VENLAFAXINE HYDROCHLORIDE- venlafaxine hydrochloride tablet, extended release

United States - English - NLM (National Library of Medicine)

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Active ingredient:
VENLAFAXINE HYDROCHLORIDE (UNII: 7D7RX5A8MO) (VENLAFAXINE - UNII:GRZ5RCB1QG)
Available from:
Nivagen Pharmaceuticals, Inc.
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Venlafaxine extended-release tablets are indicated for the treatment of major depressive disorder (MDD). Efficacy of venlafaxine in MDD was shown in both short-term trials and a longer-term trial in MDD [see Clinical Studies (14.1) ]. A major depressive episode (DSM-IV) implies a prominent and relatively persistent (nearly every day for at least 2 weeks) depressed mood or the loss of interest or pleasure in nearly all activities, representing a change from previous functioning, and includes the presence of at least five of the following nine symptoms during the same two-week period: depressed mood, markedly diminished interest or pleasure in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, a suicide attempt or suicidal ideation. Venlafaxine extended-release tablets are indicated for the treatment of Social Anxiety Disorder (SAD), also k
Product summary:
Venlafaxine extended-release tablets 75 mg are white to off - white, round, coated tablets imprinted with black ink "C46" on one side and plain on the other side. They are supplied as follows: Venlafaxine extended-release tablets 150 mg are white to off - white, round, coated tablets imprinted with black ink "C34" on one side and plain on the other side. They are supplied as follows: Venlafaxine extended-release tablets 225 mg are white to off - white, round, coated tablets imprinted with black ink "C49" on one side and plain on the other side. They are supplied as follows: Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. Protect from moisture and humidity.
Authorization status:
Abbreviated New Drug Application
Authorization number:
75834-217-00, 75834-217-30, 75834-217-90, 75834-218-00, 75834-218-30, 75834-218-90, 75834-219-00, 75834-219-30, 75834-219-90

VENLAFAXINE HYDROCHLORIDE- venlafaxine hydrochloride tablet, extended release

Nivagen Pharmaceuticals, Inc.

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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

Who should not take venlafaxine extended-release tablets?

take a monoamine oxidase inhibitor (MAOI). Ask your healthcare provider or pharmacist if you are

not sure if you take an MAOI, including the antibiotic linezolid.

Do not take an MAOI within 7 days of stopping venlafaxine extended-release tablets unless directed

to do so by your physician.

Do not start venlafaxine extended-release tablets if you stopped taking an MAOI in the last 2 weeks

unless directed to do so by your physician.

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, 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

Visual Problems: Eye pain, change in vision, swelling or redness around eye

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.

Visual Problems. Only some people are at risk for these problems. You may want to undergo an eye

examination to see if you are at risk and receive preventative treatment if you are.

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.

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

1088.

Trademarks are the properties of their respective owners.

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

Manufactured by:

Cadila Pharmaceuticals Limited

1389, Dholka, District - Ahmedabad,

Gujarat State, INDIA.

Manufactured for:

Nivagen Pharmaceuticals, Inc.

Sacramento, CA 95827

Toll free number: 1-877-977-0687

Rev. 09/2019

Revised: 9/2019

Document Id: 70a22fca-6613-4f4f-bbe5-5863f4c38081

34391-3

Set id: 45cb4c19-fbf4-4ff5-af6f-b25a31ebc1e1

Version: 1

Effective Time: 20190916

Nivagen Pharmaceuticals, Inc.

VENLAFAXINE HYDROCHLORIDE- venlafaxine hydrochloride tablet, extended release

Nivagen Pharmaceuticals, Inc.

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use VENLAFAXINE EXTENDED-RELEASE

TABLETS safely and effectively. See full prescribing information for VENLAFAXINE EXTENDED-RELEASE

TABLETS.

VENLAFAXINE extended-release tablets, for oral use

Initial U.S. Approval: 1993

WARNING: Suicidality and Antidepressants

See full prescribing information for complete boxed warning.

Increased risk of suicidal thinking and behavior in children, adolescents and young adults taking

antidepressants for major depressive disorder (MDD) and other psychiatric disorders. Venlafaxine

extended-release tablets are not approved for use in pediatric patients. (5.1)

INDICATIONS AND USAGE

Venlafaxine extended-release tablets are a selective serotonin and norepinephrine reuptake inhibitor (SNRI) indicated for:

Major Depressive Disorder (MDD) (1.1)

Social Anxiety Disorder (SAD) (1.2)

DOSAGE AND ADMINISTRATION

Initial Treatment (2.1)

Indic atio n

Starting Dose

Dose Increase

Maximum Dose

Major Depressive Disorder

75 mg/day (in some patients,

37.5 mg/day for 4 to 7 days)

75 mg/day increments at

intervals of 4 days or longer

225 mg/day

Social Anxiety Disorder

75 mg/day

No benefit at higher doses

75 mg/day

Venlafaxine extended-release tablets should be taken as a single daily dose with food in either the morning or evening

at the same time each day. (2)

Discontinuation: Gradual; individualized as necessary. (2.4)

DOSAGE FORMS AND STRENGTHS

75mg, 150 mg, and 225 mg tablets (3)

CONTRAINDICATIONS

Serotonin Syndrome and MAOIs: Do not use MAOI's intended to treat psychiatric disorders with venlafaxine

extended-release tablets or within 7 days of stopping treatment with venlafaxine extended-release tablets.

Do not use venlafaxine extended-release tablets within 14 days of stopping an MAOI intended to treat psychiatric

disorders. In addition, do not start venlafaxine extended-release tablets in a patient who is being treated with linezolid

or intravenous methylene blue (4.1).

WARNINGS AND PRECAUTIONS

Serotonin Syndrome: Sertotonin syndrome has been reported with SSRIs and SNRIs, including venlafaxine extended-

release tablets, both when taken alone, but especially when co-administered with other serotonergic agents (including

triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. John's

Wort). If such symptoms occur, discontinue venlafaxine extended-release tablets and initiate supportive treatment. If

concomitant use of venlafaxine extended-release tablets with other serotonergic drugs is clinically warranted, patients

should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and

dose increases. (5.2).

Suicidality: Monitor for clinical worsening and suicide risk. (5.1)

Sustained hypertension may occur. Blood pressure monitoring recommended. (5.3)

Angle Closure Glaucoma: Angle closure glaucoma has occurred in patients with untreated anatomically narrow angles

treated with antidepressants. (5.4)

Abrupt discontinuation or dose reduction: Discontinuation symptoms may occur (generally self-limiting; serious

symptoms possible). Dose reduction recommended to be gradual. (5.5)

symptoms possible). Dose reduction recommended to be gradual. (5.5)

Activation of Mania/Hypomania has occurred. (5.10)

Symptomatic hyponatremia may occur. (5.11)

Seizures have been reported. Use with caution in patients with seizure history. (5.12)

Abnormal bleeding (most commonly ecchymosis) has been reported. (5.13)

Serum cholesterol: Clinically relevant cholesterol increases may occur. Cholesterol measurements should be

considered during long-term therapy. (5.14)

Interstitial lung disease and eosinophilic pneumonia have been reported. (5.15)

ADVERSE REACTIONS

Major Depressive Disorder - Adverse events in short-term studies that occurred in at least 5% of the patients receiving

venlafaxine extended-release capsules and at a rate at least twice that of the placebo group were abnormal ejaculation,

gastrointestinal complaints (nausea, dry mouth, and anorexia), CNS complaints (dizziness, somnolence, and abnormal

dreams), and sweating. (7)

Social Anxiety Disorder - Adverse events in short-term studies that occurred in at least 5% of the patients receiving

venlafaxine extended-release capsules and at a rate at least twice that of the placebo group were asthenia, gastrointestinal

complaints (anorexia, dry mouth, nausea), CNS complaints (anxiety, insomnia, libido decreased, nervousness, somnolence,

dizziness), abnormalities of sexual function (abnormal ejaculation, orgasmic dysfunction, impotence), yawn, sweating, and

abnormal vision. (7)

To report SUSPECTED ADVERSE REACTIONS, contact Cadila Pharmaceuticals Limited at 1-202-355-9785 (fax

1-202-355-9784) or www.cadilapharma.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. (7)

DRUG INTERACTIONS

MAOI's: concomitant use contraindicated (4). Avoid MAOI's 14 days before starting venlafaxine and 7 days after

stopping venlafaxine (5.2).

Cimetidine: Caution in patients with pre-existing hypertension, in elderly patients and patients with hepatic dysfunction.

(7.2)

Haloperidol: Increase in Haloperidol AUC and C

. (7.4)

Ketoconazole: Increase in venlafaxine and O-desmethylvenlafaxine AUC and C

. Caution when using venlafaxine

with substances that inhibit both CYP2D6 and CYP3A4. (7.7)

Metoprolol: Possibly reduced blood-pressure lowering effect despite increased metoprolol plasma levels. Caution

should be exercised with co-administration of venlafaxine and metoprolol. (7.8)

CNS-active drugs: Caution when using venlafaxine with such drugs. (7.10)

Serotonergic drugs (e.g., triptans, SSRIs, other SNRIs, linezolid, lithium, tramadol, or St. John's Wort): Potential for

serotonin syndrome. Careful patient observation advised. (7.10)

Tryptophan supplements: Concomitant use not recommended. (7.10)

USE IN SPECIFIC POPULATIONS

Pregnancy: Use during pregnancy only if clearly needed. Neonates exposed to venlafaxine in the third trimester have

developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Benefits and risk of

venlafaxine use in the third trimester should be carefully considered. (2.3; 8.1)

Nursing: Potential for serious adverse reactions in the infant. Discontinue nursing or drug, considering the importance

of the drug to the mother. (8.3)

Pediatric use: Not approved for use in pediatric patients. When considering use in a child or adolescent, balance

potential risks with clinical need. (8.4)

Hepatic impairment: Reduction of total daily dose by 50% recommended in patients with mild to moderate impairment.

In patients with cirrhosis, further reduction may be necessary and dosing individualization may be desirable. (2.3; 8.6)

Renal impairment: Reduction of daily dose by 25 to 50% recommended. Dosing individualization may be necessary.

(2.3; 8.7)

Hemodialysis: Reduction of daily dose by 50%. (2.3; 8.7)

See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

Revised: 2/2019

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: SUICIDALITY AND ANTIDEPRESSANT DRUGS

1 INDICATIONS AND USAGE

1.1 Major Depressive Disorder

m ax

m ax

1.2 Social Anxiety Disorder

2 DOSAGE AND ADMINISTRATION

2.1 Initial Treatment

2.2 Maintenance Treatment

2.3 Special Populations

2.4 Discontinuing Venlafaxine Extended-Release Tablets

2.5 Switching Patients from Venlafaxine Hydrochloride Immediate-Release Tablets

2.6 Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat

Psychiatric Disorders

2.7 Use of Venlafaxine Extended-Release Tablets with Other MAOIs, Such as Linezolid or

Methylene Blue

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

4.1 Monoamine Oxidase Inhibitors (MAOIs)

5 WARNINGS AND PRECAUTIONS

5.1 Clinical Worsening and Suicide Risk

5.2 Serotonin Syndrome

5.3 Sustained Hypertension

5.4 Angle Closure Glaucoma

5.5 Discontinuation of Treatment with Venlafaxine Extended-Release Tablets

5.6 Insomnia and Nervousness

5.7 Changes in Weight

5.8 Changes in Height

5.9 Changes in Appetite

5.10 Activation of Mania/Hypomania

5.11 Hyponatremia

5.12 Seizures

5.13 Abnormal Bleeding

5.14 Serum Cholesterol Elevation

5.15 Interstitial Lung Disease and Eosinophilic Pneumonia

5.16 Use in Patients With Heart Disease

5.17 Laboratory Tests

6 ADVERSE REACTIONS

6.1 Clinical Studies Experience

6.2 Post-Marketing Experience

7 DRUG INTERACTIONS

7.1 Alcohol

7.2 Cimetidine

7.3 Diazepam

7.4 Haloperidol

7.5 Lithium

7.6 Drugs Highly Bound to Plasma Proteins

7.7 Drugs that Inhibit Cytochrome P450 Isoenzymes

7.8 Drugs Metabolized by Cytochrome P450 Isoenzymes

7.9 Monoamine Oxidase Inhibitors

7.10 Serotonergic Drugs

7.11 Drugs that Interfere with Hemostasis (e.g., NSAID's, Aspirin, and Warfarin)

7.12 Electroconvulsive Therapy

7.13 Postmarketing Spontaneous Drug Interaction Reports

7.14 Drug-Laboratory Test Interactions

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Labor and Delivery

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Patients with Hepatic Impairment

8.7 Patients with Renal Impairment

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

9.2 Abuse

9.3 Dependence

10 OVERDOSAGE

10.1 Human Experience

10.2 Management of Overdosage

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

14.1 Major Depressive Disorder

14.2 Social Anxiety Disorder (Social Phobia)

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

17.1 Clinical Worsening and Suicide Risk

17.2 Interference with Cognitive and Motor Performance

17.3 Concomitant Medication

17.4 Alcohol

17.5 Allergic Reactions

17.6 Pregnancy

17.7 Nursing

17.8 Angle Closure Glaucoma

17.9 FDA-Approved Medication Guide

FULL PRESCRIBING INFORMATION

Venlafaxine Extended-Release Tablets

Sections or subsections omitted from the full prescribing information are not listed.

WARNING: 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 Disorder (MDD) and other psychiatric disorders. Anyone considering the use

of venlafaxine extended-release tablets 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.

Venlafaxine extended-release tablets are not approved for use in pediatric patients. [See

Warnings and Precautions (5.1) and Patient Counseling Information (17.1)]

1 INDICATIONS AND USAGE

1.1 Major Depressive Disorder

Venlafaxine extended-release tablets are indicated for the treatment of major depressive disorder

(MDD).

Efficacy of venlafaxine in MDD was shown in both short-term trials and a longer-term trial in MDD [see

Clinical Studies (14.1)].

A major depressive episode (DSM-IV) implies a prominent and relatively persistent (nearly every day

for at least 2 weeks) depressed mood or the loss of interest or pleasure in nearly all activities,

representing a change from previous functioning, and includes the presence of at least five of the

following nine symptoms during the same two-week period: depressed mood, markedly diminished

interest or pleasure in usual activities, significant change in weight and/or appetite, insomnia or

hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or

worthlessness, slowed thinking or impaired concentration, a suicide attempt or suicidal ideation.

1.2 Social Anxiety Disorder

Venlafaxine extended-release tablets are indicated for the treatment of Social Anxiety Disorder (SAD),

also known as Social Phobia, as defined in DSM-IV.

Social Anxiety Disorder (DSM-IV) is characterized by a marked and persistent fear of 1 or more social

or performance situations in which the person is exposed to unfamiliar people or to possible scrutiny

by others. Exposure to the feared situation almost invariably provokes anxiety, which may approach the

intensity of a panic attack. The feared situations are avoided or endured with intense anxiety or distress.

The avoidance, anxious anticipation, or distress in the feared situation(s) interferes significantly with

the person's normal routine, occupational or academic functioning, or social activities or relationships,

or there is a marked distress about having the phobias. Lesser degrees of performance anxiety or

shyness generally do not require psychopharmacological treatment.

Efficacy of venlafaxine extended release in the treatment of SAD was established in short-term SAD

trials [see Clinical Studies (14.2)].

2 DOSAGE AND ADMINISTRATION

Venlafaxine extended-release tablets should be administered in a single dose with food either in the

morning or in the evening at approximately the same time each day. Each tablet should be swallowed

whole with fluid and not divided, crushed, chewed, or placed in water.

2.1 Initial Treatment

Major Depressive Disorder

For most patients, the recommended starting dose for venlafaxine extended-release tablets are 75

mg/day, administered in a single dose. In the clinical trials establishing the efficacy of venlafaxine

hydrochloride extended-release capsules in moderately depressed outpatients, the initial dose of

venlafaxine was 75 mg/day. For some patients, it may be desirable to start at 37.5 mg/day for 4 to 7 days,

to allow new patients to adjust to the medication before increasing to 75 mg/day. While the relationship

between dose and antidepressant response for venlafaxine hydrochloride extended-release capsules has

not been adequately explored, patients not responding to the initial 75 mg/day dose may benefit from

dose increases to a maximum of approximately 225 mg/day. Dose increases should be in increments of

up to 75 mg/day, as needed, and should be made at intervals of not less than 4 days, since steady state

plasma levels of venlafaxine and its major metabolites are achieved in most patients by day 4. In the

clinical trials establishing efficacy, upward titration was permitted at intervals of 2 weeks or more; the

average doses were about 140 to 180 mg/day [see Clinical Studies (14)].

It should be noted that, while the maximum recommended dose for moderately depressed outpatients is

also 225 mg/day for venlafaxine hydrochloride immediate-release tablets, more severely depressed

inpatients in one study of the development program for that product responded to a mean dose of 350

mg/day (range of 150 to 375 mg/day). Whether or not higher doses of venlafaxine extended-release

tablets are needed for more severely depressed patients is unknown; however, the experience with

venlafaxine hydrochloride extended-release capsule doses higher than 225 mg/day is very limited. [See

Warnings and Precautions (5.17)]

Social Anxiety Disorder (Social Phobia)

The recommended dose is 75 mg/day, administered in a single dose. There was no evidence that higher

doses confer any additional benefit. [See Warnings and Precautions (5.17)]

2.2 Maintenance Treatment

There is no body of evidence available from controlled trials to indicate how long patients with major

depressive disorder should be treated with venlafaxine extended-release tablets.

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

which patients responding during 8 weeks of acute treatment with venlafaxine hydrochloride extended-

release capsules were assigned randomly to placebo or to the same dose of venlafaxine hydrochloride

extended-release capsules (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 venlafaxine hydrochloride immediate-

release tablets in maintaining a response in patients with recurrent major depressive disorder who had

responded and continued to be improved during an initial 26 weeks of treatment and were then randomly

assigned to placebo or venlafaxine immediate-release tablets for periods of up to 52 weeks on the same

dose (100 to 200 mg/day, on a b.i.d. schedule) [see Clinical Studies (14)]. Based on these limited data, it

is not known whether or not the dose of venlafaxine extended-release tablets 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.

2.3 Special Populations

Treatment of Pregnant Women During the Third Trimester

Neonates exposed to venlafaxine hydrochloride extended-release capsules, other SNRIs, or SSRIs, late

in the third trimester have developed complications requiring prolonged hospitalization, respiratory

support, and tube feeding [see Use in Specific Populations (8.1)]. When treating pregnant women with

venlafaxine extended-release tablets during the third trimester, the physician should carefully consider

the potential risks and benefits of treatment.

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 with

normal subjects [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)], 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 patients with cirrhosis, it

may be necessary to reduce the dose even more than 50%, and individualization of dosing may be

desirable in some patients.

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 with normal subjects [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)], it

is recommended that the total daily dose be reduced by 25% to 50%.

In patients undergoing hemodialysis, it is recommended that the total daily dose be reduced by 50%.

Because there was much individual variability in clearance between patients with renal impairment,

individualization of dosage may be desirable in some patients.

Elderly Patients

No dose adjustment is recommended for elderly patients solely on the basis of age. As with any drug

for the treatment of major depressive disorder or Social Anxiety Disorder, however, caution should be

exercised in treating the elderly. When individualizing the dosage, extra care should be taken when

increasing the dose.

2.4 Discontinuing Venlafaxine Extended-Release Tablets

Symptoms associated with discontinuation of venlafaxine hydrochloride extended-release capsules,

other SNRI's, and SSRI's have been reported [see Warnings and Precautions (5.5)]. 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. In clinical trials with venlafaxine hydrochloride extended-release capsules, tapering was achieved

by reducing the daily dose by 75 mg at 1 week intervals. Individualization of tapering may be necessary.

2.5 Switching Patients from Venlafaxine Hydrochloride Immediate-Release Tablets

Depressed patients who are currently being treated at a therapeutic dose with venlafaxine hydrochloride

immediate-release tablets may be switched to venlafaxine extended-release tablets at the nearest

equivalent dose (mg/day), e.g., 37.5 mg venlafaxine two-times-a-day to 75 mg venlafaxine extended-

release tablets once daily. However, individual dosage adjustments may be necessary.

2.6 Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat

Psychiatric Disorders

At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric

disorders and initiation of therapy with venlafaxine extended-release tablets. Conversely, at least 7 days

should be allowed after stopping venlafaxine extended-release tablets before starting an MAOI intended

to treat psychiatric disorders [see Contraindications (4.1)].

2.7 Use of Venlafaxine Extended-Release Tablets with Other MAOIs, Such as Linezolid or

Methylene Blue

Do not start venlafaxine extended-release tablets in a patient who is being treated with linezolid or

intravenous methylene blue because there is increased risk of serotonin syndrome. In a patient who

requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization,

should be considered [see CONTRAINDICATIONS (4.1)].

In some cases, a patient already receiving venlafaxine extended-release tablets therapy may require

urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or

intravenous methylene blue treatment are not available and the potential benefits of linezolid or

intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a

particular patient, venlafaxine extended-release tablets should be stopped promptly, and linezolid or

intravenous methylene blue can be administered. The patient should be monitored for symptoms of

serotonin syndrome for 7 days or until 24 hours after the last dose of linezolid or intravenous methylene

blue, whichever comes first. Therapy with venlafaxine extended-release tablets may be resumed 24

hours after the last dose of linezolid or intravenous methylene blue [see WARNINGS AND

PRECAUTIONS (5.2)].

The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local

injection) or in intravenous doses much lower than 1 mg/kg with venlafaxine extended-release tablets

are unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of

serotonin syndrome with such use [see WARNINGS AND PRECAUTIONS (5.2)].

3 DOSAGE FORMS AND STRENGTHS

Venlafaxine extended-release tablets are available as:

75 mg tablets (white to off - white, round, coated tablets imprinted with black ink "C46" on one side

and plain on the other side)

150 mg tablets (white to off - white, round, coated tablets imprinted with black ink "C34" on one side

and plain on the other side)

225 mg tablets (white to off - white, round, coated tablets imprinted with black ink "C49" on one side

and plain on the other side)

4 CONTRAINDICATIONS

4.1 Monoamine Oxidase Inhibitors (MAOIs)

The use of MAOI's intended to treat psychiatric disorders with venlafaxine extended-release tablets or

within 7 days of stopping treatment with venlafaxine extended-release tablets are contraindicated

because of an increased risk of serotonin syndrome. The use of venlafaxine extended-release tablets

within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated. [see

DOSAGE AND ADMINISTRATION (2.6) and WARNINGS AND PRECAUTIONS (5.2)].

Starting venlafaxine extended-release tablets in a patient who is being treated with MAOIs such as

linezolid or intravenous methylene blue is also contraindicated because of an increased risk of

serotonin syndrome [see DOSAGE AND ADMINISTRATION (2.7) and WARNINGS AND

PRECAUTIONS (5.2)].

5 WARNINGS AND PRECAUTIONS

5.1 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 to 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 4,400 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 1,000 patients treated)

are provided in Table 1.

Table 1

Age Range

Drug-Placebo Difference in Number of Cases of Suicidality

per 1,000 Patients Treated

Increases Compared to Placebo

<18

14 additional cases

18 to 24

5 additional cases

Decreases Compared to Placebo

25 to 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

Dosage and Administration (2.5) and Warnings and Precautions (5.5)].

Families and caregivers of patients being treated with antidepressants for major depressive

disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the

need to monitor patients for the emergence of agitation, irritability, 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 venlafaxine extended-release tablets should

be written for the smallest quantity of tablets consistent with good patient management, in order to

reduce the risk of overdose.

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 venlafaxine extended-release tablets are not approved for use in

treating bipolar depression.

5.2 Serotonin Syndrome

The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and

SSRIs, including venlafaxine extended-release tablets, alone but particularly with concomitant use of

other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol,

tryptophan, busipirone, amphetamines, and St. John's Wort), and with drugs that impair metabolism of

serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such

as linezolid and intravenous methylene blue).

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations,

delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness,

diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus,

hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting,

diarrhea). Patients should be monitored for the emergence of serotonin syndrome.

The concomitant use of venlafaxine extended-release tablets with MAOIs intended to treat psychiatric

disorders is contraindicated. Venlafaxine extended-release tablets should also not be started in a patient

who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with

methylene blue that provided information on the route of administration involved intravenous

administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of

methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses.

There may be circumstances when it is necessary to initiate treatment with a MAOI such as linezolid or

intravenous methylene blue in a patient taking venlafaxine extended-release tablets. Venlafaxine

extended-release tablets should be discontinued before initiating treatment with the MAOI. [see

CONTRAINDICATIONS (4.1) and DOSAGE AND ADMINISTRATION (2.6 and 2.7)].

If concomitant use of venlafaxine extended-release tablets with other serotonergic drugs, including

triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, amphetamines, and

St. John's Wort is clinically warranted, patients should be aware of a potential increased risk for

serotonin syndrome, particularly during treatment initiation and dose increases.

Treatment with venlafaxine extended-release tablets and any concomitant serotonergic agents should be

discontinued immediately if the above events occur and supportive symptomatic treatment should be

initiated.

5.3 Sustained Hypertension

Venlafaxine hydrochloride extended-release capsule treatment is associated with sustained

hypertension (defined as treatment-emergent supine diastolic blood pressure (SDBP) ≥90 mm Hg and

≥10 mm Hg above baseline for 3 consecutive on-therapy visits) (see Table 2).

An analysis for patients in venlafaxine hydrochloride immediate-release tablet studies meeting criteria

for sustained hypertension revealed a dose-dependent increase in the incidence of sustained

hypertension for immediate-release venlafaxine hydrochloride (see Table 3).

An insufficient number of patients received mean doses of venlafaxine hydrochloride extended-release

capsules over 300 mg/day to fully evaluate the incidence of sustained increases in blood pressure at

these higher doses.

Table 2: Number (%) of Sustained Elevations in SDBP in Venlafaxine Hydrochloride

Extended-Release Capsule Premarketing Studies by Indication

Major Depressive Disorder (75 to 375

mg/day)

Other Clinical Trials (75 to 225 mg/day)

19/705 (3)

5/771 (0.6)

Table 3: Incidence (%) of Sustained Elevations in SDBP in Venlafaxine Hydrochloride

Immediate-Release Tablet Studies

Venlafaxine mg/day

Incidence

<100

>100 to ≤200

>200 to ≤300

>300

In premarketing major depressive disorder studies, 0.7% (5/705) of the venlafaxine hydrochloride

extended-release capsule-treated patients discontinued treatment because of elevated blood pressure.

Among these patients, most of the blood pressure increases were in a modest range (12 to 16 mm Hg,

SDBP). In other clinical studies, 0.6% (5/771) of the venlafaxine hydrochloride extended-release

capsule-treated patients discontinued treatment because of elevated blood pressure. In these patients, the

blood pressure increases were modest (1 to 24 mm Hg, SDBP).

Sustained increases of SDBP 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 recommended

that patients receiving venlafaxine extended-release tablets 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.

Elevations in Systolic and Diastolic Blood Pressure

In placebo-controlled premarketing studies, there were changes in mean blood pressure (see Table 4

for mean change in supine systolic and supine diastolic blood pressure). Across most indications, a

dose-related increase in supine systolic and diastolic blood pressure was evident in venlafaxine

hydrochloride extended-release capsule-treated patients.

Table 4: Final On-Therapy Mean Changes from Baseline in Supine Systolic and

Diastolic Blood Pressure (mm Hg) Results by Indication, Study Duration, and Dose in

Placebo-Controlled Trials

Venlafaxine Hydrochloride Extended-

Release Capsules mg/day

Placebo

≤75

>75

SSBP

SDBP

SSBP

SDBP

SSBP

SDBP

Major Depressive

Disorder

8 to 12 weeks

-0.28

0.37

2.93

3.56

-1.08

-0.10

Other Clinical Trials

12 weeks

-0.29

-1.26

1.18

1.34

-1.96

-1.22

Across all clinical trials, 1.4% of patients in the venlafaxine hydrochloride extended-release capsule-

treated groups experienced a ≥15 mm Hg increase in supine diastolic blood pressure with blood

pressure ≥105 mm Hg compared to 0.9% of patients in the placebo groups. Similarly, 1% of patients in

the venlafaxine hydrochloride extended-release capsule-treated groups experienced a ≥20 mm Hg

increase in supine systolic blood pressure with blood pressure ≥180 mm Hg compared to 0.3% of

patients in the placebo groups.

5.4 Angle Closure Glaucoma

Angle-Closure Glaucoma: The pupillary dilation that occurs following use of many antidepressant

drugs including venlafaxine may trigger an angle closure attack in a patient with anatomically narrow

angles who does not have a patent iridectomy.

5.5 Discontinuation of Treatment with Venlafaxine Extended-Release Tablets

Discontinuation symptoms have been systematically evaluated in patients taking venlafaxine, to include

prospective analyses of clinical trials and retrospective surveys of trials in major depressive disorder

and social anxiety 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, headaches, hypomania, insomnia, nausea, nervousness,

nightmares, sensory disturbances (including shock-like electrical sensations), somnolence, sweating,

tremor, vertigo, and vomiting.

During marketing of venlafaxine hydrochloride extended-release capsules, other SNRI's (Serotonin and

Norepinephrine Reuptake Inhibitors), and SSRI's (Selective Serotonin Reuptake Inhibitors), there have

been spontaneous reports of adverse reactions 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 reactions are

generally self-limiting, there have been reports of serious discontinuation symptoms.

Patients should be monitored for these symptoms when discontinuing treatment with venlafaxine

extended-release tablets. 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.

*

Supine Systolic Blood Pressure

Supine Diastolic Blood Pressure

Subsequently, the physician may continue decreasing the dose but at a more gradual rate [see Dosage and

Administration (2.4)].

5.6 Insomnia and Nervousness

Treatment-emergent insomnia and nervousness were more commonly reported for patients treated with

venlafaxine hydrochloride extended-release capsules than with placebo in pooled analyses of short-

term major depressive disorder and other clinical studies, as shown in Table 5.

Table 5 Incidence of Insomnia and Nervousness in Placebo-Controlled Major

Depressive Disorder and Other Trials

Major Depressive

Dis order

Other Trials

Venlafaxine

Hydrochloride

Extended-Releas e

Caps ules

Placebo

Venlafaxine

Hydrochloride

Extended-

Releas e

Caps ules

Placebo

Symptom

n = 357

n = 285

N = 819

n = 695

Insomnia

Nervousness

Insomnia and nervousness each led to drug discontinuation in 0.9% of the patients treated with

venlafaxine hydrochloride extended-release capsules in major depressive disorder studies.

In other clinical trials, insomnia and nervousness led to drug discontinuation in 2% and 1%, respectively,

of the patients treated with venlafaxine hydrochloride extended-release capsules up to 12 weeks.

5.7 Changes in Weight

Adult Patients: A loss of 5% or more of body weight occurred in 7% of patients treated with

venlafaxine hydrochloride extended-release capsules and 2% of placebo-treated patients in the short-

term placebo-controlled major depressive disorder trials. The discontinuation rate for weight loss

associated with venlafaxine hydrochloride extended-release capsules was 0.1% in major depressive

disorder studies. In other placebo-controlled trials, 4% of the patients treated with venlafaxine

hydrochloride extended-release capsules and 1% of the placebo-treated patients sustained a loss of 7%

or more of body weight during up to 6 months of treatment. None of the patients receiving venlafaxine

hydrochloride extended-release capsules in other studies discontinued for weight loss.

The safety and efficacy of venlafaxine therapy in combination with weight loss agents, including

phentermine, have not been established. Co-administration of venlafaxine extended-release tablets and

weight loss agents is not recommended. Venlafaxine extended-release tablets are not indicated for

weight loss alone or in combination with other products.

Pediatric Patients: Weight loss has been observed in pediatric patients (ages 6 to 17) receiving

venlafaxine hydrochloride extended-release capsules. In a pooled analysis of four eight-week, double-

blind, placebo-controlled, flexible dose outpatient trials for major depressive disorder (MDD) and

another disorder, patients treated with venlafaxine hydrochloride extended-release capsules 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 venlafaxine hydrochloride extended-release capsules than with placebo

experienced a weight loss of at least 3.5% in the studies (18% of patients treated with venlafaxine

hydrochloride extended-release capsules vs. 3.6% of placebo-treated patients; p<0.001). In a 16-week,

double-blind, placebo-controlled, flexible dose outpatient study for another disorder, venlafaxine

hydrochloride extended-release capsule-treated patients lost an average of 0.75 kg (n=137), while

placebo-treated patients gained an average of 0.76 kg (n=148). More patients treated with venlafaxine

hydrochloride extended-release capsules than with placebo experienced a weight loss of at least 3.5%

in the study (47% of patients treated with venlafaxine hydrochloride extended-release capsules vs. 14%

of placebo-treated patients; p<0.001). Weight loss was not limited to patients with treatment-emergent

anorexia [see Warnings and Precautions (5.9)].

The risks associated with longer-term use of venlafaxine hydrochloride extended-release capsules

were assessed in an open-label MDD study of children and adolescents who received venlafaxine

hydrochloride extended-release capsules for up to six months. The children and adolescents in the

study had increases in weight that were less than expected based on data from age- and sex-matched

peers. The difference between observed weight gain and expected weight gain was larger for children

(<12 years old) than for adolescents (≥12 years old).

5.8 Changes in Height

Pediatric Patients: During an eight-week, placebo-controlled non-MDD study, venlafaxine

hydrochloride extended-release capsule-treated patients (ages 6 to 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, venlafaxine hydrochloride extended-release capsule-treated patients grew an

average of 0.8 cm (n = 146), while placebo-treated patients grew an average of 0.7 cm (n = 147).

During a 16-week, placebo-controlled non-MDD study, both the venlafaxine hydrochloride extended-

release capsule-treated patients (n=109) and the placebo-treated (n=112) patients each grew an average

of 1.0 cm. In the six-month, open-label MDD 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).

5.9 Changes in Appetite

Adult Patients: Treatment-emergent anorexia was more commonly reported for patients treated with

venlafaxine hydrochloride extended-release capsules (8%) than for placebo-treated patients (4%) in the

pool of short-term, double-blind, placebo-controlled major depressive disorder studies. The

discontinuation rate for anorexia associated with venlafaxine hydrochloride extended-release capsules

was 1.0% in major depressive disorder studies. Treatment-emergent anorexia was more commonly

reported for patients treated with venlafaxine hydrochloride extended-release capsules (20%) than for

placebo-treated patients (2%) in the pool of short-term, double-blind, placebo-controlled Social

Anxiety Disorder studies. The discontinuation rate for anorexia was 0.4% for patients receiving

venlafaxine hydrochloride extended-release capsules for up to 12 weeks in Social Anxiety Disorder

studies.

Pediatric Patients: Decreased appetite has been observed in pediatric patients receiving venlafaxine

hydrochloride extended-release capsules. In placebo-controlled trials in MDD and another disorder,

10% of patients aged 6 to 17 treated with venlafaxine hydrochloride extended-release capsules for up

to eight weeks and 3% of patients treated with placebo reported treatment-emergent anorexia (decreased

appetite). None of the patients receiving venlafaxine hydrochloride extended-release capsules

discontinued for anorexia or weight loss.

In a placebo-controlled non-MDD trial, 22% and 3% of patients aged 8 to 17 treated for up to 16 weeks

with venlafaxine hydrochloride extended-release capsules and placebo, respectively, reported

treatment-emergent anorexia (decreased appetite). The discontinuation rates for anorexia were 0.7% and

0.0% for patients receiving venlafaxine hydrochloride extended-release capsules and placebo,

respectively; the discontinuation rates for weight loss were 0.7% for patients receiving either

venlafaxine hydrochloride extended-release capsules or placebo.

5.10 Activation of Mania/Hypomania

During premarketing major depressive disorder studies, mania or hypomania occurred in 0.3% of

patients treated with venlafaxine hydrochloride extended-release capsules and 0.0% placebo patients. In

premarketing Social Anxiety Disorder studies, no patients treated with venlafaxine hydrochloride

extended-release capsules and no placebo-treated patients experienced mania or hypomania. In all

premarketing major depressive disorder trials with venlafaxine hydrochloride immediate-release

tablets, mania or hypomania occurred in 0.5% of venlafaxine-treated patients compared with 0% of

placebo patients. Mania/hypomania has also been reported in a small proportion of patients with mood

disorders who were treated with other marketed drugs to treat major depressive disorder. As with all

drugs effective in the treatment of major depressive disorder, venlafaxine extended-release tablets

should be used cautiously in patients with a history of mania.

5.11 Hyponatremia

Hyponatremia may occur as a result of treatment with SSRI's and SNRI's, including venlafaxine

extended-release tablets. 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 Use in Specific Populations (8.5)]. Discontinuation of venlafaxine extended-release

tablets 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.

5.12 Seizures

During premarketing experience, no seizures occurred among 705 patients treated with venlafaxine

hydrochloride extended-release capsules in the major depressive disorder studies or among 277

patients treated with venlafaxine hydrochloride extended-release capsules in Social Anxiety Disorder

studies. In all premarketing major depressive disorder trials with venlafaxine hydrochloride immediate-

release tablets, seizures were reported at various doses in 0.3% (8/3,082) of venlafaxine-treated

patients. Venlafaxine extended-release tablets, like many antidepressants, should be used cautiously in

patients with a history of seizures and should be discontinued in any patient who develops seizures.

5.13 Abnormal Bleeding

SSRIs and SNRIs, including venlafaxine extended-release tablets, may increase the risk of bleeding

events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other

anticoagulants 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

venlafaxine extended-release tablets and NSAIDs, aspirin, or other drugs that affect coagulation.

5.14 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 (6.1)]. Measurement of serum cholesterol levels should be considered during

long-term treatment.

5.15 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 reactions 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.

5.16 Use in Patients With Heart Disease

Premarketing experience with venlafaxine in patients with concomitant systemic illness is limited.

Caution is advised in administering venlafaxine extended-release tablets to patients with diseases or

conditions that could affect hemodynamic responses.

Venlafaxine has not been evaluated or used to any appreciable extent in patients with a recent history of

myocardial infarction or unstable heart disease. Patients with these diagnoses were systematically

excluded from many clinical studies during venlafaxine's premarketing testing. The electrocardiograms

were analyzed for 275 patients who received venlafaxine hydrochloride extended-release capsules and

220 patients who received placebo in 8- to 12-week double-blind, placebo-controlled trials in major

depressive disorder as well as for 195 patients who received venlafaxine hydrochloride extended-

release capsules and 228 patients who received placebo in 12-week double-blind, placebo-controlled

trials in Social Anxiety Disorder. The mean change from baseline in corrected QT interval (QTc) for

patients treated with venlafaxine hydrochloride extended-release capsules in major depressive disorder

studies was increased relative to that for placebo-treated patients (increase of 4.7 msec for venlafaxine

hydrochloride extended-release capsules and decrease of 1.9 msec for placebo). The mean change

from baseline in QTc for patients treated with venlafaxine hydrochloride extended-release capsules in

the Social Anxiety Disorder studies was increased relative to that for placebo-treated patients (increase

of 2.8 msec for venlafaxine hydrochloride extended-release capsules and decrease of 2.0 msec for

placebo).

In these same trials, the mean change from baseline in heart rate for patients treated with venlafaxine

hydrochloride extended-release capsules in the major depressive disorder studies was significantly

higher than that for placebo (a mean increase of 4 beats per minute for venlafaxine hydrochloride

extended-release capsules and 1 beat per minute for placebo). The mean change from baseline in heart

rate for patients treated with venlafaxine hydrochloride extended-release capsules in the Social Anxiety

Disorder studies was significantly higher than that for placebo (a mean increase of 5 beats per minute

for venlafaxine hydrochloride extended-release capsules and no change for placebo).

In a flexible-dose study, with doses of venlafaxine hydrochloride immediate-release tablets in the range

of 200 to 375 mg/day and mean dose greater than 300 mg/day, patients treated with venlafaxine

hydrochloride immediate-release tablets 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 (e.g., patients with hyperthyroidism,

heart failure, or recent myocardial infarction).

Evaluation of the electrocardiograms for 769 patients who received venlafaxine hydrochloride

immediate-release tablets in 4- to 6-week double-blind, placebo-controlled trials showed that the

incidence of trial-emergent conduction abnormalities did not differ from that with placebo.

5.17 Laboratory Tests

There are no specific laboratory tests recommended.

6 ADVERSE REACTIONS

6.1 Clinical Studies Experience

Data Sources

The information included in subsection "Adverse Findings Observed in Short-Term, Placebo-

Controlled Studies with Venlafaxine Hydrochloride Extended-Release Capsules" is based on data from

a pool of three 8- and 12-week controlled clinical trials in major depressive disorder (includes two

U.S. trials and one European trial), and on data up to 12 weeks from a pool of two controlled clinical

trials in Social Anxiety Disorder. Information on additional adverse reactions associated with

venlafaxine hydrochloride extended-release capsules in the entire development program for the

formulation and with venlafaxine hydrochloride immediate-release tablets is included in the subsection

"Other Adverse Reactions Observed During the Premarketing Evaluation of Venlafaxine

Hydrochloride Immediate-Release Tablets and Venlafaxine Hydrochloride Extended-Release

Capsules" [see also Warnings and Precautions (5)].

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed

in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug

and may not reflect the rates observed in practice.

Adverse Findings Observed in Short-Term, Placebo-Controlled Studies with Venlafaxine

Hydrochloride Extended-Release Capsules

Adverse Reactions Associated with Discontinuation of Treatment

Major Depressive Disorder: Approximately 11% of the 357 patients who received venlafaxine

hydrochloride extended-release capsules in placebo-controlled clinical trials for major depressive

disorder discontinued treatment due to an adverse reaction, compared with 6% of the 285 placebo-

treated patients in those studies. Adverse reactions that led to treatment discontinuation in a least 2% of

drug-treated patients were nausea, dizziness, and somnolence.

Social Anxiety Disorder: Approximately 17% of the 277 patients who received venlafaxine

hydrochloride extended-release capsules in placebo-controlled clinical trials for Social Anxiety

Disorder discontinued treatment due to an adverse reaction, compared with 5% of the 274 placebo-

treated patients in those studies. Adverse reactions that led to treatment discontinuation in a least 2% of

drug-treated patients were nausea, insomnia, impotence, headache, dizziness, and somnolence.

Adverse Reactions Occurring at an Incidence of 5% or More

Major Depressive Disorder: Note in particular the following adverse reactions that occurred in at least

5% of the patients receiving venlafaxine hydrochloride extended-release capsules and at a rate at least

twice that of the placebo group for all placebo-controlled trials for the major depressive disorder

indication (see Table 6): Abnormal ejaculation, gastrointestinal complaints (nausea, dry mouth, and

anorexia), CNS complaints (dizziness, somnolence, and abnormal dreams), and sweating. In the two U.S.

placebo-controlled trials, the following additional reactions occurred in at least 5% of patients treated

with venlafaxine hydrochloride extended-release capsules (n = 192) and at a rate at least twice that of

the placebo group: Abnormalities of sexual function (impotence in men, anorgasmia in women, and

libido decreased), gastrointestinal complaints (constipation and flatulence), CNS complaints (insomnia,

nervousness, and tremor), problems of special senses (abnormal vision), cardiovascular effects

(hypertension and vasodilatation), and yawning.

Social Anxiety Disorder: Note in particular the following adverse reactions that occurred in at least 5%

of the patients receiving venlafaxine hydrochloride extended-release capsules and at a rate at least

twice that of the placebo group for the 2 placebo-controlled trials for the Social Anxiety Disorder

indication (see Table 7): Asthenia, gastrointestinal complaints (anorexia, constipation, dry mouth,

nausea), CNS complaints (dizziness, insomnia, libido decreased, nervousness, somnolence),

abnormalities of sexual function (abnormal ejaculation, impotence, libido decreased, orgasmic

dysfunction), yawn, sweating, and abnormal vision.

Adverse Reactions Occurring at an Incidence of 2% or More Among Patients Treated with Venlafaxine

Hydrochloride Extended-Release Capsules

Tables 6 and 7 enumerate the incidence, rounded to the nearest percent, of adverse reactions that

occurred during acute therapy of major depressive disorder (up to 12 weeks; dose range of 75 mg/day

to 225 mg/day) and of Social Anxiety Disorder (up to 12 weeks; dose range of 75 mg/day to 225

mg/day), respectively, in 2% or more of patients treated with venlafaxine hydrochloride extended-

release capsules where the incidence in patients treated with venlafaxine hydrochloride extended-

release capsules was greater than the incidence for the respective placebo-treated patients. The table

shows the percentage of patients in each group who had at least one episode of a reaction at some time

during their treatment. Reported adverse reactions 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 adverse

reactions 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 adverse reaction incidence rate in

the population studied.

Table 6 Treatment-Emergent Adverse Reaction Incidence in Short-Term Placebo-

Controlled Clinical Trials with Venlafaxine Hydrochloride Extended-Release Capsules

in Patients with Major Depressive Disorder

% Reporting Reaction

Body System

Preferred Term

Venlafaxine

Hydrochloride Extended-

Release Capsules

Placebo

(n = 357)

(n = 285)

Body as a Whole

Asthenia

Cardiovascular System

Vasodilatation

Hypertension

Digestive System

Nausea

Constipation

Anorexia

Vomiting

Flatulence

Metabolic/Nutritional

Weight Loss

Nervous System

Dizziness

Somnolence

Insomnia

Dry Mouth

Nervousness

Abnormal Dreams

Tremor

Depression

<1%

Paresthesia

Libido Decreased

<1%

Agitation

*,†

Respiratory System

Pharyngitis

Yawn

Skin

Sweating

Special Senses

Abnormal Vision

<1%

Urogenital System

Abnormal Ejaculation (male)

<1%

Impotence

<1%

Anorgasmia (female)

<1%

Table 7 Treatment-Emergent Adverse Reaction Incidence in Short-Term Placebo-

Controlled Clinical Trials with Venlafaxine Hydrochloride Extended-Release Capsules

in Social Anxiety Disorder Patients

% Reporting Reaction

Body System

Preferred Term

Venlafaxine Hydrochloride

Extended-Release Capsules

(n = 277)

Placebo

(n = 274)

Body as a Whole

Headache

Asthenia

Flu Syndrome

Accidental Injury

Abdominal Pain

Cardiovascular System

Hypertension

Vasodilatation

Palpitation

Digestive System

Nausea

Anorexia

Constipation

Diarrhea

Vomiting

Eructation

Incidence, rounded to the nearest %, for reactions reported by at least 2% of patients treated with

venlafaxine hydrochloride extended-release capsules, except for reactions which had an incidence

equal to or less than placebo.

<1% indicates an incidence greater than zero but less than 1%.

Mostly "hot flashes."

Mostly "vivid dreams," "nightmares," and "increased dreaming."

Mostly "blurred vision" and "difficulty focusing eyes."

Mostly "delayed ejaculation."

Incidence is based on the number of male patients.

Mostly "delayed orgasm" or "anorgasmia."

Incidence is based on the number of female patients.

#,Þ

ß,à

*,†

Metabolic/Nutritional

Weight Loss

Nervous System

Insomnia

Dry Mouth

Dizziness

Somnolence

Nervousness

Libido Decreased

<1%

Anxiety

Agitation

Tremor

<1%

Abnormal Dreams

<1%

Paraesthesia

<1%

Twitching

Respiratory System

Yawn

<1%

Sinusitis

Skin

Sweating

Special Senses

Abnormal Vision

Urogenital System

Abnormal Ejaculation

Impotence

Orgasmic Dysfunction

Vital Sign Changes

Treatment with venlafaxine hydrochloride extended-release capsules treatment for up to 12 weeks in

premarketing placebo-controlled major depressive disorder trials was associated with a mean final on-

therapy increase in pulse rate of approximately 2 beats per minute, compared with 1 beat per minute for

placebo.

Treatment with venlafaxine hydrochloride extended-release capsules for up to 12 weeks in

premarketing placebo-controlled Social Anxiety Disorder trials was associated with a mean final on-

therapy increase in pulse rate of approximately 4 beats per minute, compared with an increase of 1 beat

per minute for placebo. [See Warnings and Precautions (5.4) for effects on blood pressure.]

Adverse reactions for which the venlafaxine hydrochloride extended-release capsules reporting rate

was less than or equal to the placebo rate are not included.

<1% means greater than zero but less than 1%.

Mostly "hot flashes."

Mostly "decreased appetite" and "loss of appetite."

Mostly "vivid dreams," "nightmares," and "increased dreaming."

Mostly "blurred vision."

Includes "delayed ejaculation" and "anorgasmia."

Percentage based on the number of males (venlafaxine hydrochloride extended-release capsules =

158, placebo = 153).

Includes "abnormal orgasm" and "anorgasmia."

Percentage based on the number of females (venlafaxine hydrochloride extended-release capsules =

119, placebo = 121).

Þ,ß

à,è

In a flexible-dose study in MDD, with doses of venlafaxine hydrochloride immediate-release tablets 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. [See

Warnings and Precautions (5.16) for effects on heart rate.]

Laboratory Changes

Serum Cholesterol

Venlafaxine hydrochloride extended-release capsules treatment for up to 12 weeks in premarketing

placebo-controlled trials for major depressive disorder was associated with a mean final on-therapy

increase in serum cholesterol concentration of approximately 1.5 mg/dL compared with a mean final

decrease of 7.4 mg/dL for placebo. Venlafaxine hydrochloride extended-release capsules treatment for

up to 12 weeks in other premarketing placebo-controlled trials was associated with mean final on-

therapy increases in serum cholesterol concentration of approximately 7.9 mg/dL compared with a mean

final decrease of 2.9 mg/dL for placebo.

Patients treated with venlafaxine hydrochloride immediate-release 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 Warnings and Precautions (5.14)].

Serum Triglycerides

Venlafaxine hydrochloride extended-release capsules treatment for up to 12 weeks in pooled

premarketing trials was associated with a mean final on-therapy increase in fasting serum triglyceride

concentration of approximately 8.2 mg/dl, compared with a mean final increase of 0.4 mg/dl for

placebo.

ECG Changes

In a flexible-dose MDD study with doses of venlafaxine hydrochloride immediate-release tablets in the

range of 200 mg/day 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 Warnings and

Precautions (5.16)]

Other Adverse Reactions Observed During the Premarketing Evaluation of Venlafaxine Hydrochloride

Immediate-Release Tablets and Venlafaxine Hydrochloride Extended-Release Capsules

During its premarketing assessment, multiple doses of venlafaxine hydrochloride extended-release

capsules were administered to 705 patients in Phase 3 major depressive disorder studies and venlafaxine

hydrochloride immediate-release tablets was administered to 96 patients. During its premarketing

assessment, multiple doses of venlafaxine hydrochloride extended-release capsules were also

administered to 3,514 patients in other Phase 3 studies. In addition, in premarketing assessment of

venlafaxine hydrochloride immediate-release tablets, multiple doses were administered to 2,897

patients in Phase 2 to Phase 3 studies for major depressive disorder. 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 (venlafaxine

hydrochloride immediate-release tablets only) and outpatient studies, fixed-dose, and titration studies.

Adverse reactions associated with this 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 reactions without first grouping similar types of

untoward events into a smaller number of standardized reaction categories.

In the tabulations that follow, reported adverse reactions were classified using a standard COSTART-

based Dictionary terminology. The frequencies presented, therefore, represent the proportion of the

7,212 patients exposed to multiple doses of either formulation of venlafaxine who experienced a

reaction of the type cited on at least one occasion while receiving venlafaxine. All reported reactions

are included except those already listed in Tables 6 and 7 and those reactions for which a drug cause

was remote.

If the COSTART term for a reaction was so general as to be uninformative, it was replaced with a more

informative term. It is important to emphasize that, although the reactions reported occurred during

treatment with venlafaxine, they were not necessarily caused by it.

Reactions are further categorized by body system and listed in order of decreasing frequency using the

following definitions: frequent adverse reactions are defined as those occurring on one or more

occasions in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to

1/1,000 patients; rare reactions are those occurring in fewer than 1/1,000 patients.

Body as a whole - Frequent: chest pain substernal, chills, fever, neck pain; Infrequent: face edema,

intentional injury, malaise, moniliasis, neck rigidity, pelvic pain, photosensitivity reaction, suicide

attempt, withdrawal syndrome; Rare: appendicitis, bacteremia, cellulitis, granuloma.

Cardiovascular system - Frequent: migraine, tachycardia; Infrequent: angina pectoris, bradycardia,

extrasystoles, hypotension, peripheral vascular disorder (mainly cold feet and/or cold hands), postural

hypotension, syncope; Rare: aortic aneurysm, arteritis, first-degree atrioventricular block, bigeminy,

bundle branch block, capillary fragility, cerebral ischemia, coronary artery disease, congestive heart

failure, heart arrest, hematoma, cardiovascular disorder (mitral valve and circulatory disturbance),

mucocutaneous hemorrhage, myocardial infarct, pallor, sinus arrhythmia, thrombophlebitis.

Digestive system - Frequent: increased appetite; Infrequent: bruxism, colitis, dysphagia, tongue

edema, eructation, esophagitis, gastritis, gastroenteritis, gastrointestinal ulcer, gingivitis, glossitis,

rectal hemorrhage, hemorrhoids, melena, oral moniliasis, stomatitis, mouth ulceration; Rare: abdominal

distension, biliary pain, cheilitis, cholecystitis, cholelithiasis, esophageal spasms, duodenitis,

hematemesis, gastroesophageal reflux disease, gastrointestinal hemorrhage, gum hemorrhage, hepatitis,

ileitis, jaundice, intestinal obstruction, liver tenderness, parotitis, periodontitis, proctitis, salivary gland

enlargement, increased salivation, soft stools, tongue discoloration.

Endocrine system - Rare: galactorrhoea, goiter, hyperthyroidism, hypothyroidism, thyroid nodule,

thyroiditis.

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

lymphadenopathy, thrombocythemia; Rare: basophilia, bleeding time increased, cyanosis, eosinophilia,

lymphocytosis, multiple myeloma, purpura, thrombocytopenia.

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

dehydration, hypercholesteremia, hyperglycemia, hyperlipidemia, 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 spurs, bursitis, leg cramps, myasthenia,

tenosynovitis; Rare: pathological fracture, muscle cramp, muscle spasms, musculoskeletal stiffness,

myopathy, osteoporosis, osteosclerosis, plantar fasciitis, rheumatoid arthritis, tendon rupture.

Nervous system - Frequent: amnesia, confusion, depersonalization, hypesthesia, 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, stupor, suicidal

ideation; Rare: akinesia, alcohol abuse, aphasia, bradykinesia, buccoglossal syndrome, cerebrovascular

accident, feeling drunk, loss of consciousness, delusions, dementia, dystonia, energy increased, facial

paralysis, abnormal gait, Guillain-Barre Syndrome, homicidal ideation, hyperchlorhydria, hypokinesia,

hysteria, impulse control difficulties, motion sickness, neuritis, nystagmus, paranoid reaction, paresis,

psychotic depression, reflexes decreased, reflexes increased, torticollis.

Respiratory system - Frequent: cough increased, dyspnea; Infrequent: asthma, chest congestion,

epistaxis, hyperventilation, laryngismus, laryngitis, pneumonia; Rare: atelectasis, hemoptysis,

hypoventilation, hypoxia, larynx edema, pleurisy, pulmonary embolus, sleep apnea.

Skin and appendages - Frequent: pruritus; Infrequent: acne, alopecia, contact dermatitis, dry skin,

eczema, maculopapular rash, psoriasis, urticaria; Rare: brittle nails, erythema nodosum, exfoliative

dermatitis, lichenoid dermatitis, furunculosis, hirsutism, leukoderma, miliaria, petechial rash, pruritic

rash, pustular rash, vesiculobullous rash, seborrhea, skin atrophy, skin hypertrophy, skin striae,

sweating decreased.

Special senses - Frequent: abnormality of accommodation, mydriasis, taste perversion; Infrequent:

conjunctivitis, diplopia, dry eyes, otitis media, parosmia, photophobia, taste loss; Rare: blepharitis,

cataract, chromatopsia, conjunctival edema, corneal lesion, deafness, exophthalmos, eye hemorrhage,

angle-closure glaucoma, retinal hemorrhage, subconjunctival hemorrhage, hyperacusis, keratitis,

labyrinthitis, miosis, papilledema, decreased pupillary reflex, otitis externa, scleritis, uveitis, visual

field defect.

Urogenital system - Frequent: albuminuria, urination impaired; Infrequent: amenorrhea,

cystitis,

dysuria, hematuria, kidney calculus, kidney pain, leukorrhea,

menorrhagia,

metrorrhagia,

nocturia,

breast pain, polyuria, pyuria, prostatic disorder (prostatitis, enlarged prostate, and prostate irritability),

urinary incontinence, urinary retention, urinary urgency, vaginal hemorrhage,

vaginitis

; Rare:

abortion,

anuria, breast discharge, breast engorgement, balanitis,

breast enlargement, endometriosis,

female lactation,

fibrocystic breast, calcium crystalluria, cervicitis,

orchitis,

ovarian cyst,

bladder

pain, prolonged erection,

gynecomastia (male),

hypomenorrhea,

mastitis, menopause,

pyelonephritis,

oliguria, salpingitis,

urolithiasis, uterine hemorrhage,

uterine spasm,

vaginal dryness.

6.2 Post-Marketing Experience

Voluntary reports of other adverse reactions temporally associated with the use of venlafaxine have

been received since market introduction. Because these reactions are reported from a population of

uncertain size, it is not always possible to reliably estimate their frequency or establish a causal

relationship to drug exposure. These reports include the following reactions: agranulocytosis,

anaphylaxis, aplastic anemia, catatonia, congenital anomalies, impaired coordination and balance, CPK

increased, deep vein thrombophlebitis, delirium, Takotsubo cardiomyopathy, EKG abnormalities such

as QT prolongation; cardiac arrhythmias including atrial fibrillation, supraventricular tachycardia,

ventricular extrasystoles, 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 reactions (including GGT

elevation; abnormalities of unspecified liver function tests; liver damage, necrosis, or failure; and fatty

liver), interstitial lung disease, involuntary movements, LDH increased, neuroleptic malignant

syndrome-like reactions (including a case of a 10-year-old who may have been taking methylphenidate,

was treated and recovered), neutropenia, night sweats, pancreatitis, pancytopenia, panic, prolactin

increased, renal failure, rhabdomyolysis, serotonin syndrome, 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).

7 DRUG INTERACTIONS

Based on the number of men and women as appropriate.

7.1 Alcohol

A single dose of ethanol (0.5 g/kg) had no effect on the pharmacokinetics of venlafaxine or O-

desmethylvenlafaxine (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.

7.2 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 of

venlafaxine was reduced by about 43%, and the exposure (AUC) and maximum concentration (C

) of

the drug were increased by about 60%. However, coadministration of cimetidine had no apparent effect

on the pharmacokinetics of ODV, which is present in much greater quantity in the circulation than

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.

7.3 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.

7.4 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 C

increased 88% when coadministered

with venlafaxine, but the haloperidol elimination half-life (t

) was unchanged. The mechanism

explaining this finding is unknown.

7.5 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. ODV also was

unaffected. Venlafaxine had no effect on the pharmacokinetics of lithium (see also CNS-Active Drugs,

below).

7.6 Drugs Highly Bound to Plasma Proteins

Venlafaxine is not highly bound to plasma proteins; therefore, administration of venlafaxine extended-

release tablets to a patient taking another drug that is highly protein bound should not cause increased

free concentrations of the other drug.

7.7 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 of venlafaxine, reducing the metabolism of venlafaxine

to ODV, resulting in increased plasma concentrations of venlafaxine and decreased concentrations of

the active metabolite. CYP2D6 inhibitors such as quinidine would be expected to do this, but the effect

would be similar to what is seen in patients who are genetically CYP2D6 poor metabolizers [see

Clinical Pharmacology (12.3)]. 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-desmethylvenlafaxine

(ODV) in most subjects following administration of ketoconazole. Venlafaxine C

increased by 26%

in EM subjects and 48% in PM subjects. C

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 PM's -2% to

206%), and AUC values for ODV increased by 23% and 33% in EM and PM (range in PM's - 38% to

105%) subjects, respectively. Combined AUC's of venlafaxine and ODV increased on average by

approximately 23% in EM's and 53% in PM's, (range in PM's 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.

7.8 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 with 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, C

, and C

increased by about 35% in the presence of venlafaxine.

The 2-OH-desipramine AUC's 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 to 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 venlafaxine extended-release tablets have regular

monitoring of blood pressure [see Warnings and Precautions (5.3)].

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 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 C

. 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).

7.9 Monoamine Oxidase Inhibitors

[See Dosage and Administration (2.6 and 2.7), Contraindications (4.1), and Warnings and Precautions

(5.2).]

7.10 Serotonergic Drugs

[See Dosage and Administration (2.6 and 2.7), Contraindications (4.1), and Warnings and Precautions

(5.2).]

7.11 Drugs that Interfere with Hemostasis (e.g., NSAID's, 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

drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.

These studies 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 SSRI's

and SNRI's are coadministered with warfarin. Patients receiving warfarin therapy should be carefully

monitored when venlafaxine extended- release tablets are initiated or discontinued. [See Warnings and

Precautions (5.13)].

7.12 Electroconvulsive Therapy

There are no clinical data establishing the benefit of electroconvulsive therapy combined with

venlafaxine extended-release tablets treatment.

7.13 Postmarketing Spontaneous Drug Interaction Reports

There have been reports of elevated clozapine levels that were temporally associated with adverse

reactions, 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.

7.14 Drug-Laboratory Test Interactions

False-positive urine immunoassay screening tests for phencyclidine (PCP) and amphetamine have been

reported in patients taking venlafaxine. This is due to lack of specificity of the screening tests. False

positive test results may be expected for several days following discontinuation of venlafaxine therapy.

Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish venlafaxine from

PCP and amphetamine.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Teratogenic Effects

Pregnancy Category C

Venlafaxine did not cause malformations in offspring of rats or rabbits given doses up to 2.5 times (rat)

or 4 times (rabbit) the maximum recommended human daily dose on a mg/m 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 2.5 times (mg/m ) the

maximum human daily dose. The no effect dose for rat pup mortality was 0.25 times the human dose on a

mg/m 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 venlafaxine hydrochloride extended-release capsules, 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 Warnings and Precautions (5.2)]. When treating a pregnant

woman with venlafaxine extended-release tablets during the third trimester, the physician should

carefully consider the potential risks and benefits of treatment [see Dosage and Administration (2)].

8.2 Labor and Delivery

The effect of venlafaxine on labor and delivery in humans is unknown.

8.3 Nursing Mothers

Venlafaxine and ODV have been reported to be excreted in human milk. Because of the potential for

serious adverse reactions in nursing infants from venlafaxine extended-release tablets, 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.

8.4 Pediatric Use

Safety and effectiveness in the pediatric population have not been established [see BOXED WARNING

and Warnings and Precautions (5.1)]. Two placebo-controlled trials in 766 pediatric patients with MDD

and two placebo-controlled trials in another disorder in 793 pediatric patients have been conducted with

venlafaxine hydrochloride extended-release capsules, and the data were not sufficient to support a

claim for use in pediatric patients.

Anyone considering the use of venlafaxine extended-release tablets in a child or adolescent must

balance the potential risks with the clinical need.

Although no studies have been designed to primarily assess impact of venlafaxine hydrochloride

extended-release capsules on the growth, development, and maturation of children and adolescents, the

studies that have been done suggest that venlafaxine extended-release tablets may adversely affect

weight and height [see Warnings and Precautions (5.7, 5.8, and 5.9)]. Should the decision be made to treat

a pediatric patient with venlafaxine extended-release tablets, regular monitoring of weight and height is

recommended during treatment, particularly if it is to be continued long term. The safety of venlafaxine

extended-release tablets 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 to 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 and Precautions (5.3 and 5.14)].

8.5 Geriatric Use

Approximately 4% (14/357) and 2% (6/277) of patients treated with venlafaxine hydrochloride

extended-release capsules in placebo-controlled premarketing major depressive disorder and Social

Anxiety Disorder trials, respectively, were 65 years of age or over. Of 2,897 patients treated with

venlafaxine hydrochloride immediate-release tablets in premarketing phase major depressive disorder

studies, 12% (357) were 65 years of age or over. No overall differences in effectiveness or safety

were observed between geriatric patients and younger patients, and other reported clinical experience

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

venlafaxine hydrochloride extended-release capsules have been associated with cases of clinically

significant hyponatremia in elderly patients, who may be at greater risk for this adverse reaction [see

Warnings and Precautions (5.11)].

The pharmacokinetics of venlafaxine and ODV are not substantially altered in the elderly [see Clinical

Pharmacology (12.3)]. 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 (2.3)].

8.6 Patients with Hepatic Impairment

In patients with cirrhosis of the liver, the clearances of venlafaxine and its active metabolite (ODV)

were decreased, thus prolonging the elimination half-lives of these substances. A large degree of

intersubject variability was noted. [See Clinical Pharmacology (12.3).] A lower dose and

individualization of dosing may be necessary [see Dosage and Administration (2.3)]. Venlafaxine

extended-release tablets, like all drugs effective in the treatment of major depressive disorder, should

be used with caution in such patients.

8.7 Patients with Renal Impairment

In patients with renal impairment (GFR = 10 to 70 mL/min), the clearances of venlafaxine and its active

metabolites were decreased, thus prolonging the elimination half-lives of these substances [see Clinical

Pharmacology (12.3)]. It is recommended that the total daily dose be reduced by 25% to 50% in patients

with renal impairment. Because there was much individual variability in clearance between patients with

renal impairment, individualization of dosage may be desirable in some patients. In patients undergoing

hemodialysis, it is recommended that the total daily dose be reduced by 50%. [See Dosage and

Administration (2.3).] Venlafaxine extended-release tablets, like all drugs effective in the treatment of

major depressive disorder, should be used with caution in such patients.

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

Venlafaxine extended-release tablets are not a controlled substance.

9.2 Abuse

While venlafaxine 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

venlafaxine (e.g., development of tolerance, incrementations of dose, drug-seeking behavior).

9.3 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 (2.4) and Warnings and Precautions (5.5)].

10 OVERDOSAGE

10.1 Human Experience

Among the patients included in the premarketing evaluation of venlafaxine hydrochloride extended-

release capsules, there were 2 reports of acute overdosage with venlafaxine hydrochloride extended-

release capsules in major depressive disorder trials, either alone or in combination with other drugs.

One patient took a combination of 6 g of venlafaxine hydrochloride extended-release capsules and 2.5

mg of lorazepam. This patient was hospitalized, treated symptomatically, and recovered without any

untoward effects. The other patient took 2.85 g of venlafaxine hydrochloride extended-release

capsules. This patient reported paresthesia of all four limbs but recovered without sequelae.

There were no reports of acute overdose with venlafaxine hydrochloride extended-release capsules in

Social Anxiety Disorder trials.

Among the patients included in the premarketing evaluation with venlafaxine hydrochloride immediate-

release tablets, there were 14 reports of acute overdose with venlafaxine, either alone or in

combination with other drugs and/or alcohol. The majority of the reports involved ingestion in which

the total dose of venlafaxine 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 mcg/mL, respectively, and the peak plasma levels of O-

desmethylvenlafaxine were 3.37 and 1.30 mcg/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 reactions in overdosage include tachycardia,

changes in level of consciousness (ranging from somnolence to coma), mydriasis, seizures, and

vomiting. Electrocardiogram changes (e.g., prolongation of QT interval, bundle branch 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 venlafaxine extended-release tablets should be written for the smallest quantity of

tablets consistent with good patient management, in order to reduce the risk of overdose.

10.2 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).

11 DESCRIPTION

Venlafaxine extended-release tablets are extended-release tablets for oral administration that contain

venlafaxine hydrochloride, USP a structurally novel antidepressant. Venlafaxine hydrochloride,USP is

a selective serotonin and norepinephrine reuptake inhibitor (SNRI). It is designated (R/S)-1-[2-

(dimethylamino)-1-(4-methoxyphenyl)ethyl] cyclohexanol hydrochloride or (±)1-[α-

[(dimethylamino)methyl]-p-methoxybenzyl] cyclohexanol hydrochloride and has the empirical formula

of C

H NO HCl. Its molecular weight is 313.87. The structural formula is shown below.

Venlafaxine hydrochloride

Venlafaxine hydrochloride, USP 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.

Venlafaxine extended-release tablets are formulated as extended-release tablet for once-a-day oral

administration. Venlafaxine extended-release tablets is a matrix with reservoir drug delivery system. It

contains hydrophilic polymers surrounded by an insoluble, but permeable coat. When administer orally,

the soluble component of the coat gets dissolved and fluid from the gastrointestinal tract enters in the

tablet through the porous coat and hydrates the polymers to swell. Drug gets slowly released from the

tablet in to the system by diffusion process and erosion of the polymeric matrix resulting in robust drug

release.

Tablets contain venlafaxine hydrochloride, USP equivalent to 75 mg, 150 mg and 225 mg venlafaxine.

Inactive ingredients consist of colloidal silicon dioxide, magnesium stearate, hypromellose and

microcrystalline cellulose.

Imprinting ink contains ammonium hydroxide, black iron oxide, isopropyl alcohol, N-butyl alcohol,

propylene glycol and shellac.

Film-coating material contains ammonium hydroxide, ethyl cellulose 20cP, hypromellose, medium chain

triglycerides, oleic acid, polyethylene glycol, propylene glycol, talc and titanium dioxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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.

12.2 Pharmacodynamics

Venlafaxine and its active metabolite, O-desmethylvenlafaxine (ODV) have no significant affinity for

muscarinic cholinergic, H -histaminergic, or α -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.

12.3 Pharmacokinetics

Steady-state concentrations of venlafaxine and O-desmethylvenlafaxine (ODV) in plasma are attained

within 3 days of oral multiple dose therapy. Venlafaxine and ODV exhibited linear kinetics over the

dose range of 75 to 450 mg/day. The mean ± SD apparent elimination half-life for venlafaxine and ODV

after administration of 75 mg venlafaxine extended-release tablets under fed conditions were 10.7±3.2

hours and 12.5±3.0 hours respectively. Venlafaxine and ODV are minimally bound at therapeutic

concentrations to plasma proteins (27% and 30%, respectively).

Absorption and Distribution

Venlafaxine is well absorbed and extensively metabolized in the liver. ODV is the only major active

metabolite. On the basis of mass balance studies, at least 92% of a single oral dose of venlafaxine is

absorbed. The absolute bioavailability of venlafaxine is about 45%. Administration of 75 mg

venlafaxine extended-release tablets under fed conditions resulted in mean ± SD venlafaxine C

26.9 ± 13.4 ng/mL and AUC of 1,536.3 ± 496.8 ng·hr/mL. T

was 6.3 ± 2.3 hours. ODV mean ± SD

AUC, T

after administration of 75 mg venlafaxine extended-release tablets under fed

conditions were 97.9 ± 29.4 ng/mL, 2,926.0 ± 746.1 ng·hr/mL, and 11.6 ± 2.9 hours, respectively.

Administration of venlafaxine hydrochloride extended-release capsules (150 mg q24 hours) generally

resulted in lower Cmax (150 ng/mL for venlafaxine and 260 ng/mL for ODV) and later T

(5.5 hours

for venlafaxine and 9 hours for ODV) than for immediate release venlafaxine tablets (Cmax's for

immediate release 75 mg q12 hours were 225 ng/mL for venlafaxine and 290 ng/mL for ODV; T

were 2 hours for venlafaxine and 3 hours for ODV). When equal daily doses of venlafaxine were

max,

max'

administered as either an immediate release tablet or the extended-release form of venlafaxine, the

exposure to both venlafaxine and ODV would be similar for the two treatments. Venlafaxine extended-

release tablets would, therefore, provide a slower rate of absorption, but the same extent of absorption

compared with the immediate release tablet.

Food did not affect the pharmacokinetic parameters AUC, C

, and T

of venlafaxine or its active

metabolite, ODV, after administration of venlafaxine extended-release tablets. Time of administration

(AM vs PM) would not affect the pharmacokinetics of venlafaxine and ODV.

Equal doses of venlafaxine extended-release tablets are bioequivalent to venlafaxine hydrochloride

extended-release capsules when administered under fed conditions.

Metabolism and Excretion

Following absorption, venlafaxine undergoes extensive presystemic metabolism in the liver, primarily

to ODV, but also to N-desmethylvenlafaxine, N,O-didesmethylvenlafaxine, and other minor metabolites.

In vitro studies indicate that the formation of ODV is catalyzed by CYP2D6; this has been confirmed in a

clinical study showing that patients with low CYP2D6 levels ("poor metabolizers") had increased

levels of venlafaxine and reduced levels of ODV compared to people with normal CYP2D6 ("extensive

metabolizers"). The differences between the CYP2D6 poor and extensive metabolizers, however, are

not expected to be clinically important because the sum of venlafaxine and ODV is similar in the two

groups and venlafaxine and ODV are pharmacologically approximately equiactive and equipotent.

Approximately 87% of a venlafaxine dose is recovered in the urine within 48 hours as unchanged

venlafaxine (5%), unconjugated ODV (29%), conjugated ODV (26%), or other minor inactive

metabolites (27%). Renal elimination of venlafaxine and its metabolites is thus the primary route of

excretion.

Special Populations

Age and Gender: A population 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 by age or gender differences. Dosage adjustment based on

the age or gender of a patient is generally not necessary [see Dosage and Administration (2)].

Extensive/Poor Metabolizers: Plasma concentrations of venlafaxine were higher in CYP2D6 poor

metabolizers than extensive metabolizers. Because the total exposure (AUC) of venlafaxine and ODV

was similar in poor and extensive metabolizer groups, however, there is no need for different

venlafaxine dosing regimens for these two groups.

Liver Disease: In 9 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 to 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

(2.3) and Use in Specific Populations (8.6)].

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 to 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 to 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 (2.3) and Use in Specific

Populations (8.7)].

13 NONCLINICAL TOXICOLOGY

13.1 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 1.7 times the maximum recommended human dose on a mg/m basis. 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 concentrations of venlafaxine at necropsy were 1 times (male rats) and 6 times (female rats)

the plasma concentrations 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.

Mutagenesis

Venlafaxine and the major human metabolite, O-desmethylvenlafaxine (ODV), were not mutagenic in the

Ames reverse mutation assay in Salmonella bacteria or the Chinese hamster ovary/HGPRT mammalian

cell forward gene mutation assay. Venlafaxine was also not mutagenic or clastogenic in the in vitro

BALB/c-3T3 mouse cell transformation assay, the sister chromatid exchange assay in cultured Chinese

hamster ovary cells, or in the in vivo chromosomal aberration assay in rat bone marrow. ODV was not

clastogenic in the in vitro Chinese hamster ovary cell chromosomal aberration assay, but elicited a

clastogenic response in the in vivo chromosomal aberration assay in rat bone marrow.

Impairment of Fertility

Reproduction and fertility studies in rats showed no effects on male or female fertility at oral doses of

up to 2 times the maximum recommended human dose on a mg/m basis.

14 CLINICAL STUDIES

14.1 Major Depressive Disorder

The efficacy of venlafaxine hydrochloride extended-release capsules as a treatment for major

depressive disorder was established in two placebo-controlled, short-term, flexible-dose studies in

adult outpatients meeting DSM-III-R or DSM-IV criteria for major depressive disorder.

A 12-week study utilizing venlafaxine hydrochloride extended-release capsules doses in a range 75

mg/day to 150 mg/day (mean dose for completers was 136 mg/day) and an 8-week study utilizing

venlafaxine hydrochloride extended-release capsules doses in a range 75 mg/day to 225 mg/day (mean

dose for completers was 177 mg/day) both demonstrated superiority of venlafaxine hydrochloride

extended-release capsules over placebo on the HAM-D total score, HAM-D Depressed Mood Item, the

MADRS total score, the Clinical Global Impressions (CGI) Severity of Illness item, and the CGI Global

Improvement item. In both studies, venlafaxine hydrochloride extended-release capsules were also

significantly better than placebo for certain factors of the HAM-D, including the anxiety/somatization

factor, the cognitive disturbance factor, and the retardation factor, as well as for the psychic anxiety

score.

A 4-week study of inpatients meeting DSM-III-R criteria for major depressive disorder with

melancholia utilizing venlafaxine hydrochloride immediate-release tablets in a range of 150 mg/day to

375 mg/day (t.i.d. schedule) demonstrated superiority of venlafaxine hydrochloride immediate-release

tablets over placebo. The mean dose in completers was 350 mg/day.

Examination of gender subsets of the population studied did not reveal any differential responsiveness

on the basis of gender.

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 venlafaxine hydrochloride extended-release capsules (75,

150, or 225 mg, qAM) were randomized to continuation of their same venlafaxine hydrochloride

extended-release capsules 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 venlafaxine hydrochloride extended-release

capsules 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 depressive

disorder, 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 venlafaxine

hydrochloride immediate-release tablets (100 mg/day to 200 mg/day, on a b.i.d. schedule) were

randomized to continuation of their same dose of venlafaxine hydrochloride immediate-release tablets

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 treatment with venlafaxine

hydrochloride immediate-release tablets experienced significantly lower relapse rates over the

subsequent 52 weeks compared with those receiving placebo.

14.2 Social Anxiety Disorder (Social Phobia)

The efficacy of venlafaxine hydrochloride extended-release capsules as a treatment for Social Anxiety

Disorder (also known as Social Phobia) was established in two double-blind, parallel group, 12-week,

multicenter, placebo-controlled, flexible-dose studies in adult outpatients meeting DSM-IV criteria for

Social Anxiety Disorder. Patients received doses in a range of 75 mg/day to 225 mg/day. Efficacy was

assessed with the Liebowitz Social Anxiety Scale (LSAS). In these two trials, venlafaxine

hydrochloride extended-release capsules were significantly more effective than placebo on change

from baseline to endpoint on the LSAS total score.

Examination of subsets of the population studied did not reveal any differential responsiveness on the

basis of gender. There was insufficient information to determine the effect of age or race on outcome

in these studies.

16 HOW SUPPLIED/STORAGE AND HANDLING

Venlafaxine extended-release tablets 75 mg are white to off - white, round, coated tablets imprinted

with black ink "C46" on one side and plain on the other side. They are supplied as follows:

Unit of use bottles of 30

NDC 75834-217-30

tablets

NDC 75834-217-30

Unit of use bottles of 90

tablets

NDC 75834-217-90

Bottles of 1000 tablets

NDC 75834-217-00

Venlafaxine extended-release tablets 150 mg are white to off - white, round, coated tablets imprinted

with black ink "C34" on one side and plain on the other side. They are supplied as follows:

Unit of use bottles of 30

tablets

NDC 75834-218-30

Unit of use bottles of 90

tablets

NDC 75834-218-90

Bottles of 1000 tablets

NDC 75834-218-00

Venlafaxine extended-release tablets 225 mg are white to off - white, round, coated tablets imprinted

with black ink "C49" on one side and plain on the other side. They are supplied as follows:

Unit of use bottles of 30

tablets

NDC 75834-219-30

Unit of use bottles of 90

tablets

NDC 75834-219-90

Bottles of 1000 tablets

NDC 75834-219-00

Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [See

USP Controlled Room Temperature]. Protect from moisture and humidity.

17 PATIENT COUNSELING INFORMATION

See FDA-approved Medication Guide (17.9)

Prescribers or other health professionals should inform patients, their families, and their caregivers

about the benefits and risks associated with treatment with venlafaxine extended-release tablets 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 venlafaxine extended-release tablets. The prescriber or 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 venlafaxine extended-release tablets.

17.1 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.

17.2 Interference with Cognitive and Motor Performance

Clinical studies were performed to examine the effects of venlafaxine on behavioral performance of

healthy individuals. The results revealed no clinically significant impairment of psychomotor,

cognitive, or complex behavior performance. However, since any psychoactive drug may impair

judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery,

including automobiles, until they are reasonably certain that venlafaxine therapy does not adversely

affect their ability to engage in such activities.

17.3 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

venlafaxine extended-release tablets and triptans, tricyclic antidepressants, fentanyl, lithium, tramadol,

amphetamines, tryptophan, buspirone, and St. John's Wort supplements or other serotonergic agents [see

Warnings and Precautions (5.2) and Drug Interactions (7.10)].

Patients should be cautioned about the concomitant use of venlafaxine extended-release tablets and

NSAID's, 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 Warnings and Precautions (5.13) and Drug Interactions (7.11)].

17.4 Alcohol

Although venlafaxine has not been shown to increase the impairment of mental and motor skills caused

by alcohol, patients should be advised to avoid alcohol while taking venlafaxine.

17.5 Allergic Reactions

Patients should be advised to notify their physician if they develop a rash, hives, or a related allergic

phenomenon.

17.6 Pregnancy

Patients should be advised to notify their physician if they become pregnant or intend to become

pregnant during therapy.

17.7 Nursing

Patients should be advised to notify their physician if they are breast-feeding an infant.

17.8 Angle Closure Glaucoma

Patients should be advised that taking venlafaxine can cause mild pupillary dilation, which in susceptible

individuals, can lead to an episode of angle closure glaucoma. Pre-existing glaucoma is almost always

open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with

iridectomy. Open-angle glaucoma is not a risk factor for angle closure glaucoma. Patients may wish to

be examined to determine whether they are susceptible to angle closure, and have a prophylactic

procedure (e.g., iridectomy), if they are susceptible. [see Warnings and Precautions (5.4)]

17.9 FDA-Approved Medication Guide

Manufactured by:

Cadila Pharmaceuticals Limited

1389, Dholka, District - Ahmedabad,

Gujarat State, INDIA.

Manufactured for:

Nivagen Pharmaceuticals, Inc.

Sacramento, CA 95827

Toll free number: 1-877-977-0687

Rev. 09/2019

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

Who should not take venlafaxine extended-release tablets?

take a monoamine oxidase inhibitor (MAOI). Ask your healthcare provider or pharmacist if you are

not sure if you take an MAOI, including the antibiotic linezolid.

Do not take an MAOI within 7 days of stopping venlafaxine extended-release tablets unless directed

to do so by your physician.

Do not start venlafaxine extended-release tablets if you stopped taking an MAOI in the last 2 weeks

unless directed to do so by your physician.

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,

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

Visual Problems: Eye pain, change in vision, swelling or redness around eye

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.

Visual Problems. Only some people are at risk for these problems. You may want to undergo an

eye examination to see if you are at risk and receive preventative treatment if you are.

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.

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

800-FDA-1088.

Trademarks are the properties of their respective owners.

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

antidepressants.

Manufactured by:

Cadila Pharmaceuticals Limited

1389, Dholka, District - Ahmedabad,

Gujarat State, INDIA.

Manufactured for:

Nivagen Pharmaceuticals, Inc.

Sacramento, CA 95827

Toll free number: 1-877-977-0687

Rev. 09/2019

PRINCIPAL DISPLAY PANEL - 75 mg Tablet Bottle Label

NDC 75834-217-00

Venlafaxine

Extended-Release

Tablets

75 mg

1000 Tablets

Pharmacist: Dispense the accompanying

Medication Guide to each patient.

NIVAGEN

Rx only

PRINCIPAL DISPLAY PANEL - 150 mg Tablet Bottle Label

NDC 75834-218-00

Venlafaxine

Extended-Release

Tablets

150 mg

1000 Tablets

Pharmacist: Dispense the accompanying

Medication Guide to each patient.

NIVAGEN

Rx only

PRINCIPAL DISPLAY PANEL - 225 mg Tablet Bottle Label

NDC 75834-219-00

Venlafaxine

Extended-Release

Tablets

225 mg

1000 Tablets

Pharmacist: Dispense the accompanying

Medication Guide to each patient.

NIVAGEN

Rx only

VENLAFAXINE HYDROCHLORIDE

venlafaxine hydrochloride tablet, extended release

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:758 34-217

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength Strength

VENLAFAXINE HYDRO CHLO RIDE (UNII: 7D7RX5A8 MO) (VENLAFAXINE - UNII:GRZ5RCB1QG)

VENLAFAXINE

75 mg

Inactive Ingredients

Ingredient Name

Stre ng th

SILICO N DIO XIDE (UNII: ETJ7Z6 XBU4)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

MICRO CRYSTALLINE CELLULO SE (UNII: OP1R32D6 1U)

HYPRO MELLO SE 2 2 0 8 ( 10 0 MPA.S) (UNII: B1QE5P712K)

HYPRO MELLO SE, UNSPECIFIED (UNII: 3NXW29 V3WO)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

TALC (UNII: 7SEV7J4R1U)

FERRO SO FERRIC O XIDE (UNII: XM0 M8 7F357)

PRO PYLENE GLYCO L (UNII: 6 DC9 Q16 7V3)

SHELLAC (UNII: 46 N10 7B71O)

ISO PRO PYL ALCO HO L (UNII: ND2M416 30 2)

BUTYL ALCO HO L (UNII: 8 PJ6 1P6 TS3)

AMMO NIA (UNII: 5138 Q19 F1X)

MEDIUM-CHAIN TRIGLYCERIDES (UNII: C9 H2L21V7U)

HYPRO MELLO SE 2 9 10 ( 5 MPA.S) (UNII: R75537T0 T4)

ETHYLCELLULO SE ( 2 0 MPA.S) (UNII: BJG0 S321QY)

PO LYETHYLENE GLYCO L 8 0 0 0 (UNII: Q6 6 2QK8 M3B)

Product Characteristics

Color

WHITE

S core

no sco re

S hap e

ROUND

S iz e

8 mm

Flavor

Imprint Code

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:758 34-217-30

30 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 9 /0 6 /20 19

2

NDC:758 34-217-9 0

9 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 9 /0 6 /20 19

3

NDC:758 34-217-0 0

10 0 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 9 /0 6 /20 19

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA211323

0 9 /0 6 /20 19

VENLAFAXINE HYDROCHLORIDE

venlafaxine hydrochloride tablet, extended release

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:758 34-218

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength Strength

VENLAFAXINE HYDRO CHLO RIDE (UNII: 7D7RX5A8 MO) (VENLAFAXINE - UNII:GRZ5RCB1QG)

VENLAFAXINE

150 mg

Inactive Ingredients

Ingredient Name

Stre ng th

SILICO N DIO XIDE (UNII: ETJ7Z6 XBU4)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

MICRO CRYSTALLINE CELLULO SE (UNII: OP1R32D6 1U)

HYPRO MELLO SE 2 9 10 ( 5 MPA.S) (UNII: R75537T0 T4)

HYPRO MELLO SE, UNSPECIFIED (UNII: 3NXW29 V3WO)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

TALC (UNII: 7SEV7J4R1U)

FERRO SO FERRIC O XIDE (UNII: XM0 M8 7F357)

PRO PYLENE GLYCO L (UNII: 6 DC9 Q16 7V3)

SHELLAC (UNII: 46 N10 7B71O)

ISO PRO PYL ALCO HO L (UNII: ND2M416 30 2)

BUTYL ALCO HO L (UNII: 8 PJ6 1P6 TS3)

AMMO NIA (UNII: 5138 Q19 F1X)

MEDIUM-CHAIN TRIGLYCERIDES (UNII: C9 H2L21V7U)

HYPRO MELLO SE 2 2 0 8 ( 10 0 MPA.S) (UNII: B1QE5P712K)

ETHYLCELLULO SE ( 2 0 MPA.S) (UNII: BJG0 S321QY)

PO LYETHYLENE GLYCO L 8 0 0 0 (UNII: Q6 6 2QK8 M3B)

Product Characteristics

Color

WHITE

S core

no sco re

S hap e

ROUND

S iz e

10 mm

Flavor

Imprint Code

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:758 34-218 -30

30 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 9 /0 6 /20 19

2

NDC:758 34-218 -9 0

9 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 9 /0 6 /20 19

3

NDC:758 34-218 -0 0

10 0 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 9 /0 6 /20 19

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA211323

0 9 /0 6 /20 19

VENLAFAXINE HYDROCHLORIDE

venlafaxine hydrochloride tablet, extended release

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:758 34-219

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength Strength

VENLAFAXINE HYDRO CHLO RIDE (UNII: 7D7RX5A8 MO) (VENLAFAXINE - UNII:GRZ5RCB1QG)

VENLAFAXINE

225 mg

Inactive Ingredients

Ingredient Name

Stre ng th

SILICO N DIO XIDE (UNII: ETJ7Z6 XBU4)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

MICRO CRYSTALLINE CELLULO SE (UNII: OP1R32D6 1U)

HYPRO MELLO SE 2 9 10 ( 5 MPA.S) (UNII: R75537T0 T4)

HYPRO MELLO SE, UNSPECIFIED (UNII: 3NXW29 V3WO)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

TALC (UNII: 7SEV7J4R1U)

FERRO SO FERRIC O XIDE (UNII: XM0 M8 7F357)

PRO PYLENE GLYCO L (UNII: 6 DC9 Q16 7V3)

SHELLAC (UNII: 46 N10 7B71O)

ISO PRO PYL ALCO HO L (UNII: ND2M416 30 2)

BUTYL ALCO HO L (UNII: 8 PJ6 1P6 TS3)

AMMO NIA (UNII: 5138 Q19 F1X)

MEDIUM-CHAIN TRIGLYCERIDES (UNII: C9 H2L21V7U)

HYPRO MELLO SE 2 2 0 8 ( 10 0 MPA.S) (UNII: B1QE5P712K)

ETHYLCELLULO SE ( 2 0 MPA.S) (UNII: BJG0 S321QY)

PO LYETHYLENE GLYCO L 8 0 0 0 (UNII: Q6 6 2QK8 M3B)

Product Characteristics

Nivagen Pharmaceuticals, Inc.

Color

WHITE

S core

no sco re

S hap e

ROUND

S iz e

12mm

Flavor

Imprint Code

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:758 34-219 -30

30 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 9 /0 6 /20 19

2

NDC:758 34-219 -9 0

9 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 9 /0 6 /20 19

3

NDC:758 34-219 -0 0

10 0 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 9 /0 6 /20 19

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA211323

0 9 /0 6 /20 19

Labeler -

Nivagen Pharmaceuticals, Inc. (052032418)

Revised: 9/2019

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