WARNINGS
Potential for Interaction with Monoamine
Oxidase Inhibitors
Adverse reactions, some of which were serious, have been
reported in patients who have recently been discontinued
from a monoamine oxidase inhibitor (MAOI) and started
on venlafaxine HCl, or who have recently had venlafaxine
HCl therapy discontinued prior to initiation of an MAOI.
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 a 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 hyperthermia 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. The effects of combined use of venlafaxine
and MAOIs have not been evaluated in humans or animals.
Therefore, it is recommended that venlafaxine HCl not
be used in combination with an MAOI, or within at least
14 days of discontinuing treatment with an MAOI. Based
on the half-life of venlafaxine HCl, at least 7 days should
be allowed after stopping venlafaxine HCl before starting
an MAOI.
Sustained Hypertension
Immediate Release Tablets: Venlafaxine
treatment is associated with sustained increases in blood
pressure. (1) In a premarketing study comparing three fixed
doses of venlafaxine (75, 225, and 375 mg/day) and placebo,
a mean increase in supine diastolic blood pressure (SDBP)
of 7.2 mm Hg was seen in the 375 mg/day group at week 6
compared to essentially no changes in the 75 and 225 mg/day
groups and a mean decrease in SDBP of 2.2 mm Hg in the placebo
group. (2) An analysis for patients meeting criteria for
sustained hypertension (defined as treatment-emergent SDBP
³ 90 mm Hg and ³ 10 mm Hg above baseline for 3
consecutive visits) revealed a dose-dependent increase in
the incidence of sustained hypertension for venlafaxine
(see TABLE 1).
| TABLE 1 Probability
of Sustained Elevation in SDBP (Pool of Premarketing
Venlafaxine Studies) |
| Treatment Group |
|
Incidence of Sustained
Elevation in SDBP |
| Venlafaxine |
< 100
mg/day |
3% |
| 101-200
mg/day |
5% |
| 201-300
mg/day |
7% |
| >
300 mg/day |
13% |
| Placebo |
|
2% |
An analysis of the patients with sustained hypertension
and the 19 venlafaxine patients who were discontinued from
treatment because of hypertension (<1% of total venlafaxine
treated group) revealed that most of the blood pressure
increases were in a modest range (10-15 mm Hg, SDBP).
Nevertheless, sustained increases of this magnitude could
have adverse consequences. Therefore, it is recommended
that patients receiving venlafaxine have regular monitoring
of blood pressure. For patients who experience a sustained
increase in blood pressure while receiving venlafaxine,
either dose reduction or discontinuation should be considered.
Extended Release Tablets: Venlafaxine
is associated with sustained increases in blood pressure
in some patients. Among patients treated with 75-375 mg
per day of venlafaxine HCl (extended release) in premarketing
studies, 3% (19/705) experienced sustained hypertension
[defined as treatment-emergent supine diastolic blood
pressure (SDBP) ³90 mm Hg and ³10 mm Hg above
baseline for 3 consecutive on-therapy visits]. Experience
with the immediate-release venlafaxine showed that sustained
hypertension was dose-related, increasing from 3-7% at
100-300 mg per day to 13% at doses above 300 mg per day.
An insufficient number of patients received mean doses
of venlafaxine HCl (extended release) > 300 mg/day
to fully evaluate the incidence of sustained blood pressure
at these higher doses.
In placebo-controlled premarketing depression studies
with venlafaxine HCl (extended release) 75-225 mg/day,
a final on-drug mean increase in supine diastolic blood
pressure (SDBP) of 1.2 mm Hg was observed for extended
release venlafaxine HCl-treated patients compared with
a mean decrease of 0.2 mm Hg for placebo-treated patients.
In premarketing depression studies, 0.7% (5/705) of the
extended release venlafaxine HCl-treated patients discontinued
treatment because of elevated blood pressure. Among these
patients, most of the blood pressure increases were in
a modest range (12-16 mm Hg, SDBP).
Sustained increases of SDBP could have adverse consequences.
Therefore, it is recommended that patients receiving venlafaxine
HCl (extended release) have regular monitoring of blood
pressure. For patients who experience a sustained increase
in blood pressure while receiving venlafaxine, either dose
reduction or discontinuation should be considered.
PRECAUTIONS
General
Insomnia and Nervousness
Immediate Release Tablets: Treatment-emergent
anxiety, nervousness, and insomnia were more commonly reported
for venlafaxine-treated patients compared to placebo-treated
patients in a pooled analysis of short-term, double-blind,
placebo-controlled depression studies, as shown in TABLE
2.
| TABLE 2 |
| Symptom |
Venlafaxine n = 1033 |
Placebo n = 609 |
| Anxiety |
6% |
3% |
| Nervousness |
13% |
6% |
| Insomnia |
18% |
10% |
Anxiety, nervousness, and insomnia led to drug discontinuation
in 2%, 2%, and 3%, respectively, of the patients treated
with venlafaxine in the phase 2-3 depression studies.
Extended Release Capsules: Treatment-emergent
insomnia and nervousness were more commonly reported for
patients treated with venlafaxine hydrochloride extended
release capsules than with placebo in a pooled analysis
of short-term depression studies, as shown in TABLE 3.
| TABLE 3 Incidence
of Insomnia and Nervousness in Placebo-Controlled
Trials |
| Symptom |
Depression |
GAD |
Venlafaxine
HCl (extended release)
(n = 357) |
Placebo
(n = 285) |
Venlafaxine
HCl (extended release)
(n = 476) |
Placebo
(n = 285) |
| Insomnia |
17% |
11% |
22% |
11% |
| Nervousness |
10% |
5% |
12% |
5% |
Insomnia and nervousness each led to drug discontinuation
in 0.9% of the patients treated with venlafaxine HCl (extended
release) in Phase 3 studies.
In Phase 3 GAD trials, insomnia and nervousness led to
drug discontinuation in 5% and 3%, respectively, of the
patients treated with venlafaxine HCl extended-release.
Changes in Appetite and Weight
Treatment-emergent anorexia was more commonly reported
for venlafaxine-treated (11% tablets/ 8% extended-release)
than placebo treated patients (2% tablets/ 4% extended-release)
in the pool of short-term, double-blind, placebo-controlled
depression studies. A dose-dependent weight loss was often
noted in patients treated with venlafaxine for several
weeks. Significant weight loss, especially in underweight
depressed patients, may be an undesirable result of venlafaxine
treatment. A loss of 5% or more of body weight occurred
in 6% (7% extended-release) of patients treated with venlafaxine
compared with 1% (2% extended-release) of patients treated
with placebo and 3% of patients treated with another antidepressant.
However, discontinuation for weight loss associated with
venlafaxine tablets was uncommon (0.1% of venlafaxine-treated
patients in the phase 2-3 depression trials). Discontinuation
rates for anorexia and weight loss associated with venlafaxine
HCl (extended release) were low (1.0% and 0.1%, respectively,
of extended release venlafaxine HCl-treated patients in
Phase 3 studies).
In the pool of short-term GAD studies, treatment-emergent
anorexia was reported in 13% and 2% of patients receiving
venlafaxine HCl extended-release and placebo, respectively.
A loss of 7% or more of body weight occurred in 3% of
the venlafaxine HCl extended-release-treated and 0% of
the placebo-treated patients in these trials. Discontinuation
rates for anorexia and weight loss were low (1.7% and
0.2% respectively, of venlafaxine HCl extended-release-treated
patients).
Activation of Mania/Hypomania
During premarketing depression studies, mania or hypomania
occurred in 0.3% of extended-release venlafaxine HCl-treated
patients compared with 0.0% of placebo patients. In premarketing
GAD studies, 0.0% of venlafaxine HCl extended-release
patients and 0.5% of placebo-treated patients experienced
mania or hypomania. In all premarketing depression trials
with venlafaxine HCl, mania or hypomania occurred in 0.5%
of venlafaxine-treated patients compared with 0% of placebo
patients. Mania/hypomania has also been reported in a
small proportion of patients with mood disorders who were
treated with other marketed antidepressants. As with all
antidepressants, venlafaxine HCl extended-release should
be used cautiously in patients with a history of mania.
Seizures
During premarketing experience, no seizures occurred
among 705 extended-release venlafaxine HCl-treated patients
in the depression studies or among 476 venlafaxine HCl
extended-release-treated patients in GAD studies. In all
premarketing depression trials with venlafaxine HCl, seizures
were reported at various doses in 0.3% (8/3082) of venlafaxine-treated
patients. Venlafaxine HCl, like other antidepressants,
should be used cautionsly in patients with a history of
seizures and should be discontinued in any patient who
develops seizures.
Suicide
The possibility of a suicide attempt is inherent in depression
and may persist until significant remission occurs. Close
supervision of high-risk patients should accompany initial
drug therapy. Prescriptions for venlafaxine HCl should
be written for the smallest quantity of tablets or capsules
consistent with good patient management in order to reduce
the risk of overdose. The same precautions observed when
treating patients with depression should be observed when
treating patients with GAD.
Use in Patients with Concomitant Illness
Clinical experience with venlafaxine HCl in patients
with concomitant systemic illness is limited. Caution
is advised in administering venlafaxine HCl to patients
with diseases or conditions that could affect hemodynamic
responses or metabolism.
In patients with renal impairment (GFR=10-70 ml/min)
or cirrhosis of the liver, the clearances of venlafaxine
and its active metabolite were decreased, thus prolonging
the elimination half-lives of these substances. A lower
dose may be necessary (see DOSAGE AND ADMINISTRATION).
Venlafaxine hydrochloride, like all antidepressants, should
be used with caution in such patients.
Venlafaxine HCl 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 premarketing
testing.
Immediate-Release Tablets
Evaluation of the electrocardiograms for 769 patients
who received venlafaxine HCl in 4 to 6 week double-blind
placebo-controlled trials, however, showed that the incidence
of trial-emergent conduction abnormalities did not differ
from that with placebo. The mean heart rate in venlafaxine
HCl-treated patients was increased relative to baseline
by about 4 beats per minute.
Extended-Release Capsules
The electrocardiograms for 357 patients who received
venlafaxine HCl extended-release and 285 patients who
received placebo in 8- to 12-week double-blind, placebo-controlled
trials in depression and the electrocardiograms for 311
patients who received venlafaxine HCl extended-release
and 153 patients who received placebo in 8-week double-blind,
placebo-controlled trials in GAD were analyzed. The mean
change from baseline in corrected QT interval (QT) for
extended-release venlafaxine HCl-treated patients was
increased relative to that for placebo-treated patients
(increase of 4.7 msec for venlafaxine HCl extended-release
and decrease of 1.9 msec for placebo). The clinical significance
of these changes is unknown. The mean change from baseline
in corrected QT interval (QTc) for venlafaxine HCl extended-release-treated
patients in the GAD studies did not differ significantly
from that with placebo.
In these same trials, the mean change from baseline in
heart rate for extended release venlafaxine HCl-treated
patients was significantly higher than that for placebo
(a mean increase of 4 beats per minute for venlafaxine
HCl (extended release) and 1 beat per minute for placebo).
The mean change from baseline in heart rate for venlafaxine
HCl extended-release-treated patients in the GAD studies
was significantly higher than that for placebo (a mean
increase of 3 beats per minut for venlafaxine HCl extended-release
and no change for placebo.) The clinical significance
of these changes is unknown.
Information for Patients
Physicians are advised to discuss the following issues
with patients for whom they prescribe venlafaxine HCl:
Interference with Cognitive and Motor Performance:
Clinical studies were performed to examine
the effects of venlafaxine on behavioral performance of
healthy individuals. The results revealed no clinically
significant impairment of psychomotor, cognitive, or complex
behavior performance. However, since any psychoactive
drug may impair judgment, thinking, or motor skills, patients
should be cautioned about operating hazardous machinery,
including automobiles, until they are reasonably certain
that venlafaxine HCl therapy does not adversely affect
their ability to engage in such activities.
Concomitant Modification: Patients
should be advised to inform their physicians if they are
taking, or plan to take, any prescription or over-the-counter
drugs, since there is a potential for interactions.
Alcohol: Although venlafaxine
HCl has not been shown to increase the impairment of mental
and motor skills caused by alcohol, patients should be
advised to avoid alcohol while taking venlafaxine HCl.
Allergic Reactions: Patients
should be advised to notify their physician if they develop
a rash, hives, or a related allergic phenomenon.
Pregnancy: Patients should
be advised to notify their physician if they become pregnant
or intend to become pregnant during therapy.
Nursing: Patients should be
advised to notify their physician if they are breast-feeding
an infant.
Laboratory Tests
There are no specific laboratory tests recommended.
Carcinogenesis, Mutagenesis, Impairment of
Fertility
Carcinogenesis: Venlafaxine
was given by oral gavage to mice for 18 months at doses
up to 120 mg/kg per day, which was 16 times, on a mg/kg
basis, and 1.7 times on a mg/m2 basis, the maximum recommended
human dose. 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 levels of
venlafaxine were 1 times (male rats) and 6 times (female
rats) the plasma levels of patients receiving the maximum
recommended human dose. Plasma levels of the O-desmethyl
metabolite 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
the major human metabolite, O-desmethylvenlafaxine (ODV),
were not mutagenic in the Ames reverse mutation assay
in Salmonella bacteria or the CHO/HGPRT mammalian cell
forward gene mutation assay. Venlafaxine was also not
mutagenic in the in vitro BALB/c-313 mouse cell transformation
assay, the sister chromatid exchange assay in cultured
CHO cells, or the in vivo chromosomal aberration assay
in rat bone marrow. ODV was not mutagenic in the in vitro
CHO cell chromosomal aberration assay. There was a clastogenic
response in the in vivo chromosomal aberration assay in
rat bone marrow in male rats receiving 200 times, on a
mg/kg basis, or 50 times, on a mg/m2 basis, the maximum
human daily dose. The no effect dose was 67 times (mg/kg)
or 17 times (mg/m2) the human dose.
Impairment of Fertility: Reproduction
and fertility studies in rats showed no effects 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 up to 2 times on a mg/m2 basis.
Pregnancy, Teratogenic Effects, Pregnancy
Category C
Venlafaxine did not cause malformations in offspring
of rats or rabbits given doses up to 11 times (rat) or
12 times (rabbit) the maximum recommended human daily
dose on a mg/kg basis, or 2.5 times (rat) and 4 times
(rabbit) the human daily dose on a mg/m2 basis. However,
in rats, there was a decrease in pup weight, an increase
in stillborn pups, and an increase in pup deaths during
the first 5 days of lactation, when dosing began during
pregnancy and continued until weaning. The cause of these
deaths is not known. These effects occurred at 10 times
(mg/kg) or 2.5 times (mg/m2) the maximum human daily dose.
The no effect dose for rat pup mortality was 1.4 times
the human dose on a mg/kg basis or 0.25 times the human
dose on a mg/m2 basis. There are no adequate and well-controlled
studies in pregnant women. Because animal reproduction
studies are not always predictive of human response, this
drug should be used during pregnancy only if clearly needed.
Labor and Delivery
The effect of venlafaxine HCl on labor and delivery in
humans is unknown.
Nursing Mothers
Venlafaxine and ODV have been reported to be excreted
in human milk. Because of the potential for serious adverse
reactions in nursing infants from venlafaxine HCl extended-release,
a decision should be made whether to discontinue nursing
or to discontinue the drug, taking into account the importance
of the drug to the mother.
Pediatric Use
Safety and effectiveness in pediatric patients have not
been established.
Geriatric Use
Approximately 4% of extended-release venlafaxine HCl-treated
patients in placebo-controlled premarketing depression
and GAD trials were 65 years of age or over. Of 2897 immediate
use venlafaxine HCl-treated patients in premarketing phase
depression studies, 12% (357) were 65 years of age or
over. No overall differences in effectiveness or safety
were observed between geriatric patients and younger patients,
and other reported clinical experience has not identified
differences in response between the elderly and younger
patients. However, greater sensitivity of some older individuals
cannot be ruled out. As with other antidepressants, several
cases of hyponatremia and syndrome of inappropriate antidiuretic
hormone secretion (SIADH) have been reported, usually
in the elderly.
The pharmacokinetics of venlafaxine and ODV are not substantially
altered in the elderly (see CLINICAL PHARMACOLOGY). No
dose adjustment is recommended for the elderly on the
basis of age alone, although other clinical circumstances,
some of which may be more common in the elderly, such
as renal or hepatic impairment, may warrant a dose reduction
(see DOSAGE AND ADMINISTRATION).
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