “Improved”
was defined as the following criteria being met for days 56 through 180: (1) no
HAM-D-21 total score ≥ 20; (2) no more than 2 HAM-D-21 total scores
>10, and (3) no single CGI Severity of Illness item score ≥ 4 (moderately
ill). “Relapse” was defined as a CGI Severity of Illness item score
≥ 4 during the double-blind phase.} during an initial 26 weeks of
treatment on venlafaxine tablets (100 to 200 mg/day, on a b.i.d. schedule) and
continued to be “improved”, were randomized to continuation of their same dose
or to placebo. The follow-up period to observe patients for “relapse” was for
up to 52 weeks. Patients receiving continued treatment experienced
significantly lower relapse rates over the subsequent 52 weeks compared with
those receiving placebo.
Effexor XR Capsules (Extended release): The
efficacy of Effexor 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. An 8-week study utilizing Effexor XR
doses in a range 75-225 mg/day (mean dose for completers was 177 mg/day) and a
12-week study utilizing Effexor XR doses in a range 75-150 mg/day (mean dose
for completers was 136 mg/day) both demonstrated superiority of Effexor XR
over placebo on the HAM-D total score, the HAM-D Depressed Mood Item, the MADRS
total score, the CGI Severity of illness scale, and the CGI Global Improvement
scale. In both studies, Effexor 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 for
the psychic anxiety score.
In the 12-week study
comparing venlafaxine immediate release tablets with Effexor XR capsules, once
daily, Effexor XR was significantly more effective at weeks 8 and 12, compared
with venlafaxine immediate release tablets given twice daily for treating major
depression.
In one longer term
study, outpatients meeting DSM-IV criteria for major depressive disorder who
had “responded”{*For the purposes of this study: “ Responded” during
the open phase was defined as a CGI Severity of Illness item score 3 and a
HAM-D-21 total score of ≤ 10 at the day 56 evaluation. “Relapse”
during the double-blind phase was defined as follows: (1) a reappearance of
major depressive disorder as defined by DSM-IV criteria and a CGI Severity of
Illness item score of ≥ 4 (moderately ill), (2) 2 consecutive CGI
Severity of Illness item scores of ≥ 4, or (3) a final CGI Severity of
Illness item score of ≥ 4 for any patient who withdrew from the study for
any reason.} during an 8-week open trial on Effexor XR capsules (75, 150,
or 225 mg, in the morning (qAM) were randomized to continuation of their same
Effexor XR dose or to placebo, for up to 26 weeks of observation for “relapse”.
Patients receiving continued Effexor XR treatment experienced significantly
lower “relapse” rates compared with those on placebo.
Generalized Anxiety Disorder (GAD): The efficacy
of venlafaxine extended release capsules in the treatment of GAD has been
demonstrated in 3 fixed dose studies and 1 flexible dose study for time periods
ranging from 8 to 28 weeks. In these studies, venlafaxine extended release was
shown to have a statistically significant superiority over placebo on the
following 3 measures: Hamilton Anxiety Rating Scale (total score),
Hamilton anxious mood item, and Clinical Global Impression of Severity of Illness
rating.
In the 3 fixed dose
studies, response rates at week 8 of treatment, as defined by the proportion of
patients achieving Clinical Global Impression of Improvement Scores of “much”
or “very much improved”, were as follows (last observation carried forward):
see Table 1.
CPS:Effexor_t1Click here for Table 1
Table 1: Effexor XR
Efficacy of Effexor XR in the Treatment of GAD
|
|
Placebo
|
37.5 mg
|
75.0 mg
|
150 mg
|
225 mg
|
|
Study #
|
N
|
%
|
N
|
%
|
N
|
%
|
N
|
%
|
N
|
%
|
|
|
210 US
|
96
|
49
|
|
|
86
|
57
|
81
|
58
|
86
|
65
|
|
|
378 EU
|
130
|
45
|
138
|
59
|
130
|
69
|
131
|
78
|
|
|
|
|
214 US
|
98
|
39
|
|
|
87
|
62
|
87
|
49
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
For the 2 long-term
studies, response rates at month 6 were as follows for last observation carried
forward (LOCF): see Table 2.
CPS:Effexor_t2Click here for Table 2
Table 2: Effexor XR
Efficacy of Effexor XR in the Treatment of GAD
|
|
|
Placebo
|
37.5 mg
|
75.0 mg
|
150 mg
|
75–225 mg
|
|
Study #
|
|
N
|
%
|
N
|
%
|
N
|
%
|
N
|
%
|
N
|
%
|
|
|
218 US
|
LOCF
|
123
|
33
|
|
|
|
|
|
|
115
|
67
|
|
|
378 EU
|
LOCF
|
130
|
48
|
138
|
66
|
130
|
75
|
131
|
81
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Social Anxiety Disorder (Social Phobia): The
efficacy of Effexor XR capsules as a treatment for Social Anxiety Disorder
(also known as Social Phobia) was established in two 12-week, multicenter,
placebo-controlled, flexible-dose studies in adult outpatients meeting DSM-IV
criteria for Social Anxiety Disorder. These studies evaluating Effexor XR
doses in a range of 75-225 mg/day demonstrated that Effexor XR was
significantly more effective than placebo for the Liebowitz Social Anxiety
Scale Total score.
Examination of subsets
of the population studied did not reveal any differential responsiveness on the
basis of age or gender.
Indications
Depression: Effexor XR Capsules (extended
release) are indicated for the symptomatic relief of major depressive disorder.
The short-term efficacy
of Effexor Tablets (immediate release) has been demonstrated in placebo
controlled trials of up to 6 weeks.
The short-term efficacy
of Effexor XR Capsules (extended release) has been demonstrated in placebo
controlled trials of up to 12 weeks.
The efficacy of
venlafaxine tablets (immediate release) in maintaining an antidepressant
response in patients with recurrent depression was demonstrated in a 52 week
placebo-controlled trial (see Pharmacology, Clinical Trials).
The efficacy of Effexor
XR Capsules (extended release) in maintaining an antidepressant response for up
to 26 weeks following response to 8 weeks of acute treatment was demonstrated
in a placebo-controlled trial (see Pharmacology, Clinical Trials).
Generalized Anxiety Disorder (GAD): Venlafaxine
extended release capsules are indicated for the symptomatic relief of anxiety
causing clinically significant distress in patients with GAD. Anxiety or
tension associated with the stress of everyday life usually does not require
treatment with an anxiolytic. The effectiveness of venlafaxine extended release
in long-term use has been evaluated for up to 6 months in controlled
clinical trials.
Social Anxiety Disorder (Social Phobia): Effexor
XR is indicated for the symptomatic relief of Social Anxiety Disorder, also
known as Social Phobia.
Social Anxiety Disorder
is characterized by a marked and persistent fear of one or more social or
performance situations, in which the person is exposed to unfamiliar people or
to possible scrutiny by others. Exposure to the feared situation almost
invariably provokes anxiety, which may approach the intensity of a panic
attack. The feared situations are avoided or endured with intense anxiety or
distress. Fear, anxious anticipation, distress in the feared situation(s) or
avoidance of social and/or performance situations that does not interfere
significantly with the person's normal routine, occupational or academic
functioning, or social life usually does not require treatment with an
anxiolytic.
The physician who
elects to use Effexor XR for extended periods in the treatment of depression,
GAD, or Social Anxiety Disorder should periodically re-evaluate the long-term
usefulness of the drug for the individual patient (see Dosage).
Contraindications
Hypersensitivity: In patients with known
hypersensitivity to venlafaxine or to any of the components of the
formulations.
MAOIs: Venlafaxine should not be used in
combination with MAOIs or within 2 weeks of terminating treatment with MAOIs.
Treatment with MAOIs should not be started until 2 weeks after discontinuation
of venlafaxine therapy.
Adverse reactions, some
serious, have been reported when venlafaxine therapy is initiated soon after
discontinuing an MAOI and when an MAOI is initiated soon after discontinuation
of venlafaxine. These reactions have included tremor, myoclonus, diaphoresis,
nausea, vomiting, flushing, dizziness, hyperthermia with features resembling
neuroleptic malignant syndrome, seizures and death. In patients receiving
antidepressants with pharmacological properties similar to venlafaxine in
combination with an MAOI, there have also been reports of serious, sometimes
fatal, reactions. For a selective serotonin reuptake inhibitor, these reactions
have included hyperthermia, rigidity, myoclonus, autonomic instability with
possible rapid fluctuations of vital signs, and mental status changes that
include extreme agitation progressing to delirium and coma. Some cases
presented with features resembling neuroleptic malignant syndrome. Severe
hypothermia and seizures, sometimes fatal, have been reported in association
with the combined use of tricyclic antidepressants and MAOIs. These reactions
have also been reported in patients who have recently discontinued these drugs
and have been started on an MAOI.
Warnings
Potential Association with Behavioural and
Emotional Changes, Including Self-Harm:
Pediatrics: Placebo-Controlled Clinical Trial
Data: Recent analyses of placebo-controlled clinical trial safety databases
from SSRIs and other newer antidepressants suggest that use of these drugs in
patients under the age of 18 may be associated with behavioural and emotional
changes, including an increased risk of suicidal ideation and behaviour over
that of placebo.
The small
denominators in the clinical trial database, as well as the variability in
placebo rates, preclude reliable conclusions on the relative safety profiles
among the drugs in the class.
Adults and Pediatrics: Additional data: There
are clinical trial and post-marketing reports with SSRIs and other newer
antidepressants, in both pediatrics and adults, of severe agitation-type
adverse events coupled with self-harm or harm to others. The agitation-type
events include: akathisia, agitation, disinhibition, emotional lability, hostility,
aggression, depersonalization. In some cases, the events occurred within
several weeks of starting treatment.
Rigorous clinical
monitoring for suicidal ideation or other indicators of potential for suicidal
behaviour is advised in patients of all ages. This includes monitoring for
agitation-type emotional and behavioural changes.
Discontinuation: Patients currently taking
Effexor XR should not be discontinued abruptly, due to risk of discontinuation
symptoms (see Precautions). At the time that a medical decision is made to
discontinue an SSRI or other newer antidepressant drug, a gradual reduction in
the dose, rather than an abrupt cessation, is recommended.
Sustained Hypertension: Venlafaxine Immediate
Release Tablets: Sustained increases in blood pressure could have adverse
consequences. Therefore, it is recommended that patients receiving venlafaxine
have their blood pressure monitored regularly. For patients who experience a
sustained increase in blood pressure while receiving venlafaxine, either dose
reduction or discontinuation should be considered after a benefit-risk
assessment is made.
Treatment with
venlafaxine tablets was associated with modest but sustained increases in blood
pressure during premarketing studies. Sustained hypertension, defined as
treatment-emergent supine diastolic blood pressure (SDBP) ≥ 90 mmHg
and ≥ 10 mmHg above baseline for 3 consecutive visits, showed
the following incidence and dose-relationship in Table 3.
CPS:Effexor_t3Click here for Table 3
Table 3: Effexor XR
Probability of Sustained Elevation in SDBP (Pool
of Premarketing Studies with Venlafaxine)
|
Treatment Group
|
(%)
Incidence of Sustained
Elevation in SDBP
|
|
Venlafaxine
|
Immediate Release
|
Extended Release
|
|
|
<100 mg/day
|
2
|
3
|
|
|
101–200 mg/day
|
5
|
2
|
|
|
201–300 mg/day
|
6
|
4
|
|
|
>300 mg/day
|
13
|
NEa
|
|
|
Placebo
|
2
|
0
|
|
a Not evaluable.
An analysis of the
blood pressure increases in patients with sustained hypertension and in the
19 patients who were discontinued from treatment because of hypertension
(<1% of total venlafaxine-treated group) showed that most of the blood
pressure increases were in the range of 10 to 15 mmHg, SDBP.
Effexor XR Capsules: Depression: In
placebo-controlled premarketing depression studies with venlafaxine extended
release, a final on-therapy mean increase in supine diastolic pressure (SDBP)
of <1.2 mmHg was observed for venlafaxine extended release-treated
patients compared with a mean decrease of 0.2 mmHg for placebo-treated
patients.
Less than 3% of
venlafaxine extended release patients treated with doses of 75 to
300 mg/day had sustained elevations in blood pressure (defined as
treatment-emergent SDBP ≥ 90 mmHg and ≥ 10 mmHg above
baseline for 3 consecutive on-therapy visits). An insufficient number of
patients received doses of venlafaxine extended release >300 mg/day to
evaluate systematically sustained blood pressure increases. Less than 1% of
venlafaxine extended release-treated patients in double-blind,
placebo-controlled premarketing depression studies discontinued treatment
because of elevated blood pressure compared with 0.4% of placebo-treated
patients.
In placebo-controlled
premarketing anxiety studies with venlafaxine extended release 37.5 to 225
mg/day, a final on-drug mean increase in SDBP of 0.4 mmHg was observed for
venlafaxine extended release-treated patients compared with a mean decrease of
0.8 mmHg for placebo-treated patients.
Sustained increases in
blood pressure could have adverse consequences. Therefore, it is recommended
that patients receiving venlafaxine have their blood pressure monitored
regularly. For patients who experience a sustained increase in blood pressure
while receiving venlafaxine, either dose reduction or discontinuation should be
considered after a benefit-risk assessment is made.
GAD: In placebo-controlled premarketing anxiety
studies with Effexor XR 37.5-225 mg/day, a final on-drug mean increase in SDBP
of 0.4 mm Hg was observed for Effexor XR treated patients compared with a mean
decrease of 0.8 mm Hg for placebo treated patients.
Social Anxiety Disorder (Social Phobia): In
placebo-controlled premarketing Social Anxiety Disorder studies with Effexor XR
75-225 mg/day up to 12 weeks, a final on-drug mean increase in SDBP of 1.6 mm
Hg was observed for Effexor XR-treated patients compared with a mean decrease
of 1.1 mm Hg for placebo-treated patients.
Among patients treated
with 75-225 mg per day of Effexor XR in premarketing Social Anxiety Disorder
studies, 1.4% (4/277) experienced sustained hypertension.
In premarketing Social
Anxiety Disorder studies up to 12 weeks with patients treated with 75-225 mg
per day, 0.4% (1/277) of the Effexor XR-treated patients discontinued treatment
because of elevated blood pressure. In this patient, the blood pressure
increase was modest (13 mm Hg, SDBP).
Precautions
General
Suicide: The possibility of a suicide attempt in
seriously depressed patients is inherent to the illness and may persist until
significant remission occurs. Close supervision of patients should accompany
initial drug therapy, and consideration should be given to the need for
hospitalization of high risk patients. In order to reduce the risk of overdose,
prescriptions for venlafaxine capsules should be written for the smallest
quantity of tablets/capsules consistent with good patient management.
The same precautions
observed when treating patients with depression should be observed when
treating patients with GAD or Social Anxiety Disorder (see Warnings, Potential
Association with Behavioural and Emotional Changes, Including Self-Harm).
Seizures: Venlafaxine tablets and extended
release capsules should be used cautiously in patients with a history of
seizures, and should be promptly discontinued in any patient who develops
seizures. Seizures have also been reported as a discontinuation symptom (see
also Precautions, Discontinuation Symptoms; Adverse Effects, Discontinuation
Symptoms; Dosage, Discontinuing Venlafaxine).
During premarketing
testing, seizures were reported in 8 out of 3082 venlafaxine tablet-treated
patients (0.26%). In 5 of the 8 cases with immediate release tablets,
patients were receiving doses of 150 mg/day or less. During premarketing
depression studies no seizures were seen in 705 venlafaxine extended release
capsule-treated patients. Premarketing, no seizures occurred among 1381 Effexor
XR-treated patients in Generalized Anxiety Disorder studies or among 277
Effexor XR-treated patients in Social Anxiety Disorder Studies. However,
patients with a history of convulsive disorders were excluded from most of
these studies. Venlafaxine should be used cautiously in patients with a history
of seizures, and should be promptly discontinued in any patient who develops
seizures.
Serum Cholesterol Elevation: Clinically relevant
increases in total serum cholesterol were recorded in 5.3% of
venlafaxine-treated patients and 0.0% of placebo-treated patients treated for
at least 3 months in placebo-controlled trials in Major Depressive Disorders
(see Adverse Effects, Laboratory Changes).
Consistent with the above
findings, elevations of High Density Lipoprotein Cholesterol (HDL), Low Density
Lipoprotein Cholesterol (LDL) and the overall ratio of Total Cholesterol/HDL
have been observed in placebo controlled clinical trials for Social Anxiety
Disorder (SAD). Measurement of serum cholesterol levels (including a complete
lipid profile/fractionation and an assessment of the patient’s individual risk
factors) should be considered especially during long-term treatment.
Abnormal Bleeding: There have been reports of
abnormal bleeding (most commonly ecchymosis) associated with venlafaxine
treatment. While a causal relationship to venlafaxine is unclear, impaired
platelet aggregation may result from platelet serotonin depletion and
contribute to such occurrences. Skin and other mucous membrane bleedings
have been reported following treatment with venlafaxine. Venlafaxine should
therefore be used with caution in patients concomitantly treated with drugs
that give an increased risk for bleeding (e.g. anticoagulants, nonsteroidal
anti-inflammatories and ASA) and in patients with a known tendency for bleeding
or those with predisposing conditions.
Discontinuation Symptoms: Discontinuation
symptoms have been assessed both in patients with depression and those with
anxiety. Abrupt discontinuation, dose reduction, or tapering of venlafaxine at
various doses has been found to be associated with the appearance of new
symptoms, the frequency of which increased with increased dose level and with
longer duration of treatment. If venlafaxine is used until or shortly before
birth, discontinuation effects in the newborn should be considered.
Reported symptoms
include anorexia, anxiety, agitation, confusion, convulsions, coordination
impaired, diarrhea, dizziness, dry mouth, dysphoric mood, fasciculation,
fatigue, headache, hypomania, insomnia, nausea, nervousness, nightmares,
paresthesia, electric shock sensations, sensory disturbances (including shock
like electrical sensations), sleep disturbances, somnolence, sweating, tinnitus,
vertigo, and vomiting. Where such symptoms occurred they were usually
self-limiting but in a few patients continued for several weeks.
Discontinuation effects
are well known to occur with antidepressants, and, therefore, it is recommended
that the dosage be tapered gradually and the patient monitored (see Dosage).
Activation of Mania/Hypomania: During Phase II
and III trials, mania or hypomania occurred in 0.5% of venlafaxine
tablet-treated patients and in 0.3% and 0% of venlafaxine capsule-treated
patients in depression and anxiety studies respectively. In premarketing Social
Anxiety Disorder studies, no Effexor XR-treated patients and no placebo-treated
patients experienced mania or hypomania. Mania or hypomania occurred in 0.5% of
all venlafaxine-treated patients. Mania/hypomania has also been reported in a
small proportion of patients with major affective disorder who were treated
with other marketed antidepressants. As with all antidepressants, venlafaxine
should be used cautiously in patients with a history of mania.
Allergic Reactions: Patients should be advised
to notify their physician if they develop a rash, hives or a related allergic
phenomenon.
Hyponatremia: As with some other
antidepressants, several cases of hyponatremia have been reported with
venlafaxine, usually in volume-depleted or dehydrated patients including those
taking diuretics. The hyponatremia appeared to be reversible when venlafaxine
was discontinued. The majority of these occurrences have been in elderly
individuals.
Inappropriate Antidiuretic Hormone Secretion:
Rare events of Syndrome of Inappropriate Antidiuretic Hormone (SIADH) secretion
have been reported, usually in volume-depleted or dehydrated patients including
elderly patients and patients taking diuretics treated with venlafaxine.
Although the reported events occurred coincident with treatment with
venlafaxine, the relationship to treatment is unknown.
Patients with Concomitant Illness: Clinical
experience with venlafaxine in patients with concomitant systemic illness is
limited. Caution is advised in administering venlafaxine to patients with
diseases or conditions that could affect hemodynamic responses or metabolism.
Patients should be questioned about any prescription or “over the counter
drugs, herbal or natural products or dietary supplements” that they are taking,
or planning to take, since there is a potential for interactions.
Cardiac Disease: Venlafaxine has not been
evaluated or used to any appreciable extent in patients with a recent history
of myocardial infarction or unstable heart disease. Patients with these
diagnoses were systematically excluded from many clinical studies during the
product's clinical trials. Therefore it should be used with caution in these
patients. Evaluation of the ECGs for 769 patients who received venlafaxine
immediate release tablets in 4- to 6-week double-blind trials showed
that the incidence of trial-emergent conduction abnormalities did not differ
from that with placebo.
The ECGs for 357
patients who received venlafaxine extended release and 285 patients who
received placebo in 8- to 12-week double-blind, placebo-controlled trials
were analyzed. The mean change from baseline in corrected QT interval (QTc) for
venlafaxine extended release-treated patients was increased relative to that
for placebo-treated patients (increase of 4.7 msec for venlafaxine extended
release and decrease of 1.9 msec for placebo). The clinical significance of
this change is unknown. Three of 705 venlafaxine extended release-treated
patients in phase III studies experienced QTc prolongation to 500 msec during
treatment. Baseline QTc was >450 msec for all 3 patients.
ECGs are available for
815 patients who received venlafaxine extended release and 379 patients who
received placebo in up to 6-month, double-blind, placebo-controlled trials in
generalized anxiety disorder. The mean change from baseline in the corrected QT
interval (QTc) for venlafaxine extended release-treated patients in the GAD
studies did not differ significantly from that with placebo. One of the 815
venlafaxine extended release-treated patients experienced QTc prolongation to
593 msec. Baseline QTc was 460 msec for this one patient.
Electrocardiograms were
evaluated for 277 patients who received Effexor XR and 274 patients who
received placebo in 12-week double-blind, placebo-controlled trials in Social
Anxiety Disorder. the mean change from baseline QTc for Effexor XR-treated
patients in the Social Anxiety Disorder studies was increased relative to that
for placebo-treated patients (increase of 2.8 msec for Effexor XR and decrease
of 2.0 msec for placebo).
No case of sudden
unexplained death or serious ventricular arrhythmia, which are possible
clinical sequelae of QTc prolongation, was reported in venlafaxine extended
release premarketing studies.
The mean heart rate was
increased by about 3-4 beats per minute during treatment with Effexor and
Effexor XR in clinical trials of depression and GAD. The mean change from
baseline in heart rate for Effexor XR-treated patients in the Social Anxiety
Disorder studies was significantly higher than that for placebo (a mean
increase of 5 beats per minute for Effexor XR and no change for placebo).
Increases in heart rate
can occur, particularly at higher doses. Caution should be exercised in
patients whose underlying conditions might be compromised by increases in heart
rate.
Venlafaxine treatment
has been associated with sustained hypertension (see Warnings).
Hepatic and Renal Disease: In patients with
hepatic or renal impairment (GFR=10 to 70 mL/min), the pharmacokinetic
disposition of both venlafaxine and the active metabolite ODV are significantly
altered. Dosage adjustment is necessary in these patients (see Dosage).
Insomnia and Nervousness: Treatment-emergent
insomnia and nervousness were more commonly reported for patients treated with
Effexor and Effexor XR than with placebo (see Adverse Effects) in depression,
GAD, and Social Anxiety Disorder studies, as shown in Table 4.
CPS:Effexor_t4Click here for Table 4
Table 4: Effexor XR
Incidence of Insomnia and Nervousness in
Placebo-Controlled Depression, GAD, and Social Anxiety Disorder Trials
|
|
Depression
|
GAD
|
Social Anxiety
Disorder
|
|
Symptom
|
Effexor XR
n=357
|
Placebo
n=285
|
Effexor XR
n=1381
|
Placebo
n=555
|
Effexor XR
n=277
|
Placebo
n=274
|
|
|
Insomnia
|
17%
|
11%
|
15%
|
10%
|
23%
|
|
