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Effexor Prescribing Information

Package insert / product label
Generic name: venlafaxine hydrochloride
Dosage form: tablets
Drug class: Serotonin-norepinephrine reuptake inhibitors

Medically reviewed by Drugs.com. Last updated on Mar 24, 2023.

On This Page

Description

Clinical Pharmacology

Clinical Studies

Indications and Usage

Contraindications

Warnings

Precautions

Patient Counseling Information

Drug Interactions

Adverse Reactions/Side Effects

Drug Abuse and Dependence

Overdosage

Dosage and Administration

How Supplied/Storage and Handling

Medication Guide

Rx only

Suicidality and Antidepressant Drugs

Antidepressants increased the risk compared to placebo of suicidal thinking and behavior
(suicidality) in children, adolescents, and young adults in short-term studies of Major Depressive

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Disorder (MDD) and other psychiatric disorders. Anyone considering the use of Effexor or any
other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical
need. Short-term studies did not show an increase in the risk of suicidality with antidepressants
compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants
compared to placebo in adults aged 65 and older. Depression and certain other psychiatric
disorders are themselves associated with increases in the risk of suicide. Patients of all ages
who are started on antidepressant therapy should be monitored appropriately and observed
closely for clinical worsening, suicidality, or unusual changes in behavior. Families and
caregivers should be advised of the need for close observation and communication with the
prescriber. Effexor is not approved for use in pediatric patients. (See WARNINGS: Clinical
Worsening and Suicide Risk, PRECAUTIONS: Information for Patients, and PRECAUTIONS:
Pediatric Use)

Effexor Description
Effexor (venlafaxine hydrochloride) is a structurally novel antidepressant for oral administration. It is
designated (R/S)-1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl] cyclohexanol hydrochloride or
(±)-1-[α-[(dimethyl-amino)methyl]-p-methoxybenzyl] cyclohexanol hydrochloride and has the empirical
formula of C17H27NO2 HCl. Its molecular weight is 313.87. The structural formula is shown below.

Venlafaxine hydrochloride is a white to off-white crystalline solid with a solubility of 572 mg/mL in
water (adjusted to ionic strength of 0.2 M with sodium chloride). Its octanol:water (0.2 M sodium
chloride) partition coefficient is 0.43.

Compressed tablets contain venlafaxine hydrochloride equivalent to 25 mg, 37.5 mg, 50 mg, 75 mg,
or 100 mg venlafaxine. Inactive ingredients consist of cellulose, iron oxides, lactose, magnesium
stearate, and sodium starch glycolate.

Effexor - Clinical Pharmacology

Pharmacodynamics

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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, histaminergic, or α-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
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. 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%). Renal elimination of venlafaxine and its metabolites
is the primary route of excretion. The relative bioavailability of venlafaxine from a tablet was 100%
when compared to an oral solution. Food has no significant effect on the absorption of venlafaxine or
on the formation of ODV.

The degree of binding of venlafaxine to human plasma is 27% ± 2% at concentrations ranging from
2.5 to 2215 ng/mL. The degree of ODV binding to human plasma is 30% ± 12% at concentrations
ranging from 100 to 500 ng/mL. Protein-binding-induced drug interactions with venlafaxine are not
expected.

Steady-state concentrations of both 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). Plasma clearance, elimination half-life and
steady-state volume of distribution were unaltered for both venlafaxine and ODV after multiple-
dosing. Mean ± SD steady-state plasma clearance of venlafaxine and ODV is 1.3 ± 0.6 and 0.4 ± 0.2
L/h/kg, respectively; elimination half-life is 5 ± 2 and 11 ± 2 hours, respectively; and steady-state
volume of distribution is 7.5 ± 3.7 L/kg and 5.7 ± 1.8 L/kg, respectively. When equal daily doses of
venlafaxine were administered as either b.i.d. or t.i.d. regimens, the drug exposure (AUC) and
fluctuation in plasma levels of venlafaxine and ODV were comparable following both regimens.

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

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of a patient is generally not necessary (see DOSAGE AND ADMINISTRATION).

Liver Disease
In 9 subjects 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 subjects compared to
normal subjects. ODV elimination half-life was prolonged by about 60% and clearance decreased by
about 30% in cirrhotic subjects 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.

In a second study, venlafaxine was administered orally and intravenously in normal (n = 21) subjects,
and in Child-Pugh A (n = 8) and Child-Pugh B (n = 11) subjects (mildly and moderately impaired,
respectively). Venlafaxine oral bioavailability was increased 2-3 fold, oral elimination half-life was
approximately twice as long and oral clearance was reduced by more than half, compared to normal
subjects. In hepatically impaired subjects, ODV oral elimination half-life was prolonged by about 40%,
while oral clearance for ODV was similar to that for normal subjects. A large degree of intersubject
variability was noted.

Dosage adjustment is necessary in these hepatically impaired 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).

Related/similar drugs
Vraylar, sertraline, trazodone, fluoxetine, Lexapro, venlafaxine, Zoloft

Clinical Studies

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The efficacy of Effexor (venlafaxine hydrochloride) as a treatment for major depressive disorder was
established in 5 placebo-controlled, short-term trials. Four of these were 6-week trials in adult
outpatients meeting DSM-III or DSM-III-R criteria for major depression: two involving dose titration
with Effexor in a range of 75 to 225 mg/day (t.i.d. schedule), the third involving fixed Effexor 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 adult inpatients meeting DSM-III-R criteria for major
depression with melancholia whose Effexor doses were titrated in a range of 150 to 375 mg/day (t.i.d.
schedule). In these 5 studies, Effexor 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 Impression-Severity 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.

In one longer-term study, adult outpatients meeting DSM-IV criteria for major depressive disorder who
had responded during an 8-week open trial on Effexor XR (75, 150, or 225 mg, qAM) were
randomized to continuation of their same Effexor XR dose or to placebo, for up to 26 weeks of
observation for relapse. Response during the open phase was defined as a CGI Severity of Illness
item score of ≤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. Patients receiving continued Effexor
XR treatment experienced significantly lower relapse rates over the subsequent 26 weeks compared
with those receiving placebo.

In a second longer-term trial, adult outpatients meeting DSM-III-R criteria for major depression,
recurrent type, who had responded (HAM-D-21 total score ≤12 at the day 56 evaluation) and
continued to be improved [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)] during an initial 26 weeks of treatment on Effexor
(100 to 200 mg/day, on a b.i.d. schedule) were randomized to continuation of their same Effexor dose

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or to placebo. The follow-up period to observe patients for relapse, defined as a CGI Severity of
Illness item score ≥4, was for up to 52 weeks. Patients receiving continued Effexor treatment
experienced significantly lower relapse rates over the subsequent 52 weeks compared with those
receiving placebo.

Indications and Usage for Effexor

Effexor (venlafaxine hydrochloride) is indicated for the treatment of major depressive disorder.

The efficacy of Effexor in the treatment of major depressive disorder was established in 6-week
controlled trials of adult outpatients whose diagnoses corresponded most closely to the DSM-III or
DSM-III-R category of major depression and in a 4-week controlled trial of inpatients meeting
diagnostic criteria for major depression with melancholia (see CLINICAL TRIALS).

A major depressive episode implies a prominent and relatively persistent depressed or dysphoric
mood that usually interferes with daily functioning (nearly every day for at least 2 weeks); it should
include at least 4 of the following 8 symptoms: change in appetite, change in sleep, psychomotor
agitation or retardation, loss of interest in usual activities or decrease in sexual drive, increased
fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, and a suicide
attempt or suicidal ideation.

The efficacy of Effexor XR in maintaining an antidepressant response for up to 26 weeks following 8

weeks of acute treatment was demonstrated in a placebo-controlled trial. The efficacy of Effexor in
maintaining an antidepressant response in patients with recurrent depression who had responded
and continued to be improved during an initial 26 weeks of treatment and were then followed for a
period of up to 52 weeks was demonstrated in a second placebo-controlled trial (see CLINICAL
TRIALS). Nevertheless, the physician who elects to use Effexor/Effexor XR for extended periods
should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

Contraindications
Hypersensitivity to venlafaxine hydrochloride or to any excipients in the formulation.

Effexor must not be used concomitantly in patients taking MAOIs or in patients who have taken
MAOIs within the preceding 14 days due to the risk of serious, sometimes fatal, drug interactions with
SNRI or SSRI treatment or with other serotonergic drugs. These interactions have been associated
with symptoms that include tremor, myoclonus, diaphoresis, nausea, vomiting, flushing, dizziness,
hyperthermia with features resembling neuroleptic malignant syndrome, seizures, rigidity, autonomic
instability with possible rapid fluctuations of vital signs, and mental status changes that include
extreme agitation progressing to delirium and coma. Based on the half-life of venlafaxine, at least 7

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days should be allowed after stopping Effexor before starting an MAOI (see DOSAGE AND
ADMINISTRATION).

Warnings
Clinical Worsening and Suicide Risk
Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening
of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual
changes in behavior, whether or not they are taking antidepressant medications, and this risk may
persist until significant remission occurs. Suicide is a known risk of depression and certain other
psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There
has been a long standing concern, however, that antidepressants may have a role in inducing
worsening of depression and the emergence of suicidality in certain patients during the early phases
of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs
and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in
children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and
other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with
antidepressants compared to placebo in adults beyond age 24; there was a reduction with
antidepressants compared to placebo in adults aged 65 and older.

The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive
compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9
antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults
with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2
months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk
of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all
drugs studied. There were differences in absolute risk of suicidality across the different indications,
with the highest incidence in MDD. The risk differences (drug vs placebo), however, were relatively
stable within age strata and across indications. These risk differences (drug-placebo difference in the
number of cases of suicidality per 1000 patients treated) are provided in Table 1.

Table 1

Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated

Increases Compared to Placebo

<18 14 additional cases

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18-24 5 additional cases

Decreases Compared to Placebo

25-64 1 fewer case

≥65 6 fewer cases

No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the
number was not sufficient to reach any conclusion about drug effect on suicide.

It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months.
However, there is substantial evidence from placebo-controlled maintenance trials in adults with
depression that the use of antidepressants can delay the recurrence of depression.

All patients being treated with antidepressants for any indication should be monitored
appropriately and observed closely for clinical worsening, suicidality, and unusual changes in
behavior, especially during the initial few months of a course of drug therapy, or at times of
dose changes, either increases or decreases.

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, there is concern that such symptoms may
represent precursors to emerging suicidality.

Consideration should be given to changing the therapeutic regimen, including possibly discontinuing
the medication, in patients whose depression is persistently worse, or who are experiencing emergent
suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if
these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.

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, Discontinuation of Treatment with
Effexor, for a description of the risks of discontinuation of Effexor).

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

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need to monitor patients for the emergence of agitation, irritability, unusual changes in
behavior, and the other symptoms described above, as well as the emergence of suicidality,
and to report such symptoms immediately to health care providers. Such monitoring should
include daily observation by families and caregivers. 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.

Screening Patients for Bipolar Disorder

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 with depressive symptoms
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.

Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions

The development of a potentially life-threatening serotonin syndrome or Neuroleptic Malignant
Syndrome (NMS)-like reactions have been reported with SNRIs and SSRIs alone, including Effexor
treatment, but particularly with concomitant use of serotonergic drugs (including triptans) with drugs
which impair metabolism of serotonin (including MAOIs), or with antipsychotics or other dopamine
antagonists. Serotonin syndrome symptoms may include mental status changes (e.g., agitation,
hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia),
neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms
[e.g., nausea, vomiting diarrhea] (see PRECAUTIONS, Drug Interactions). Serotonin syndrome, in
its most severe form can resemble neuroleptic malignant syndrome, which includes hyperthermia,
muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status
changes. Patients should be monitored for the emergence of serotonin syndrome or NMS-like signs
and symptoms.

The concomitant use of Effexor with MAOIs intended to treat depression is contraindicated (see
CONTRAINDICATIONS).

If concomitant treatment of Effexor with a 5-hydroxytryptamine receptor agonist (triptan) is clinically

warranted, careful observation of the patient is advised, particularly during treatment initiation and
dose increases (see PRECAUTIONS, Drug Interactions).

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The concomitant use of Effexor with serotonin precursors (such as tryptophan) is not recommended
(see PRECAUTIONS, Drug Interactions).

Treatment with Effexor and any concomitant serotonergic or antidopaminergic agents, including
antipsychotics, should be discontinued immediately if the above events occur and supportive
symptomatic treatment should be initiated.

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 ≥ 90 mm Hg and ≥
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. Cases of
elevated blood pressure requiring immediate treatment have been reported in post marketing
experience. Pre-existing hypertension should be controlled before treatment with venlafaxine. It is

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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.

Mydriasis
Mydriasis has been reported in association with venlafaxine; therefore patients with raised intraocular
pressure or at risk of acute narrow-angle glaucoma (angle-closure glaucoma) should be monitored
(see PRECAUTIONS, Information for Patients).

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, impaired coordination and
balance, diarrhea, dizziness, dry mouth, dysphoric mood, fasciculation, fatigue, flu-like symptoms,
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

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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:

Symptom Venlafaxine Placebo

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-

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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 may occur as a result of treatment with SSRIs and SNRIs, including Effexor. In many
cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic
hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported.
Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also,
patients taking diuretics or who are otherwise volume depleted may be at greater risk (see

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PRECAUTIONS, Geriatric Use). Discontinuation of Effexor should be considered in patients with

symptomatic hyponatremia and appropriate medical intervention should be instituted.

Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment,
confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated
with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory
arrest, and death.

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
SSRIs and SNRIs, including Effexor, may increase the risk of bleeding events. Concomitant use of
aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anti-coagulants may add to this risk.
Case reports and epidemiological studies (case-control and cohort design) have demonstrated an
association between use of drugs that interfere with serotonin reuptake and the occurrence of
gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs use have ranged from
ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages.

Patients should be cautioned about the risk of bleeding associated with the concomitant use of
Effexor and NSAIDs, aspirin, or other drugs that affect coagulation.

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.

Interstitial Lung Disease and Eosinophilic Pneumonia

Interstitial lung disease and eosinophilic pneumonia associated with venlafaxine therapy have been
rarely reported. The possibility of these adverse events should be considered in venlafaxine-treated
patients who present with progressive dyspnea, cough or chest discomfort. Such patients should
undergo a prompt medical evaluation, and discontinuation of venlafaxine therapy should be
considered.

Use in Patients with Concomitant Illness

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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

Prescribers or other health professionals should inform patients, their families, and their caregivers
about the benefits and risks associated with treatment with Effexor and should counsel them in its
appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and Other
Serious Mental Illness, and Suicidal Thoughts or Actions” is available for Effexor. The prescriber or

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health professional should instruct patients, their families, and their caregivers to read the Medication
Guide and should assist them in understanding its contents. Patients should be given the opportunity
to discuss the contents of the Medication Guide and to obtain answers to any questions they may
have. The complete text of the Medication Guide is reprinted at the end of this document.

Patients should be advised of the following issues and asked to alert their prescriber if these occur
while taking Effexor.

Clinical Worsening and Suicide Risk: Patients, their families, and their caregivers should be
encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability,
hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other
unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during
antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of
patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since
changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health
professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting
symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking
and behavior and indicate a need for very close monitoring and possibly changes in the medication.

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.

Mydriasis
Mydriasis (prolonged dilation of the pupils of the eye) has been reported with venlafaxine. Patients
should be advised to notify their physician if they have a history of glaucoma or a history of increased
intraocular pressure (see WARNINGS).

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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 and nutritional supplements,
since there is a potential for interactions.

Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of
Effexor and triptans, tramadol, tryptophan supplements or other serotonergic agents (see
WARNINGS, Serotonin Syndrome and PRECAUTIONS, Drug Interactions, CNS-Active Drugs).

Patients should be cautioned about the concomitant use of Effexor and NSAIDs, aspirin, warfarin, or
other drugs that affect coagulation since combined use of psychotropic drugs that interfere with
serotonin reuptake and these agents has been associated with an increased risk of bleeding (see
PRECAUTIONS, Abnormal Bleeding).

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.

Drug Interactions
As with all drugs, the potential for interaction by a variety of mechanisms is a possibility.

Alcohol
A single dose of ethanol (0.5 g/kg) had no effect on the pharmacokinetics of venlafaxine or ODV
when venlafaxine was administered at 150 mg/day in 15 healthy male subjects. Additionally,
administration of venlafaxine in a stable regimen did not exaggerate the psychomotor and
psychometric effects induced by ethanol in these same subjects when they were not receiving
venlafaxine.

Cimetidine
Concomitant administration of cimetidine and venlafaxine in a steady-state study for both drugs
resulted in inhibition of first-pass metabolism of venlafaxine in 18 healthy subjects. The oral clearance

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of venlafaxine was reduced by about 43%, and the exposure (AUC) and maximum concentration
(Cmax) of the drug were increased by about 60%. However, co-administration of cimetidine had no
apparent effect on the pharmacokinetics of ODV, which is present in much greater quantity in the
circulation than is venlafaxine. The overall pharmacological activity of venlafaxine plus ODV is
expected to increase only slightly, and no dosage adjustment should be necessary for most normal
adults. However, for patients with pre-existing hypertension, and for elderly patients or patients with
hepatic dysfunction, the interaction associated with the concomitant use of venlafaxine and cimetidine
is not known and potentially could be more pronounced. Therefore, caution is advised with such
patients.

Diazepam
Under steady-state conditions for venlafaxine administered at 150 mg/day, a single 10 mg dose of
diazepam did not appear to affect the pharmacokinetics of either venlafaxine or ODV in 18 healthy
male subjects. Venlafaxine also did not have any effect on the pharmacokinetics of diazepam or its
active metabolite, desmethyldiazepam, or affect the psychomotor and psychometric effects induced
by diazepam.

Haloperidol
Venlafaxine administered under steady-state conditions at 150 mg/day in 24 healthy subjects
decreased total oral-dose clearance (Cl/F) of a single 2 mg dose of haloperidol by 42%, which
resulted in a 70% increase in haloperidol AUC. In addition, the haloperidol Cmax increased 88% when
coadministered with venlafaxine, but the haloperidol elimination half-life (t1/2) was unchanged. The
mechanism explaining this finding is unknown.

Lithium
The steady-state pharmacokinetics of venlafaxine administered at 150 mg/day were not affected
when a single 600 mg oral dose of lithium was administered to 12 healthy male subjects. O-
desmethylvenlafaxine (ODV) also was unaffected. Venlafaxine had no effect on the pharmacokinetics
of lithium (see also CNS-Active Drugs, below).

Drugs Highly Bound to Plasma Protein

Venlafaxine is not highly bound to plasma proteins; therefore, administration of Effexor to a patient
taking another drug that is highly protein bound should not cause increased free concentrations of the
other drug.

Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin)
Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the
case-control and cohort design that have demonstrated an association between use of psychotropic

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drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding
have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding.
Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs and
SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully
monitored when Effexor is initiated or discontinued.

Drugs that Inhibit Cytochrome P450 Isoenzymes

CYP2D6 Inhibitors: In vitro and in vivo studies indicate that venlafaxine is metabolized to its active
metabolite, ODV, by CYP2D6, the isoenzyme that is responsible for the genetic polymorphism seen in
the metabolism of many antidepressants. Therefore, the potential exists for a drug interaction
between drugs that inhibit CYP2D6-mediated metabolism and venlafaxine. However, although
imipramine partially inhibited the CYP2D6-mediated metabolism of venlafaxine, resulting in higher
plasma concentrations of venlafaxine and lower plasma concentrations of ODV, the total
concentration of active compounds (venlafaxine plus ODV) was not affected. Additionally, in a clinical
study involving CYP2D6-poor and -extensive metabolizers, the total concentration of active
compounds (venlafaxine plus ODV), was similar in the two metabolizer groups. Therefore, no dosage
adjustment is required when venlafaxine is coadministered with a CYP2D6 inhibitor.

Ketoconazole: A pharmacokinetic study with ketoconazole 100 mg b.i.d. with a single dose of
venlafaxine 50 mg in extensive metabolizers (EM; n = 14) and 25 mg in poor metabolizers (PM; n = 6)
of CYP2D6 resulted in higher plasma concentrations of both venlafaxine and O-desvenlafaxine
(ODV) in most subjects following administration of ketoconazole. Venlafaxine Cmax increased by 26%
in EM subjects and 48% in PM subjects. Cmax values for ODV increased by 14% and 29% in EM and
PM subjects, respectively.

Venlafaxine AUC increased by 21% in EM subjects and 70% in PM subjects (range in PMs -2% to
206%), and AUC values for ODV increased by 23% and 33% in EM and PM subjects (range in PMs
-38% to 105%) subjects, respectively. Combined AUCs of venlafaxine and ODV increased on
average by approximately 23% in EMS and 53% in PMs (range in PMs 4% to 134%).

Concomitant use of CYP3A4 inhibitors and venlafaxine may increase levels of venlafaxine and ODV.
Therefore, caution is advised if a patient's therapy includes a CYP3A4 inhibitor and venlafaxine
concomitantly.

CYP3A4 Inhibitors: In vitro studies indicate that venlafaxine is likely metabolized to a minor, less
active metabolite, N-desmethylvenlafaxine, by CYP3A4. Because CYP3A4 is typically a minor
pathway relative to CYP2D6 in the metabolism of venlafaxine, the potential for a clinically significant
drug interaction between drugs that inhibit CYP3A4-mediated metabolism and venlafaxine is small.

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The concomitant use of venlafaxine with a drug treatment(s) that potently inhibits both CYP2D6 and
CYP3A4, the primary metabolizing enzymes for venlafaxine, has not been studied. Therefore, caution
is advised should a patient's therapy include venlafaxine and any agent(s) that produce potent
simultaneous inhibition of these two enzyme systems.

Drugs Metabolized by Cytochrome P450 Isoenzymes

CYP2D6: In vitro studies indicate that venlafaxine is a relatively weak inhibitor of CYP2D6. These
findings have been confirmed in a clinical drug interaction study comparing the effect of venlafaxine to
that of fluoxetine on the CYP2D6-mediated metabolism of dextromethorphan to dextrorphan.

Imipramine—Venlafaxine did not affect the pharmacokinetics of imipramine and 2-OH-imipramine.

However, desipramine AUC, Cmax, and Cmin increased by about 35% in the presence of venlafaxine.
The 2-OH-desipramine AUCs increased by at least 2.5 fold (with venlafaxine 37.5 mg q12h) and by
4.5 fold (with venlafaxine 75 mg q12h). Imipramine did not affect the pharmacokinetics of venlafaxine
and ODV. The clinical significance of elevated 2-OH-desipramine levels is unknown.

Metoprolol—Concomitant administration of venlafaxine (50 mg every 8 hours for 5 days) and

metoprolol (100 mg every 24 hours for 5 days) to 18 healthy male subjects in a pharmacokinetic
interaction study for both drugs resulted in an increase of plasma concentrations of metoprolol by
approximately 30-40% without altering the plasma concentrations of its active metabolite, α-
hydroxymetoprolol. Metoprolol did not alter the pharmacokinetic profile of venlafaxine or its active
metabolite, O-desmethylvenlafaxine.

Venlafaxine appeared to reduce the blood pressure lowering effect of metoprolol in this study. The
clinical relevance of this finding for hypertensive patients is unknown. Caution should be exercised
with co-administration of venlafaxine and metoprolol.

Venlafaxine treatment has been associated with dose-related increases in blood pressure in some
patients. It is recommended that patients receiving Effexor have regular monitoring of blood pressure
(see WARNINGS).

Risperidone—Venlafaxine administered under steady-state conditions at 150 mg/day slightly inhibited

the CYP2D6-mediated metabolism of risperidone (administered as a single 1 mg oral dose) to its
active metabolite, 9-hydroxyrisperidone, resulting in an approximate 32% increase in risperidone
AUC. However, venlafaxine coadministration did not significantly alter the pharmacokinetic profile of
the total active moiety (risperidone plus 9-hydroxyrisperidone).

CYP3A4: Venlafaxine did not inhibit CYP3A4 in vitro. This finding was confirmed in vivo by clinical
drug interaction studies in which venlafaxine did not inhibit the metabolism of several CYP3A4

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substrates, including alprazolam, diazepam, and terfenadine.

Indinavir—In a study of 9 healthy volunteers, venlafaxine administered under steady-state conditions

at 150 mg/day resulted in a 28% decrease in the AUC of a single 800 mg oral dose of indinavir and a
36% decrease in indinavir Cmax. Indinavir did not affect the pharmacokinetics of venlafaxine and ODV.
The clinical significance of this finding is unknown.

CYP1A2: Venlafaxine did not inhibit CYP1A2 in vitro. This finding was confirmed in vivo by a clinical
drug interaction study in which venlafaxine did not inhibit the metabolism of caffeine, a CYP1A2
substrate.

CYP2C9: Venlafaxine did not inhibit CYP2C9 in vitro. In vivo, venlafaxine 75 mg by mouth every 12
hours did not alter the pharmacokinetics of a single 500 mg dose of tolbutamide or the CYP2C9
mediated formation of 4-hydroxy-tolbutamide.

CYP2C19: Venlafaxine did not inhibit the metabolism of diazepam which is partially metabolized by
CYP2C19 (see Diazepam above).

Monoamine Oxidase Inhibitors

See CONTRAINDICATIONS.

CNS-Active Drugs
The risk of using venlafaxine in combination with other CNS-active drugs has not been systematically
evaluated (except in the case of those CNS-active drugs noted above). Consequently, caution is
advised if the concomitant administration of venlafaxine and such drugs is required.

Serotonergic Drugs: Based on the mechanism of action of Effexor and the potential for serotonin
syndrome, caution is advised when Effexor is co-administered with other drugs that may affect the
serotonergic neurotransmitter systems, such as triptans, SSRIs, other SNRIs, linezolid (an antibiotic
which is a reversible non-selective MAOI), lithium, tramadol, or St. John's Wort (see WARNINGS,
Serotonin Syndrome). If concomitant treatment of Effexor with these drugs is clinically warranted,
careful observation of the patient is advised, particularly during treatment initiation and dose
increases (see WARNINGS, Serotonin Syndrome). The concomitant use of Effexor with tryptophan
supplements is not recommended (see WARNINGS, Serotonin Syndrome).

Triptans: There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and
a triptan. If concomitant treatment of Effexor with a triptan is clinically warranted, careful observation
of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS,
Serotonin Syndrome).

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Electroconvulsive Therapy
There are no clinical data establishing the benefit of electroconvulsive therapy combined with Effexor
treatment.

Postmarketing Spontaneous Drug Interaction Reports

See ADVERSE REACTIONS, Postmarketing Reports.

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)

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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
Safety and effectiveness in the pediatric population have not been established (see BOX WARNING
and WARNINGS, Clinical Worsening and Suicide Risk). Two placebo-controlled trials in 766
pediatric patients with MDD and two placebo-controlled trials in 793 pediatric patients with GAD have
been conducted with Effexor XR, and the data were not sufficient to support a claim for use in

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pediatric patients.

Anyone considering the use of Effexor in a child or adolescent must balance the potential risks with
the clinical need.

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. SSRIs and SNRIs, including Effexor, have been
associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater
risk for this adverse event (see PRECAUTIONS, Hyponatremia).

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).

Adverse Reactions/Side Effects

Associated with Discontinuation of Treatment
Nineteen percent (537/2897) of venlafaxine patients in Phase 2 and Phase 3 depression studies
discontinued treatment due to an adverse event. The more common events (≥ 1%) associated with

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discontinuation and considered to be drug-related (ie, those events associated with dropout at a rate
approximately twice or greater for venlafaxine compared to placebo) included:

* Percentages based on the number of males.

— Less than 1%

CNS Venlafaxine Placebo

Somnolence 3% 1%

Insomnia 3% 1%

Dizziness 3% —

Nervousness 2% —

Dry mouth 2% —

Anxiety 2% 1%

Gastrointestinal

Nausea 6% 1%

Urogenital

Abnormal ejaculation* 3% —

Other

Headache 3% 1%

Asthenia 2% —

Sweating 2% —

Incidence in Controlled Trials

Commonly Observed Adverse Events in Controlled Clinical Trials

The most commonly observed adverse events associated with the use of Effexor® (incidence of 5%
or greater) and not seen at an equivalent incidence among placebo-treated patients (ie, incidence for
Effexor at least twice that for placebo), derived from the 1% incidence table below, were asthenia,
sweating, nausea, constipation, anorexia, vomiting, somnolence, dry mouth, dizziness, nervousness,
anxiety, tremor, and blurred vision as well as abnormal ejaculation/orgasm and impotence in men.

Adverse Events Occurring at an Incidence of 1% or More Among Effexor-Treated Patients

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The table that follows enumerates adverse events that occurred at an incidence of 1% or more, and
were more frequent than in the placebo group, among Effexor-treated patients who participated in
short-term (4- to 8-week) placebo-controlled trials in which patients were administered doses in a
range of 75 to 375 mg/day. This table shows the percentage of patients in each group who had at
least one episode of an event at some time during their treatment. Reported adverse events were
classified using a standard COSTART-based Dictionary terminology.

The prescriber should be aware that these figures cannot be used to predict the incidence of side
effects in the course of usual medical practice where patient characteristics and other factors differ
from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared
with figures obtained from other clinical investigations involving different treatments, uses and
investigators. The cited figures, however, do provide the prescribing physician with some basis for
estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the
population studied.

TABLE 2 Treatment-Emergent Adverse Experience Incidence in 4- to 8-Week Placebo-Controlled Clinical Trials1

Body System Preferred Term Effexor Placebo

(n=1033) (n=609)

1 Events reported by at least 1% of patients treated with Effexor (venlafaxine hydrochloride) are included, and are
rounded to the nearest %. Events for which the Effexor incidence was equal to or less than placebo are not listed in the
table, but included the following: abdominal pain, pain, back pain, flu syndrome, fever, palpitation, increased appetite,
myalgia, arthralgia, amnesia, hypesthesia, rhinitis, pharyngitis, sinusitis, cough increased, and dysmenorrhea3.
— Incidence less than 1%.
2 Incidence based on number of male patients.
3 Incidence based on number of female patients.

Body as a Whole Headache 25% 24%

Asthenia 12% 6%

Infection 6% 5%

Chills 3% —

Chest pain 2% 1%

Trauma 2% 1%

Cardiovascular Vasodilatation 4% 3%

Increased blood pressure/hypertension 2% —

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Tachycardia 2% —

Postural hypotension 1% —

Dermatological Sweating 12% 3%

Rash 3% 2%

Pruritus 1% —

Gastrointestinal Nausea 37% 11%

Constipation 15% 7%

Anorexia 11% 2%

Diarrhea 8% 7%

Vomiting 6% 2%

Dyspepsia 5% 4%

Flatulence 3% 2%

Metabolic Weight loss 1% —

Nervous System Somnolence 23% 9%

Dry mouth 22% 11%

Dizziness 19% 7%

Insomnia 18% 10%

Nervousness 13% 6%

Anxiety 6% 3%

Tremor 5% 1%

Abnormal dreams 4% 3%

Hypertonia 3% 2%

Paresthesia 3% 2%

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Libido decreased 2% —

Agitation 2% —

Confusion 2% 1%

Thinking abnormal 2% 1%

Depersonalization 1% —

Depression 1% —

Urinary retention 1% —

Twitching 1% —

Respiration Yawn 3% —

Special Senses Blurred vision 6% 2%

Taste perversion 2% —

Tinnitus 2% —

Mydriasis 2% —

Urogenital System Abnormal ejaculation/ orgasm 12%2 —2

Impotence 6%2 —2

Urinary frequency 3% 2%

Urination impaired 2% —

Orgasm disturbance 2%3 —3

Dose Dependency of Adverse Events

A comparison of adverse event rates in a fixed-dose study comparing Effexor (venlafaxine
hydrochloride) 75, 225, and 375 mg/day with placebo revealed a dose dependency for some of the
more common adverse events associated with Effexor use, as shown in the table that follows. The
rule for including events was to enumerate those that occurred at an incidence of 5% or more for at
least one of the venlafaxine groups and for which the incidence was at least twice the placebo
incidence for at least one Effexor group. Tests for potential dose relationships for these events

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(Cochran-Armitage Test, with a criterion of exact 2-sided p-value ≤ 0.05) suggested a dose-
dependency for several adverse events in this list, including chills, hypertension, anorexia, nausea,
agitation, dizziness, somnolence, tremor, yawning, sweating, and abnormal ejaculation.

TABLE 3 Treatment-Emergent Adverse Experience Incidence in a Dose Comparison Trial

Effexor (mg/day)

Body System/ Preferred Term

Placebo (n=92) 75 (n=89) 225 (n=89) 375 (n=88)

Body as a Whole

Abdominal pain 3.3% 3.4% 2.2% 8.0%

Asthenia 3.3% 16.9% 14.6% 14.8%

Chills 1.1% 2.2% 5.6% 6.8%

Infection 2.2% 2.2% 5.6% 2.3%

Cardiovascular System

Hypertension 1.1% 1.1% 2.2% 4.5%

Vasodilatation 0.0% 4.5% 5.6% 2.3%

Digestive System

Anorexia 2.2% 14.6% 13.5% 17.0%

Dyspepsia 2.2% 6.7% 6.7% 4.5%

Nausea 14.1% 32.6% 38.2% 58.0%

Vomiting 1.1% 7.9% 3.4% 6.8%

Nervous System

Agitation 0.0% 1.1% 2.2% 4.5%

Anxiety 4.3% 11.2% 4.5% 2.3%

Dizziness 4.3% 19.1% 22.5% 23.9%

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Insomnia 9.8% 22.5% 20.2% 13.6%

Libido decreased 1.1% 2.2% 1.1% 5.7%

Nervousness 4.3% 21.3% 13.5% 12.5%

Somnolence 4.3% 16.9% 18.0% 26.1%

Tremor 0.0% 1.1% 2.2% 10.2%

Respiratory System

Yawn 0.0% 4.5% 5.6% 8.0%

Skin and Appendages

Sweating 5.4% 6.7% 12.4% 19.3%

Special Senses

Abnormality of accommodation 0.0% 9.1% 7.9% 5.6%

Urogenital System

Abnormal ejaculation/orgasm 0.0% 4.5% 2.2% 12.5%

Impotence 0.0% 5.8% 2.1% 3.6%

(Number of men) (n=63) (n=52) (n=48) (n=56)

Adaptation to Certain Adverse Events

Over a 6-week period, there was evidence of adaptation to some adverse events with continued
therapy (eg, dizziness and nausea), but less to other effects (eg, abnormal ejaculation and dry
mouth).

Vital Sign Changes

Effexor (venlafaxine hydrochloride) treatment (averaged over all dose groups) in clinical trials was
associated with a mean increase in pulse rate of approximately 3 beats per minute, compared to no
change for placebo. In a flexible-dose study, with doses in the range of 200 to 375 mg/day and mean
dose greater than 300 mg/day, the mean pulse was increased by about 2 beats per minute compared
with a decrease of about 1 beat per minute for placebo.

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In controlled clinical trials, Effexor was associated with mean increases in diastolic blood pressure
ranging from 0.7 to 2.5 mm Hg averaged over all dose groups, compared to mean decreases ranging
from 0.9 to 3.8 mm Hg for placebo. However, there is a dose dependency for blood pressure increase
(see WARNINGS).

Laboratory Changes
Of the serum chemistry and hematology parameters monitored during clinical trials with Effexor, a
statistically significant difference with placebo was seen only for serum cholesterol. In premarketing
trials, treatment with Effexor tablets was associated with a mean final on-therapy increase in total
cholesterol of 3 mg/dL.

Patients treated with Effexor tablets for at least 3 months in placebo-controlled 12-month extension
trials had a mean final on-therapy increase in total cholesterol of 9.1 mg/dL compared with a
decrease of 7.1 mg/dL among placebo-treated patients. This increase was duration dependent over
the study period and tended to be greater with higher doses. Clinically relevant increases in serum
cholesterol, defined as 1) a final on-therapy increase in serum cholesterol ≥50 mg/dL from baseline
and to a value ≥261 mg/dL or 2) an average on-therapy increase in serum cholesterol ≥50 mg/dL
from baseline and to a value ≥261 mg/dL, were recorded in 5.3% of venlafaxine-treated patients and
0.0% of placebo-treated patients (see PRECAUTIONS-General-Serum Cholesterol Elevation).

ECG Changes
In an analysis of ECGs obtained in 769 patients treated with Effexor and 450 patients treated with
placebo in controlled clinical trials, the only statistically significant difference observed was for heart
rate, ie, a mean increase from baseline of 4 beats per minute for Effexor. In a flexible-dose study, with
doses in the range of 200 to 375 mg/day and mean dose greater than 300 mg/day, the mean change
in heart rate was 8.5 beats per minute compared with 1.7 beats per minute for placebo (see
PRECAUTIONS, General, Use in Patients with Concomitant Illness).

Other Events Observed During the Premarketing Evaluation of Venlafaxine

During its premarketing assessment, multiple doses of Effexor were administered to 2897 patients in
Phase 2 and Phase 3 studies. In addition, in premarketing assessment of Effexor XR (the extended
release form of venlafaxine), multiple doses were administered to 705 patients in Phase 3 major
depressive disorder studies and Effexor was administered to 96 patients. During its premarketing
assessment, multiple doses of Effexor XR were also administered to 1381 patients in Phase 3 GAD
studies and 277 patients in Phase 3 Social Anxiety Disorder studies. The conditions and duration of
exposure to venlafaxine in both development programs varied greatly, and included (in overlapping
categories) open and double-blind studies, uncontrolled and controlled studies, inpatient (Effexor
only) and outpatient studies, fixed-dose and titration studies. Untoward events associated with this

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exposure were recorded by clinical investigators using terminology of their own choosing.
Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals
experiencing adverse events without first grouping similar types of untoward events into a smaller
number of standardized event categories.

In the tabulations that follow, reported adverse events were classified using a standard COSTART-
based Dictionary terminology. The frequencies presented, therefore, represent the proportion of the
5356 patients exposed to multiple doses of either formulation of venlafaxine who experienced an
event of the type cited on at least one occasion while receiving venlafaxine. All reported events are
included except those already listed in Table 2 and those events for which a drug cause was remote.
If the COSTART term for an event was so general as to be uninformative, it was replaced with a more
informative term. It is important to emphasize that, although the events reported occurred during
treatment with venlafaxine, they were not necessarily caused by it.

Events are further categorized by body system and listed in order of decreasing frequency using the
following definitions: frequent adverse events are defined as those occurring on one or more
occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to
1/1000 patients; rare events are those occurring in fewer than 1/1000 patients.

Body as a whole—Frequent: accidental injury, chest pain substernal, neck pain; Infrequent: face
edema, intentional injury, malaise, moniliasis, neck rigidity, pelvic pain, photosensitivity reaction,
suicide attempt, withdrawal syndrome; Rare: appendicitis, bacteremia, carcinoma, cellulitis.

Cardiovascular system—Frequent: migraine; Infrequent: angina pectoris, arrhythmia, extrasystoles,

hypotension, peripheral vascular disorder (mainly cold feet and/or cold hands), syncope,
thrombophlebitis; Rare: aortic aneurysm, arteritis, first-degree atrioventricular block, bigeminy,
bradycardia, bundle branch block, capillary fragility, cardiovascular disorder (mitral valve and
circulatory disturbance), cerebral ischemia, coronary artery disease, congestive heart failure, heart
arrest, mucocutaneous hemorrhage, myocardial infarct, pallor.

Digestive system—Frequent: eructation; Infrequent: bruxism, colitis, dysphagia, tongue edema,

esophagitis, gastritis, gastroenteritis, gastrointestinal ulcer, gingivitis, glossitis, rectal hemorrhage,
hemorrhoids, melena, oral moniliasis, stomatitis, mouth ulceration; Rare: cheilitis, cholecystitis,
cholelithiasis, duodenitis, esophageal spasm, hematemesis, gastrointestinal hemorrhage, gum
hemorrhage, hepatitis, ileitis, jaundice, intestinal obstruction, parotitis, periodontitis, proctitis,
increased salivation, soft stools, tongue discoloration.

Endocrine system—Rare: goiter, hyperthyroidism, hypothyroidism, thyroid nodule, thyroiditis.

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Hemic and lymphatic system—Frequent: ecchymosis; Infrequent: anemia, leukocytosis, leukopenia,

lymphadenopathy, thrombocythemia, thrombocytopenia; Rare: basophilia, bleeding time increased,
cyanosis, eosinophilia, lymphocytosis, multiple myeloma, purpura.

Metabolic and nutritional—Frequent: edema, weight gain; Infrequent: alkaline phosphatase

increased, dehydration, hypercholesteremia, hyperglycemia, hyperlipemia, hypokalemia, SGOT
(AST) increased, SGPT (ALT) increased, thirst; Rare: alcohol intolerance, bilirubinemia, BUN
increased, creatinine increased, diabetes mellitus, glycosuria, gout, healing abnormal,
hemochromatosis, hypercalcinuria, hyperkalemia, hyperphosphatemia, hyperuricemia,
hypocholesteremia, hypoglycemia, hyponatremia, hypophosphatemia, hypoproteinemia, uremia.

Musculoskeletal system—Infrequent: arthritis, arthrosis, bone pain, bone spurs, bursitis, leg cramps,
myasthenia, tenosynovitis; Rare: pathological fracture, myopathy, osteoporosis, osteosclerosis,
plantar fasciitis, rheumatoid arthritis, tendon rupture.

Nervous system—Frequent: trismus, vertigo; Infrequent: akathisia, apathy, ataxia, circumoral

paresthesia, CNS stimulation, emotional lability, euphoria, hallucinations, hostility, hyperesthesia,
hyperkinesia, hypotonia, incoordination, libido increased, manic reaction, myoclonus, neuralgia,
neuropathy, psychosis, seizure, abnormal speech, stupor; Rare: akinesia, alcohol abuse, aphasia,
bradykinesia, buccoglossal syndrome, cerebrovascular accident, loss of consciousness, delusions,
dementia, dystonia, facial paralysis, feeling drunk, abnormal gait, Guillain-Barre Syndrome,
hyperchlorhydria, hypokinesia, impulse control difficulties, neuritis, nystagmus, paranoid reaction,
paresis, psychotic depression, reflexes decreased, reflexes increased, suicidal ideation, torticollis.

Respiratory system—Frequent: bronchitis, dyspnea; Infrequent: asthma, chest congestion,

epistaxis, hyperventilation, laryngismus, laryngitis, pneumonia, voice alteration; Rare: atelectasis,
hemoptysis, hypoventilation, hypoxia, larynx edema, pleurisy, pulmonary embolus, sleep apnea.

Skin and appendages—Infrequent: acne, alopecia, brittle nails, contact dermatitis, dry skin, eczema,
skin hypertrophy, maculopapular rash, psoriasis, urticaria; Rare: erythema nodosum, exfoliative
dermatitis, lichenoid dermatitis, hair discoloration, skin discoloration, furunculosis, hirsutism,
leukoderma, petechial rash, pustular rash, vesiculobullous rash, seborrhea, skin atrophy, skin striae.

Special senses—Frequent: abnormality of accommodation, abnormal vision; Infrequent: cataract,

conjunctivitis, corneal lesion, diplopia, dry eyes, eye pain, hyperacusis, otitis media, parosmia,
photophobia, taste loss, visual field defect; Rare: blepharitis, chromatopsia, conjunctival edema,
deafness, exophthalmos, glaucoma, retinal hemorrhage, subconjunctival hemorrhage, keratitis,
labyrinthitis, miosis, papilledema, decreased pupillary reflex, otitis externa, scleritis, uveitis.

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Urogenital system—Frequent: metrorrhagia*, prostatic disorder (prostatitis and enlarged prostate)*,

vaginitis*; Infrequent: albuminuria, amenorrhea*, cystitis, dysuria, hematuria, leukorrhea*,
menorrhagia*, nocturia, bladder pain, breast pain, polyuria, pyuria, urinary incontinence, urinary
urgency, vaginal hemorrhage*; Rare: abortion*, anuria, balanitis*, breast discharge, breast
engorgement, breast enlargement, endometriosis*, fibrocystic breast, calcium crystalluria, cervicitis*,
ovarian cyst*, prolonged erection*, gynecomastia (male)*, hypomenorrhea*, kidney calculus, kidney
pain, kidney function abnormal, female lactation*, mastitis, menopause*, oliguria, orchitis*,
pyelonephritis, salpingitis*, urolithiasis, uterine hemorrhage*, uterine spasm*, vaginal dryness*.

* Based on the number of men and women as appropriate.

Postmarketing Reports
Voluntary reports of other adverse events temporally associated with the use of venlafaxine that have
been received since market introduction and that may have no causal relationship with the use of
venlafaxine include the following: agranulocytosis, anaphylaxis, angioedema, aplastic anemia,
catatonia, congenital anomalies, impaired coordination and balance, CPK increased, deep vein
thrombophlebitis, delirium, EKG abnormalities such as QT prolongation; cardiac arrhythmias including
atrial fibrillation, supraventricular tachycardia, ventricular extrasystole, and rare reports of ventricular
fibrillation and ventricular tachycardia, including torsade de pointes; toxic epidermal necrolysis/
Stevens-Johnson Syndrome, erythema multiforme, extrapyramidal symptoms (including dyskinesia
and tardive dyskinesia), angle-closure glaucoma, hemorrhage (including eye and gastrointestinal
bleeding), hepatic events (including GGT elevation; abnormalities of unspecified liver function tests;
liver damage, necrosis, or failure; and fatty liver), interstitial lung disease, involuntary movements,
LDH increased, neutropenia, night sweats, pancreatitis, pancytopenia, panic, prolactin increased,
renal failure, rhabdomyolysis, shock-like electrical sensations or tinnitus (in some cases, subsequent
to the discontinuation of venlafaxine or tapering of dose), and syndrome of inappropriate antidiuretic
hormone secretion (usually in the elderly).

There have been reports of elevated clozapine levels that were temporally associated with adverse
events, including seizures, following the addition of venlafaxine. There have been reports of increases
in prothrombin time, partial thromboplastin time, or INR when venlafaxine was given to patients
receiving warfarin therapy.

Drug Abuse and Dependence

Controlled Substance Class
Effexor (venlafaxine hydrochloride) is not a controlled substance.

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Physical and Psychological Dependence

In vitro studies revealed that venlafaxine has virtually no affinity for opiate, benzodiazepine,
phencyclidine (PCP), or N-methyl-D-aspartic acid (NMDA) receptors.

Venlafaxine was not found to have any significant CNS stimulant activity in rodents. In primate drug
discrimination studies, venlafaxine showed no significant stimulant or depressant abuse liability.

Discontinuation effects have been reported in patients receiving venlafaxine (see DOSAGE AND
ADMINISTRATION).

While Effexor has not been systematically studied in clinical trials for its potential for abuse, there was
no indication of drug-seeking behavior in the clinical trials. However, it is not possible to predict on the
basis of premarketing experience the extent to which a CNS active drug will be misused, diverted,
and/or abused once marketed. Consequently, physicians should carefully evaluate patients for history
of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of
Effexor (eg, development of tolerance, incrementation of dose, drug-seeking behavior).

Overdosage
Human Experience
There were 14 reports of acute overdose with Effexor (venlafaxine hydrochloride), either alone or in
combination with other drugs and/or alcohol, among the patients included in the premarketing
evaluation. The majority of the reports involved ingestions in which the total dose of Effexor taken
was estimated to be no more than several-fold higher than the usual therapeutic dose. The 3 patients
who took the highest doses were estimated to have ingested approximately 6.75 g, 2.75 g, and 2.5 g.
The resultant peak plasma levels of venlafaxine for the latter 2 patients were 6.24 and 2.35 μg/mL,
respectively, and the peak plasma levels of O-desmethylvenlafaxine were 3.37 and 1.30 μg/mL,
respectively. Plasma venlafaxine levels were not obtained for the patient who ingested 6.75 g of
venlafaxine. All 14 patients recovered without sequelae. Most patients reported no symptoms. Among
the remaining patients, somnolence was the most commonly reported symptom. The patient who
ingested 2.75 g of venlafaxine was observed to have 2 generalized convulsions and a prolongation of
QTc to 500 msec, compared with 405 msec at baseline. Mild sinus tachycardia was reported in 2 of
the other patients.

In postmarketing experience, overdose with venlafaxine has occurred predominantly in combination

with alcohol and/or other drugs. The most commonly reported events in overdosage include
tachycardia, changes in level of consciousness (ranging from somnolence to coma), mydriasis,
seizures, and vomiting. Electrocardiogram changes (eg, prolongation of QT interval, bundle branch

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block, QRS prolongation), ventricular tachycardia, bradycardia, hypotension, rhabdomyolysis, vertigo,

liver necrosis, serotonin syndrome, and death have been reported.

Published retrospective studies report that venlafaxine overdosage may be associated with an
increased risk of fatal outcomes compared to that observed with SSRI antidepressant products, but
lower than that for tricyclic antidepressants. Epidemiological studies have shown that venlafaxine-
treated patients have a higher pre-existing burden of suicide risk factors than SSRI-treated patients.
The extent to which the finding of an increased risk of fatal outcomes can be attributed to the toxicity
of venlafaxine in overdosage as opposed to some characteristic(s) of venlafaxine-treated patients is
not clear. 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.

Management of Overdosage
Treatment should consist of those general measures employed in the management of overdosage
with any antidepressant.

Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs.
General supportive and symptomatic measures are also recommended. Induction of emesis is not
recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if
needed, may be indicated if performed soon after ingestion or in symptomatic patients. Activated
charcoal should be administered. Due to the large volume of distribution of this drug, forced diuresis,
dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit. No specific antidotes
for venlafaxine are known.

In managing overdosage, consider the possibility of multiple drug involvement. The physician should
consider contacting a poison control center for additional information on the treatment of any
overdose. Telephone numbers for certified poison control centers are listed in the Physicians' Desk
Reference (PDR).

Effexor Dosage and Administration

Initial Treatment
The recommended starting dose for Effexor is 75 mg/day, administered in two or three divided doses,
taken with food. Depending on tolerability and the need for further clinical effect, the dose may be
increased to 150 mg/day. If needed, the dose should be further increased up to 225 mg/day. When
increasing the dose, increments of up to 75 mg/day should be made at intervals of no less than 4
days. In outpatient settings there was no evidence of usefulness of doses greater than 225 mg/day
for moderately depressed patients, but more severely depressed inpatients responded to a mean

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dose of 350 mg/day. Certain patients, including more severely depressed patients, may therefore
respond more to higher doses, up to a maximum of 375 mg/day, generally in three divided doses (see
PRECAUTIONS, General, Use in Patients with Concomitant Illness).

Special Populations

Treatment of Pregnant Women During the Third Trimester

Neonates exposed to Effexor, other SNRIs, or SSRIs, late in the third trimester have developed
complications requiring prolonged hospitalization, respiratory support, and tube feeding (see
PRECAUTIONS). When treating pregnant women with Effexor during the third trimester, the
physician should carefully consider the potential risks and benefits of treatment. The physician may
consider tapering Effexor in the third trimester.

Dosage for Patients with Hepatic Impairment

Given the decrease in clearance and increase in elimination half-life for both venlafaxine and ODV
that is observed in patients with hepatic cirrhosis and mild and moderate hepatic impairment
compared to normal subjects (see CLINICAL PHARMACOLOGY), it is recommended that the total
daily dose be reduced by 50% in patients with mild to moderate hepatic impairment. Since there was
much individual variability in clearance between subjects with cirrhosis, it may be necessary to reduce
the dose even more than 50%, and individualization of dosing may be desirable in some patients.

Dosage for Patients with Renal Impairment

Given the decrease in clearance for venlafaxine and the increase in elimination half-life for both
venlafaxine and ODV that is observed in patients with renal impairment (GFR = 10 to 70 mL/min)
compared to normals (see CLINICAL PHARMACOLOGY), it is recommended that the total daily
dose be reduced by 25% in patients with mild to moderate renal impairment. It is recommended that
the total daily dose be reduced by 50% in patients undergoing hemodialysis. Since there was much
individual variability in clearance between patients with renal impairment, individualization of dosing
may be desirable in some patients.

Dosage for Elderly Patients

No dose adjustment is recommended for elderly patients on the basis of age. As with any
antidepressant, however, caution should be exercised in treating the elderly. When individualizing the
dosage, extra care should be taken when increasing the dose.

Maintenance Treatment
It is generally agreed that acute episodes of major depressive disorder require several months or
longer of sustained pharmacological therapy beyond response to the acute episode. In one study, in

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which patients responding during 8 weeks of acute treatment with Effexor XR were assigned
randomly to placebo or to the same dose of Effexor XR (75, 150, or 225 mg/day, qAM) during 26
weeks of maintenance treatment as they had received during the acute stabilization phase, longer-
term efficacy was demonstrated. A second longer-term study has demonstrated the efficacy of
Effexor in maintaining an antidepressant response in patients with recurrent depression who had
responded and continued to be improved during an initial 26 weeks of treatment and were then
randomly assigned to placebo or Effexor for periods of up to 52 weeks on the same dose (100 to 200
mg/day, on a b.i.d. schedule) (see CLINICAL TRIALS). Based on these limited data, it is not known
whether or not the dose of Effexor/Effexor XR needed for maintenance treatment is identical to the
dose needed to achieve an initial response. Patients should be periodically reassessed to determine
the need for maintenance treatment and the appropriate dose for such treatment.

Discontinuing Effexor (venlafaxine hydrochloride)

Symptoms associated with discontinuation of Effexor, other SNRIs, and SSRIs, have been reported
(see PRECAUTIONS). Patients should be monitored for these symptoms when discontinuing
treatment. 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.

SWITCHING PATIENTS TO OR FROM A MONOAMINE OXIDASE INHIBITOR

At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with
Effexor. In addition, at least 7 days should be allowed after stopping Effexor before starting an MAOI
(see CONTRAINDICATIONS).

How is Effexor supplied

Effexor® (venlafaxine hydrochloride) Tablets are available as follows:

25 mg, peach, shield-shaped tablet with “25” and a “W” on one side and “701” on scored reverse
side.

NDC 0008-0701-08, bottle of 60 tablets in unit of use package.

37.5 mg, peach, shield-shaped tablet with “37.5” and a “W” on one side and “781” on scored reverse
side.

NDC 0008-0781-08, bottle of 60 tablets in unit of use package.

50 mg, peach, shield-shaped tablet with “50” and a “W” on one side and “703” on scored reverse

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side.

NDC 0008-0703-07, bottle of 30 tablets in unit of use package.

75 mg, peach, shield-shaped tablet with “75” and a “W” on one side and “704” on scored reverse
side.

NDC 0008-0704-07, bottle of 30 tablets in unit of use package.

100 mg, peach, shield-shaped tablet with “100” and a “W” on one side and “705” on scored reverse
side.

NDC 0008-0705-07, bottle of 20 tablets in unit of use package.

The appearance of these tablets is a trademark of Wyeth Pharmaceuticals.

Store at controlled room temperature 20° to 25°C (68° to 77°F) in a dry place.

Dispense in a well-closed container as defined in the USP.

The unit of use package is intended to be dispensed as a unit.

U.S. Patent Nos. 5,916,923, 6,310,101 and 6,444,708

MEDICATION GUIDE

Antidepressant Medicines, Depression and Other Serious Mental Illnesses, and Suicidal
Thoughts or Actions

Read the Medication Guide that comes with your or your family member's antidepressant medicine.
This Medication Guide is only about the risk of suicidal thoughts and actions with antidepressant
medicines.

Talk to your, or your family member's, healthcare provider about:

• all risks and benefits of treatment with antidepressant medicines

• all treatment choices for depression or other serious mental illness

What is the most important information I should know about antidepressant medicines,
depression and other serious mental illnesses, and suicidal thoughts or actions?

1. Antidepressant medicines may increase suicidal thoughts or actions in some children,

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teenagers, and young adults within the first few months of treatment.

2. Depression and other serious mental illnesses are the most important causes of suicidal
thoughts and actions. Some people may have a particularly high risk of having suicidal
thoughts or actions. These include people who have (or have a family history of) bipolar illness
(also called manic-depressive illness) or suicidal thoughts or actions.

3. How can I watch for and try to prevent suicidal thoughts and actions in myself or a family
member?

• Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or
feelings. This is very important when an antidepressant medicine is started or when the dose is
changed.

• Call the healthcare provider right away to report new or sudden changes in mood, behavior,
thoughts, or feelings.

• Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare provider
between visits as needed, especially if you have concerns about symptoms.

Call a healthcare provider right away if you or your family member has any of the following
symptoms, especially if they are new, worse, or worry you:

• thoughts about suicide or dying • trouble sleeping (insomnia)

• attempts to commit suicide • new or worse irritability

• new or worse depression • acting aggressive, being angry, or violent

• new or worse anxiety • acting on dangerous impulses

• feeling very agitated or restless • an extreme increase in activity and talking (mania)

• panic attacks • other unusual changes in behavior or mood

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-
FDA-1088.

What else do I need to know about antidepressant medicines?

• Never stop an antidepressant medicine without first talking to a healthcare provider.

Stopping an antidepressant medicine suddenly can cause other symptoms.

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• Antidepressants are medicines used to treat depression and other illnesses. It is important
to discuss all the risks of treating depression and also the risks of not treating it. Patients and
their families or other caregivers should discuss all treatment choices with the healthcare
provider, not just the use of antidepressants.

• Antidepressant medicines have other side effects. Talk to the healthcare provider about the
side effects of the medicine prescribed for you or your family member.

• Antidepressant medicines can interact with other medicines. Know all of the medicines that
you or your family member takes. Keep a list of all medicines to show the healthcare provider. Do
not start new medicines without first checking with your healthcare provider.

• Not all antidepressant medicines prescribed for children are FDA approved for use in
children. Talk to your child's healthcare provider for more information.

This Medication Guide has been approved by the U.S. Food and Drug Administration for all
antidepressants.

This product's label may have been updated. For current package insert and further product information,
please visit www.wyeth.com or call our medical communications department toll-free at 1-800-934-5556.

Wyeth®

Wyeth Pharmaceuticals Inc.

Philadelphia, PA 19101

W10402C035

ET01

Rev 01/10

PACKAGE LABEL – PRINCIPAL DISPLAY PANEL – 25 MG LABEL

NDC 0008-0701-08

Effexor®

(venlafaxine HCl) Tablets

Equivalent to 25 mg venlafaxine

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SEALED FOR YOUR PROTECTION

Note to authorized dispenser: Each time Effexor is dispensed, give the patient the attached
Medication Guide.

Unit of Use 60 Tablets

Rx only

Wyeth®

PACKAGE LABEL – PRINCIPAL DISPLAY PANEL – 37.5 MG LABEL

NDC 0008-0781-08

Effexor®

(venlafaxine HCl) Tablets

Equivalent to 37.5 mg venlafaxine

SEALED FOR YOUR PROTECTION

Note to authorized dispenser: Each time Effexor is dispensed, give the patient the attached
Medication Guide.

Unit of Use 60 Tablets

Rx only

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Wyeth®

PACKAGE LABEL – PRINCIPAL DISPLAY PANEL – 50 MG LABEL

NDC 0008-0703-07

Effexor®

(venlafaxine HCl) Tablets

Equivalent to 50 mg venlafaxine

SEALED FOR YOUR PROTECTION

Note to authorized dispenser: Each time Effexor is dispensed, give the patient the attached
Medication Guide.

Unit of Use 30 Tablets

Rx only

Wyeth®

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PACKAGE LABEL – PRINCIPAL DISPLAY PANEL – 75 MG LABEL

NDC 0008-0704-07

Effexor®

(venlafaxine HCl) Tablets

Equivalent to 75 mg venlafaxine

SEALED FOR YOUR PROTECTION

Note to authorized dispenser: Each time Effexor is dispensed, give the patient the attached
Medication Guide.

Unit of Use 30 Tablets

Rx only

Wyeth®

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PACKAGE LABEL – PRINCIPAL DISPLAY PANEL – 100 MG LABEL

NDC 0008-0705-07

Effexor®

(venlafaxine HCl) Tablets

Equivalent to 100 mg venlafaxine

SEALED FOR YOUR PROTECTION

Note to authorized dispenser: Each time Effexor is dispensed, give the patient the attached
Medication Guide.

Unit of Use 20 Tablets

Rx only

Wyeth®

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EFFEXOR
venlafaxine hydrochloride tablet

Product Information

Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0008-0701

Route of Administration ORAL

Active Ingredient/Active Moiety

Ingredient Name Basis of Strength

Strength

VENLAFAXINE HYDROCHLORIDE (UNII: 7D7RX5A8MO) (VENLAFAXINE - VENLAFAXINE 25 mg

UNII:GRZ5RCB1QG)

Inactive Ingredients

Ingredient Name Strength

FERRIC OXIDE RED (UNII: 1K09F3G675)

LACTOSE (UNII: J2B2A4N98G)

MAGNESIUM STEARATE (UNII: 70097M6I30)

SODIUM STARCH GLYCOLATE TYPE A POTATO (UNII: 5856J3G2A2)

POWDERED CELLULOSE (UNII: SMD1X3XO9M)

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Product Characteristics

Color ORANGE (PEACH) Score 2 pieces

Shape PENTAGON (5 sided) (SHIELD-SHAPED) Size 6mm

Flavor Imprint Code 25;W;701

Contains

Packaging

# Item Code Package Description Marketing Start Date Marketing End Date

1 NDC:0008-0701-08 60 in 1 BOTTLE

Marketing Information

Marketing Application Number or Monograph Marketing Start Marketing End

Category Citation Date Date

NDA NDA020151 12/01/1993

EFFEXOR
venlafaxine hydrochloride tablet

Product Information

Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0008-0781

Route of Administration ORAL

Active Ingredient/Active Moiety

Ingredient Name Basis of Strength

Strength

VENLAFAXINE HYDROCHLORIDE (UNII: 7D7RX5A8MO) (VENLAFAXINE - VENLAFAXINE 37.5 mg

UNII:GRZ5RCB1QG)

Inactive Ingredients

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Ingredient Name Strength

FERRIC OXIDE RED (UNII: 1K09F3G675)

LACTOSE (UNII: J2B2A4N98G)

MAGNESIUM STEARATE (UNII: 70097M6I30)

SODIUM STARCH GLYCOLATE TYPE A POTATO (UNII: 5856J3G2A2)

POWDERED CELLULOSE (UNII: SMD1X3XO9M)

Product Characteristics

Color ORANGE (PEACH) Score 2 pieces

Shape PENTAGON (5 sided) (SHIELD-SHAPED) Size 7mm

Flavor Imprint Code 375;W;781

Contains

Packaging

# Item Code Package Description Marketing Start Date Marketing End Date

1 NDC:0008-0781-08 60 in 1 BOTTLE

Marketing Information

Marketing Application Number or Monograph Marketing Start Marketing End

Category Citation Date Date

NDA NDA020151 12/01/1993

EFFEXOR
venlafaxine hydrochloride tablet

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Product Information

Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0008-0703

Route of Administration ORAL

Active Ingredient/Active Moiety

Ingredient Name Basis of Strength

Strength

VENLAFAXINE HYDROCHLORIDE (UNII: 7D7RX5A8MO) (VENLAFAXINE - VENLAFAXINE 50 mg

UNII:GRZ5RCB1QG)

Inactive Ingredients

Ingredient Name Strength

FERRIC OXIDE RED (UNII: 1K09F3G675)

LACTOSE (UNII: J2B2A4N98G)

MAGNESIUM STEARATE (UNII: 70097M6I30)

SODIUM STARCH GLYCOLATE TYPE A POTATO (UNII: 5856J3G2A2)

POWDERED CELLULOSE (UNII: SMD1X3XO9M)

Product Characteristics

Color ORANGE (PEACH) Score 2 pieces

Shape PENTAGON (5 sided) (SHIELD-SHAPED) Size 8mm

Flavor Imprint Code 50;W;703

Contains

Packaging

# Item Code Package Description Marketing Start Date Marketing End Date

1 NDC:0008-0703-07 30 in 1 BOTTLE

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Marketing Information

Marketing Application Number or Monograph Marketing Start Marketing End

Category Citation Date Date

NDA NDA020151 12/01/1993

EFFEXOR
venlafaxine hydrochloride tablet

Product Information

Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0008-0704

Route of Administration ORAL

Active Ingredient/Active Moiety

Ingredient Name Basis of Strength

Strength

VENLAFAXINE HYDROCHLORIDE (UNII: 7D7RX5A8MO) (VENLAFAXINE - VENLAFAXINE 75 mg

UNII:GRZ5RCB1QG)

Inactive Ingredients

Ingredient Name Strength

FERRIC OXIDE RED (UNII: 1K09F3G675)

LACTOSE (UNII: J2B2A4N98G)

MAGNESIUM STEARATE (UNII: 70097M6I30)

SODIUM STARCH GLYCOLATE TYPE A POTATO (UNII: 5856J3G2A2)

POWDERED CELLULOSE (UNII: SMD1X3XO9M)

Product Characteristics

Color ORANGE (PEACH) Score 2 pieces

Shape PENTAGON (5 sided) (SHIELD-SHAPED) Size 9mm

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Flavor Imprint Code 75;W;704

Contains

Packaging

# Item Code Package Description Marketing Start Date Marketing End Date

1 NDC:0008-0704-07 30 in 1 BOTTLE

Marketing Information

Marketing Application Number or Monograph Marketing Start Marketing End

Category Citation Date Date

NDA NDA020151 12/01/1993

EFFEXOR
venlafaxine hydrochloride tablet

Product Information

Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0008-0705

Route of Administration ORAL

Active Ingredient/Active Moiety

Ingredient Name Basis of Strength

Strength

VENLAFAXINE HYDROCHLORIDE (UNII: 7D7RX5A8MO) (VENLAFAXINE - VENLAFAXINE 100 mg

UNII:GRZ5RCB1QG)

Inactive Ingredients

Ingredient Name Strength

FERRIC OXIDE RED (UNII: 1K09F3G675)

LACTOSE (UNII: J2B2A4N98G)

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MAGNESIUM STEARATE (UNII: 70097M6I30)

SODIUM STARCH GLYCOLATE TYPE A POTATO (UNII: 5856J3G2A2)

POWDERED CELLULOSE (UNII: SMD1X3XO9M)

Product Characteristics

Color ORANGE (PEACH) Score 2 pieces

Shape PENTAGON (5 sided) (SHIELD-SHAPED) Size 10mm

Flavor Imprint Code 100;W;705

Contains

Packaging

# Item Code Package Description Marketing Start Date Marketing End Date

1 NDC:0008-0705-07 20 in 1 BOTTLE

Marketing Information

Marketing Application Number or Monograph Marketing Start Marketing End

Category Citation Date Date

NDA NDA020151 12/01/1993

Labeler - Wyeth Pharmaceuticals Company (071170729)

Establishment

Name Address ID/FEI Business Operations

Wyeth Pharmaceuticals Company 071170729 MANUFACTURE, ANALYSIS

Frequently asked questions

• Can antidepressants be used for arthritis pain?

• How long do venlafaxine withdrawal symptoms last?

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• SSRI’s vs SNRI’s - What's the difference between them?

View more FAQ…

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