VENLAFAXINE HYDROCHLORIDE- venlafaxine hydrochloride capsule, 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:
REMEDYREPACK INC.
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Venlafaxine hydrochloride extended-release capsules are indicated for the treatment of major depressive disorder (MDD). Efficacy was established in three short-term (4, 8, and 12 weeks) and two long-term, maintenance trials. Venlafaxine hydrochloride extended-release capsules are indicated for the treatment of Generalized Anxiety Disorder (GAD). Efficacy was established in two 8-week and two 26-week placebo-controlled trials. Venlafaxine hydrochloride extended-release capsules are indicated for the treatment of Social Anxiety Disorder (SAD), also known as social phobia. Efficacy was established in four 12-week and one 26-week, placebo-controlled trials. Venlafaxine hydrochloride extended-release capsules are indicated for the treatment of Panic Disorder (PD), with or without agoraphobia. Efficacy was established in two 12-week placebo-controlled trials. Hypersensitivity to venlafaxine hydrochloride, desvenlafaxine succinate or to any excipients in the formulation The use of MAOIs (intended to treat psychiatri
Product summary:
Venlafaxine Hydrochlorid e Extended-Release Capsules USP , 37.5 mg are white to off white spherical to oval pellets filled in empty hard gelatin capsule shell (size ‘3’) of opaque grey color cap and opaque peach color body imprinted with “E” on cap and “73” on the body with edible black ink. Bottles of 15                                       NDC 65862-527-47 Bottles of 30                                       NDC 65862-527-30 Bottles of 90                                       NDC 65862-527-90 Bottles of 100                                     NDC 65862-527-01 Bottles of 1,000                                  NDC 65862-527-99 Bottles of 5,000                                  NDC 65862-527-59 10 x 10 Unit-dose Capsules                NDC 65862-527-10 Venlafaxine Hydrochlorid e Extended-Release Capsules USP , 75 mg are white to off white spherical to oval pellets filled in empty hard gelatin capsule shell (size ‘1’) of opaque peach color cap and opaque peach color body imprinted with “E” on cap and “74” on the body with edible black ink. Bottles of 15                                       NDC 65862-528-47 Bottles of 30                                       NDC 65862-528-30 Bottles of 90                                       NDC 65862-528-90 Bottles of 100                                     NDC 65862-528-01 Bottles of 1,000                                  NDC 65862-528-99 Bottles of 3,500                                  NDC 65862-528-35 10 x 10 Unit-dose Capsules                NDC 65862-528-10 Venlafaxine Hydrochlorid e Extended-Release Capsules USP , 150 mg are white to off white spherical to oval pellets filled in empty hard gelatin capsule shell (size ‘0’) of opaque dark orange color cap and opaque dark orange color body imprinted with “E” on cap and “89” on the body with edible black ink. Bottles of 15                                      NDC 65862-697-47 Bottles of 30                                      NDC 65862-697-30 Bottles of 90                                      NDC 65862-697-90 Bottles of 100                                    NDC 65862-697-01 Bottles of 500                                    NDC 65862-697-05 Bottles of 2,500                                 NDC 65862-697-26 10 x 10 Unit-dose Capsules               NDC 65862-697-10 Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]
Authorization status:
Abbreviated New Drug Application
Authorization number:
70518-2259-0

VENLAFAXINE HYDROCHLORIDE- venlafaxine hydrochloride capsule, extended release

REMEDYREPACK INC.

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Medication Guide

Venlafaxine Hydrochloride Extended-Release Capsules USP

(ven'' la fax' een hye'' droe klor' ide)

Read the Medication Guide that comes with venlafaxine hydrochloride extended-release capsules before you

start taking them and each time you get a refill. There may be new information. This Medication Guide does

not take the place of talking to your healthcare provider about your medical condition or treatment. Talk with

your healthcare provider if there is something you do not understand or want to learn more about.

What is the most important information I should know about venlafaxine hydrochloride extended-release

capsules?

Venlafaxine hydrochloride extended-release capsules and other antidepressant medicines may cause serious

side effects, including:

1. Suicidal thoughts or actions:

Venlafaxine hydrochloride extended-release capsules and other antidepressant medicines may

increase suicidal thoughts or actions in some children, teenagers, or young adults within the first few

months of treatment or when the dose is changed.

Depression or other serious mental illnesses are the most important causes of suicidal thoughts or

actions.

Watch for these changes and call your healthcare provider right away if you notice:

New or sudden changes in mood, behavior, actions, thoughts, or feelings, especially if severe.

Pay particular attention to such changes when venlafaxine hydrochloride extended-release capsules

are started or when the dose is changed.

Keep all follow-up visits with your healthcare provider and call between visits if you are worried about

symptoms.

Call your healthcare provider right away if you have any of the following symptoms, or call 911 if an

emergency, especially if they are new, worse, or worry you:

attempts to commit suicide

acting on dangerous impulses

acting aggressive or violent

thoughts about suicide or dying

new or worse depression

new or worse anxiety or panic attacks

feeling agitated, restless, angry or irritable

trouble sleeping

an increase in activity or talking more than what is normal for you

other unusual changes in behavior or mood

Visual problems

eye pain

changes in vision

swelling or redness in or around the eye

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.

Call your healthcare provider right away if you have any of the following symptoms, or call 911 if an

emergency. Venlafaxine hydrochloride extended-release capsules may be associated with these serious side

effects:

2. Serotonin Syndrome

This condition can be life-threatening and may include:

agitation, hallucinations, coma or other changes in mental status

coordination problems or muscle twitching (overactive reflexes)

racing heartbeat, high or low blood pressure

sweating or fever

nausea, vomiting, or diarrhea

muscle rigidity

3. Changes in blood pressure. Venlafaxine hydrochloride extended-release capsules may:

increase your blood pressure. Control high blood pressure before starting treatment and monitor blood

pressure regularly

4. Enlarged pupils (mydriasis).

5. Anxiety and insomnia.

6. Changes in appetite or weight.

7. Manic/hypomanic episodes:

greatly increased energy

severe trouble sleeping

racing thoughts

reckless behavior

unusually grand ideas

excessive happiness or irritability

talking more or faster than usual

8. Low salt (sodium) levels in the blood.

Elderly people may be at greater risk for this. Symptoms may include:

headache

weakness or feeling unsteady

confusion, problems concentrating or thinking or memory problems

9. Seizures or convulsions.

10. Abnormal bleeding: Venlafaxine hydrochloride extended-release capsules and other antidepressant

medicines may increase your risk of bleeding or bruising, especially if you take the blood thinner warfarin

(Coumadin ®, Jantoven ®), a non-steroidal anti-inflammatory drug (NSAIDs, like ibuprofen or naproxen), or

aspirin.

11. Elevated cholesterol.

12. Lung disease and pneumonia: Venlafaxine hydrochloride extended-release capsules may cause rare lung

problems. Symptoms include:

worsening shortness of breath

cough

chest discomfort

13. Severe allergic reactions:

trouble breathing

swelling of the face, tongue, eyes or mouth

rash, itchy welts (hives) or blisters, alone or with fever or joint pain.

Do not stop venlafaxine hydrochloride extended-release capsules without first talking to your healthcare

provider. Stopping venlafaxine hydrochloride extended-release capsules too quickly or changing from

another antidepressant too quickly may cause serious symptoms including:

anxiety, irritability

feeling tired, restless or problems sleeping

headache, sweating, dizziness

electric shock-like sensations, shaking, confusion, nightmares

vomiting, nausea, diarrhea

What are venlafaxine hydrochloride extended-release capsules?

Venlafaxine hydrochloride extended-release capsules are a prescription medicine used to treat depression. It

is important to talk with your healthcare provider about the risks of treating depression and also the risks of

not treating it. You should discuss all treatment choices with your healthcare provider. Venlafaxine

hydrochloride extended-release capsules are also used to treat:

Generalized Anxiety Disorder (GAD)

Social Anxiety Disorder (SAD)

Panic Disorder (PD)

Talk to your healthcare provider if you do not think that your condition is getting better with venlafaxine

hydrochloride extended-release capsules treatment.

Who should not take venlafaxine hydrochloride extended-release capsules?

Do not take venlafaxine hydrochloride extended-release capsules if you:

are allergic to venlafaxine hydrochloride or any of the ingredients in venlafaxine hydrochloride

extended-release capsules. See the end of this Medication Guide for a complete list of ingredients in

venlafaxine hydrochloride extended-release capsules.

have uncontrolled angle-closure glaucoma

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 hydrochloride extended-release capsules

unless directed to do so by your physician.

Do not start venlafaxine hydrochloride extended-release capsules if you stopped taking an MAOI in

the last 2 weeks unless directed to do so by your physician.

People who take venlafaxine hydrochloride extended-release capsules close in time to an MAOI may have

serious or even life-threatening side effects. Get medical help right away if you have any of these symptoms:

high fever

uncontrolled muscle spasms

stiff muscles

rapid changes in heart rate or blood pressure

confusion

loss of consciousness (pass out)

What should I tell my healthcare provider before taking venlafaxine hydrochloride extended-release

capsules? Ask if you are not sure.

Before starting venlafaxine hydrochloride extended-release capsules, tell your healthcare provider if you:

Are taking certain drugs such as:

Amphetamines

Medicines used to treat migraine headaches such as:

triptans

Medicines used to treat mood, anxiety, psychotic or thought disorders, such as:

tricyclic antidepressants

lithium

SSRIs

SNRIs

antipsychotic drugs

Medicines used to treat pain such as:

tramadol

Medicines used to thin your blood such as:

warfarin

Medicines used to treat heartburn such as:

Cimetidine

Over-the-counter medicines or supplements such as:

Aspirin or other NSAIDs

Tryptophan

St. John’s Wort

have heart problems

have diabetes

have liver problems

have kidney problems

have thyroid problems

have or had seizures or convulsions

have bipolar disorder or mania

have low sodium levels in your blood

have high blood pressure

have high cholesterol

have or had bleeding problems

are pregnant or plan to become pregnant. It is not known if venlafaxine

hydrochloride extended-release capsules will harm your unborn baby. Talk to

your healthcare provider about the benefits and risks of treating depression

during pregnancy

are breast-feeding or plan to breast-feed. Some venlafaxine hydrochloride may

pass into your breast milk. Talk to your healthcare provider about the best way

to feed your baby while taking venlafaxine hydrochloride extended-release

capsules.

Tell your healthcare provider about all the medicines that you take, including prescription and non-

prescription medicines, vitamins, and herbal supplements. Venlafaxine hydrochloride extended-release

capsules and some medicines may interact with each other, may not work as well, or may cause serious side

effects.

Your healthcare provider or pharmacist can tell you if it is safe to take venlafaxine hydrochloride extended-

release capsules with your other medicines. Do not start or stop any medicine while taking venlafaxine

hydrochloride extended-release capsules without talking to your healthcare provider first.

If you take venlafaxine hydrochloride extended-release capsules, you should not take any other medicines

that contain (venlafaxine) including: venlafaxine hydrochloride.

How should I take venlafaxine hydrochloride extended-release capsules?

Take venlafaxine hydrochloride extended-release capsules exactly as prescribed. Your healthcare

provider may need to change the dose of venlafaxine hydrochloride extended-release capsules until it

is the right dose for you.

Venlafaxine hydrochloride extended-release capsules are to be taken with food.

If you miss a dose of venlafaxine hydrochloride extended-release capsules, take the missed dose as

soon as you remember. If it is almost time for the next dose, skip the missed dose and take your next

dose at the regular time. Do not take two doses of venlafaxine hydrochloride extended-release

capsules at the same time.

If you take too much venlafaxine hydrochloride, call your healthcare provider or poison control center

right away, or get emergency treatment.

When switching from another antidepressant to venlafaxine hydrochloride extended-release capsules

your doctor may want to lower the dose of the initial antidepressant first to avoid side effects.

What should I avoid while taking venlafaxine hydrochloride extended-release capsules?

Venlafaxine hydrochloride extended-release capsules can cause sleepiness or may affect your ability to make

decisions, think clearly, or react quickly. You should not drive, operate heavy machinery, or do other

dangerous activities until you know how venlafaxine hydrochloride extended-release capsules affect you. Do

not drink alcohol while using venlafaxine hydrochloride extended-release capsules.

What are the possible side effects of venlafaxine hydrochloride extended-release capsules?

Venlafaxine hydrochloride extended-release capsules may cause serious side effects, including:

See “What is the most important information I should know about venlafaxine hydrochloride

extended-release capsules?”

Increased cholesterol- have your cholesterol checked regularly

Newborns whose mothers take venlafaxine hydrochloride extended-release capsules in the third

trimester may have problems right after birth including:

problems feeding and breathing

seizures

shaking, jitteriness or constant crying

Angle-closure glaucoma

Common possible side effects in people who take venlafaxine hydrochloride extended-release capsules

include :

unusual dreams

sexual problems

loss of appetite, constipation, diarrhea, nausea or vomiting, or dry mouth

feeling tired, fatigued or overly sleepy

change in sleep habits, problems sleeping

yawning

tremor or shaking

dizziness, blurred vision

sweating

feeling anxious, nervous or jittery

headache

increase in heart rate

Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are

not all the possible side effects of venlafaxine hydrochloride extended-release capsules. For more

information, ask your healthcare provider or pharmacist.

CALL YOUR DOCTOR FOR MEDICAL ADVICE ABOUT SIDE EFFECTS. YOU MAY REPORT SIDE

EFFECTS TO THE FDA AT 1-800-FDA-1088.

How should I store venlafaxine hydrochloride extended-release capsules?

Store venlafaxine hydrochloride extended-release capsules at room temperature between 20° to 25°C

(68° to 77°F).

Keep venlafaxine hydrochloride extended-release capsules in a dry place.

Keep venlafaxine hydrochloride extended-release capsules and all medicines out of the reach of children.

General information about venlafaxine hydrochloride extended-release capsules

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use

venlafaxine hydrochloride extended-release capsules for a condition for which it was not prescribed. Do not

give venlafaxine hydrochloride extended-release capsules to other people, even if they have the same

condition. They may harm them.

This Medication Guide summarizes the most important information about venlafaxine hydrochloride

extended-release capsules. If you would like more information, talk with your healthcare provider. You may

ask your healthcare provider or pharmacist for information about venlafaxine hydrochloride extended-release

capsules that is written for healthcare professionals.

For more information about venlafaxine hydrochloride extended-release capsules call 1-866-850-2876.

What are the ingredients in venlafaxine hydrochloride extended-release capsules?

Active ingredient: Venlafaxine hydrochloride

Inactive ingredients:

Extended-Release Capsules: Ethyl cellulose, hypromellose, sugar spheres, and talc. The empty hard gelatin

capsule shells contain iron oxide red, gelatin, titanium dioxide, and sodium lauryl sulphate. In addition, the

37.5 mg empty hard gelatin capsule shells contain iron oxide black. The capsules are printed with edible ink

containing black iron oxide and shellac.

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

Coumadin ® is a registered trademark of Bristol Myers Squibb.

Jantoven ® is a registered trademark of Upsher-Smith Laboratories Inc.

Dispense with Medication Guide available at: www.aurobindousa.com/product-medication-guides

Distributed by:

Aurobindo Pharma USA, Inc.

279 Princeton-Hightstown Road

East Windsor, NJ 08520

Manufactured by:

Aurobindo Pharma Limited

Hyderabad-500 038, India

Revised: 05/2018

Revised: 8/2019

Document Id: 8fe07833-63eb-d143-e053-2995a90abffa

34391-3

Set id: 50d3b487-9f65-4e2f-b6eb-9533964f8972

Version: 1

Effective Time: 20190811

REMEDYREPACK INC.

VENLAFAXINE HYDROCHLORIDE- venlafaxine hydrochloride capsule, extended release

REMEDYREPACK INC.

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use VENLAFAXINE HYDROCHLORIDE

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

HYDROCHLORIDE EXTENDED-RELEASE CAPSULES.

VENLAFAXINE HYDROCHLORIDE extended-release capsules, for oral use

Initial U.S. Approval: 1997

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS

See full prescribing information for complete boxed warning.

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

antidepressants (5.1)

Monitor for worsening and emergence of suicidal thoughts and behaviors (5.1)

Venlafaxine hydrochloride extended-release capsules are not approved for use in pediatric patients

(8 .4 )

INDICATIONS AND USAGE

Venlafaxine hydrochloride extended-release capsules are a serotonin and norepinephrine reuptake inhibitor (SNRI)

indicated for the treatment of:

Major Depressive Disorder ( MDD)

Social Anxiety Disorder ( SAD)

Generalized Anxiety Disorder ( GAD)

Panic Disorder ( PD)

DOSAGE AND ADMINISTRATION

Indication

Starting Dose

Target Dose

Maximum Dose

MDD (2.1)

37.5 to 75 mg/day

75 mg/day

225 mg/day

GAD (2.2)

37.5 to 75 mg/day

75 mg/day

225 mg/day

SAD (2.3)

75 mg/day

75 mg/day

75 mg/day

PD (2.4)

37.5 mg/day

75 mg/day

225 mg/day

Take once daily with food (2). Capsules should be taken whole; do not divide, crush, chew, or dissolve ( 2).

When discontinuing treatment, reduce the dose gradually ( 2.8, 5.7).

Renal impairment: reduce the total daily dose by 25% to 50% in patients with renal impairment. Reduce the total daily

dose by 50% or more in patients undergoing dialysis or with severe renal impairment ( 2.6).

Hepatic impairment: reduce the daily dose by 50% in patients with mild to moderate hepatic impairment. In patients

with severe hepatic impairment or hepatic cirrhosis, it may be necessary to reduce the dose by more than 50% ( 2.6).

DOSAGE FORMS AND STRENGTHS

Venlafaxine hydrochloride extended-release capsules USP are available as 37.5 mg, 75 mg and 150 mg strengths ( 3).

Each capsule contains venlafaxine hydrochloride equivalent to 37.5 mg, 75 mg or 150 mg of venlafaxine ( 3).

CONTRAINDICATIONS

Hypersensitivity to venlafaxine hydrochloride, desvenlafaxine succinate, or any excipients in the venlafaxine

hydrochloride extended-release capsules formulation ( 4.1).

Do not use with an MAOI or within 14 days of stopping an MAOI. Allow 7 days after stopping venlafaxine hydrochloride

extended-release capsules before starting an MAOI, because of the risk of serotonin syndrome ( 4.2, 5.2, 7.3).

WARNINGS AND PRECAUTIONS

Clinical Worsening/Suicide Risk: Monitor for clinical worsening and suicide risk ( 5.1).

Serotonin Syndrome: Risk increases with concomitant use of other serotonergic drugs. Discontinue venlafaxine

hydrochloride extended-release capsules and initiate supportive treatment if serotonin syndrome occurs ( 4.2, 5.2, 7.3).

Elevations in Blood Pressure: Control hypertension before initiating treatment. Monitor blood pressure regularly

during treatment ( 5.3).

Abnormal Bleeding: Venlafaxine hydrochloride extended-release capsules may increase risk of bleeding events.

Caution patients about the risk of bleeding associated with the concomitant use of venlafaxine hydrochloride extended-

release capsules and NSAIDs, aspirin, or other drugs that affect coagulation ( 5.4).

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

angles treated with antidepressants ( 5.5).

Activation of Mania/Hypomania: Use cautiously in patients with bipolar disorder. Caution patients about the risk of

activation of mania/hypomania ( 5.6).

ADVERSE REACTIONS

Most common adverse reactions (incidence ≥ 5% and at least twice the rate of placebo): nausea, somnolence, dry mouth,

sweating, abnormal ejaculation, anorexia, constipation, erectile dysfunction, and libido decreased ( 6.1).

To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or

FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

Serotonergic Drugs (e.g., MAOIs, triptans, SSRIs, other SNRIs, linezolid, lithium, tramadol, or St. John’s

wort): Potential for serotonin syndrome. Careful patient observation is advised ( 4.2, 5.2, 7.3).

USE IN SPECIFIC POPULATIONS

Pregnancy: Based on animal data, may cause fetal harm ( 8.1).

Nursing Mothers: Discontinue drug or nursing, taking into consideration importance of drug to mother ( 8.3)

See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

Revised: 8/2019

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS

1 INDICATIONS AND USAGE

1.1 Major Depressive Disorder

1.2 Generalized Anxiety Disorder

1.3 Social Anxiety Disorder

1.4 Panic Disorder

2 DOSAGE AND ADMINISTRATION

2.1 Major Depressive Disorder

2.2 Generalized Anxiety Disorder

2.3 Social Anxiety Disorder (Social Phobia)

2.4 Panic Disorder

2.5 Switching Patients from Venlafaxine Hydrochloride Tablets

2.6 Specific Populations

2.7 Maintenance Treatment

2.8 Discontinuing Venlafaxine Hydrochloride Extended-Release Capsules

2.9 Switching Patients to or from a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat

Psychiatric Disorders

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

4.1 Hypersensitivity

4.2 Concomitant Use with Monoamine Oxidase Inhibitors (MAOIs)

5 WARNINGS AND PRECAUTIONS

5.1 Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults

5.2 Serotonin Syndrome

5.3 Elevations in Blood Pressure

5.4 Abnormal Bleeding

5.5 Angle Closure Glaucoma

5.6 Activation of Mania/Hypomania

5.7 Discontinuation Syndrome

5.8 Seizures

5.9 Hyponatremia

5.10 Weight and Height Changes in Pediatric Patients

5.11 Appetite Changes in Pediatric Patients

5.12 Interstitial Lung Disease and Eosinophilic Pneumonia

6 ADVERSE REACTIONS

6.1 Clinical Studies Experience

6.2 Vital Sign Changes

6.3 Laboratory Changes

6.4 Pediatric Patients

6.5 Adverse Reactions Identified During Postapproval Use

7 DRUG INTERACTIONS

7.1 Central Nervous System (CNS)-Active Drugs

7.2 Monoamine Oxidase Inhibitors

7.3 Serotonergic Drugs

7.4 Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin)

7.5 Weight Loss Agents

7.6 Effects of Other Drugs on Venlafaxine Hydrochloride Extended-Release Capsules

7.7 Effects of Venlafaxine Hydrochloride Extended-Release Capsules on Other Drugs

7.8 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 Age and Gender

8.7 Use in Patient Subgroups

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 Generalized Anxiety Disorder

14.3 Social Anxiety Disorder (also known as Social Phobia)

14.4 Panic Disorder

14.5 Pediatric Patients

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS

Antidepressants increased the risk of suicidal thoughts and behavior in children,

adolescents, and young adults in short-term studies. These studies did not show an

increase in the risk of suicidal thoughts and behavior with antidepressant use in patients

over age 24; there was a reduction in risk with antidepressant use in patients aged 65 and

older [see Warnings and Precautions (5.1)].

In patients of all ages who are started on antidepressant therapy monitor closely for clinical

worsening and emergence of suicidal thoughts and behaviors. Advise families and

caregivers of the need for close observation and communication with the prescriber [see

Warnings and Precautions (5.1) and Patient Counseling Information (17)] .

1 INDICATIONS AND USAGE

1.1 Major Depressive Disorder

Venlafaxine hydrochloride extended-release capsules are indicated for the treatment of major

depressive disorder (MDD). Efficacy was established in three short-term (4, 8, and 12 weeks) and two

long-term, maintenance trials.

1.2 Generalized Anxiety Disorder

Venlafaxine hydrochloride extended-release capsules are indicated for the treatment of Generalized

Anxiety Disorder (GAD). Efficacy was established in two 8-week and two 26-week placebo-controlled

trials.

1.3 Social Anxiety Disorder

Venlafaxine hydrochloride extended-release capsules are indicated for the treatment of Social Anxiety

Disorder (SAD), also known as social phobia. Efficacy was established in four 12-week and one 26-

week, placebo-controlled trials.

1.4 Panic Disorder

Venlafaxine hydrochloride extended-release capsules are indicated for the treatment of Panic Disorder

(PD), with or without agoraphobia. Efficacy was established in two 12-week placebo-controlled trials.

2 DOSAGE AND ADMINISTRATION

Venlafaxine hydrochloride extended-release capsules should be administered in a single dose with

food, either in the morning or in the evening at approximately the same time each day [see Clinical

Pharmacology (12.3)] . Each capsule should be swallowed whole with fluid and not divided, crushed,

chewed, or placed in water or it may be administered by carefully opening the capsule and sprinkling the

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

entire contents on a spoonful of applesauce. This drug/food mixture should be swallowed immediately

without chewing and followed with a glass of water to ensure complete swallowing of the pellets

(spheroids).

2.1 Major Depressive Disorder

For most patients, the recommended starting dose for venlafaxine hydrochloride extended-release

capsules are 75 mg per day, administered in a single dose. For some patients, it may be desirable to start

at 37.5 mg per day for 4 to 7 days to allow new patients to adjust to the medication before increasing to

75 mg per day. Patients not responding to the initial 75 mg per day dose may benefit from dose increases

to a maximum of 225 mg per day. Dose increases should be in increments of up to 75 mg per 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 [see Clinical Pharmacology

(12.3)] . In the clinical studies establishing efficacy, upward titration was permitted at intervals of 2

weeks or more.

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

also 225 mg per day for venlafaxine hydrochloride (immediate-release), more severely depressed

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

per day (range of 150 to 375 mg per day). Whether or not higher doses of venlafaxine hydrochloride

extended-release capsules are needed for more severely depressed patients is unknown; however, the

experience with venlafaxine hydrochloride extended-release capsules doses higher than 225 mg per

day is very limited.

2.2 Generalized Anxiety Disorder

For most patients, the recommended starting dose for venlafaxine hydrochloride extended-release

capsules is 75 mg per day, administered in a single dose. For some patients, it may be desirable to start

at 37.5 mg per day for 4 to 7 days to allow new patients to adjust to the medication before increasing to

75 mg per day. Patients not responding to the initial 75 mg per day dose may benefit from dose increases

to a maximum of 225 mg per day. Dose increases should be in increments of up to 75 mg per 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 [ see Clinical Pharmacology

(12.3)] .

2.3 Social Anxiety Disorder (Social Phobia)

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

higher doses confer any additional benefit.

2.4 Panic Disorder

The recommended starting dose is 37.5 mg per day of venlafaxine hydrochloride extended-release

capsules for 7 days. Patients not responding to 75 mg per day may benefit from dose increases to a

maximum of approximately 225 mg per day. Dose increases should be in increments of up to 75 mg per

day, as needed, and should be made at intervals of not less than 7 days.

2.5 Switching Patients from Venlafaxine Hydrochloride Tablets

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

(immediate release) may be switched to venlafaxine hydrochloride extended-release capsules at the

nearest equivalent dose (mg per day), e.g., 37.5 mg venlafaxine twice a day to 75 mg venlafaxine

hydrochloride extended-release capsules once daily. However, individual dosage adjustments may be

necessary.

2.6 Specific Populations

Patients with Hepatic Impairment

The total daily dose should be reduced by 50% in patients with mild (Child-Pugh=5 to 6) to moderate

(Child-Pugh=7 to 9) hepatic impairment. In patients with severe hepatic impairment (Child-Pugh=10 to

15) or hepatic cirrhosis, it may be necessary to reduce the dose by 50% or more [see Use in Specific

Populations (8.7)] .

Patients with Renal Impairment

The total daily dose should be reduced by 25% to 50% in patients with mild (CLcr= 60 to 89 mL/min)

or moderate (CLcr= 30 to 59 mL/min) renal impairment. In patients undergoing hemodialysis or with

severe renal impairment (CLcr < 30 mL/min), the total daily dose should be reduced by 50% or more.

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

individualization of dosage may be desirable in some patients [see Use in Specific Populations (8.7)] .

2.7 Maintenance Treatment

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

MDD, GAD, SAD, or PD should be treated with venlafaxine hydrochloride extended-release capsules.

It is generally agreed that acute episodes of MDD require several months or longer of sustained

pharmacological therapy beyond response to the acute episode. Venlafaxine hydrochloride extended-

release capsules/venlafaxine hydrochloride have demonstrated continuation of response in clinical

studies up to 52 weeks, at the same dose at which patients responded during the initial treatment [see

Clinical Studies (14.1)] . It is not known whether or not the dose of venlafaxine hydrochloride extended-

release capsules 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.

In patients with GAD and SAD, venlafaxine hydrochloride extended-release capsules have been shown

to be effective in 6-month clinical studies. The need for continuing medication in patients with GAD and

SAD who improve with venlafaxine hydrochloride extended-release capsules treatment should be

periodically reassessed.

In a clinical study for PD, patients continuing venlafaxine hydrochloride extended-release capsules at

the same dose at which they responded during the initial 12 weeks of treatment experienced a

statistically significantly longer time to relapse than patients randomized to placebo [see Clinical Studies

(14.4)] . The need for continuing medication in patients with PD who improve with venlafaxine

hydrochloride extended-release capsules treatment should be periodically reassessed.

2.8 Discontinuing Venlafaxine Hydrochloride Extended-Release Capsules

A gradual reduction in the dose, rather than abrupt cessation, is recommended whenever possible. In

clinical studies with venlafaxine hydrochloride extended-release capsules, tapering was achieved by

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

[see Warnings and Precautions (5.7)] .

2.9 Switching Patients 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 hydrochloride extended-release capsules. In

addition, at least 7 days should be allowed after stopping venlafaxine hydrochloride extended-release

capsules before starting an MAOI intended to treat psychiatric disorders [see Contraindications (4.2),

Warnings and Precautions (5.2), and Drug Interactions (7.2)] .

Use of Venlafaxine Hydrochloride Extended-Release Capsules with other MAOIs such as

Linezolid or Intravenous Methylene Blue

Do not start venlafaxine hydrochloride extended-release capsules in a patient who is being treated with

linezolid or intravenous methylene blue, because there is an 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 (4.2)] .

In some cases, a patient already receiving venlafaxine hydrochloride extended-release capsules therapy

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

linezolid or intravenous methylene blue 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 hydrochloride extended-release capsules should be stopped promptly,

and linezolid or intravenous methylene blue can be administered. Monitor the patient 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 hydrochloride extended-release capsules can 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 concomitantly with venlafaxine

hydrochloride extended-release capsules 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 hydrochloride extended-release capsules USP are available in the following strengths:

37.5 mg capsules are white to off white spherical to oval pellets filled in empty hard gelatin

capsule shell (size ‘3’) of opaque grey color cap and opaque peach color body imprinted with “E”

on cap and “73” on the body with edible black ink.

75 mg capsules are white to off white spherical to oval pellets filled in empty hard gelatin capsule

shell (size ‘1’) of opaque peach color cap and opaque peach color body imprinted with “E” on cap

and “74” on the body with edible black ink.

150 mg capsules are white to off white spherical to oval pellets filled in empty hard gelatin

capsule shell (size ‘0’) of opaque dark orange color cap and opaque dark orange color body

imprinted with “E” on cap and “89” on the body with edible black ink.

4 CONTRAINDICATIONS

4.1 Hypersensitivity

Hypersensitivity to venlafaxine hydrochloride, desvenlafaxine succinate or to any excipients in the

formulation

4.2 Concomitant Use with Monoamine Oxidase Inhibitors (MAOIs)

The use of MAOIs (intended to treat psychiatric disorders) concomitantly with venlafaxine

hydrochloride extended-release capsules or within 7 days of discontinuing treatment with venlafaxine

hydrochloride extended-release capsules are contraindicated because of an increased risk of serotonin

syndrome. The use of venlafaxine hydrochloride extended-release capsules within 14 days of

discontinuing treatment with an MAOI (intended to treat psychiatric disorders) is also contraindicated

[see Dosage and Administration (2.9), Warnings and Precautions (5.2), and Drug Interactions (7.2)].

Starting venlafaxine hydrochloride extended-release capsules in a patient who is being treated with an

MAOI such as linezolid or intravenous methylene blue is also contraindicated, because of an increased

risk of serotonin syndrome [see Dosage and Administration (2.9), Warnings and Precautions (5.2), and

Drug Interactions (7.3)] .

5 WARNINGS AND PRECAUTIONS

5.1 Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults

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 studies 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 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 studies in children and adolescents with MDD, Obsessive

Compulsive Disorder (OCD), or other psychiatric disorders included a total of 24 short-term studies of

9 antidepressant drugs in over 4,400 patients. The pooled analyses of placebo-controlled studies in

adults with MDD or other psychiatric disorders included a total of 295 short-term studies (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 versus 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: Difference in the Number of Cases of Suicidality per 1,000 Patients Treated versus

Placebo

Age Range

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 studies. There were suicides in the adult studies, 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 studies 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 MDD, 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

Warnings and Precautions (5.7) and Dosage and Administration (2.8)] .

Families and caregivers of patients being treated with antidepressants for MDD 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 healthcare

providers. Such monitoring should include daily observation by families and caregivers . Prescriptions

for venlafaxine hydrochloride extended-release capsules should be written for the smallest quantity of

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

Screening Patients for Bipolar Disorder

A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed

(though not established in controlled studies) 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 hydrochloride extended-release capsules are not

approved for use in treating bipolar depression.

5.2 Serotonin Syndrome

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

SSRIs, including venlafaxine hydrochloride extended-release capsules alone, but particularly with

concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl,

lithium, tramadol, tryptophan, buspirone, 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

others, such as linezolid or intravenous methylene blue). The development of a potentially life-

threatening serotonin syndrome has been reported with SNRIs and SSRIs, including venlafaxine

hydrochloride extended-release capsules alone, but particularly with concomitant use of other

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

buspirone, 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 others, such as linezolid or

intravenous methylene blue).

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

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

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

hyperreflexia, incoordination); seizures and gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

Patients should be monitored for the emergence of serotonin syndrome.Serotonin syndrome symptoms

may include mental status changes (e.g., agitation, hallucinations, delirium, coma) autonomic instability

(e.g., tachycardia, labile blood pressure, hyperthermia, diaphoresis, flushing, and dizziness),

neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination); seizures and

gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the

emergence of serotonin syndrome.

The concomitant use of venlafaxine hydrochloride extended-release capsules with MAOIs (intended to

treat psychiatric disorders) is contraindicated. Venlafaxine hydrochloride extended-release capsules

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 hydrochloride extended-

release capsules. Venlafaxine hydrochloride extended-release capsules should be discontinued before

initiating treatment with the MAOI .

The concomitant use of venlafaxine hydrochloride extended-release capsules with MAOIs (intended to

treat psychiatric disorders) is contraindicated. Venlafaxine hydrochloride extended-release capsules

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 hydrochloride extended-

release capsules. Venlafaxine hydrochloride extended-release capsules should be discontinued before

initiating treatment with the MAOI [see Contraindications (4.2), Dosage and Administration (2.6), and

Drug Interactions (7.3)] .

If concomitant use of venlafaxine hydrochloride extended-release capsules with other serotonergic

drugs (e.g., triptans, tricyclic antidepressants, mirtazapine, fentanyl, lithium, tramadol, buspirone,

amphetamines, tryptophan, or St. John's wort) is clinically warranted, careful observation of the patient

is advised, particularly during treatment initiation and dose increases . Patients should be made aware of

the potential risk of serotonin syndrome. Treatment with venlafaxine hydrochloride extended-release

capsules and any concomitant serotonergic agents should be discontinued immediately if the above

events occur, and supportive symptomatic treatment should be initiated. If concomitant use of

venlafaxine hydrochloride extended-release capsules with other serotonergic drugs (e.g., triptans,

tricyclic antidepressants, mirtazapine, fentanyl, lithium, tramadol, buspirone, amphetamines, tryptophan,

or St. John's wort) is clinically warranted, careful observation of the patient is advised, particularly

during treatment initiation and dose increases [see Drug Interactions (7.3)] . Patients should be made

aware of the potential risk of serotonin syndrome. Treatment with venlafaxine hydrochloride extended-

release capsules and any concomitant serotonergic agents should be discontinued immediately if the

above events occur, and supportive symptomatic treatment should be initiated.

5.3 Elevations in Blood Pressure

In controlled trials, there were dose-related increases in systolic and diastolic blood pressure, as well

as cases of sustained hypertension [see Adverse Reactions (6.2)].

Monitor blood pressure before initiating treatment with venlafaxine hydrochloride extended-release

capsules and regularly during treatment. Control pre-existing hypertension before initiating treatment

with venlafaxine hydrochloride extended-release capsules. Use caution in treating patients with pre-

existing hypertension or cardiovascular or cerebrovascular conditions that might be compromised by

increases in blood pressure. Sustained blood pressure elevation can lead to adverse outcomes. Cases of

elevated blood pressure requiring immediate treatment have been reported with venlafaxine

hydrochloride extended-release capsules. Consider dose reduction or discontinuation of treatment for

patients who experience a sustained increase in blood pressure.

Across all clinical studies with venlafaxine hydrochloride, 1.4% of patients in the venlafaxine

hydrochloride extended-release capsules treated groups experienced a ≥15 mm Hg increase in supine

diastolic blood pressure (SDBP) ≥ 105 mm Hg, compared to 0.9% of patients in the placebo groups.

Similarly, 1% of patients in the venlafaxine hydrochloride extended-release capsules treated groups

experienced a ≥ 20 mm Hg increase in supine systolic blood pressure (SSBP) with blood pressure ≥

180 mm Hg, compared to 0.3% of patients in the placebo groups [see Table 10 in Adverse Reactions

(6.2)]. Venlafaxine hydrochloride extended-release capsules treatment was associated with sustained

hypertension (defined as treatment-emergent SDBP ≥ 90 mm Hg and ≥ 10 mm Hg above baseline for

three consecutive on-therapy visits [see Table 11 in Adverse Reactions (6.2)]. An insufficient number of

patients received mean doses of venlafaxine hydrochloride extended-release capsules over 300 mg per

day in clinical studies to fully evaluate the incidence of sustained increases in blood pressure at these

higher doses.

5.4 Abnormal Bleeding

SSRIs and SNRIs, including venlafaxine hydrochloride extended-release capsules, may increase the

risk of bleeding events, ranging from ecchymoses, hematomas, epistaxis, petechiae, and gastrointestinal

hemorrhage to life-threatening hemorrhage. Concomitant use of aspirin, Nonsteroidal Anti-

Inflammatory Drugs (NSAIDs), warfarin, and other anti-coagulants or other drugs known to affect

platelet function 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. Caution patients about the risk of bleeding associated

with the concomitant use of venlafaxine hydrochloride extended-release capsules and NSAIDs, aspirin,

or other drugs that affect coagulation.

5.5 Angle Closure Glaucoma

The pupillary dilation that occurs following use of many antidepressant drugs including venlafaxine

hydrochloride extended-release capsules may trigger an angle closure attack in a patient with

anatomically narrow angles who does not have a patent iridectomy.

5.6 Activation of Mania/Hypomania

Mania or hypomania was reported in venlafaxine hydrochloride extended-release capsules treated

patients in the premarketing studies in MDD, SAD, and PD (see Table 2). Mania/hypomania has also

been reported in a small proportion of patients with mood disorders who were treated with other

marketed drugs to treat MDD. Venlafaxine hydrochloride extended-release capsules should be used

cautiously in patients with a history of mania or hypomania.

Table 2: Incidence (%) of Mania or Hypomania Reported in Venlafaxine Hydrochloride

Extended-Release Capsules Treated Patients in the Premarketing Studies

Indication

Venlafaxine Hydrochloride

Extended-Release Capsules

Placebo

5.7 Discontinuation Syndrome

Discontinuation symptoms have been systematically evaluated in patients taking venlafaxine, including

prospective analyses of clinical studies in GAD and retrospective surveys of studies in MDD and SAD.

Abrupt discontinuation or dose reduction of venlafaxine at various doses has been found to be

associated with the appearance of new symptoms, the frequency of which increased with increased

dose level and with longer duration of treatment. Reported symptoms include agitation, anorexia,

anxiety, confusion, impaired coordination and balance, diarrhea, dizziness, dry mouth, dysphoric mood,

fasciculation, fatigue, flu-like symptoms, headaches, hypomania, insomnia, nausea, nervousness,

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

tremor, vertigo, and vomiting.

During marketing of venlafaxine hydrochloride extended-release capsules, other SNRIs, and SSRIs,

there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs,

particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness,

sensory disturbances (e.g., paresthesia, such as electric shock sensations), anxiety, confusion,

headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. While these events

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

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

hydrochloride extended-release capsules. A gradual reduction in the dose, rather than abrupt cessation,

is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or

upon discontinuation of treatment, then resuming the previously prescribed dose may be considered.

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

and Administration (2.8)] .

5.8 Seizures

Seizures have occurred with venlafaxine therapy. Venlafaxine hydrochloride extended-release

capsules, like many antidepressants, should be used cautiously in patients with a history of seizures and

should be discontinued in any patient who develops seizures. [Must mitigate the risk: Risk factors,

concomitant meds that lower the seizure threshold.]

5.9 Hyponatremia

Hyponatremia can occur as a result of treatment with SSRIs and SNRIs, including venlafaxine

hydrochloride extended-release capsules. In many cases, the hyponatremia appears to be the result of

the Syndrome of Inappropriate Antidiuretic Hormone (SIADH) secretion. 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 [see Use in Specific Populations (8.5)] . Also, patients taking

diuretics, or those who are otherwise volume-depleted, may be at greater risk. Consider discontinuation

of venlafaxine hydrochloride extended-release capsules in patients with symptomatic hyponatremia, and

institute appropriate medical intervention.

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.

5.10 Weight and Height Changes in Pediatric Patients

Weight Changes

The average change in body weight and incidence of weight loss (percentage of patients who lost 3.5%

or more) in the placebo-controlled pediatric studies in MDD, GAD, and SAD are shown in Tables 3 and

Table 3: Average Change in Body Weight (kg) From Beginning of Treatment in Pediatric Patients

in Double-blind, Placebo-controlled Studies of Venlafaxine Hydrochloride Extended-Release

Caps ules

Indication

(Duration)

Venlafaxine Hydrochloride

Extended-Release Capsules

Placebo

MDD and GAD

(4 pooled studies, 8 weeks)

-0.45 (n = 333)

+0.77 (n = 333)

SAD (16 weeks)

-0.75 (n = 137)

+0.76 (n = 148)

Table 4: Incidence (%) of Pediatric Patients Experiencing Weight Loss (3.5% or more) in

Double-blind, Placebo-controlled Studies of Venlafaxine Hydrochloride Extended-Release

Caps ules

p < 0.001 versus placebo

Indication

(Duration)

Venlafaxine Hydrochloride

Extended-Release Capsules

Placebo

MDD and GAD

(4 pooled studies, 8 weeks)

(n = 333)

3.6 (n = 333)

SAD (16 weeks)

(n = 137)

14 (n = 148)

Weight loss was not limited to patients with treatment-emergent anorexia [see Warnings and Precautions

(5.11)] .

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

Height Changes

Table 5 shows the average height increase in pediatric patients in the short-term, placebo-controlled

MDD, GAD, and SAD studies. The differences in height increases in GAD and MDD studies were

most notable in patients younger than twelve.

Table 5: Average Height Increases (cm) in Pediatric Patients in Placebo-controlled Studies of

Venlafaxine Hydrochloride Extended-Release Capsules

p = 0.041

Indication

(Duration)

Venlafaxine Hydrochloride

Extended-Release Capsules

Placebo

MDD (8 weeks)

0.8 (n = 146)

0.7 (n = 147)

GAD (8 weeks)

(n = 122)

1 (n = 132)

SAD (16 weeks)

1 (n = 109)

1 (n = 112)

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 and

expected growth rates was larger for children (< 12 years old) than for adolescents (≥ 12 years old).

5.11 Appetite Changes in Pediatric Patients

Decreased appetite (reported as treatment-emergent anorexia) was more commonly observed in

venlafaxine hydrochloride extended-release capsules treated patients versus placebo-treated patients in

the premarketing evaluation of venlafaxine hydrochloride extended-release capsules for MDD, GAD,

and SAD (see Table 6).

Table 6: Incidence (%) of Decreased Appetite and Associated Discontinuation Rates

(%) in

Pediatric Patients in Placebo-controlled Studies of Venlafaxine Hydrochloride Extended-Release

Caps ules

The discontinuation rates for weight loss were 0.7% for patients receiving either venlafaxine

hydrochloride extended-release capsules or placebo.

Indication (Duration)

Venlafaxine Hydrochloride

Extended-Release Capsules

Incidence

Discontinuation

Placebo

Incidence

Discontinuation

MDD and GAD

(pooled, 8 weeks)

SAD (16 weeks)

5.12 Interstitial Lung Disease and Eosinophilic Pneumonia

Interstitial lung disease and eosinophilic pneumonia associated with venlafaxine therapy have been

rarely reported. The possibility of these adverse events should be considered in venlafaxine-treated

patients who present with progressive dyspnea, cough or chest discomfort. Such patients should

a

undergo a prompt medical evaluation, and discontinuation of venlafaxine therapy should be considered.

6 ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in other sections of the label:

Hypersensitivity [see Contraindications (4.1)]

Suicidal Thoughts and Behaviors in Children, Adolescents, and Adults [see Warnings and

Precautions (5.1)]

Serotonin Syndrome [see Warnings and Precautions (5.2)]

Elevations in Blood Pressure [see Warnings and Precautions (5.3)]

Abnormal Bleeding [see Warnings and Precautions (5.4)]

Angle Closure Glaucoma [see Warnings and Precautions (5.5)]

Activation of Mania/Hypomania [see Warnings and Precautions (5.6)]

Discontinuation Syndrome [see Warnings and Precautions (5.7)]

Seizure [see Warnings and Precautions (5.8)]

Hyponatremia [see Warnings and Precautions (5.9)]

Weight and Height changes in Pediatric Patients [see Warnings and Precautions (5.10)]

Appetite Changes in Pediatric Patients [see Warnings and Precautions (5.11)]

Interstitial Lung Disease and Eosinophilic Pneumonia [see Warnings and Precautions (5.12)]

6.1 Clinical Studies Experience

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

observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of

another drug and may not reflect the rates observed in practice.

Most Common Adverse Reactions

The most commonly observed adverse reactions in the clinical study database in venlafaxine

hydrochloride extended-release capsules treated patients in MDD, GAD, SAD, and PD (incidence ≥ 5%

and at least twice the rate of placebo) were: nausea (30%), somnolence (15.3%), dry mouth (14.8%),

sweating (11.4%), abnormal ejaculation (9.9%), anorexia (9.8%), constipation (9.3%), impotence (5.3%)

and decreased libido (5.1%).

Adverse Reactions Reported as Reasons for Discontinuation of Treatment

Combined across short-term, placebo-controlled premarketing studies for all indications, 12% of the

3,558 patients who received venlafaxine hydrochloride extended-release capsules (37.5 to 225 mg)

discontinued treatment due to an adverse experience, compared with 4% of the 2,197 placebo-treated

patients in those studies.

The most common adverse reactions leading to discontinuation in ≥ 1% of the venlafaxine

hydrochloride extended-release capsules treated patients in the short-term studies (up to 12 weeks)

across indications are shown in Table 7.

Table 7: Incidence (%) of Patients Reporting Adverse Reactions Leading to Discontinuation in

Placebo-controlled Clinical Studies (up to 12 Weeks Duration)

Body System Adverse Reaction

Venlafaxine Hydrochloride

Extended-Release Capsules

Placebo

Body System Adverse Reaction

Extended-Release Capsules

n = 3,558

n = 2,197

Body as a whole

Asthenia

Headache

Digestive system

Nausea

Nervous system

Dizziness

Insomnia

Somnolence

Skin and appendages

Sweating

Common Adverse Reactions in Placebo-controlled Studies

The number of patients receiving multiple doses of venlafaxine hydrochloride extended-release

capsules during the premarketing assessment for each approved indication is shown in Table 8. The

conditions and duration of exposure to venlafaxine in all development programs varied greatly, and

included (in overlapping categories) open and double-blind studies, uncontrolled and controlled studies,

inpatient (venlafaxine hydrochloride only) and outpatient studies, fixed-dose, and titration studies.

Table 8: Patients Receiving Venlafaxine Hydrochloride Extended-Release Capsules in

Premarketing Clinical Studies

In addition, in the premarketing assessment of venlafaxine hydrochloride, multiple doses were

administered to 2,897 patients in studies for MDD.

Indication

Venlafaxine

Hydrochloride

Extended-Releas e

Capsules

1,381

1,314

The incidences of common adverse reactions (those that occurred in ≥ 2% of venlafaxine

hydrochloride extended-release capsules treated patients [357 MDD patients, 1,381 GAD patients, 819

SAD patients, and 1,001 PD patients] and more frequently than placebo) in venlafaxine hydrochloride

extended-release capsules treated patients in short-term, placebo-controlled, fixed- and flexible-dose

clinical studies (doses 37.5 to 225 mg per day) are shown in Table 9.

The adverse reaction profile did not differ substantially between the different patient populations.

Table 9: Common Adverse Reactions: Percentage of Patients Reporting Adverse Reactions (≥

2% and > placebo) in Placebo-controlled Studies (up to 12 Weeks Duration) across All

Indications

Body System

Adverse Reaction

Venlafaxine Hydrochloride

Extended-Release Capsules

n = 3,558

Placebo

n = 2,197

Percentages based on the number of men (venlafaxine hydrochloride extended-release capsules, n =

1,440; placebo, n = 923)

Percentages based on the number of women (venlafaxine hydrochloride extended-release capsules, n

= 2,118; placebo, n = 1,274)

Body as a whole

Asthenia

12.6

Cardiovascular system

Hypertension

Palpitation

Vasodilatation

Digestive system

Anorexia

Constipation

Diarrhea

Dry mouth

14.8

Nausea

11.8

Vomiting

Nervous system

Abnormal dreams

Dizziness

15.8

Insomnia

17.8

Libido decreased

Nervousness

Paresthesia

Somnolence

15.3

Tremor

Respiratory system

Yawn

Skin and appendages

Sweating (including night sweats)

11.4

Special senses

Abnormal vision

Urogenital system

Abnormal ejaculation/orgasm (men)

Anorgasmia (men)

Anorgasmia (women)

Impotence (men)

Other Adverse Reactions Observed in Clinical Studies

Body as a whole – Photosensitivity reaction, chills

Cardiovascular system – Postural hypotension, syncope, hypotension, tachycardia

Digestive system – Gastrointestinal hemorrhage [see Warnings and Precautions (5.4)] , bruxism

Hemic/Lymphatic system – Ecchymosis [see Warnings and Precautions (5.4)]

Metabolic/Nutritional – Hypercholesterolemia, weight gain [see Warnings and Precautions (5.10)],

weight loss [see Warnings and Precautions (5.10)]

Nervous system – Seizures [see Warnings and Precautions (5.8)] , manic reaction [see Warnings and

Precautions (5.6)] , agitation, confusion, akathisia, hallucinations, hypertonia, myoclonus,

depersonalization, apathy

depersonalization, apathy

Skin and appendages – Urticaria, pruritus, rash, alopecia

Special senses – Mydriasis, abnormality of accommodation, tinnitus, taste perversion

Urogenital system – Urinary retention, urination impaired, urinary incontinence, urinary frequency

increased, menstrual disorders associated with increased bleeding or increased irregular bleeding (e.g.,

menorrhagia, metrorrhagia)

6.2 Vital Sign Changes

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

10). Across most indications, a dose-related increase in mean supine systolic and diastolic blood

pressure was evident in patients treated with venlafaxine hydrochloride extended-release capsules.

Across all clinical studies in MDD, GAD, SAD and PD, 1.4% of patients in the venlafaxine

hydrochloride extended-release capsules groups experienced an increase in SDBP of ≥15 mm Hg

along with a 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 capsules groups

experienced an increase in SSBP of ≥ 20 mm Hg with a blood pressure ≥ 180 mm Hg, compared to

0.3% of patients in the placebo groups.

Table 10: Final On-therapy Mean Changes From Baseline in Supine Systolic (SSBP) and Diastolic

(SDBP) Blood Pressure (mm Hg) in Placebo-controlled Studies

Indication

(Duration)

Venlafaxine Hydrochloride

Extended-Release Capsules

Placebo

≤ 75 mg per day > 75 mg per day

SSBP

SDBP

SSBP

SDBP

SSBP

SDBP

(8 to 12 weeks)

-0.28

0.37

2.93

3.56

-1.08

-0.1

weeks)

-0.28

0.02

1.68

-1.26

-0.92

months)

1.27

-0.69

2.06

1.28

-1.29

-0.74

(12 weeks)

-0.29

-1.26

1.18

1.34

-1.96

-1.22

(6 months)

-0.98

-0.49

2.51

1.96

-1.84

-0.65

(10 to 12 weeks)

-1.15

0.97

-0.36

0.16

-1.29

-0.99

Venlafaxine hydrochloride extended-release capsules treatment were associated with sustained

hypertension (defined as treatment-emergent Supine Diastolic Blood Pressure [SDBP] ≥ 90 mm Hg and

≥ 10 mm Hg above baseline for three consecutive on-therapy visits (see Table 11). An insufficient

number of patients received mean doses of venlafaxine hydrochloride extended-release capsules over

300 mg per day in clinical studies to fully evaluate the incidence of sustained increases in blood

pressure at these higher doses.

Table 11: Sustained Elevations in SDBP in Venlafaxine Hydrochloride Extended-Release

Capsules Premarketing Studies

Indication

Dose Range (mg per day)

Incidence (%)

75 to 375

19/705 (3)

37.5 to 225

5/1011 (0.5)

75 to 225

5/771 (0.6)

75 to 225

9/973 (0.9)

Venlafaxine hydrochloride extended-release capsules were associated with mean increases in pulse

rate compared with placebo in premarketing placebo-controlled studies (see Table 12) [see Warnings

and Precautions (5.3, 5.4)] .

Table 12: Approximate Mean Final On-therapy Increase in Pulse Rate (beats/min) in Venlafaxine

Hydrochloride Extended-Release Capsules Premarketing Placebo-controlled Studies (up to 12

Weeks Duration)

Indication

(Duration)

Venlafaxine Hydrochloride

Extended-Release Capsules

Placebo

MDD (12 weeks)

GAD (8 weeks)

<1

SAD (12 weeks)

PD (12 weeks)

<1

6.3 Laboratory Changes

Serum Cholesterol

Venlafaxine hydrochloride extended-release capsule was associated with mean final increases in serum

cholesterol concentrations compared with mean final decreases for placebo in premarketing MDD,

GAD, SAD and PD clinical studies (Table 13).

Table 13: Mean Final On-therapy Changes in Cholesterol Concentrations (mg/dL) in Venlafaxine

Hydrochloride Extended-Release Capsules Premarketing Studies

Indication

(Duration)

Venlafaxine Hydrochloride

Extended-Release Capsules

Placebo

(12 weeks)

+1.5

-7.4

(8 weeks)

(6 months)

+2.3

-4.9

-7.7

(12 weeks)

(6 months)

+7.9

+5.6

-2.9

-4.2

(12 weeks)

-3.7

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 8 weeks and up to 6 months in premarketing placebo-controlled GAD trials was associated with

mean final on-therapy increases in serum cholesterol concentration of approximately 1 mg/dL and 2.3

mg/dL, respectively while placebo subjects experienced mean final decreases of 4.9 mg/dL and 7.7

mg/dL, respectively. Venlafaxine hydrochloride extended-release capsules treatment for up to 12

mg/dL, respectively. Venlafaxine hydrochloride extended-release capsules treatment for up to 12

weeks and up to 6 months in premarketing placebo-controlled Social Anxiety Disorder trials was

associated with mean final on-therapy increases in serum cholesterol concentration of approximately

7.9 mg/dL and 5.6 mg/dL, respectively, compared with mean final decreases of 2.9 and 4.2 mg/dL,

respectively, for placebo. Venlafaxine hydrochloride extended-release capsules treatment for up to 12

weeks in premarketing placebo-controlled panic disorder trials was associated with mean final on-

therapy increases in serum cholesterol concentration of approximately 5.8 mg/dL compared with a mean

final decrease of 3.7 mg/dL for placebo.

Patients treated with venlafaxine hydrochloride (immediate release) 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% of placebo-treated patients.

Serum Triglycerides

Venlafaxine hydrochloride extended-release capsule was associated with mean final on-therapy

increases in fasting serum triglycerides compared with placebo in premarketing clinical studies of SAD

and PD up to 12 weeks (pooled data) and 6 months duration (Table 14).

Table 14: Mean Final On-therapy Increases in Triglyceride Concentrations (mg/dL) in

Venlafaxine Hydrochloride Extended-Release Capsules Premarketing Studies

Indication

(Duration)

Venlafaxine Hydrochloride

Extended-Release Capsules

Placebo

(12 weeks)

(6 months)

11.8

(12 weeks)

(6 months)

6.4 Pediatric Patients

In general, the adverse reaction profile of venlafaxine (in placebo-controlled clinical studies) in

children and adolescents (ages 6 to 17) was similar to that seen for adults. As with adults, decreased

appetite, weight loss, increased blood pressure, and increased serum cholesterol were observed [see

Warnings and Precautions (5.3, 5.10, 5.11) and Use in Specific Populations (8.4)] .

In pediatric clinical studies, the adverse reaction, suicidal ideation, was observed.

Particularly, the following adverse reactions were observed in pediatric patients: abdominal pain,

agitation, dyspepsia, ecchymosis, epistaxis, and myalgia.

6.5 Adverse Reactions Identified During Postapproval Use

The following adverse reactions have been identified during postapproval use of venlafaxine

hydrochloride extended-release capsules. Because these reactions are reported voluntarily from a

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

causal relationship to drug exposure:

Body as a whole – Anaphylaxis, angioedema

Cardiovascular system – QT prolongation, ventricular fibrillation, ventricular tachycardia (including

torsade de pointes), takotsubo cardiomyopathy

Digestive system – Pancreatitis

Hemic/Lymphatic system – Mucous membrane bleeding [see Warnings and Precautions (5.4 )] , blood

dyscrasias (including agranulocytosis, aplastic anemia, neutropenia and pancytopenia), prolonged

bleeding time, thrombocytopenia

Metabolic/Nutritional – Hyponatremia [see Warnings and Precautions (5.9)] , Syndrome of Inappropriate

Antidiuretic Hormone (SIADH) secretion [see Warnings and Precautions (5.9)] , abnormal liver function

tests, hepatitis, prolactin increased

Musculoskeletal – Rhabdomyolysis

Nervous system – Neuroleptic Malignant Syndrome (NMS) [see Warnings and Precautions (5.2)] ,

serotonergic syndrome [see Warnings and Precautions (5.2)] , delirium, extrapyramidal reactions

(including dystonia and dyskinesia), impaired coordination and balance, tardive dyskinesia

Respiratory system – Dyspnea, interstitial lung disease, pulmonary eosinophilia [see Warnings and

Precautions (5.12)]

Skin and appendages – Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme

Special senses – Angle-closure glaucoma [see Warnings and Precautions (5.5)]

7 DRUG INTERACTIONS

7.1 Central Nervous System (CNS)-Active Drugs

The risk of using venlafaxine in combination with other CNS-active drugs has not been systematically

evaluated. Consequently, caution is advised when venlafaxine hydrochloride extended-release

capsules are taken in combination with other CNS-active drugs.

7.2 Monoamine Oxidase Inhibitors

Adverse reactions, some of which were serious, have been reported in patients who have recently been

discontinued from an MAOI and started on antidepressants with pharmacological properties similar to

venlafaxine hydrochloride extended-release capsules (SNRIs or SSRIs), or who have recently had

SNRI or SSRI therapy discontinued prior to initiation of an MAOI [see Dosage and Administration (2.9),

Contraindications (4.2) and Warnings and Precautions (5.2)] .

7.3 Serotonergic Drugs

Based on the mechanism of action of venlafaxine hydrochloride extended-release capsules and the

potential for serotonin syndrome, caution is advised when venlafaxine hydrochloride extended-release

capsules are coadministered with other drugs that may affect the serotonergic neurotransmitter systems,

such as triptans, SSRIs, other SNRIs, linezolid (an antibiotic which is a reversible non-selective

MAOI), lithium, tramadol, or St. John’s wort. If concomitant treatment with venlafaxine hydrochloride

extended-release capsules and these drugs is clinically warranted, careful observation of the patient is

advised, particularly during treatment initiation and dose increases. The concomitant use of venlafaxine

hydrochloride extended-release capsules with tryptophan supplements are not recommended [see

Dosage and Administration (2.9), Contraindications (4.2), and Warnings and Precautions (5.2)] .

7.4 Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin)

Serotonin release by platelets plays an important role in hemostasis. The use of psychotropic drugs that

interfere with serotonin reuptake is associated with the occurrence of upper gastrointestinal bleeding

and concurrent use of an NSAID or aspirin may potentiate this risk of bleeding [see Warnings and

Precautions (5.4)]. Altered anticoagulant effects, including increased bleeding, have been reported when

SSRIs and SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be

carefully monitored when venlafaxine hydrochloride extended-release capsules are initiated or

discontinued.

7.5 Weight Loss Agents

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

phentermine, have not been established. Coadministration of venlafaxine hydrochloride extended-

release capsules and weight loss agents are not recommended. Venlafaxine hydrochloride extended-

release capsules are not indicated for weight loss alone or in combination with other products.

7.6 Effects of Other Drugs on Venlafaxine Hydrochloride Extended-Release Capsules

Figure 1: Effect of interacting drugs on the pharmacokinetics of venlafaxine and active metabolite

O-desmethylvenlafaxine (ODV).

Abbreviations: ODV, O-desmethylvenlafaxine; AUC, area under the curve; C

, peak plasma

concentrations; EM’s, extensive metabolizers; PM’s, poor metabolizers

* No dose adjustment on co-administration with CYP2D6 inhibitors (Fig 3 and Metabolism Section 12.3)

7.7 Effects of Venlafaxine Hydrochloride Extended-Release Capsules on Other Drugs

Figure 2: Effect of venlafaxine on the pharmacokinetics interacting drugs and their active

metabolites.

Abbreviations: AUC, area under the curve; C

, peak plasma concentrations; OH, hydroxyl

* Data for 2-OH desipramine were not plotted to enhance clarity; the fold change and 90% CI for C

and AUC of 2-OH desipramine were 6.6 (5.5, 7.9) and 4.4 (3.8, 5), respectively.

Note:

*: 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.

7.8 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. In

reproductive developmental studies in rats and rabbits with O-desmethylvenlafaxine (ODV), the major

human metabolite of venlafaxine, evidence of teratogenicity was not observed at exposure margins of

13 in rats and 0.3 in rabbits. There are no adequate and well-controlled studies in pregnant women.

Venlafaxine hydrochloride extended-release capsules should be used during pregnancy only if the

potential benefit justifies the potential risk to the fetus. 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, or SSRIs, 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) and Drug Interactions (7.3)] .

When treating a pregnant woman with venlafaxine hydrochloride extended-release capsules during the

third trimester, the physician should carefully consider the potential risks and benefits of treatment.

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 hydrochloride extended-release capsules,

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

Two placebo-controlled trials in 766 pediatric patients with MDD and two placebo-controlled trials in

793 pediatric patients with GAD have been conducted with 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 hydrochloride extended-release capsules in a child or

adolescent must balance the potential risks with the clinical need [see Boxed Warning, Warnings and

Precautions (5.1, 5.10, 5.11) and Adverse Reactions (6.4 )] .

Although no studies have been designed to primarily assess venlafaxine hydrochloride extended-

release capsule's impact on the growth, development, and maturation of children and adolescents, the

studies that have been done suggest that venlafaxine hydrochloride extended-release capsules may

adversely affect weight and height [see Warnings and Precautions (5.10)]. Should the decision be made

to treat a pediatric patient with venlafaxine hydrochloride extended-release capsules, regular

monitoring of weight and height is recommended during treatment, particularly if treatment is to be

continued long-term [see Warnings and Precautions (5.10, 5.11)] . The safety of venlafaxine

hydrochloride extended-release capsules 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, 6.3)] .

8.5 Geriatric Use

The percentage of patients in clinical studies for venlafaxine hydrochloride extended-release capsules

for MDD, GAD, SAD, and PD who were 65 years of age or older are shown in Table 15.

Table 15: Percentage (and Number of Patients Studied) of Patients 65 Years of Age and Older by

Indication

In addition, in the premarketing assessment of venlafaxine hydrochloride (immediate release), 12%

(357/2,897) of patients were ≥ 65 years of age.

Indication

Venlafaxine Hydrochloride Extended-Release

Capsules

4 (14/357)

6 (77/1,381)

1 (10/819)

2 (16/1,001)

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 event [see Warnings and Precautions (5.9)] .

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

Pharmacology (12.3)] (see Figure 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 (2.6)] .

a

8.6 Age and Gender

A population pharmacokinetic analysis of 404 venlafaxine hydrochloride-treated patients from two

studies involving both twice daily and three times daily 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 (2.6)] (see Table 15).

8.7 Use in Patient Subgroups

Figure 3: Pharmacokinetics of venlafaxine and its metabolite O-desmethylvenlafaxine (ODV) in

special populations.

Abbreviations: ODV, O-desmethylvenlafaxine; AUC, area under the curve; C

, peak plasma

concentrations;

*Similar effect is expected with strong CYP2D6 inhibitors

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

Venlafaxine hydrochloride extended-release capsule is not a controlled substance.

9.2 Abuse

While venlafaxine has not been systematically studied in clinical studies for its potential for abuse,

there was no indication of drug-seeking behavior in the clinical studies. 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, incrementation 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 (2.8)] .

10 OVERDOSAGE

10.1 Human Experience

During the premarketing evaluations of venlafaxine hydrochloride extended-release capsules (for

MDD, GAD, SAD, and PD) and venlafaxine hydrochloride (for MDD), there were twenty reports of

acute overdosage with venlafaxine hydrochloride (6 and 14 reports in venlafaxine hydrochloride

extended-release capsules and venlafaxine hydrochloride patients, respectively), either alone or in

combination with other drugs and/or alcohol.

Somnolence was the most commonly reported symptom. Among the other reported symptoms were

paresthesia of all four limbs, moderate dizziness, nausea, numb hands and feet, and hot-cold spells 5

days after the overdose. In most cases, no signs or symptoms were associated with overdose. 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. One patient who ingested 2.75 g of

venlafaxine was observed to have two generalized convulsions and a prolongation of QTc to 500 msec,

compared with 405 msec at baseline. Mild sinus tachycardia was reported in two of the other patients.

Actions taken to treat the overdose included no treatment, hospitalization and symptomatic treatment, and

hospitalization plus treatment with activated charcoal. All patients recovered.

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

alcohol and/or other drugs. The most commonly reported events in overdosage include tachycardia,

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

vomiting. Electrocardiogram changes (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 preexisting 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 hydrochloride extended-release capsules should be written for the

smallest quantity of capsules consistent with good patient management, in order to reduce the risk of

overdose.

10.2 Management of Overdosage

Consult a Certified Poison Control Center for up-to-date guidance and advice (1-800-222-1222 or

www.poison.org). In case of an overdose, provide supportive care, including close medical

supervision and monitoring. Treatment should consist of those general measures employed in the

management of overdosage with any drug. Consider the possibility of multiple drug overdose. Ensure

an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. Provide

supportive and symptomatic measures.

11 DESCRIPTION

Venlafaxine hydrochloride extended-release capsule USP is an extended-release capsule for once-a-

day oral administration that contains venlafaxine hydrochloride USP, a serotonin and norepinephrine

reuptake inhibitor (SNRI).

Venlafaxine 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 molecular formula of C

HCl. Its molecular weight is 313.86. The structural formula

is shown as follows:

Venlafaxine hydrochloride USP is a white or almost white crystalline powder, 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.

Drug release is controlled by diffusion through the coating membrane on the spheroids and is not pH-

dependent. Capsules contain venlafaxine hydrochloride USP equivalent to 37.5 mg, 75 mg, or 150 mg

venlafaxine. Inactive ingredients consist of ethyl cellulose, hypromellose, sugar spheres, and talc. The

empty hard gelatin capsule shells contain iron oxide red, gelatin, titanium dioxide, and sodium lauryl

sulphate. In addition, the 37.5 mg empty hard gelatin capsule shells contain iron oxide black. The

capsules are printed with edible ink containing black iron oxide and shellac.

Meets the USP Dissolution Test - 4

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The exact mechanism of the antidepressant action of venlafaxine in humans is unknown, but is thought to

be related to the potentiation of serotonin and norepinephrine in the central nervous system, through

inhibition of their reuptake. Non- clinical studies have demonstrated that venlafaxine and its active

metabolite, ODV, are potent and selective inhibitors of neuronal serotonin and norepinephrine reuptake

and weak inhibitors of dopamine reuptake.

12.2 Pharmacodynamics

Venlafaxine and 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.

Cardiac Electrophysiology

The effect of venlafaxine on the QT interval was evaluated in a randomized, double-blind, placebo-and

positive-controlled three-period crossover thorough QT study in 54 healthy adult subjects. No

significant QT prolongation effect of venlafaxine 450 mg was detected.

12.3 Pharmacokinetics

Steady-state concentrations of venlafaxine and 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 per day. Mean±SD steady-state plasma clearance of venlafaxine and ODV is 1.3±0.6 and 0.4±0.2

L/h/kg, respectively; apparent elimination half-life is 5±2 and 11±2 hours, respectively; and apparent

(steady-state) volume of distribution is 7.5±3.7 and 5.7±1.8 L/kg, respectively. Venlafaxine and ODV

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 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 approximately 45%.

Administration of venlafaxine hydrochloride extended-release capsules (150 mg once daily) generally

resulted in lower C

and later T

values than for venlafaxine hydrochloride (immediate release)

administered twice daily (Table 16). When equal daily doses of venlafaxine were administered as either

an immediate-release tablet or the extended-release capsule, the exposure to both venlafaxine and ODV

was similar for the two treatments, and the fluctuation in plasma concentrations was slightly lower with

the venlafaxine hydrochloride extended-release capsules. Therefore, venlafaxine hydrochloride

extended-release capsules provide a slower rate of absorption, but the same extent of absorption

compared with the immediate-release tablet.

Table 16: Comparison of C

and T

Values for Venlafaxine and ODV Following Oral

Administration of Venlafaxine Hydrochloride Extended-Release Capsules and Venlafaxine

Hydrochloride (Immediate Release)

Venlafaxine

ODV

C

(ng/mL)

T

(h)

C

(ng/mL)

T

(h)

Venlafaxine

Hydrochloride

Extended-Release Capsules (150

mg once daily)

Venlafaxine Hydrochloride (75

mg twice daily)

Food did not affect the bioavailability of venlafaxine or its active metabolite, ODV. Time of

administration (AM versus PM) did not affect the pharmacokinetics of venlafaxine and ODV from the 75

mg venlafaxine hydrochloride extended-release capsules.

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

hydrochloride extended-release capsules to a patient taking another drug that is highly protein-bound

should not cause increased free concentrations of the other drug.

Metabolism and Elimination

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 levels (extensive

metabolizers) [see Use in Specific Populations (8.7)] .

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.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Tumors were not increased by venlafaxine treatment in mice or rats. 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

(ODV) were lower in rats than in patients receiving the maximum recommended dose. O-

desmethylvenlafaxine (ODV), the major human metabolite of venlafaxine, administered by oral gavage to

mice and rats for 2 years did not increase the incidence of tumors in either study. Mice received ODV at

dosages up to 500/300 mg/kg/day (dosage lowered after 45 weeks of dosing). The exposure at the 300

mg/kg/day dose is 9 times that of a human dose of 225 mg/day. Rats received ODV at dosages up to 300

max

max

max

max

max

max

mg/kg/day (males) or 500 mg/kg/day (females). The exposure at the highest dose is approximately 8

(males) or 11 (females) times that of a human dose of 225 mg/day.

Mutagenesis

Venlafaxine and the major human metabolite, 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 or in the in vivo chromosomal aberration

assay in rats.

Impairment of Fertility

Reproduction and fertility studies of venlafaxine in rats showed no adverse effects of venlafaxine on

male or female fertility at oral doses of up to 2 times the maximum recommended human dose of 225

mg/day on a mg/m

basis. However, reduced fertility was observed in a study in which male and female

rats were treated with O-desmethylvenlafaxine (ODV), the major human metabolite of venlafaxine, prior

to and during mating and gestation. This occurred at an ODV exposure (AUC) approximately 2 to 3

times that associated with a human venlafaxine dose of 225 mg/day.

14 CLINICAL STUDIES

14.1 Major Depressive Disorder

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

Depressive Disorder (MDD) was established in two placebo-controlled, short-term (8 weeks for study

1; 12 weeks for study 2), flexible-dose studies, with doses starting at 75 mg per day and ranging to 225

mg per day in adult outpatients meeting DSM-III-R or DSM-IV criteria for MDD. In moderately

depressed outpatients, the initial dose of venlafaxine was 75 mg per day. In both studies, venlafaxine

hydrochloride extended-release capsules demonstrated superiority over placebo on the primary

efficacy measure defined as change from baseline in the HAM-D-21 total score to the endpoint visit,

venlafaxine hydrochloride extended-release capsules also demonstrated superiority over placebo on

the key secondary efficacy endpoint, the Clinical Global Impressions (CGI) Severity of Illness scale.

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

on the basis of gender.

A 4-week study of inpatients meeting DSM-III-R criteria for MDD with melancholia utilizing

venlafaxine hydrochloride in a range of 150 to 375 mg per day (divided in a three-times-a-day schedule)

demonstrated superiority of venlafaxine hydrochloride over placebo based on the HAM-D-21 total

score. The mean dose in completers was 350 mg per day (study 3).

In a longer-term study, adult outpatients with MDD who had responded during an 8-week open-label

study on venlafaxine hydrochloride extended-release capsules (75, 150, or 225 mg, once daily every

morning) 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-

label 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 statistically significantly lower relapse rates over the subsequent 26 weeks compared with

those receiving placebo (study 4).

In a second longer term trial, adult outpatients with MDD, 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 [100 to 200 mg per day, on a twice

daily schedule] were randomized to continuation of their same venlafaxine hydrochloride dose 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 venlafaxine hydrochloride

treatment experienced statistically significantly lower relapse rates over the subsequent 52 weeks

compared with those receiving placebo (study 5).

Table 17: Major Depressive Disorder Studies:

SD: standard deviation; LS Mean: least-squares mean; CI: confidence interval.

Difference (drug minus placebo) in least-squares mean change from baseline

* Doses statistically significantly superior to placebo.

Study

number

Treatment

Group

Primary Efficacy Measure: HAM-D Score

Mean Baseline

Score (SD)

LS Mean

Change from

Baseline

Placebo Subtracted

Difference

(95%CI)

Study 1

Venlafaxine

Hydrochloride

Extended-Release

Capsules (75 to 225

mg/day)*

24.5

-11.7

-4.45(-6.66, -2.25)

Placebo

23.6

-7.24

Study 2

Venlafaxine

Hydrochloride

Extended-Release

Capsules (75 to 225

mg/day)*

24.5

-15.11

-6.4(-8.45,-4.34)

Placebo

24.9

-8.71

Study 3

Venlafaxine

Hydrochloride

(immediate

release)(150 to 375

mg/day)*

28.2 (0.5)

-14.9

-10.2 (-14.4,-6)

Placebo

28.6 (0.6)

-4.7

14.2 Generalized Anxiety Disorder

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

Anxiety Disorder (GAD) was established in two 8-week, placebo-controlled, fixed-dose studies (75 to

225 mg per day), one 6-month, placebo-controlled, flexible-dose study (75 to 225 mg per day), and one

a

6-month, placebo-controlled, fixed-dose study (37.5, 75, and 150 mg per day) in adult outpatients

meeting DSM-IV criteria for GAD.

In one 8-week study, venlafaxine hydrochloride extended-release capsules demonstrated superiority

over placebo for the 75, 150, and 225 mg per day doses as measured by the Hamilton Rating Scale for

Anxiety (HAM-A) total score, both the HAM-A anxiety and tension items, and the Clinical Global

Impressions (CGI) scale. However, the 75 and 150 mg per day doses were not as consistently effective

as the highest dose (study 1). A second 8-week study evaluating doses of 75 and 150 mg per day and

placebo showed that both doses were more effective than placebo on some of these same outcomes;

however, the 75 mg per day dose was more consistently effective than the 150 mg per day dose (study

2). A dose-response relationship for effectiveness in GAD was not clearly established in the 75 to 225

mg per day dose range studied.

Two 6-month studies, one evaluating venlafaxine hydrochloride extended-release capsules doses of

37.5, 75, and 150 mg per day (study 3) and the other evaluating venlafaxine hydrochloride extended-

release capsules doses of 75 to 225 mg per day (study 4), showed that daily doses of 75 mg or higher

were more effective than placebo on the HAM-A total, both the HAM-A anxiety and tension items, and

the CGI scale during 6 months of treatment. While there was also evidence for superiority over placebo

for the 37.5 mg per day dose, this dose was not as consistently effective as the higher doses.

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

on the basis of gender.

Table 18: Generalized Anxiety Disorder Studies:

Study Number

Treatment Group

Primary Efficacy Measure: HAM-A Score

Mean Baseline

Score (SD)

LS Mean

Change from

Baseline (SE)

Placebo Subtracted

Difference

(95% CI)

Study 1

Venlafaxine

Hydrochloride Extended-

Release Capsules 75 mg

24.7

-11.1 (0.95)

-1.5 (-3.8, 0.8)

Venlafaxine

Hydrochloride Extended-

Release Capsules 150 mg

24.5

-11.7 (0.87)

-2.2 (-4.5, 0.1)

Venlafaxine

Hydrochloride Extended-

Release Capsules 225

23.6

-12.1 (0.81)

-2.6 (-4.9, -0.3)

Placebo

24.1

-9.5 (0.85)

Study 2

Venlafaxine

Hydrochloride Extended-

Release Capsules 75 mg

23.7

-10.6 (0.82)

-2.6 (-4.6, -0.5)

Venlafaxine

Hydrochloride Extended-

Release Capsules 150 mg

-9.8 (0.86)

-1.7 (-3.8, 0.3)

Placebo

23.7

-8 (0.73)

Venlafaxine

Hydrochloride Extended-

26.6 (0.4)

-13.8

-2.8 (-5.1, -0.6)

a

SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval.

Difference (drug minus placebo) in least-squares mean change from baseline

* Doses statistically significantly superior to placebo.

Study 3

Release Capsules 37.5 mg

26.6 (0.4)

-13.8

Venlafaxine

Hydrochloride Extended-

Release Capsules 75 mg

26.3 (0.4)

-15.5

-4.6 (-6.9, -2.3)

Venlafaxine

Hydrochloride Extended-

Release Capsules 150 mg

26.3 (0.4)

-16.4

-5.5 (-7.8, -3.1)

Placebo

26.7 (0.5)

Study 4 Venlafaxine

Hydrochloride

Extended-

Release

Capsules

225 mg

-13.4 (0.79)

-4.7 (-6.6, -2.9)

Placebo

24.9

-8.7 (0.7)

14.3 Social Anxiety Disorder (also known as Social Phobia)

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

Disorder (SAD) was established in four double-blind, parallel-group, 12-week, multicenter, placebo-

controlled, flexible-dose studies (studies 1 to 4) and one double-blind, parallel-group, 6-month,

placebo-controlled, fixed/flexible-dose study, which included doses in a range of 75 to 225 mg per day

in adult outpatients meeting DSM-IV criteria for SAD (study 5).

In these five studies, venlafaxine hydrochloride extended-release capsules were statistically

significantly more effective than placebo on change from baseline to endpoint on the Liebowitz Social

Anxiety Scale (LSAS) total score. There was no evidence for any greater effectiveness of the 150 to

225 mg per day group compared to the 75 mg per day group in the 6-month study.

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.

Table 19: Social Anxiety Disorder Studies

Study

Number

Treatment Group

Primary Efficacy Measure: LSAS Score

Mean

Baseline

Score (SD)

LS Mean Change from

Baseline (SE)

Placebo Subtracted

Difference

(95% CI)

Study 1

Venlafaxine

Hydrochloride Extended-

Release Capsules (75 to

225 mg)

91.1

-31 (2.22)

-11.2 (-5.3, -17.1)

Placebo

86.7

-19.9 (2.22)

Study 2

Venlafaxine

Hydrochloride Extended-

Release Capsules (75 to

225 MG)

90.8

-32.8 (2.69)

-10.7 (-3.7, -17.6)

a

SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval.

Difference (drug minus placebo) in least-squares mean change from baseline

* Doses statistically significantly superior to placebo.

Placebo

87.4

-22.1 (2.66)

Study 3

Venlafaxine

Hydrochloride Extended-

Release Capsules (75 to

225 MG)

83.2

-36 (2.35)

-16.9 (-22.6, -11.2)

Placebo

83.6

-19.1 (2.40)

-12.7 (-6.5, -19)

Study 4

Venlafaxine

Hydrochloride Extended-

Release Capsules (75 to

225 mg)

86.2

-35 (2.64)

-14.6 (-21.8, -7.4)

Placebo

86.1

-22.2 (2.47)

Study 5

Venlafaxine

Hydrochloride Extended-

Release Capsules 75 mg

91.8

-38.1 (3.16)

-14.6 (-21.8, -7.4)

Venlafaxine

Hydrochloride Extended-

Release Capsules (150 to

225 mg)

86.2

-37.6 (3.05)

-14.1 (-21.3, -6.9)

Placebo

89.3

-23.5 (3.08)

14.4 Panic Disorder

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

(PD) was established in two double-blind, 12-week, multicenter, placebo-controlled studies in adult

outpatients meeting DSM-IV criteria for PD, with or without agoraphobia. Patients received fixed

doses of 75 or 150 mg per day in one study (study 1) and 75 or 225 mg per day in the other study (study

Efficacy was assessed on the basis of outcomes in three variables: (1) percentage of patients free of

full-symptom panic attacks on the Panic and Anticipatory Anxiety Scale (PAAS); (2) mean change from

baseline to endpoint on the Panic Disorder Severity Scale (PDSS) total score; and (3) percentage of

patients rated as responders (much improved or very much improved) on the Clinical Global

Impressions (CGI) Improvement scale. In these two studies, venlafaxine hydrochloride extended-release

capsules were statistically significantly more effective than placebo (for each fixed dose) on all three

endpoints, but a dose-response relationship was not clearly established.

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.

In a longer term study (study 3), adult outpatients meeting DSM-IV criteria for PD who had responded

during a 12-week open phase with venlafaxine hydrochloride extended-release capsules (75 to 225 mg

per day) were randomly assigned to continue the same venlafaxine hydrochloride extended-release

capsules dose (75, 150, or 225 mg) or switch to placebo for observation for relapse under double-blind

conditions. Response during the open phase was defined as ≤ 1 full-symptom panic attack per week

during the last 2 weeks of the open phase and a CGI Improvement score of 1 (very much improved) or 2

(much improved). Relapse during the double-blind phase was defined as having 2 or more full-symptom

panic attacks per week for 2 consecutive weeks or having discontinued due to loss of effectiveness as

determined by the investigators during the study. Randomized patients were in response status for a

mean time of 34 days prior to being randomized. In the randomized phase following the 12-week open-

label period, patients receiving continued venlafaxine hydrochloride extended-release capsules

experienced a statistically significantly longer time to relapse.

Table 20: Panic Disorder Studies:

Odds ratio (drug to placebo) in terms of probability of free of full-symptom panic attacks based on

logistic regression model.

95% CI: 95% confidence interval without adjusting for multiple dose arms.

Doses statistically significantly superior to placebo.

Study Number Treatment GroupPrimary

Efficacy

Measure:

Whether

Free

of

Full-s ymptom

Panic Attacks

Percent of patients Free

of Full symptom panic

attack

Adjusted Odds Ratio

to placebo

Adjusted Odds Ratio

95% Confidence

Interval

Study 1

Venlafaxine

Hydrochloride

Extended-Release

Capsules 75 mg

54.1% (85/157)

2. 268

(1.43, 3.59)

Venlafaxine

Hydrochloride

Extended-Release

Capsules 150 mg

61.4% (97/158)

3.035

(1.91, 4.82)

Placebo

34.4% (53/154)

Study 2

Venlafaxine

Hydrochloride

Extended-Release

Capsules 75 mg

64.1% (100/156)

2.350

(1.46, 3.78)

Venlafaxine

Hydrochloride

Extended-Release

Capsules 225 mg

70% (112/160)

2.890

(1.80, 4.64)

Placebo

46.5% (73/157)

14.5 Pediatric Patients

Two placebo-controlled studies in 766 pediatric patients with MDD and two placebo-controlled studies

in 793 pediatric patients with GAD have been conducted with venlafaxine hydrochloride extended-

release capsules, and the data were not sufficient to support a claim for use in pediatric patients.

16 HOW SUPPLIED/STORAGE AND HANDLING

Venlafaxine Hydrochloride Extended-Release Capsules USP, 37.5 mg are white to off white

spherical to oval pellets filled in empty hard gelatin capsule shell (size ‘3’) of opaque grey color cap

and opaque peach color body imprinted with “E” on cap and “73” on the body with edible black ink.

Bottles of 15 NDC 65862-527-47

Bottles of 30 NDC 65862-527-30

Bottles of 90 NDC 65862-527-90

Bottles of 100 NDC 65862-527-01

Bottles of 1,000 NDC 65862-527-99

Bottles of 5,000 NDC 65862-527-59

10 x 10 Unit-dose Capsules NDC 65862-527-10

Venlafaxine Hydrochlorid e Extended-Release Capsules USP, 75 mg are white to off white

spherical to oval pellets filled in empty hard gelatin capsule shell (size ‘1’) of opaque peach color cap

and opaque peach color body imprinted with “E” on cap and “74” on the body with edible black ink.

Bottles of 15 NDC 65862-528-47

Bottles of 30 NDC 65862-528-30

Bottles of 90 NDC 65862-528-90

Bottles of 100 NDC 65862-528-01

Bottles of 1,000 NDC 65862-528-99

Bottles of 3,500 NDC 65862-528-35

10 x 10 Unit-dose Capsules NDC 65862-528-10

Venlafaxine Hydrochlorid e Extended-Release Capsules USP, 150 mg are white to off white

spherical to oval pellets filled in empty hard gelatin capsule shell (size ‘0’) of opaque dark orange

color cap and opaque dark orange color body imprinted with “E” on cap and “89” on the body with

edible black ink.

Bottles of 15 NDC 65862-697-47

Bottles of 30 NDC 65862-697-30

Bottles of 90 NDC 65862-697-90

Bottles of 100 NDC 65862-697-01

Bottles of 500 NDC 65862-697-05

Bottles of 2,500 NDC 65862-697-26

10 x 10 Unit-dose Capsules NDC 65862-697-10

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

17 PATIENT COUNSELING INFORMATION

See FDA-approved patient labeling (Medication Guide).

Prescribers or other healthcare professionals should inform patients, their families, and their

caregivers about the benefits and risks associated with treatment with venlafaxine hydrochloride

extended-release capsules and should counsel them in its appropriate use. A patient Medication Guide

about “Antidepressant Medicines, Depression and Other Serious Mental Illnesses, and Suicidal

Thoughts or Actions” is available for venlafaxine hydrochloride extended-release capsules. The

prescriber or healthcare 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 should be asked to alert their prescriber if these

occur while taking venlafaxine hydrochloride extended-release capsules.

Suicidal Thoughts and Behaviors

Advise patients, their families and caregivers to look for the emergence of suicidality, worsening of

depression, and other psychiatric symptoms (anxiety, agitation, panic attacks, insomnia, irritability,

hostility, aggressiveness, impulsivity, akathisia, psychomotor restlessness, hypomania, mania, other

unusual changes in behavior), especially early during treatment and when the dose is adjusted up or

down. 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 [see Boxed Warning and Warnings and Precautions (5.1)] .

Concomitant Medication

Advise patients taking venlafaxine hydrochloride extended-release capsules not to use concomitantly

other products containing venlafaxine or desvenlafaxine. Healthcare professionals should instruct

patients not to take venlafaxine hydrochloride extended-release capsules with an MAOI or within 14

days of stopping an MAOI and to allow 7 days after stopping venlafaxine hydrochloride extended-

release capsules before starting an MAOI [see Contraindications (4.2)] .

Serotonin Syndrome

Patients should be cautioned about the risk of serotonin syndrome, with the concomitant use of

venlafaxine hydrochloride extended-release capsules and triptans, tramadol, amphetamines, tryptophan

supplements, with antipsychotics or other dopamine antagonists, or other serotonergic agents [see

Warnings and Precautions (5.2) and Drug Interactions (7.3)] .

Elevated Blood Pressure

Advise patients that they should have regular monitoring of blood pressure when taking venlafaxine

hydrochloride extended-release capsules [see Warnings and Precautions (5.3)] .

Abnormal Bleeding

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

capsules and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of

psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an

increased risk of bleeding [see Warnings and Precautions (5.4)] .

Angle Closure Glaucoma

Patients should be advised that taking venlafaxine hydrochloride extended-release capsules 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 (5.5)] .

Activation of Mania/Hypomania

Advise patients, their families and caregivers to observe for signs of activation of mania/hypomania [see

Warnings and Precautions (5.6)] .

Cardiovascular/Cerebrovascular Disease

Caution is advised in administering venlafaxine hydrochloride extended-release capsules to patients

with cardiovascular, cerebrovascular, or lipid metabolism disorders [see Adverse Reactions (6.1)] .

Serum Cholesterol and Triglyceride Elevation

Advise patients that elevations in total cholesterol, LDL and triglycerides may occur and that

measurement of serum lipids may be considered [see Warnings and Precautions (6.3)] .

Discontinuation [Symptoms]

Advise patients not to stop taking venlafaxine hydrochloride extended-release capsules without talking

first with their healthcare professional. Patients should be aware that discontinuation effects may occur

when stopping venlafaxine hydrochloride extended-release capsules [see Warnings and Precautions

(5.7) and Adverse Reactions (6.1)] .

Interference with Cognitive and Motor Performance

Caution patients about operating hazardous machinery, including automobiles, until they are reasonably

certain that venlafaxine hydrochloride extended-release capsules therapy does not adversely affect

their ability to engage in such activities.

Alcohol

Advise patients to avoid alcohol while taking venlafaxine hydrochloride extended-release capsules [see

Drug Interactions (7.6)] .

Allergic Reactions

Advise patients to notify their physician if they develop allergic phenomena such as rash, hives,

swelling, or difficulty breathing.

Pregnancy

Advise patients to notify their physician if they become pregnant or intend to become pregnant during

therapy [see Use in Specific Populations (8.1)] .

Nursing

Advise patients to notify their physician if they are breast-feeding an infant [see Use in Specific

Populations (8.3)] .

Residual Spheroids

Venlafaxine hydrochloride extended-release capsule contains spheroids, which release the drug

slowly into the digestive tract. The insoluble portion of these spheroids is eliminated, and patients may

notice spheroids passing in the stool or via colostomy. Patients should be informed that the active

medication has already been absorbed by the time the patient sees the spheroids.

Dispense with Medication Guide available at: www.aurobindousa.com/product-medication-guides

Medication Guide

Venlafaxine Hydrochloride Extended-Release Capsules USP

(ven'' la fax' een hye'' droe klor' ide)

Read the Medication Guide that comes with venlafaxine hydrochloride extended-release capsules

before you start taking them and each time you get a refill. There may be new information. This

Medication Guide does not take the place of talking to your healthcare provider about your medical

condition or treatment. Talk with your healthcare provider if there is something you do not understand

or want to learn more about.

What is the most important information I should know about venlafaxine hydrochloride extended-

release capsules?

Venlafaxine hydrochloride extended-release capsules and other antidepressant medicines may cause

serious side effects, including:

1. Suicidal thoughts or actions:

Venlafaxine hydrochloride extended-release capsules and other antidepressant medicines

may increase suicidal thoughts or actions in some children, teenagers, or young adults within the

first few months of treatment or when the dose is changed.

Depression or other serious mental illnesses are the most important causes of suicidal thoughts or

actions.

Watch for these changes and call your healthcare provider right away if you notice:

New or sudden changes in mood, behavior, actions, thoughts, or feelings, especially if severe.

Pay particular attention to such changes when venlafaxine hydrochloride extended-release

capsules are started or when the dose is changed.

Keep all follow-up visits with your healthcare provider and call between visits if you are worried

about symptoms.

Call your healthcare provider right away if you have any of the following symptoms, or call

911 if an emergency, especially if they are new, worse, or worry you:

attempts to commit suicide

acting on dangerous impulses

acting aggressive or violent

thoughts about suicide or dying

new or worse depression

new or worse anxiety or panic attacks

feeling agitated, restless, angry or irritable

trouble sleeping

an increase in activity or talking more than what is normal for you

other unusual changes in behavior or mood

Visual problems

eye pain

changes in vision

swelling or redness in or around the eye

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.

Call your healthcare provider right away if you have any of the following symptoms, or call 911 if

an emergency. Venlafaxine hydrochloride extended-release capsules may be associated with

these serious side effects:

2. Serotonin Syndrome

This condition can be life-threatening and may include:

agitation, hallucinations, coma or other changes in mental status

coordination problems or muscle twitching (overactive reflexes)

racing heartbeat, high or low blood pressure

sweating or fever

nausea, vomiting, or diarrhea

muscle rigidity

3. Changes in blood pressure. Venlafaxine hydrochloride extended-release capsules may:

increase your blood pressure. Control high blood pressure before starting treatment and monitor

blood pressure regularly

4. Enlarged pupils (mydriasis).

5. Anxiety and insomnia.

6. Changes in appetite or weight.

7. Manic/hypomanic episodes:

greatly increased energy

severe trouble sleeping

racing thoughts

reckless behavior

unusually grand ideas

excessive happiness or irritability

talking more or faster than usual

8. Low salt (sodium) levels in the blood.

Elderly people may be at greater risk for this. Symptoms may include:

headache

weakness or feeling unsteady

confusion, problems concentrating or thinking or memory problems

9. Seizures or convulsions.

10. Abnormal bleeding: Venlafaxine hydrochloride extended-release capsules and other

antidepressant medicines may increase your risk of bleeding or bruising, especially if you take the

blood thinner warfarin (Coumadin

, Jantoven

), a non-steroidal anti-inflammatory drug (NSAIDs, like

ibuprofen or naproxen), or aspirin.

11. Elevated cholesterol.

12. Lung disease and pneumonia: Venlafaxine hydrochloride extended-release capsules may cause

rare lung problems. Symptoms include:

worsening shortness of breath

cough

chest discomfort

13. Severe allergic reactions:

trouble breathing

swelling of the face, tongue, eyes or mouth

rash, itchy welts (hives) or blisters, alone or with fever or joint pain.

Do not stop venlafaxine hydrochloride extended-release capsules without first talking to your

healthcare provider. Stopping venlafaxine hydrochloride extended-release capsules too quickly or

changing from another antidepressant too quickly may cause serious symptoms including:

anxiety, irritability

feeling tired, restless or problems sleeping

headache, sweating, dizziness

electric shock-like sensations, shaking, confusion, nightmares

vomiting, nausea, diarrhea

What are venlafaxine hydrochloride extended-release capsules?

Venlafaxine hydrochloride extended-release capsules are a prescription medicine used to treat

depression. It is important to talk with your healthcare provider about the risks of treating depression

and also the risks of not treating it. You should discuss all treatment choices with your healthcare

provider. Venlafaxine hydrochloride extended-release capsules are also used to treat:

Generalized Anxiety Disorder (GAD)

Social Anxiety Disorder (SAD)

Panic Disorder (PD)

Talk to your healthcare provider if you do not think that your condition is getting better with

venlafaxine hydrochloride extended-release capsules treatment.

Who should not take venlafaxine hydrochloride extended-release capsules?

Do not take venlafaxine hydrochloride extended-release capsules if you:

are allergic to venlafaxine hydrochloride or any of the ingredients in venlafaxine hydrochloride

extended-release capsules. See the end of this Medication Guide for a complete list of ingredients

in venlafaxine hydrochloride extended-release capsules.

have uncontrolled angle-closure glaucoma

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 hydrochloride extended-release

capsules unless directed to do so by your physician.

Do not start venlafaxine hydrochloride extended-release capsules if you stopped taking an MAOI

in the last 2 weeks unless directed to do so by your physician.

People who take venlafaxine hydrochloride extended-release capsules close in time to an MAOI

may have serious or even life-threatening side effects. Get medical help right away if you have any

of these symptoms:

high fever

uncontrolled muscle spasms

stiff muscles

rapid changes in heart rate or blood pressure

confusion

loss of consciousness (pass out)

What should I tell my healthcare provider before taking venlafaxine hydrochloride extended-

release capsules? Ask if you are not sure.

Before starting venlafaxine hydrochloride extended-release capsules, tell your healthcare provider

if you:

Are taking certain drugs such as:

Amphetamines

Medicines used to treat migraine headaches such as:

triptans

Medicines used to treat mood, anxiety, psychotic or thought disorders, such as:

tricyclic antidepressants

lithium

SSRIs

SNRIs

antipsychotic drugs

Medicines used to treat pain such as:

tramadol

Medicines used to thin your blood such as:

warfarin

Medicines used to treat heartburn such as:

Cimetidine

Over-the-counter medicines or supplements such as:

Aspirin or other NSAIDs

Tryptophan

St. John’s Wort

have heart problems

have diabetes

have liver problems

have kidney problems

have thyroid problems

have or had seizures or convulsions

have bipolar disorder or mania

have low sodium levels in your blood

have high blood pressure

have high cholesterol

have or had bleeding problems

are pregnant or plan to become pregnant. It is not known if venlafaxine hydrochloride

extended-release capsules will harm your unborn baby. Talk to your healthcare

provider about the benefits and risks of treating depression during pregnancy

are breast-feeding or plan to breast-feed. Some venlafaxine hydrochloride may pass into

your breast milk. Talk to your healthcare provider about the best way to feed your baby

while taking venlafaxine hydrochloride extended-release capsules.

Tell your healthcare provider about all the medicines that you take, including prescription and non-

prescription medicines, vitamins, and herbal supplements. Venlafaxine hydrochloride extended-

release capsules and some medicines may interact with each other, may not work as well, or may cause

serious side effects.

Your healthcare provider or pharmacist can tell you if it is safe to take venlafaxine hydrochloride

extended-release capsules with your other medicines. Do not start or stop any medicine while taking

venlafaxine hydrochloride extended-release capsules without talking to your healthcare provider

first.

If you take venlafaxine hydrochloride extended-release capsules, you should not take any other

medicines that contain (venlafaxine) including: venlafaxine hydrochloride.

How should I take venlafaxine hydrochloride extended-release capsules?

Take venlafaxine hydrochloride extended-release capsules exactly as prescribed. Your

healthcare provider may need to change the dose of venlafaxine hydrochloride extended-release

capsules until it is the right dose for you.

Venlafaxine hydrochloride extended-release capsules are to be taken with food.

If you miss a dose of venlafaxine hydrochloride extended-release capsules, take the missed dose

as soon as you remember. If it is almost time for the next dose, skip the missed dose and take your

next dose at the regular time. Do not take two doses of venlafaxine hydrochloride extended-

release capsules at the same time.

If you take too much venlafaxine hydrochloride, call your healthcare provider or poison control

center right away, or get emergency treatment.

When switching from another antidepressant to venlafaxine hydrochloride extended-release

capsules your doctor may want to lower the dose of the initial antidepressant first to avoid side

effects.

What should I avoid while taking venlafaxine hydrochloride extended-release capsules?

Venlafaxine hydrochloride extended-release capsules can cause sleepiness or may affect your

ability to make decisions, think clearly, or react quickly. You should not drive, operate heavy

machinery, or do other dangerous activities until you know how venlafaxine hydrochloride extended-

release capsules affect you. Do not drink alcohol while using venlafaxine hydrochloride extended-

release capsules.

What are the possible side effects of venlafaxine hydrochloride extended-release capsules?

Venlafaxine hydrochloride extended-release capsules may cause serious side effects, including:

See “What is the most important information I should know about venlafaxine hydrochloride

extended-release capsules?”

Increased cholesterol- have your cholesterol checked regularly

Newborns whose mothers take venlafaxine hydrochloride extended-release capsules in the third

trimester may have problems right after birth including:

problems feeding and breathing

seizures

shaking, jitteriness or constant crying

Angle-closure glaucoma

Common possible side effects in people who take venlafaxine hydrochloride extended-release

capsules include :

unusual dreams

sexual problems

loss of appetite, constipation, diarrhea, nausea or vomiting, or dry mouth

feeling tired, fatigued or overly sleepy

change in sleep habits, problems sleeping

yawning

tremor or shaking

dizziness, blurred vision

sweating

feeling anxious, nervous or jittery

headache

increase in heart rate

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of venlafaxine hydrochloride extended-release capsules.

For more information, ask your healthcare provider or pharmacist.

CALL YOUR DOCTOR FOR MEDICAL ADVICE ABOUT SIDE EFFECTS. YOU MAY

REPORT SIDE EFFECTS TO THE FDA AT 1-800-FDA-1088.

How should I store venlafaxine hydrochloride extended-release capsules?

Store venlafaxine hydrochloride extended-release capsules at room temperature between 20° to

25°C (68° to 77°F).

Keep venlafaxine hydrochloride extended-release capsules in a dry place.

Keep venlafaxine hydrochloride extended-release capsules and all medicines out of the reach of

children.

General information about venlafaxine hydrochloride extended-release capsules

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not

use venlafaxine hydrochloride extended-release capsules for a condition for which it was not

prescribed. Do not give venlafaxine hydrochloride extended-release capsules to other people, even

if they have the same condition. They may harm them.

This Medication Guide summarizes the most important information about venlafaxine hydrochloride

extended-release capsules. If you would like more information, talk with your healthcare provider.

You may ask your healthcare provider or pharmacist for information about venlafaxine hydrochloride

extended-release capsules that is written for healthcare professionals.

For more information about venlafaxine hydrochloride extended-release capsules call 1-866-850-

2876.

What are the ingredients in venlafaxine hydrochloride extended-release capsules?

Active ingredient: Venlafaxine hydrochloride

Inactive ingredients:

Extended-Release Capsules: Ethyl cellulose, hypromellose, sugar spheres, and talc. The empty hard

gelatin capsule shells contain iron oxide red, gelatin, titanium dioxide, and sodium lauryl sulphate. In

addition, the 37.5 mg empty hard gelatin capsule shells contain iron oxide black. The capsules are

printed with edible ink containing black iron oxide and shellac.

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

antidepressants.

Coumadin

is a registered trademark of Bristol Myers Squibb.

Jantoven

is a registered trademark of Upsher-Smith Laboratories Inc.

Dispense with Medication Guide available at: www.aurobindousa.com/product-medication-guides

Distributed by:

Aurobindo Pharma USA, Inc.

279 Princeton-Hightstown Road

East Windsor, NJ 08520

Manufactured by:

Aurobindo Pharma Limited

Hyderabad-500 038, India

Revised: 05/2018

PRINCIPAL DISPLAY PANEL

DRUG: Venlafaxine Hydrochloride

GENERIC: Venlafaxine Hydrochloride

DOSAGE: CAPSULE, EXTENDED RELEASE

ADMINSTRATION: ORAL

NDC: 70518-2259-0

COLOR: orange

SHAPE: CAPSULE

SCORE: No score

SIZE: 21 mm

IMPRINT: E;89

PACKAGING: 90 in 1 BOTTLE, PLASTIC

ACTIVE INGREDIENT(S):

VENLAFAXINE HYDROCHLORIDE 150mg in 1

INACTIVE INGREDIENT(S):

ETHYLCELLULOSE (20 MPA.S)

TITANIUM DIOXIDE

GELATIN, UNSPECIFIED

FERROSOFERRIC OXIDE

SODIUM LAURYL SULFATE

FERRIC OXIDE RED

HYPROMELLOSE 2910 (5 MPA.S)

SHELLAC

SUCROSE

STARCH, CORN

TALC

VENLAFAXINE HYDROCHLORIDE

venlafaxine hydrochloride capsule, extended release

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:70 518 -2259 (NDC:6 58 6 2-6 9 7)

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

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

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

SUCRO SE (UNII: C151H8 M554)

STARCH, CO RN (UNII: O8 232NY3SJ)

TALC (UNII: 7SEV7J4R1U)

FERRIC O XIDE RED (UNII: 1K0 9 F3G6 75)

GELATIN, UNSPECIFIED (UNII: 2G8 6 QN327L)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

REMEDYREPACK INC.

SO DIUM LAURYL SULFATE (UNII: 36 8 GB5141J)

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

SHELLAC (UNII: 46 N10 7B71O)

Product Characteristics

Color

o range (Opaque Dark Orange)

S core

no sco re

S hap e

CAPSULE

S iz e

21mm

Flavor

Imprint Code

E;8 9

Contains

Packag ing

#

Item Code

Package Description

Marketing Start

Date

Marketing End

Date

1

NDC:70 518 -2259 -

9 0 in 1 BOTTLE, PLASTIC; Type 0 : No t a Co mbinatio n

Pro duc t

0 8 /0 9 /20 19

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA20 0 8 34

0 8 /0 9 /20 19

Labeler -

REMEDYREPACK INC. (829572556)

Revised: 8/2019

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