A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Effexor Warnings, Precautions, Pregnancy, Nursing, Abuse - Venlafaxine
Effexor Warnings, Precautions, Pregnancy, Nursing, Abuse - Venlafaxine
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 Effexor, or who have recently had Effexor 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 monoamine oxidase inhibitor, 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. Therefore, it is recommended that Effexor 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 Effexor, at least 7 days should be allowed after
stopping Effexor before starting an MAOI.
Clinical Worsening and Suicide Risk
Patients with major depressive disorder, both adult and pediatric,
may experience worsening of their depression and/or the emergence of suicidal
ideation and behavior (suicidality), whether or not they are taking antidepressant
medications, and this risk may persist until significant remission occurs. Although
there has been a long-standing concern that antidepressants may have a role
in inducing worsening of depression and the emergence of suicidality in certain
patients, a causal role for antidepressants in inducing such behaviors has not
been established.
Nevertheless, patients being treated with antidepressants
should be observed closely for clinical worsening and suicidality, especially
at the beginning of a course of drug therapy, or at the time of dose changes,
either increases or decreases. Consideration should be given to changing
the therapeutic regimen, including possibly discontinuing the medication, in
patients whose depression is persistently worse or whose emergent suicidality
is severe, abrupt in onset, or was not part of the patient’s presenting symptoms.
Because of the possibility of co-morbidity between major depressive
disorder and other psychiatric and nonpsychiatric disorders, the same precautions
observed when treating patients with major depressive disorder should be observed
when treating patients with other psychiatric and nonpsychiatric disorders.
The following symptoms, anxiety, agitation, panic attacks,
insomnia, irritability, hostility (aggressiveness), impulsivity, akathisia (psychomotor
restlessness), hypomania, and mania, have been reported in adult and pediatric
patients being treated with antidepressants for major depressive disorder as
well as for other indications, both psychiatric and nonpsychiatric.
Although a causal link between the emergence of such symptoms
and either the worsening of depression and/or the emergence of suicidal impulses
has not been established, consideration should be given to changing the therapeutic
regimen, including possibly discontinuing the medication, in patients for whom
such symptoms are severe, abrupt in onset, or were not part of the patient’s
presenting symptoms.
Families and caregivers of patients being treated with antidepressants
for major depressive disorder or other indications, both psychiatric and nonpsychiatric,
should be alerted about the need to monitor patients for the emergence of agitation,
irritability, and the other symptoms described above, as well as the emergence
of suicidality, and to report such symptoms immediately to health care providers.
Prescriptions for Effexor should be written for the smallest quantity of
tablets consistent with good patient management, in order to reduce the risk
of overdose.
If the decision has been made to discontinue treatment, medication
should be tapered, as rapidly as is feasible, but with recognition that abrupt
discontinuation can be associated with certain symptoms (see PRECAUTIONS
and DOSAGE AND ADMINISTRATION,
Discontinuing Effexor, for a description of the risks of discontinuation
of Effexor).
It should be noted that Effexor is not approved for use in
treating any indications in the pediatric population.
A major depressive episode may be the initial presentation
of bipolar disorder. It is generally believed (though not established in controlled
trials) that treating such an episode with an antidepressant alone may increase
the likelihood of precipitation of a mixed/manic episode in patients at risk
for bipolar disorder. Whether any of the symptoms described above represent
such a conversion is unknown. However, prior to initiating treatment with an
antidepressant, patients should be adequately screened to determine if they
are at risk for bipolar disorder; such screening should include a detailed psychiatric
history, including a family history of suicide, bipolar disorder, and depression.
It should be noted that Effexor is not approved for use in treating bipolar
depression.
Sustained Hypertension
Venlafaxine treatment is associated with sustained increases
in blood pressure in some patients. (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:
|
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 to 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.
PRECAUTIONS
General
Discontinuation of Treatment with Effexor
Discontinuation symptoms have been systematically evaluated
in patients taking venlafaxine, to include prospective analyses of clinical
trials in Generalized Anxiety Disorder and retrospective surveys of trials in
major depressive disorder. Abrupt discontinuation or dose reduction 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. Reported symptoms include agitation, anorexia,
anxiety, confusion, coordination impaired, diarrhea, dizziness, dry mouth, dysphoric
mood, fasciculation, fatigue, headaches, hypomania, insomnia, nausea, nervousness,
nightmares, sensory disturbances (including shock-like electrical sensations),
somnolence, sweating, tremor, vertigo, and vomiting.
During marketing of Effexor, other SNRIs (Serotonin and Norepinephrine
Reuptake Inhibitors), and SSRIs (Selective Serotonin Reuptake Inhibitors), there
have been spontaneous reports of adverse events occurring upon discontinuation
of these drugs, particularly when abrupt, including the following: dysphoric
mood, irritability, agitation, dizziness, sensory disturbances (e.g. paresthesias
such as electric shock sensations), anxiety, confusion, headache, lethargy,
emotional lability, insomnia, hypomania, tinnitus, and seizures. While these
events are generally self-limiting, there have been reports of serious discontinuation
symptoms.
Patients should be monitored for these symptoms when discontinuing
treatment with Effexor. A gradual reduction in the dose rather than abrupt cessation
is recommended whenever possible. If intolerable symptoms occur following a
decrease in the dose or upon discontinuation of treatment, then resuming the
previously prescribed dose may be considered. Subsequently, the physician may
continue decreasing the dose but at a more gradual rate (see DOSAGE
AND ADMINISTRATION).
Anxiety and Insomnia
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:
| |
Venlafaxine
|
Placebo
|
|
Symptom
|
n = 1033
|
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 and Phase 3 depression studies.
Changes in Weight
Adult Patients: A dose-dependent weight loss was noted in patients
treated with venlafaxine for several weeks. A loss of 5% or more of body weight
occurred in 6% of patients treated with venlafaxine compared with 1% of patients
treated with placebo and 3% of patients treated with another antidepressant.
However, discontinuation for weight loss associated with venlafaxine was uncommon
(0.1% of venlafaxine-treated patients in the Phase 2 and Phase 3 depression
trials).
The safety and efficacy of venlafaxine therapy in combination
with weight loss agents, including phentermine, have not been established. Co-administration
of Effexor and weight loss agents is not recommended. Effexor is not indicated
for weight loss alone or in combination with other products.
Pediatric Patients: Weight loss has been observed in pediatric
patients (ages 6-17) receiving Effexor XR. In a pooled analysis of four eight-week,
double-blind, placebo-controlled, flexible dose outpatient trials for major
depressive disorder (MDD) and generalized anxiety disorder (GAD), Effexor XR-treated
patients lost an average of 0.45 kg (n = 333), while placebo-treated patients
gained an average of 0.77 kg (n = 333). More patients treated with Effexor XR
than with placebo experienced a weight loss of at least 3.5% in both the MDD
and the GAD studies (18% of Effexor XR-treated patients vs. 3.6% of placebo-treated
patients; p<0.001). Weight loss was not limited
to patients with treatment-emergent anorexia (see PRECAUTIONS,
General, Changes in Appetite).
The risks associated with longer-term Effexor XR use were assessed
in an open-label study of children and adolescents who received Effexor XR for
up to six months. The children and adolescents in the study had increases in
weight that were less than expected based on data from age- and sex-matched
peers. The difference between observed weight gain and expected weight gain
was larger for children (<12 years old) than for
adolescents (>12 years old).
Changes in Height
Pediatric Patients: During the eight-week placebo-controlled
GAD studies, Effexor XR-treated patients (ages 6-17) grew an average of 0.3
cm (n = 122), while placebo-treated patients grew an average of 1.0 cm (n =
132); p=0.041. This difference in height increase was most notable in patients
younger than twelve. During the eight-week placebo-controlled MDD studies, Effexor
XR-treated patients grew an average of 0.8 cm (n = 146), while placebo-treated
patients grew an average of 0.7 cm (n = 147). In the six-month open-label study,
children and adolescents had height increases that were less than expected based
on data from age- and sex-matched peers. The difference between observed growth
rates and expected growth rates was larger for children (<12
years old) than for adolescents (>12 years old).
Changes in Appetite
Adult Patients: Treatment-emergent anorexia was more commonly
reported for venlafaxine-treated (11%) than placebo-treated patients (2%) in
the pool of short-term, double-blind, placebo-controlled depression studies.
Pediatric Patients: Decreased appetite has been observed in
pediatric patients receiving Effexor XR. In the placebo-controlled trials for
GAD and MDD, 10% of patients aged 6-17 treated with Effexor XR for up to eight
weeks and 3% of patients treated with placebo reported treatment-emergent anorexia
(decreased appetite). None of the patients receiving Effexor XR discontinued
for anorexia or weight loss.
Activation of Mania/Hypomania
During Phase 2 and Phase 3 trials, hypomania or mania occurred
in 0.5% of patients treated with venlafaxine. Activation of 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,
Effexor (venlafaxine hydrochloride) should be used cautiously in patients with
a history of mania.
Hyponatremia
Hyponatremia and/or the syndrome of inappropriate antidiuretic
hormone secretion (SIADH) may occur with venlafaxine. This should be taken into
consideration in patients who are, for example, volume-depleted, elderly, or
taking diuretics.
Mydriasis
Mydriasis has been reported in association with venlafaxine;
therefore patients with raised intraocular pressure or at risk of acute narrow
angle glaucoma should be monitored.
Seizures
During premarketing testing, seizures were reported in 0.26%
(8/3082) of venlafaxine-treated patients. Most seizures (5 of 8) occurred in
patients receiving doses of 150 mg/day or less. Effexor should be used cautiously
in patients with a history of seizures. It should be discontinued in any patient
who develops seizures.
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.
Serum Cholesterol Elevation
Clinically relevant increases in 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 (see ADVERSE
REACTIONS–Laboratory Changes). Measurement of serum cholesterol
levels should be considered during long-term treatment.
Use in Patients with Concomitant Illness
Clinical experience with Effexor in patients with concomitant
systemic illness is limited. Caution is advised in administering Effexor to
patients with diseases or conditions that could affect hemodynamic responses
or metabolism.
Effexor 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. Evaluation of the
electrocardiograms for 769 patients who received Effexor 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 Effexor-treated patients was increased relative to baseline by about
4 beats per minute.
The electrocardiograms for 357 patients who received Effexor
XR (the extended-release form of venlafaxine) 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 Effexor XR-treated
patients was increased relative to that for placebo-treated patients (increase
of 4.7 msec for Effexor XR and decrease of 1.9 msec for placebo). In these same
trials, the mean change from baseline in heart rate for Effexor XR-treated patients
was significantly higher than that for placebo (a mean increase of 4 beats per
minute for Effexor XR and 1 beat per minute for placebo). In a flexible-dose
study, with Effexor doses in the range of 200 to 375 mg/day and mean dose greater
than 300 mg/day, Effexor-treated patients had a mean increase in heart rate
of 8.5 beats per minute compared with 1.7 beats per minute in the placebo group.
As increases in heart rate were observed, caution should be
exercised in patients whose underlying medical conditions might be compromised
by increases in heart rate (eg, patients with hyperthyroidism, heart failure,
or recent myocardial infarction), particularly when using doses of Effexor above
200 mg/day.
In patients with renal impairment (GFR=10 to 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). Effexor (venlafaxine hydrochloride), like all antidepressants,
should be used with caution in such patients.
INFORMATION FOR PATIENTS
Physicians are advised to discuss the following issues with
patients for whom they prescribe Effexor:
Patients and their families should be encouraged to be alert
to the emergence of anxiety, agitation, panic attacks, insomnia, irritability,
hostility, impulsivity, akathisia, hypomania, mania, worsening of depression,
and suicidal ideation, especially early during antidepressant treatment. Such
symptoms should be reported to the patient’s physician, especially if they are
severe, abrupt in onset, or were not part of the patient’s presenting symptoms.
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 Effexor therapy does not
adversely affect their ability to engage in such activities.
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.
Concomitant Medication
Patients should be advised to inform their physicians if they
are taking, or plan to take, any prescription or over-the-counter drugs, including
herbal preparations, since there is a potential for interactions.
Alcohol
Although Effexor 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 Effexor.
Allergic Reactions
Patients should be advised to notify their physician if they
develop a rash, hives, or a related allergic phenomenon.
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-3T3 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.
Non-teratogenic Effects
Neonates exposed to Effexor, other SNRIs (Serotonin and Norepinephrine
Reuptake Inhibitors), or SSRIs (Selective Serotonin Reuptake Inhibitors), late
in the third trimester have developed complications requiring prolonged hospitalization,
respiratory support, and tube feeding. Such complications can arise immediately
upon delivery. Reported clinical findings have included respiratory distress,
cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting,
hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability,
and constant crying. These features are consistent with either a direct toxic
effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It
should be noted that, in some cases, the clinical picture is consistent with
serotonin syndrome (see PRECAUTIONS-Drug
Interactions-CNS-Active Drugs). When treating a pregnant woman
with Effexor during the third trimester, the physician should carefully consider
the potential risks and benefits of treatment (see DOSAGE
AND ADMINISTRATION).
Labor and Delivery
The effect of Effexor® (venlafaxine hydrochloride)
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 Effexor, 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
Effectiveness in pediatric patients has not been established.
(See WARNINGS-Clinical Worsening
and Suicide Risk.)
Although no studies have been designed to primarily assess
Effexor XR’s impact on the growth, development, and maturation of children and
adolescents, the studies that have been done suggest that Effexor XR may adversely
affect weight and height (see PRECAUTIONS,
General, Changes in Height and Changes in Weight). Should
the decision be made to treat a pediatric patient with Effexor, regular monitoring
of weight and height is recommended during treatment, particularly if it is
to be continued long term. The safety of Effexor XR treatment for pediatric
patients has not been systematically assessed for chronic treatment longer than
six months in duration.
In the studies conducted in pediatric patients (ages 6-17),
the occurrence of blood pressure and cholesterol increases considered to be
clinically relevant in pediatric patients was similar to that observed in adult
patients. Consequently, the precautions for adults apply to pediatric patients
(see WARNINGS, Sustained Hypertension,
and PRECAUTIONS, General, Serum
Cholesterol Elevation).
Geriatric Use
Of the 2,897 patients in Phase 2 and Phase 3 depression studies
with Effexor, 12% (357) were 65 years of age or over. No overall differences
in effectiveness or safety were observed between these patients and younger
patients, and other reported clinical experience generally 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).
top
