DESVENLAFAXINE- desvenlafaxine tablet, extended release

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

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Active ingredient:
DESVENLAFAXINE SUCCINATE (UNII: ZB22ENF0XR) (DESVENLAFAXINE - UNII:NG99554ANW)
Available from:
A-S Medication Solutions
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Desvenlafaxine extended-release tablets are indicated for the treatment of adults with major depressive disorder (MDD) [see Clinical Studies (14)] . - Hypersensitivity to desvenlafaxine succinate, venlafaxine hydrochloride or to any excipients in the desvenlafaxine extended-release tablets formulation. Angioedema has been reported in patients treated with desvenlafaxine extended-release tablets [see Adverse Reactions ( 6.1 )] . - The use of MAOIs intended to treat psychiatric disorders with desvenlafaxine extended-release tablets or within 7 days of stopping treatment with desvenlafaxine extended-release tablets is contraindicated because of an increased risk of serotonin syndrome. The use of desvenlafaxine extended-release tablets within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated [see Dosage and Administration (2.7 ) and Warnings and Precautions ( 5.2 )] . - Starting desvenlafaxine extended-release tablets in a patient who is being treated with MAOIs such as
Product summary:
Product: 50090-4388 NDC: 50090-4388-0 30 TABLET, EXTENDED RELEASE in a BOTTLE
Authorization status:
Abbreviated New Drug Application
Authorization number:
50090-4388-0

A-S Medication Solutions

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MEDICATION GUIDE

Desvenlafaxine (des-ven-la-fax-ine) Extended-Release Tablets

What is the most important information I should know about

desvenlafaxine extended-release tablets?

Desvenlafaxine extended-release tablets can cause serious side

effects, including:

Increased risk of suicidal thoughts or actions in some

children and young adults within the first few months of

treatment. Desvenlafaxine extended-release tablets is not for

use in children.

Depression or other serious mental illnesses are the most

important causes of suicidal thoughts or actions. How can I

watch for and try to prevent suicidal thoughts and actions?

Pay close attention to any changes, especially sudden

changes, in mood, behaviors, thoughts, or feelings. This is

very important when an antidepressant medicine is started or

when the dose is changed.

Call the healthcare provider right away to report new or

sudden changes in mood, behavior, thoughts, or feelings.

Keep all follow-up visits with the healthcare provider as

scheduled. Call the healthcare provider between visits as

needed, especially if you have concerns about symptoms.

Call your healthcare provider right away if you have any of the

following symptoms, especially if they are new, worse, or worry

you:

thoughts about

suicide or dying

attempts to commit

suicide

new or worse

depression

new or worse

anxiety

feeling very agitated

or restless

panic attacks

trouble sleeping (insomnia)

new or worse irritability

acting aggressive, being angry,

or violent

acting on dangerous impulses

an extreme increase in activity

and talking (mania)

other unusual changes in

behavior or mood

What are desvenlafaxine extended-release tablets?

Desvenlafaxine extended-release tablets are a prescription

medicine used to treat adults with a certain type of

depression called major depressive disorder (MDD).

Desvenlafaxine extended-release tablets belong to a class of

medicines known as serotonin and norepinephrine reuptake

inhibitors (SNRIs).

Do not take desvenlafaxine extended-release tablets if you:

are allergic to desvenlafaxine succinate, venlafaxine

hydrochloride, or any of the ingredients in desvenlafaxine

extended-release tablets. See the end of this Medication

Guide for a complete list of ingredients in desvenlafaxine

extended-release tablets.

take a monoamine oxidase inhibitor (MAOI)

have stopped taking an MAOI in the last 14 days. Ask your

healthcare provider or pharmacist if you are not sure if you

take an MAOI.

are being treated with the antibiotic linezolid or the

intravenous methylene blue

Do not start taking an MAOI for at least 7 days after you stop

treatment with desvenlafaxine extended-release tablets.

Before taking desvenlafaxine extended-release tablets tell your

healthcare provider about all your medical conditions, including if

you:

have high blood pressure

have heart problems

have cerebrovascular problems or had a stroke

have or had bleeding problems

have, or have a family history of, bipolar disorder, mania or

hypomania

have high cholesterol or high triglycerides

have or had depression, suicidal thoughts or behavior

have kidney or liver problems

have or had seizures or convulsions

have low sodium levels in your blood

are pregnant or plan to become pregnant. Talk to your

healthcare provider about the risk to your unborn baby if you

take desvenlafaxine extended-release tablets during

pregnancy.

Tell your healthcare provider if you become pregnant or

think you are pregnant during treatment with desvenlafaxine

extended-release tablets.

are breastfeeding or plan to breastfeed. Desvenlafaxine

extended-release tablets can pass into your breast milk. Talk

to your healthcare provider about the best way to feed your

baby during treatment with desvenlafaxine extended-release

tablets.

Tell your healthcare provider about all the medicines you take,

including prescription and over-the-counter

medicines, vitamins, and herbal supplements.

Desvenlafaxine extended-release tablets and other medicines may

affect each other causing possible serious side effects.

Desvenlafaxine extended-release tablets may affect the way other

medicines work and other medicines may affect the way

desvenlafaxine extended-release tablets work.

Especially tell your healthcare provider if you take:

·other MAOIs

medicines to treat migraine headaches known as triptans

tricyclic antidepressants

fentanyl

lithium

tramadol

tryptophan

buspirone

amphetamines

St. John’s Wort

other medicines containing desvenlafaxine or venlafaxine

medicines that can affect blood clotting such as aspirin,

nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin

medicines used to treat mood, anxiety, psychotic, or thought

disorders, including selective serotonin reuptake inhibitors

(SSRIs) and serotonin norepinephrine reuptake inhibitors

(SNRIs)

Ask your healthcare provider if you are not sure if you are taking

any of these medicines. Your healthcare provider can tell you if it is

safe to take desvenlafaxine extended-release tablets with your other

medicines.

Do not start or stop any other medicines during treatment with

desvenlafaxine extended-release tablets without talking to your

healthcare provider first. Stopping desvenlafaxine extended-release

tablets suddenly may cause you to have serious side effects. See,

“What are the possible side effects of desvenlafaxine extended-

release tablets?”

Know the medicines you take. Keep a list of them to show to your

healthcare providers when you get a new medicine.

How should I take desvenlafaxine extended-release tablets?

Take desvenlafaxine extended-release tablets exactly as your

healthcare provider tells you to.

Take desvenlafaxine extended-release tablets 1 time a day at

about the same time each day.

Desvenlafaxine extended-release tablets may be taken either

with or without food.

Swallow desvenlafaxine extended-release tablets whole,

with fluid. Do not divide, crush, chew, or dissolve

desvenlafaxine extended-release tablets.

When you take desvenlafaxine extended-release tablets, you

may see something in your stool that looks like a tablet. This

is the empty shell from the tablet after the medicine has been

absorbed by your body.

If over-exposure occurs, call your Poison Control Center at

1-800-222-1222 or go to the nearest hospital emergency

room right away.

What should I avoid while taking desvenlafaxine extended-release

tablets?

Do not drive a car or operate heavy machinery until you

know how desvenlafaxine extended-release tablets affects

you.

You should not drink alcohol while taking desvenlafaxine

extended-release tablets.

What are the possible side effects of desvenlafaxine extended-

release tablets?

Desvenlafaxine extended-release tablets can cause serious side

effects, including:

See, What is the most important information I should know

about desvenlafaxine extended-release tablets?”

Serotonin syndrome. A potentially life-threatening problem called

serotonin syndrome can happen when you take desvenlafaxine

extended-release tablets with certain other medicines. See, “Who

should not take desvenlafaxine extended-release tablets?” Call your

healthcare provider or go to the nearest hospital emergency room

right away if you have any of the following signs and symptoms of

serotonin syndrome:

agitation

confusion

fast heart beat

dizziness

flushing

tremors, stiff

muscles, or muscle

twitching

seizures

seeing or hearing things that are

not real (hallucinations)

coma

changes in blood pressure

sweating

high body temperature

(hyperthermia)

loss of coordination

nausea, vomiting, diarrhea

New or worsened high blood pressure (hypertension). Your

healthcare provider should check your blood pressure before

and during treatment with desvenlafaxine extended-release

tablets. If you have high blood pressure, it should be

controlled before you start treatment with desvenlafaxine

extended-release tablets.

Increased chance of bleeding or bruising. Taking

desvenlafaxine extended-release tablets with aspirin,

NSAIDs, or blood thinners may add to this risk. Tell your

healthcare provider right away about any unusual bleeding

or bruising.

Eye problems (angle closure glaucoma). Many

antidepressant medicines, including desvenlafaxine

extended-release tablets, may cause a certain type of eye

problem called angle-closure glaucoma. Call your healthcare

provider if you have changes in your vision or eye pain.

Discontinuation syndrome. Suddenly stopping

desvenlafaxine extended-release tablets when you take

higher doses may cause you to have serious side effects.

Your healthcare provider may want to decrease your dose

slowly. Symptoms may include:

dizziness

irritability

agitation

anxiety

sweating

seizures

ringing in

your ears

(tinnitus)

nausea

problems

sleeping

tiredness

confusion

electric

shock

sensation

(paresthesi

headache

diarrhea

abnormal dreams

changes in your mood

hypomania

Seizures (convulsions).

Low sodium levels in your blood (hyponatremia). Low

sodium levels can happen during treatment with

desvenlafaxine extended-release tablets. Low sodium levels

in your blood may be serious and may cause death. Signs

and Symptoms of low sodium levels in your blood may

include:

headache

difficulty concentrating

memory changes

confusion

weakness and unsteadiness on your feet which can lead to

falls

In severe or more sudden cases, signs and symptoms include:

hallucinations (seeing or hearing things that are not real)

fainting

seizures

coma

Lung problems. Some people who have taken the medicine

venlafaxine which is the same kind of medicine as the

medicine in desvenlafaxine extended-release tablets have

had lung problems. Symptoms of lung problems include

difficulty breathing, cough, or chest discomfort. Tell your

healthcare provider right away if you have any of these

symptoms.

The most common side effects of desvenlafaxine extended-release

tablets include:

nausea

problems sleeping

constipation

decreased appetite

sexual function

problems

dizziness

sweating

feeling sleepy

anxiety

These are not all the possible side effects of desvenlafaxine

extended-release tablets.

Call your doctor for medical advice about side effects. You may

report side effects to FDA at 1-800-FDA-1088.

How should I store desvenlafaxine extended-release tablets?

Store desvenlafaxine extended-release tablets at room

temperature between 68° to 77°F (20° to 25°C).

Keep desvenlafaxine extended-release tablets and all

medicines out of the reach of children.

General Information about the safe and effective use of

desvenlafaxine extended-release tablets

Medicines are sometimes prescribed for purposes other than those

listed in a Medication Guide. Do not take desvenlafaxine extended-

release tablets for a condition for which they were not prescribed.

Do not give desvenlafaxine extended-release tablets to other people,

even if they have the same symptoms that you have. They may

harm them. You can ask your pharmacist or healthcare provider for

information about desvenlafaxine extended-release tablets that is

written for healthcare professionals.

What are the ingredients in desvenlafaxine extended-release tablets?

Active ingredient: desvenlafaxine

Inactive ingredients: Inactive ingredients for the 25 mg, 50 mg and

100 mg tablet consist of hypromellose, microcrystalline cellulose,

talc, magnesium stearate, polyethylene oxide and colloidal silicon

dioxide and film coating, which consists of polyvinyl alcohol,

polyethylene glycol, talc, titanium dioxide, and iron oxide yellow

and iron oxide red. The imprinting ink contains hypromellose,

propylene glycol and iron oxide black.

Manufactured by:

Actavis Laboratories FL, Inc.

Fort Lauderdale, FL 33314 USA

Distributed by:

Actavis Pharma, Inc.

Parsippany, NJ 07054 USA

For more information, go to www.actavis.com or call 1-800-272-

5525.

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

Revised: 2/ 2018

Revised: 7/2019

Document Id: dc4d84d6-5594-4b3d-8850-3f2db01cb6d1

34391-3

Set id: bbbb837b-7587-4870-870f-a5b14ade4e30

Version: 1

Effective Time: 20190725

A-S Medication Solutions

DESVENLAFAXINE- desvenlafaxine tablet, extended release

A-S Medication Solutions

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HIGHLIGHTS OF PRESCRIBING INFORMATION

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

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

TABLETS.

DESVENLAFAXINE extended-release tablets, for oral use

Initial U.S. Approval: 2008

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS

See full prescribing information for complete boxed warning.

Increased the risk of suicidal thoughts and behaviors in children, adolescents and young adults taking

antidepressants (5.1).

Closely monitor for clinical worsening and emergence of suicidal thoughts and behaviors (5.1).

Desvenlafaxine extended-release tablets are not approved for use in pediatric patients (8.4).

RECENT MAJOR CHANGES

Dosage and Administration (2.5) 2/2018

Warnings and Precautions (5.2, 5.4, 5.5, 5.7) 2/2018

INDICATIONS AND USAGE

Desvenlafaxine extended-release tablets are a serotonin and norepinephrine reuptake inhibitor (SNRI) indicated for the

treatment of adults with major depressive disorder (MDD) (1).

DOSAGE AND ADMINISTRATION

Recommended dose: 50 mg once daily with or without food (2.1).

There was no evidence that doses greater than 50 mg per day confer any additional benefit (2.1).

The 25 mg per day dose is intended for a gradual reduction in dose when discontinuing treatment or dosing in severe

renal and end-stage renal disease patients (2.1).

Discontinuation: Reduce dose gradually whenever possible (2.1).

Take tablets whole; do not divide, crush, chew, or dissolve (2.1).

Moderate renal impairment: Maximum dose 50 mg per day (2.2).

Severe renal impairment and end-stage renal disease: Maximum dose 25 mg per day or 50 mg every other day (2.2).

Moderate to severe hepatic impairment: Maximum dose 100 mg per day (2.3).

DOSAGE FORMS AND STRENGTHS

Desvenlafaxine extended-release tablets: 25 mg, 50 mg and 100 mg (3).

Each tablet contains 38 mg, 76 mg or 152 mg of desvenlafaxine succinate equivalent to 25 mg, 50 mg or 100 mg of

desvenlafaxine, respectively (3).

CONTRAINDICATIONS

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

extended-release tablets formulation (4).

Serotonin Syndrome and MAOIs: Do not use MAOIs intended to treat psychiatric disorders with desvenlafaxine

extended-release tablets or within 7 days of stopping treatment with desvenlafaxine extended-release tablets. Do not

use desvenlafaxine extended-release tablets within 14 days of stopping an MAOI intended to treat psychiatric

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

linezolid or intravenous methylene blue (4).

WARNINGS AND PRECAUTIONS

Serotonin Syndrome: Increased risk when co-administered with other serotonergic agents (e.g., SSRI, SNRI, triptans),

but also when taken alone. If it occurs, discontinue desvenlafaxine extended-release tablets and initiate supportive

treatment (5.2).

Elevated Blood Pressure: Control hypertension before initiating treatment. Monitor blood pressure regularly during

treatment (5.3).

Increased Risk of Bleeding: Concomitant use of aspirin, NSAIDs, other antiplatelet drugs, warfarin, and other

anticoagulants may increase this risk (5.4).

Angle Closure Glaucoma: Avoid use of antidepressants, including desvenlaxine extended-release tablets, in patients

with untreated anatomically narrow angles treated (5.5).

Activation of Mania/Hypomania: Use cautiously in patients with Bipolar Disorder. Caution patients about risk of

activation of mania/hypomania (5.6).

Discontinuation Syndrome: Taper dose when possible and monitor for discontinuation symptoms (5.7).

Seizure: Can occur. Use cautiously in patients with seizure disorder (5.8).

Hyponatremia: Can occur in association with SIADH (5.9).

Interstitial Lung Disease and Eosinophilic Pneumonia: Can occur (5.10).

ADVERSE REACTIONS

Most common adverse reactions (incidence ≥ 5% and twice the rate of placebo in the 50 or 100 mg dose groups) were:

nausea, dizziness, insomnia, hyperhidrosis, constipation, somnolence, decreased appetite, anxiety, and specific male sexual

function disorders (6.1).

To report SUSPECTED ADVERSE REACTIONS, contact Actavis at 1-800-272-5525 or FDA at 1-800-FDA-1088

or www.fda.gov/medwatch

USE IN SPECIFIC POPULATIONS

Pregnancy: Third trimester use may result in neonatal discontinuation syndrome (8.1).

Geriatric Use: There is an increased incidence of orthostatic hypotension in desvenlafaxine treated patients ≥ 65

years (6.1 and 8.5).

See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

Revised: 7/2019

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 General Instructions for Use

2.2 Dosage Recommendations for Patients with Renal Impairment

2.3 Dosage Recommendations for Patients with Hepatic Impairment

2.4 Maintenance/Continuation/Extended Treatment

2.5 Discontinuing Desvenlafaxine Extended-Release Tablets

2.6 Switching Patients From Other Antidepressants to Desvenlafaxine Extended-Release

Tablets

2.7 Switching Patients to or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat

Psychiatric Disorders

2.8 Use of Desvenlafaxine Extended-Release Tablets with other MAOIs such as Linezolid or

Methylene Blue

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Suicidal Thoughts and Behaviors in Pediatric and Young Adult Patients

5.2 Serotonin Syndrome

5.3 Elevated Blood Pressure

5.4 Increased Risk of Bleeding

5.5 Angle Closure Glaucoma

5.6 Activation of Mania/Hypomania

5.7 Discontinuation Syndrome

5.8 Seizure

5.9 Hyponatremia

5.10 Interstitial Lung Disease and Eosinophilic Pneumonia

6 ADVERSE REACTIONS

6.1 Clinical Studies Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

7.1 Drugs Having Clinically Important Interactions with Desvenlafaxine Extended-Release

Tablets

7.2 Drugs Having No Clinically Important Interactions with Desvenlafaxine Extended-Release

Tablets

7.3 Alcohol

7.4 Drug-Laboratory Test Interactions

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Renal Impairment

8.7 Hepatic Impairment

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

10 OVERDOSAGE

10.1 Human Experience with Overdosage

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

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

worsening, and for 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)].

Desvenlafaxine extended-release tablets are not approved for use in pediatric patients [see

Use in Specific Populations (8.4)].

1 INDICATIONS AND USAGE

Desvenlafaxine extended-release tablets are indicated for the treatment of adults with major depressive

disorder (MDD) [see Clinical Studies (14)].

2 DOSAGE AND ADMINISTRATION

2.1 General Instructions for Use

The recommended dose for desvenlafaxine extended-release tablets is 50 mg once daily, with or

without food. The 50 mg dose is both a starting dose and the therapeutic dose. Desvenlafaxine

extended-release tablets should be taken at approximately the same time each day. Tablets must be

swallowed whole with fluid and not divided, crushed, chewed, or dissolved.

In clinical studies, doses of 10 mg to 400 mg per day were studied. In clinical studies, doses of 50 mg

to 400 mg per day were shown to be effective, although no additional benefit was demonstrated at

doses greater than 50 mg per day and adverse reactions and discontinuations were more frequent at

higher doses.

The 25 mg per day dose is intended for a gradual reduction in dose when discontinuing treatment. When

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

discontinuing therapy, gradual dose reduction is recommended whenever possible to minimize

discontinuation symptoms [see Dosage and Administration (2.5) and Warnings and Precautions (5.7)].

2.2 Dosage Recommendations for Patients with Renal Impairment

The maximum recommended dose in patients with moderate renal impairment (24-hr creatinine clearance

] = 30 to 50 mL/min, Cockcroft-Gault [C-G]) is 50 mg per day. The maximum recommended dose

in patients with severe renal impairment (Cl

15 to 29 mL/min, C-G) or end-stage renal disease (ESRD,

< 15 mL/min, C-G) is 25 mg every day or 50 mg every other day. Supplemental doses should not be

given to patients after dialysis [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

2.3 Dosage Recommendations for Patients with Hepatic Impairment

The recommended dose in patients with moderate to severe hepatic impairment (Child-Pugh score 7 to

15) is 50 mg per day. Dose escalation above 100 mg per day is not recommended [see Use in Specific

Populations (8.7) and Clinical Pharmacology (12.3)].

2.4 Maintenance/Continuation/Extended Treatment

It is generally agreed that acute episodes of major depressive disorder require several months or

longer of sustained pharmacologic therapy. Longer-term efficacy of desvenlafaxine extended-release

tablets (50 to 400 mg) was established in two maintenance trials [see Clinical Studies (14)]. Patients

should be periodically reassessed to determine the need for continued treatment.

2.5 Discontinuing Desvenlafaxine Extended-Release Tablets

Adverse reactions may occur upon discontinuation of desvenlafaxine extended-release tablets [see

Warnings and Precautions (5.7)]. Gradually reduce the dosage rather than stopping desvenlafaxine

extended-release tablets abruptly whenever possible.

2.6 Switching Patients From Other Antidepressants to Desvenlafaxine Extended-Release Tablets

Discontinuation symptoms have been reported when switching patients from other antidepressants,

including venlafaxine, to desvenlafaxine extended-release tablets. Tapering of the initial antidepressant

may be necessary to minimize discontinuation symptoms.

2.7 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 desvenlafaxine extended-release tablets. Conversely, at least 7

days should be allowed after stopping desvenlafaxine extended-release tablets before starting an MAOI

intended to treat psychiatric disorders [see Contraindications (4)].

2.8 Use of Desvenlafaxine Extended-Release Tablets with other MAOIs such as Linezolid or

Methylene Blue

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

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

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

should be considered [see Contraindications (4)].

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

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

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

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

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

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

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

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

hours after the last dose of linezolid or intravenous methylene blue [see Warnings and Precautions

(5.2)].

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

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

is 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

Desvenlafaxine extended-release tablets are available as 25 mg, 50 mg and 100 mg tablets.

25 mg, light pink, square, pyramid tablets imprinted with “A112” in black ink on one side

50 mg, light pink, square, pyramid tablets imprinted with “WPI” and “3659” in black ink on one side

100 mg, reddish-orange, square, pyramid tablets imprinted with “WPI” and “3660” in black ink on

one side

4 CONTRAINDICATIONS

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

desvenlafaxine extended-release tablets formulation. Angioedema has been reported in patients

treated with desvenlafaxine extended-release tablets [see Adverse Reactions (6.1)].

The use of MAOIs intended to treat psychiatric disorders with desvenlafaxine extended-release

tablets or within 7 days of stopping treatment with desvenlafaxine extended-release tablets is

contraindicated because of an increased risk of serotonin syndrome. The use of desvenlafaxine

extended-release tablets within 14 days of stopping an MAOI intended to treat psychiatric disorders

is also contraindicated [see Dosage and Administration (2.7) and Warnings and Precautions (5.2)].

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

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

serotonin syndrome [see Dosage and Administration (2.8) and Warnings and Precautions (5.2)].

5 WARNINGS AND PRECAUTIONS

5.1 Suicidal Thoughts and Behaviors in Pediatric and Young Adult Patients

Patients with 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 major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did

not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond

age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.

The pooled analyses of placebo-controlled 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 vs. placebo), however, were

relatively stable within age strata and across indications. These risk differences (drug-placebo

difference in the number of cases of suicidality per 1,000 patients treated) are provided in Table 1.

Table 1

Age

Range

Drug-Placebo Difference in Number of Cases of Suicidality per

1,000

Patients Treated

Increases Compared to Placebo

<18

14 additional cases

18 to 24

5 additional cases

Decreases Compared to Placebo

25 to 64

1 fewer case

≥65

6 fewer cases

No suicides occurred in any of the pediatric 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 major depressive disorder

as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the

emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal

impulses has not been established, there is concern that such symptoms may represent precursors to

emerging suicidality.

Consideration should be given to changing the therapeutic regimen, including possibly discontinuing

the medication, in patients whose depression is persistently worse, or who are experiencing emergent

suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if

these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.

If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is

feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms [see

Dosage and Administration (2.4), Warnings and Precautions (5.7)].

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

other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor

patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms

described above, as well as the emergence of suicidality, and to report such symptoms immediately to

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

Prescriptions for desvenlafaxine extended-release tablets should be written for the smallest quantity of

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

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 desvenlafaxine extended-release tablets are not approved for use in

treating bipolar depression.

5.2 Serotonin Syndrome

Serotonin-norepinephrine reuptake inhibitors (SNRIs) and selective-serotonin reuptake inhibitors

(SSRIs), including desvenlafaxine extended-release tablets, can precipitate serotonin syndrome, a

potentially life-threatening condition. The risk is increased 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, i.e., MAOIs [see

Contraindications (4), Drug Interactions (7.1)]. Serotonin syndrome can also occur when these drugs are

used alone.

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

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

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

myoclonus, hyperreflexia, incoordination), seizures, and gastrointestinal symptoms (e.g., nausea,

vomiting, diarrhea).

The concomitant use of desvenlafaxine extended-release tablets with MAOIs is contraindicated. In

addition, do not initiate Desvenlafaxine extended-release tablets in a patient being treated with MAOIs

such as linezolid or intravenous methylene blue. No reports involved the administration of methylene

blue by other routes (such as oral tablets or local tissue injection). If it is necessary to initiate treatment

with an MAOI such as linezolid or intravenous methylene blue in a patient taking desvenlafaxine

extended-release tablets, discontinue desvenlafaxine extended-release tablets before initiating treatment

with the MAOI [see Contraindications (4), Drug Interactions (7.1)].

Monitor all patients taking desvenlafaxine extended-release tablets for the emergence of serotonin

syndrome. Discontinue treatment with desvenlafaxine extended-release tablets and any concomitant

serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic

treatment. If concomitant use of desvenlafaxine extended-release tablets with other serotonergic drugs

is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for

symptoms.

5.3 Elevated Blood Pressure

Patients receiving desvenlafaxine extended-release tablets should have regular monitoring of blood

pressure since increases in blood pressure were observed in clinical studies [see Adverse Reactions

(6.1)]. Pre-existing hypertension should be controlled before initiating treatment with desvenlafaxine

extended-release tablets. Caution should be exercised in treating patients with pre-existing

hypertension, cardiovascular, or cerebrovascular conditions that might be compromised by increases in

blood pressure. Cases of elevated blood pressure requiring immediate treatment have been reported

with desvenlafaxine extended-release tablets.

Sustained blood pressure increases could have adverse consequences. For patients who experience a

sustained increase in blood pressure while receiving desvenlafaxine extended-release tablets, either

dose reduction or discontinuation should be considered [see Adverse Reactions (6.1)].

5.4 Increased Risk of Bleeding

Drugs that interfere with serotonin reuptake inhibition, including desvenlafaxine extended-release

tablets, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-

inflammatory drugs, warfarin, and other anticoagulants may add to this risk. Case reports and

epidemiological studies (case-control and cohort design) have demonstrated an association between use

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

events related to SSRIs and SNRIs have ranged from ecchymosis, hematoma, epistaxis, and petechiae to

life-threatening hemorrhages. Inform patients about the risk of bleeding associated with the concomitant

use of desvenlafaxine extended-release tablets and antiplatelet agents or anticoagulants. For patients

taking warfarin, carefully monitor coagulation indices when initiating, titrating, or discontinuing

desvenlafaxine extended-release tablets.

5.5 Angle Closure Glaucoma

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

extended-release tablets may trigger an angle closure attack in a patient with anatomically narrow angles

who does not have a patent iridectomy. Avoid use of antidepressants, including desvenlafaxine

extended-release tablets, in patients with untreated anatomically narrow angles.

5.6 Activation of Mania/Hypomania

During all MDD phase 2 and phase 3 studies, mania was reported for approximately 0.02% of patients

treated with desvenlafaxine extended-release tablets. Activation of mania/hypomania has also been

reported in a small proportion of patients with major affective disorder who were treated with other

marketed antidepressants. As with all antidepressants, desvenlafaxine extended-release tablets should be

used cautiously in patients with a history or family history of mania or hypomania.

5.7 Discontinuation Syndrome

Adverse reactions after discontinuation of serotonergic antidepressants, particularly after abrupt

discontinuation, include: nausea, sweating, dysphoric mood, irritability, agitation, dizziness, sensory

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

lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. A gradual reduction in dosage

rather than abrupt cessation is recommended whenever possible [see Dosage and Administration (2.5),

Adverse Reaction (6.1)].

5.8 Seizure

Cases of seizure have been reported in pre-marketing clinical studies with desvenlafaxine extended-

release tablets. Desvenlafaxine extended-release tablets have not been systematically evaluated in

patients with a seizure disorder. Patients with a history of seizures were excluded from pre-marketing

clinical studies. Desvenlafaxine extended-release tablets should be prescribed with caution in patients

with a seizure disorder.

5.9 Hyponatremia

Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including desvenlafaxine

extended-release tablets. In many cases, this hyponatremia appears to be the result of the syndrome of

inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110

mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with

SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted can be at

greater risk [see Use in Specific Populations (8.5) and Clinical Pharmacology (12.3)]. Discontinuation of

desvenlafaxine extended-release tablets should be considered in patients with symptomatic

hyponatremia and appropriate medical intervention should be instituted.

Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment,

confusion, weakness, and unsteadiness, which can 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 Interstitial Lung Disease and Eosinophilic Pneumonia

Interstitial lung disease and eosinophilic pneumonia associated with venlafaxine (the parent drug of

desvenlafaxine extended-release tablets) therapy have been rarely reported. The possibility of these

adverse events should be considered in patients treated with desvenlafaxine extended-release tablets

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

prompt medical evaluation, and discontinuation of desvenlafaxine extended-release tablets 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)]

Suicidal Thoughts and Behaviors in Pediatric and Young Adult Patients [see Warnings and

Precautions (5.1)]

Serotonin Syndrome [see Warnings and Precautions (5.2)]

Elevated Blood Pressure [see Warnings and Precautions (5.3)]

Increased Risk of 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)]

Interstitial Lung Disease and Eosinophilic Pneumonia [see Warnings and Precautions (5.10)]

6.1 Clinical Studies Experience

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

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

and may not reflect the rates observed in clinical practice.

Patient exposure

Desvenlafaxine extended-release tablets were evaluated for safety in 8,394 patients diagnosed with

major depressive disorder who participated in multiple-dose pre-marketing studies, representing 2,784

patient-years of exposure. Of the total 8,394 patients exposed to at least one dose of desvenlafaxine

extended-release tablets; 2,116 were exposed to desvenlafaxine extended-release tablets for 6 months,

representing 1,658 patient-years of exposure, and 421 were exposed for one year, representing 416

patient-years of exposure.

Adverse reactions reported as reasons for discontinuation of treatment

In the pre-marketing pooled 8-week placebo-controlled studies in patients with MDD, 1,834 patients

were exposed to desvenlafaxine extended-release tablets (50 to 400 mg). Of the 1,834 patients, 12%

discontinued treatment due to an adverse reaction, compared with 3% of the 1,116 placebo-treated

patients. At the recommended dose of 50 mg, the discontinuation rate due to an adverse reaction for

desvenlafaxine extended-release tablets (4.1%) was similar to the rate for placebo (3.8%). For the 100

mg dose of desvenlafaxine extended-release tablets the discontinuation rate due to an adverse reaction

was 8.7%.

The most common adverse reactions leading to discontinuation in at least 2% and at a rate greater than

placebo of the desvenlafaxine extended-release tablets treated patients in the short-term studies, up to 8

weeks, were: nausea (4%); dizziness, headache and vomiting (2% each). In a longer-term study, up to 9

months, the most common was vomiting (2%).

Common adverse reactions in placebo-controlled MDD studies

The most commonly observed adverse reactions in desvenlafaxine extended-release tablets treated

MDD patients in pre-marketing pooled 8-week, placebo-controlled, fixed-dose studies (incidence ≥ 5%

and at least twice the rate of placebo in the 50 or 100 mg dose groups) were: nausea, dizziness,

insomnia, hyperhidrosis, constipation, somnolence, decreased appetite, anxiety, and specific male

sexual function disorders.

Table 2 shows the incidence of common adverse reactions that occurred in ≥ 2% of desvenlafaxine

extended-release tablets treated MDD patients and twice the rate of placebo at any dose in the pre-

marketing pooled 8-week, placebo-controlled, fixed dose clinical studies.

Table 2: Common Adverse Reactions (≥2% in any Fixed-Dose Group and Twice the Rate of Placebo) in Pre-

marketing Pooled MDD 8-Week Placebo-Controlled Studies

Percentage of Patients Reporting Reaction

Desvenlafaxine Extended-Release Tablets

System Organ Class

Preferred Term

Placebo

(n=636)

50 mg

(n=317)

100 mg

(n=424)

200 mg

(n=307)

400 mg

(n=317)

Cardiac disorders

Blood pressure increased

Gastrointestinal disorders

Nausea

Dry mouth

Constipation

Vomiting

General disorders and administration site conditions

Fatigue

Chills

<1

Feeling jittery

Metabolism and nutrition disorders

Decreased appetite

Nervous system disorders

Dizziness

Somnolence

Tremor

Disturbance in attention

<1

<1

Psychiatric disorders

Insomnia

Anxiety

Nervousness

<1

Abnormal dreams

Renal and urinary disorders

Urinary hesitation

<1

Respiratory, thoracic and mediastinal disorders

Yawning

<1

Skin and subcutaneous tissue disorders

Hyperhidrosis

Special Senses

Vision blurred

Mydriasis

<1

Vertigo

Tinnitus

Dysgeusia

Vascular disorders

Hot flush

<1

Sexual function adverse reactions

Table 3 shows the incidence of sexual function adverse reactions that occurred in ≥2% of

desvenlafaxine extended-release tablets treated MDD patients in any fixed-dose group (pre-marketing

pooled 8-week, placebo-controlled, fixed-dose, clinical studies).

Table 3: Sexual Function Adverse Reactions (≥ 2% in Men or Women in any Desvenlafaxine Extended-Release

Tablets Group) During the On-Therapy Period

Desvenlafaxine Extended-Release Tablets

Placebo

(n=239)

50 mg

(n=108)

100 mg

(n=157)

200 mg

(n=131)

400 mg

(n=154)

Men only

Anorgasmia

Libido decreased

Orgasm abnormal

Ejaculation delayed

<1

Erectile dysfunction

Ejaculation disorder

Ejaculation failure

Sexual dysfunction

Desvenlafaxine Extended-Release Tablets

Placebo

(n=397)

50 mg

(n=209)

100 mg

(n=267)

200 mg

(n=176)

400 mg

(n=163)

Women only

Anorgasmia

Other adverse reactions observed in premarketing and postmarketing clinical studies

Other infrequent adverse reactions, not described elsewhere in the label, occurring at an incidence of

less than 2% in MDD patients treated with desvenlafaxine extended-release tablets were:

Cardiac disorders – Tachycardia.

General disorders and administration site conditions Asthenia.

Investigations – Weight increased, liver function test abnormal, blood prolactin increased.

Musculoskeletal and connective tissue disorders – Musculoskeletal stiffness.

Nervous system disorders – Syncope, convulsion, dystonia.

Psychiatric disorders – Depersonalization, bruxism.

Renal and urinary disorders – Urinary retention.

Skin and subcutaneous tissue disorders – Rash, alopecia, photosensitivity reaction, angioedema.

In clinical studies, there were uncommon reports of ischemic cardiac adverse reactions, including

myocardial ischemia, myocardial infarction, and coronary occlusion requiring revascularization; these

patients had multiple underlying cardiac risk factors. More patients experienced these events during

desvenlafaxine extended-release tablets treatment as compared to placebo.

Laboratory, ECG and vital sign changes observed in MDD clinical studies

The following changes were observed in pre-marketing placebo-controlled, short-term MDD studies

with desvenlafaxine extended-release tablets.

Lipids

Elevations in fasting serum total cholesterol, LDL (low density lipoproteins) cholesterol, and

triglycerides occurred in the controlled studies. Some of these abnormalities were considered

potentially clinically significant.

The percentage of patients who exceeded a predetermined threshold value is shown in Table 4.

Table 4: Incidence (%) of Patients With Lipid Abnormalities of Potential Clinical Significance*

Desvenlafaxine Extended-Release Tablets

Placebo

50 mg

100 mg

200 mg

400 mg

Total Cholesterol

*(Increase of ≥ 50 mg/dl and

an absolute value of ≥ 261 mg/dl)

LDL Cholesterol

*(Increase ≥ 50 mg/dl and

an absolute value of ≥ 190 mg/dl)

Triglycerides, fasting

*(Fasting: ≥ 327 mg/dl)

Proteinuria

Proteinuria, greater than or equal to trace, was observed in the pre-marketing fixed-dose controlled

studies (see Table 5). This proteinuria was not associated with increases in BUN or creatinine and was

generally transient.

Table 5: Incidence (%) of Patients with Proteinuria in the Fixed-dose Clinical Studies

Desvenlafaxine Extended-Release Tablets

Placebo

50 mg

100 mg

200 mg

400 mg

Proteinuria

Vital sign changes

Table 6 summarizes the changes that were observed in placebo-controlled, short-term, pre-marketing

studies with desvenlafaxine extended-release tablets in patients with MDD (doses 50 to 400 mg).

Table 6: Mean Changes in Vital Signs at Final on Therapy for All Short-term, Fixed-dose Controlled Studies

Desvenlafaxine Extended-Release Tablets

Placebo

50 mg

100 mg

200 mg

400 mg

Blood pressure

Supine systolic bp (mm Hg)

-1.4

Supine diastolic bp (mm Hg)

-0.6

Pulse rate

Supine pulse (bpm)

-0.3

Weight (kg)

-0.4

-0.6

-0.9

-1.1

Treatment with desvenlafaxine extended-release tablets at all doses from 50 mg per day to 400 mg per

day in controlled studies was associated with sustained hypertension, defined as treatment-emergent

supine diastolic blood pressure (SDBP) ≥90 mm Hg and ≥10 mm Hg above baseline for 3 consecutive

on-therapy visits (see Table 7). Analyses of patients in desvenlafaxine extended-release tablets pre-

marketing short-term controlled studies who met criteria for sustained hypertension revealed a

consistent increase in the proportion of patients who developed sustained hypertension. This was seen

at all doses with a suggestion of a higher rate at 400 mg per day.

Table 7: Proportion of Patients with Sustained Elevation of Supine Diastolic Blood Pressure

Treatment Group

Proportion of Patients

with Sustained

Hypertens ion

Placebo

0.5%

Desvenlafaxine extended-release

tablets 50 mg per day

1.3%

Desvenlafaxine extended-release

tablets 100 mg per day

0.7%

Desvenlafaxine extended-release tablets

200 mg per day

1.1%

Desvenlafaxine extended-release tablets

400 mg per day

2.3%

Orthostatic hypotension

In the pre-marketing short-term, placebo-controlled clinical studies with doses of 50 to 400 mg,

systolic orthostatic hypotension (decrease ≥30 mm Hg from supine to standing position) occurred more

frequently in patients ≥65 years of age receiving desvenlafaxine extended-release tablets (8%, 7/87)

versus placebo (2.5%, 1/40), compared to patients less than 65 years of age receiving desvenlafaxine

extended-release tablets (0.9%, 18/1,937) versus placebo (0.7%, 8/1,218).

6.2 Postmarketing Experience

The following adverse reaction has been identified during post-approval use of desvenlafaxine

extended-release tablets. 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:

Skin and subcutaneous tissue disorders – Stevens-Johnson syndrome

Gastrointestinal disorders – Pancreatitis acute

Cardiovascular system – Takotsubo cardiomyopathy

7 DRUG INTERACTIONS

7.1 Drugs Having Clinically Important Interactions with Desvenlafaxine Extended-Release

Tablets

Table 8: Clinically Important Drug Interactions with Desvenlafaxine Extended-Release Tablets

Monoamine Oxidase Inhibitors (MAOI)

Clinical Impact

The concomitant use of SSRIs and SNRIs

including desvenlafaxine extended-release

tablets with MAOIs increases the risk of

serotonin syndrome.

Concomitant use of desvenlafaxine extended-

release tablets is contraindicated:

With an MAOI intended to treat psychiatric

disorders or within 7 days of stopping

Intervention

treatment with desvenlafaxine extended-release

tablets.

Within 14 days of stopping an MAOI intended

to treat psychiatric disorders.

In a patient who is being treated with linezolid

or intravenous methylene blue. [see Dosage and

Administration (2.7), Contraindications (4) and

Warnings and Precautions (5.2)].

Examples

selegiline, tranylcypromine, isocarboxazid,

phenelzine, linezolid, methylene blue

Other Serotonergic Drugs

Clinical Impact

Concomitant use of desvenlafaxine extended-

release tablets with other serotonergic drugs

increases the risk of serotonin syndrome.

Intervention

Monitor for symptoms of serotonin syndrome

when desvenlafaxine extended-release tablets

is used concomitantly with other drugs that may

affect the serotonergic neurotransmitter

systems. If serotonin syndrome occurs,

consider discontinuation of desvenlafaxine

extended-release tablets and/or concomitant

serotonergic drugs [see Warnings and

Precautions (5.2)].

Examples

other SNRIs, SSRIs, triptans, tricyclic

antidepressants, fentanyl, lithium, tramadol,

buspirone, amphetamines, tryptophan, and St.

John's Wort

Drugs that Interfere with Hemostasis

Clinical Impact

Concomitant use of desvenlafaxine extended-

release tablets with an antiplatelet or

anticoagulant drug may potentiate the risk of

bleeding. This may be due to the effect of

desvenlafaxine extended-release tablets on the

release of serotonin by platelets.

Intervention

Closely monitor for bleeding for patients

receiving an antiplatelet or anticoagulant drug

when desvenlafaxine extended-release tablets

is initiated or discontinued [see Warnings and

Precautions (5.4)].

Examples

NSAIDs, aspirin, and warfarin

Drugs that are Primarily Metabolized by CYP2D6

Clinical Impact

Concomitant use of desvenlafaxine extended-

release tablets increases Cmax and AUC of a

drug primarily metabolized by CYP2D6 which

may increase the risk of toxicity of the

CYP2D6 substrate drug [see Clinical

Pharmacology (12.3)].

Intervention

Original dose should be taken when co-

administered with desvenlafaxine extended-

release tablets 100 mg or lower. Reduce the

dose of these drugs by up to one-half if co-

administered with 400 mg of desvenlafaxine

extended-release tablets.

Examples

desipramine, atomoxetine, dextromethorphan,

metoprolol, nebivolol, perphenazine,

tolterodine

7.2 Drugs Having No Clinically Important Interactions with Desvenlafaxine Extended-Release

Tablets

Based on pharmacokinetic studies, no dosage adjustment is required for drugs that are mainly

metabolized by CYP3A4 (e.g., midazolam), or for drugs that are metabolized by both CYP2D6 and

CYP3A4 (e.g., tamoxifen, aripiprazole), when administered concomitantly with desvenlafaxine

extended-release tablets[see Clinical Pharmacology (12.3)].

7.3 Alcohol

A clinical study has shown that desvenlafaxine extended-release tablets do not increase the impairment

of mental and motor skills caused by ethanol. However, as with all CNS-active drugs, patients should be

advised to avoid alcohol consumption while taking desvenlafaxine extended-release tablets.

7.4 Drug-Laboratory Test Interactions

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

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

positive test results may be expected for several days following discontinuation of desvenlafaxine

therapy. Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish

desvenlafaxine from PCP and amphetamine.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk summary

There are no published studies on desvenlafaxine extended-release tablets in pregnant women; however

published epidemiologic studies of pregnant women exposed to venlafaxine, the parent compound, have

not reported a clear association with adverse developmental outcomes (see Data). There are risks

associated with untreated depression in pregnancy and with exposure to SNRIs and SSRIs, including

desvenlafaxine extended-release tablets, during pregnancy (see Clinical Considerations).

In reproductive developmental studies in rats and rabbits treated with desvenlafaxine succinate, there

was no evidence of teratogenicity at a plasma exposure (AUC) that is up to 19-times (rats) and 0.5-times

(rabbits) the exposure at an adult human dose of 100 mg per day. However, fetotoxicity and pup deaths

were observed in rats at 4.5-times the AUC exposure observed with an adult human dose of 100 mg per

day.

The estimated background risk of major birth defects and miscarriage for the indicated population is

unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In

the U.S. general population, the estimated background risk of major birth defects and miscarriage in

clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

A prospective longitudinal study of 201 women with a history of major depression who were euthymic

at the beginning of pregnancy, showed that women who discontinued antidepressant medication during

pregnancy were more likely to experience a relapse of major depression than women who continued

antidepressant medication.

Maternal adverse reactions

Exposure to SNRIs in mid to late pregnancy may increase the risk for preeclampsia, and exposure to

SNRIs near delivery may increase the risk for postpartum hemorrhage.

Fetal/Neonatal adverse reactions

Exposure to SNRIs or SSRIs in late pregnancy may lead to an increased risk for neonatal complications

requiring prolonged hospitalization, respiratory support, and tube feeding. Monitor neonates who were

exposed to desvenlafaxine extended-release tablets in the third trimester of pregnancy for drug

discontinuation syndrome (see Data).

Data

Human Data

Published epidemiological studies of pregnant women exposed to the parent compound venlafaxine

have not reported a clear association with major birth defects or miscarriage. Methodological

limitations of these observational studies include possible exposure and outcome misclassification, lack

of adequate controls, adjustment for confounders, and confirmatory studies; therefore, these studies

cannot establish or exclude any drug-associated risk during pregnancy.

Retrospective cohort studies based on claims data have shown an association between venlafaxine use

and preeclampsia, compared to depressed women who did not take an antidepressant during pregnancy.

One study that assessed venlafaxine exposure in the second trimester or first half of the third trimester

and preeclampsia showed an increased risk compared to unexposed depressed women (adjusted (adj) RR

1.57, 95% CI 1.29 to 1.91). Preeclampsia was observed at venlafaxine doses equal to or greater than 75

mg/day and a duration of treatment >30 days. Another study that assessed venlafaxine exposure in

gestational weeks 10 to 20 and preeclampsia showed an increased risk at doses equal to or greater than

150 mg/day. Available data are limited by possible outcome misclassification and possible confounding

due to depression severity and other confounders.

Retrospective cohort studies based on claims data have suggested an association between venlafaxine

use near the time of delivery or through delivery and postpartum hemorrhage. One study showed an

increased risk for postpartum hemorrhage when venlafaxine exposure occurred through delivery,

compared to unexposed depressed women (adj RR 2.24 (95% CI 1.69 to 2.97). There was no increased

risk in women who were exposed to venlafaxine earlier in pregnancy. Limitations of this study include

possible confounding due to depression severity and other confounders. Another study showed an

increased risk for postpartum hemorrhage when SNRI exposure occurred for at least 15 days in in the

last month of pregnancy or through delivery, compared to unexposed women (adj RR 1.64 to 1.76). The

results of this study may be confounded by the effects of depression.

Neonates exposed to 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)].

Animal Data

When desvenlafaxine succinate was administered orally to pregnant rats and rabbits during the period of

organogenesis at doses up to 300 mg/kg/day and 75 mg/kg/day, respectively, no teratogenic effects

were observed. These doses were associated with a plasma exposure (AUC) 19 times (rats) and 0.5

times (rabbits) the AUC exposure at an adult human dose of 100 mg per day. However, fetal weights

were decreased and skeletal ossification was delayed in rats in association with maternal toxicity at the

highest dose, with an AUC exposure at the no-effect dose that is 4.5-times the AUC exposure at an

adult human dose of 100 mg per day.

When desvenlafaxine succinate was administered orally to pregnant rats throughout gestation and

lactation, there was a decrease in pup weights and an increase in pup deaths during the first four days of

lactation at the highest dose of 300 mg/kg/day. The cause of these deaths is not known. The AUC

exposure at the no-effect dose for rat pup mortality was 4.5-times the AUC exposure at an adult human

dose of 100 mg per day. Post-weaning growth and reproductive performance of the progeny were not

affected by maternal treatment with desvenlafaxine succinate at exposures 19 times the AUC exposure at

an adult human dose of 100 mg per day.

8.2 Lactation

Risk Summary

Available limited data from published literature show low levels of desvenlafaxine in human milk, and

have not shown adverse reactions in breastfed infants (see Data). There are no data on the effects of

desvenlafaxine on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s

clinical need for desvenlafaxine extended-release tablets and any potential adverse effects on the

breastfed child from desvenlafaxine extended-release tablets or from the underlying maternal condition.

Data

A lactation study was conducted in 10 breastfeeding women (at a mean of 4.3 months postpartum) who

were being treated with a 50 to 150 mg daily dose of desvenlafaxine for postpartum depression.

Sampling was performed at steady state (up to 8 samples) over a 24 hour dosing period, and included

foremilk and hindmilk. The mean relative infant dose was calculated to be 6.8% (range of 5.5 to 8.1%).

No adverse reactions were seen in the infants.

8.4 Pediatric Use

The safety and effectiveness of desvenlafaxine extended-release tablets have not been established in

pediatric patients for the treatment of MDD.

Efficacy was not demonstrated in two adequate and well controlled, 8-week, randomized, double-blind,

placebo-controlled, parallel group studies conducted in 587 patients (7 to 17 years of age) for the

treatment of MDD.

Antidepressants, such as desvenlafaxine extended-release tablets, increase the risk of suicidal thoughts

and behaviors in pediatric patients [see the Boxed Warning and Warnings and Precautions (5.1)].

Desvenlafaxine extended-release tablets was associated with a decrease in body weight in placebo-

controlled trials in pediatric patients with MDD. The incidence of weight loss (≥3.5% of baseline

weight) was 22%, 14%,

and 7% for patients treated with low dose desvenlafaxine extended-release tablets, high dose

desvenlafaxine extended-release tablets, and placebo, respectively.

The risks associated with longer term desvenlafaxine extended-release tablets use were assessed in 6-

month, open-label extension studies in pediatric patients (7 to 17 years of age) with MDD. Pediatric

patients (7 to 17 years of age) had mean changes in weight that approximated expected changes, based

on data from age- and sex-matched peers.

In clinical trials, when compared to adult patients receiving the same dose of desvenlafaxine extended-

release tablets, exposure to desvenlafaxine was similar in adolescent patients 12 to 17 years of age, and

was about 30% higher in pediatric patients 7 to 11 years of age.

Juvenile Animal Studies

In a juvenile animal study, male and female rats were treated with desvenlafaxine (75, 225 and 675

mg/kg/day) starting on postnatal day (PND) 22 through 112. Behavioral deficits (longer time immobile in

a motor activity test, longer time swimming in a straight channel test, and lack of habituation in an

acoustic startle test) were observed in males and females but were reversed after a recovery period. A

No Adverse Effect Level (NOAEL) was not identified for these deficits. The Low Adverse Effect

Level (LOAEL) was 75 mg/kg/day which was associated with plasma exposure (AUC) twice the levels

measured with a pediatric dose of 100 mg/day.

In a second juvenile animal study, male and female rats were administered desvenlafaxine (75, 225 or

675 mg/kg/day) for 8-9 weeks starting on PND 22 and were mated with naïve counterparts. Delays in

sexual maturation and decreased fertility, number of implantation sites and total live embryos were

observed in treated females at all doses. The LOAEL for these findings is 75 mg/kg/day which was

associated with an AUC twice the levels measured with a pediatric dose of 100 mg/day. These findings

were reversed at the end of a 4-week recovery period.The relevance of these findings to humans is not

known.

8.5 Geriatric Use

Of the 4,158 patients in pre-marketing clinical studies with desvenlafaxine extended-release tablets, 6%

were 65 years of age or older. No overall differences in safety or efficacy were observed between

these patients and younger patients; however, in the short-term placebo-controlled studies, there was a

higher incidence of systolic orthostatic hypotension in patients ≥ 65 years of age compared to patients

<65 years of age treated with desvenlafaxine extended-release tablets [see Adverse Reactions (6.1)]. For

elderly patients, possible reduced renal clearance of desvenlafaxine extended-release tablets should be

considered when determining dose [see Dosage and Administration (2.2) and Clinical Pharmacology

(12.3)].

SSRIs and SNRIs, including desvenlafaxine extended-release tablets, 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)].

8.6 Renal Impairment

Adjust the maximum recommended dosage in patients with moderate or severe renal impairment (CLcr

15 to 50 mL/min, C-G), or end-stage renal disease (CLcr < 15 mL/min, C-G) [see Dosage and

Administration (2.2) and Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

Adjust the maximum recommended dosage in patients with moderate to severe hepatic impairment

(Child-Pugh score 7 to 15) [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

Desvenlafaxine extended-release tablets are not a controlled substance.

10 OVERDOSAGE

10.1 Human Experience with Overdosage

There is limited clinical trial experience with desvenlafaxine succinate overdosage in humans.

However, desvenlafaxine (desvenlafaxine extended-release tablets) is the major active metabolite of

venlafaxine. Overdose experience reported with venlafaxine (the parent drug of desvenlafaxine

extended-release tablets) is presented below; the identical information can be found in the Overdosage

section of the venlafaxine package insert.

In postmarketing experience, overdose with venlafaxine (the parent drug of desvenlafaxine extended-

release tablets) 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), sinus and ventricular

tachycardia, bradycardia, hypotension, rhabdomyolysis, vertigo, liver necrosis, serotonin syndrome, and

death have been reported.

Published retrospective studies report that venlafaxine overdosage may be associated with an increased

risk of fatal outcomes compared to that observed with SSRI antidepressant products, but lower than that

for tricyclic antidepressants. Epidemiological studies have shown that venlafaxine-treated patients have

a higher pre-existing burden of suicide risk factors than SSRI-treated patients. The extent to which the

finding of an increased risk of fatal outcomes can be attributed to the toxicity of venlafaxine in

overdosage, as opposed to some characteristic(s) of venlafaxine-treated patients, is not clear.

10.2 Management of Overdosage

No specific antidotes for desvenlafaxine extended-release tablets are known. In managing over dosage,

consider the possibility of multiple drug involvement. In case of overdose, call Poison Control Center

at 1-800-222-1222 for latest recommendations.

11 DESCRIPTION

Desvenlafaxine extended-release tablets are an extended-release tablet for oral administration that

contains desvenlafaxine succinate, a structurally novel SNRI for the treatment of MDD. Desvenlafaxine

(O-desmethylvenlafaxine) is the major active metabolite of the antidepressant venlafaxine, a medication

used to treat major depressive disorder.

Desvenlafaxine is designated RS-4-[2-dimethylamino-1-(1-hydroxycyclohexyl)ethyl]phenol and has the

empirical formula of C

H NO (free base) and C

H NO C H O H O (succinate monohydrate).

Desvenlafaxine succinate monohydrate has a molecular weight of 399.48. The structural formula is

shown below.

Desvenlafaxine succinate is a white to off-white powder that is soluble in water. The solubility of

desvenlafaxine succinate is pH dependent. Its octanol:aqueous system (at pH 7.0) partition coefficient is

0.21.

Desvenlafaxine extended-release tablets are formulated as an extended-release tablet for once-a-day

oral administration.

Each tablet contains 38 mg, 76 mg or 152 mg of desvenlafaxine succinate equivalent to 25 mg, 50 mg or

100 mg of desvenlafaxine, respectively.

Inactive ingredients for the 25 mg, 50 mg and 100 mg tablet consist of hypromellose, microcrystalline

cellulose, talc, magnesium stearate, polyethylene oxide and colloidal silicon dioxide and film coating,

which consists of polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide, and iron oxide yellow

and iron oxide red. The imprinting ink contains hypromellose, propylene glycol and iron oxide black.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The exact mechanism of the antidepressant action of desvenlafaxine 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 shown that desvenlafaxine is a potent and

selective serotonin and norepinephrine reuptake inhibitor (SNRI).

12.2 Pharmacodynamics

Desvenlafaxine lacked significant affinity for numerous receptors, including muscarinic-cholinergic,

H -histaminergic, or α -adrenergic receptors in vitro. Desvenlafaxine also lacked monoamine oxidase

(MAO) inhibitory activity.

ECG changes

Electrocardiograms were obtained from 1,492 desvenlafaxine treated patients with major depressive

disorder and 984 placebo-treated patients in clinical studies lasting up to 8 weeks. No clinically

relevant differences were observed between desvenlafaxine treated and placebo-treated patients for

QT, QTc, PR, and QRS intervals. In a thorough QTc study with prospectively determined criteria,

desvenlafaxine did not cause QT prolongation. No difference was observed between placebo and

desvenlafaxine treatments for the QRS interval.

12.3 Pharmacokinetics

The single-dose pharmacokinetics of desvenlafaxine are linear and dose-proportional in a dose range

of 50 to 600 mg (1 to 12 times the recommended approved dosage) per day. With once-daily dosing,

steady-state plasma concentrations are achieved within approximately 4 to 5 days. At steady-state,

multiple-dose accumulation of desvenlafaxine is linear and predictable from the single-dose

pharmacokinetic profile.

Absorption

The absolute oral bioavailability of desvenlafaxine extended-release tablets after oral administration is

about 80%.

Effect of Food

Ingestion of a high-fat meal (800 to 1000 calories) increased desvenlafaxine C

about 16% and had

Ingestion of a high-fat meal (800 to 1000 calories) increased desvenlafaxine C

about 16% and had

no effect on AUC.

Distribution

Steady-state volume of distribution of desvenlafaxine is 3.4 L/kg. Plasma protein binding of

desvenlafaxine is 30% and is independent of drug concentration.

Elimination

Metabolism

Desvenlafaxine is primarily metabolized by conjugation (mediated by UGT isoforms) and, to a minor

extent, through oxidative metabolism. CYP3A4 mediates the oxidative metabolism (N-demethylation) of

desvenlafaxine. The CYP2D6 metabolic pathway is not involved. The pharmacokinetics of

desvenlafaxine was similar in subjects with CYP2D6 poor and extensive metabolizer phenotype.

Excretion

Approximately 45% of desvenlafaxine is excreted unchanged in urine at 72 hours after oral

administration. Approximately 19% of the administered dose is excreted as the glucuronide metabolite

and <5% as the oxidative metabolite (N,O-didesmethylvenlafaxine) in urine.

Specific populations

No clinically significant differences in the exposures of desvenlafaxine were observed based on

ethnicity (White, Black, Hispanic).

The effect of intrinsic patient factors on the pharmacokinetics of desvenlafaxine is presented in Figure

Drug Interaction Studies

Clinical Studies

Other Drugs on desvenlafaxine extended-release tablets

The effect of ketoconazole on the exposures of desvenlafaxine is summarized in Figure 2.

Figure 2. Effect of Other Drugs on Desvenlafaxine Pharmacokinetics

Desvenlafaxine extended-release tablets on Other Drugs

The effects of desvenlafaxine extended-release tablets on the exposures of other drugs are summarized

in Figure 3.

Figure 3. Effects of Desvenlafaxine Extended-Release Tablets on Pharmacokinetics of Other

Drugs

In Vitro Studies

Based on in vitro data, drugs that inhibit CYP isozymes 1A1, 1A2, 2A6, 2D6, 2C8, 2C9, 2C19, and 2E1

are not expected to have significant impact on the pharmacokinetic profile of desvenlafaxine.

Desvenlafaxine does not inhibit CYP1A2, 2A6, 2C8, 2C9, 2C19, CYP2D6, or CYP3A4 isozymes.

Desvenlafaxine does not induce CYP3A4 either.

Desvenlafaxine is not a substrate or an inhibitor for the P-glycoprotein (P-gp) transporter.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Desvenlafaxine succinate administered by oral gavage to mice and rats for 2 years did not increase the

incidence of tumors in either study.

Mice received desvenlafaxine succinate at dosages up to 500/300 mg/kg/day (dosage lowered after 45

weeks of dosing). The AUC exposure at 300 mg/kg/day dose is estimated at 10 times the AUC

exposure at an adult human dose of 100 mg per day.

Rats received desvenlafaxine succinate at dosages up to 300 mg/kg/day (males) or 500 mg/kg/day

(females). The AUC exposure at the highest dose is estimated at 11 (males) or 26 (females) times the

AUC exposure at an adult human dose of 100 mg per day.

Mutagenesis

Desvenlafaxine was not mutagenic in the in vitro bacterial mutation assay (Ames test) and was not

clastogenic in an in vitro chromosome aberration assay in cultured CHO cells, an in vivo mouse

micronucleus assay, or an in vivo chromosome aberration assay in rats. Additionally, desvenlafaxine was

not genotoxic in the in vitro CHO mammalian cell forward mutation assay and was negative in the in vitro

BALB/c-3T3 mouse embryo cell transformation assay.

Impairment of fertility

When desvenlafaxine succinate was administered orally to male and female rats, fertility was reduced at

the high dose of 300 mg/kg/day, which is 10 (males) and 19 (females) times the AUC exposure at an

adult human dose of 100 mg per day. There was no effect on fertility at 100 mg/kg/day, which is 3

(males) or 5 (females) times the AUC exposure at an adult human dose of 100 mg per day. These studies

did not address reversibility of the effect on fertility. The relevance of these findings to humans is not

known.

14 CLINICAL STUDIES

Major Depressive Disorder

The efficacy of desvenlafaxine extended-release tablets as a treatment for depression was established

in four 8-week, randomized, double-blind, placebo-controlled, fixed-dose studies (at doses of 50 mg

per day to 400 mg per day) in adult outpatients who met the Diagnostic and Statistical Manual of Mental

Disorders (DSM-IV) criteria for major depressive disorder. In the first study, patients received 100 mg

(n = 114), 200 mg (n = 116), or 400 mg (n = 113) of desvenlafaxine extended-release tablets once daily,

or placebo (n = 118). In a second study, patients received either 200 mg (n = 121) or 400 mg (n = 124)

of desvenlafaxine extended-release tablets once daily, or placebo (n = 124). In two additional studies,

patients received 50 mg (n = 150 and n = 164) or 100 mg (n = 147 and n = 158) of desvenlafaxine

extended-release tablets once daily, or placebo (n = 150 and n = 161).

Desvenlafaxine extended-release tablets showed superiority over placebo as measured by improvement

in the 17-item Hamilton Rating Scale for Depression (HAM-D ) total score in four studies and overall

improvement, as measured by the Clinical Global Impressions Scale - Improvement (CGI-I), in three of

the four studies. In studies directly comparing 50 mg per day and 100 mg per day there was no

suggestion of a greater effect with the higher dose and adverse reactions and discontinuations were

more frequent at higher doses [see Dosage and Administration (2.1)].

Table 9: Primary Efficacy (HAM-D ) Results for Short-term Studies

Desvenlafaxine Extended-Release

Tablets

Study

No.

Primary

Endpoint:

HAM-D

Placebo

50

mg/day

100

mg/day

200

mg/day

400

mg/day

Baseline

Score (SD )

23.1 (2.5)

23.2 (2.5) 22.9 (2.4) 23.0 (2.2)

Difference

from Placebo

(95% CI )

-2.9

(-5.1, -0.8)

-2.0

-3.1

(-5.2, -0.9)

Baseline

Score (SD )

25.3 (3.3)

24.8 (2.9) 25.2 (3.2)

Difference

from Placebo

(95% CI )

-3.3

(-5.3, -1.2)

-2.8

(-4.8, -0.7)

Baseline

Score (SD )

23.0 (2.6) 23.4 (2.6) 23.4 (2.6)

Difference

from Placebo

(95% CI )

-1.9

(-3.5, -0.3)

-1.5

Baseline

Score (SD )

24.3 (2.6) 24.3 (2.4) 24.4 (2.7)

17

17

Difference

from Placebo

(95% CI )

-2.5

(-4.1, -0.9)

-3.0

(-4.7, -1.4)

a Standard deviation;

b Adjusted p-value < 0.05;

c Difference between least squares means at final evaluation, calculated as

drug response minus placebo response; unadjusted 95% confidence intervals

Analyses of the relationships between treatment outcome and age and treatment outcome and gender did

not suggest any differential responsiveness on the basis of these patient characteristics. There was

insufficient information to determine the effect of race on outcome in these studies.

In a longer-term trial (Study 5), adult outpatients meeting DSM-IV criteria for major depressive

disorder, who responded to 8 weeks of open-label acute treatment with 50 mg per day desvenlafaxine

and subsequently remained stable for 12 weeks on desvenlafaxine, were assigned randomly in a double-

blind manner to remain on active treatment or switch to placebo for up to 26 weeks of observation for

relapse. Response during the open-label phase was defined as a HAM-D total score of ≤11 and CGI-I

≤2 at the day 56 evaluation; stability was defined as HAM-D total score of ≤11 and CGI-I ≤2 at week

20 and not having a HAM-D total score of ≥16 or a CGI-I score ≥4 at any office visit. Relapse during

the double-blind phase was defined as follows: (1) a HAM-D total score of ≥16 at any office visit, (2)

discontinuation for unsatisfactory efficacy response, (3) hospitalized for depression, (4) suicide

attempt, or (5) suicide. Patients receiving continued desvenlafaxine treatment experienced statistically

significantly longer time to relapse compared with placebo. At 26 weeks, the Kaplan-Meier estimated

proportion of relapse was 14% with desvenlafaxine treatment versus 30% with placebo.

Figure 4. Estimated Proportion of Relapses vs. Number of Days since Randomization (Study 5)

In another longer-term trial (Study 6), adult outpatients meeting DSM-IV criteria for major depressive

disorder and who responded to 12 weeks of acute treatment with desvenlafaxine were assigned

randomly to the same dose (200 or 400 mg per day) they had received during acute treatment or to

placebo for up to 26 weeks of observation for relapse. Response during the open-label phase was

defined as a HAM-D total score of ≤11 at the day 84 evaluation. Relapse during the double-blind

phase was defined as follows: (1) a HAM-D total score of >16 at any office visit, (2) a CGI-I score

of ≥6 (versus day 84) at any office visit, or (3) discontinuation from the trial due to unsatisfactory

response. Patients receiving continued desvenlafaxine treatment experienced statistically significantly

longer time to relapse over the subsequent 26 weeks compared with those receiving placebo. At 26

weeks, the Kaplan-Meier estimated proportion of relapse was 29% with desvenlafaxine treatment versus

49% with placebo.

Figure 5. Estimated Proportion of Relapses vs. Number of Days since Randomization (Study 6)

In a postmarketing study, the efficacy of desvenlafaxine extended-release tablets at a dose lower than 50

mg per day was evaluated in an 8-week, multicenter, randomized, double-blind, placebo-controlled,

fixed-dose study in adult outpatients with Major Depressive Disorder. The treatment arms were 25 mg

(n=232), 50 mg (n=236), and placebo (n=231). The 50 mg dose was superior to placebo, as measured by

the mean change from baseline on the HAMD-17. The 25 mg dose was not superior to placebo.

16 HOW SUPPLIED/STORAGE AND HANDLING

Product: 50090-4388

NDC: 50090-4388-0 30 TABLET, EXTENDED RELEASE in a BOTTLE

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Suicidal Thoughts and Behaviors

Advise patients and caregivers to look for the emergence of suicidality, especially early during

treatment and when the dose is adjusted up or down, and instruct them to report such symptoms to the

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

Concomitant Medication

Advise patients taking desvenlafaxine extended-release tablets not to use concomitantly other products

containing desvenlafaxine or venlafaxine. Healthcare professionals should instruct patients not to take

desvenlafaxine extended-release tablets with an MAOI or within 14 days of stopping an MAOI and to

allow 7 days after stopping desvenlafaxine extended-release tablets before starting an MAOI [see

Contraindications (4)].

Serotonin Syndrome

Caution patients about the risk of serotonin syndrome, particularly with the concomitant use of

desvenlafaxine extended-release tablets with other serotonergic agents (including triptans, tricyclic

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

supplements) [see Warnings and Precautions (5.2)].

Elevated Blood Pressure

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

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

Increased Risk of Bleeding

Inform patients about the concomitant use of desvenlafaxine extended-release tablets with NSAIDs,

aspirin, other antiplatelet drugs, warfarin, or other coagulants because the combined use of has been

associated with an increased risk of bleeding. Advise patients to inform their health care providers if

they are taking or planning to take any prescription or over-the-counter medications that increase the risk

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

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)].

Discontinuation

Advise patients not to abruptly stop taking desvenlafaxine extended-release tablets without talking first

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

stopping desvenlafaxine extended-release tablets, and a dose of 25 mg per day is available for

discontinuing therapy [see Warnings and Precautions (5.7) and Adverse Reactions (6.1)].

Switching Patients From Other Antidepressants to Desvenlafaxine Extended-Release Tablets

Discontinuation symptoms have been reported when switching patients from other antidepressants,

including venlafaxine, to desvenlafaxine extended-release tablets. Tapering of the initial antidepressant

may be necessary to minimize discontinuation symptoms.

Interference with Cognitive and Motor Performance

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

certain that desvenlafaxine extended-release tablets therapy does not adversely affect their ability to

engage in such activities.

Alcohol

Advise patients to avoid alcohol while taking desvenlafaxine extended-release tablets [see Drug

Interactions (7.3)].

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)].

Residual Inert Matrix Tablet

Patients receiving desvenlafaxine extended-release tablets may notice an inert matrix tablet 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 inert matrix tablet.

Manufactured by:

Actavis Laboratories FL, Inc.

Fort Lauderdale, FL 33314 USA

Distributed by:

Actavis Pharma, Inc.

Parsippany, NJ 07054 USA

Revised:2/2018

MEDICATION GUIDE

Desvenlafaxine (des-ven-la-fax-ine) Extended-Release Tablets

What is the most important information I should

know about desvenlafaxine extended-release

tablets ?

Desvenlafaxine extended-release tablets can cause

Desvenlafaxine extended-release tablets can cause

serious side effects, including:

Increased risk of suicidal thoughts or actions in

some children and young adults within the first

few months of treatment. Desvenlafaxine

extended-release tablets is not for use in

children.

Depression or other serious mental illnesses are the

most important causes of suicidal thoughts or

actions. How can I watch for and try to prevent

suicidal thoughts and actions?

Pay close attention to any changes, especially

sudden changes, in mood, behaviors, thoughts, or

feelings. This is very important when an

antidepressant medicine is started or when the dose

is changed.

Call the healthcare provider right away to report

new or sudden changes in mood, behavior, thoughts,

or feelings.

Keep all follow-up visits with the healthcare

provider as scheduled. Call the healthcare provider

between visits as needed, especially if you have

concerns about symptoms.

Call your healthcare provider right away if you have

any of the following symptoms, especially if they are

new, worse, or worry you:

thoughts about

suicide or dying

attempts to commit

suicide

new or worse

depression

new or worse

anxiety

feeling very

agitated or

restless

panic attacks

trouble sleeping (insomnia)

new or worse irritability

acting aggressive, being

angry, or violent

acting on dangerous impulses

an extreme increase in activity

and talking (mania)

other unusual changes in

behavior or mood

What are desvenlafaxine extended-release tablets?

Desvenlafaxine extended-release tablets are a

prescription medicine used to treat adults with a

certain type of depression called major depressive

disorder (MDD). Desvenlafaxine extended-release

tablets belong to a class of medicines known as

serotonin and norepinephrine reuptake inhibitors

(SNRIs).

Do not take desvenlafaxine extended-release tablets

if you:

are allergic to desvenlafaxine succinate, venlafaxine

hydrochloride, or any of the ingredients in

desvenlafaxine extended-release tablets. See the end

of this Medication Guide for a complete list of

ingredients in desvenlafaxine extended-release

tablets.

take a monoamine oxidase inhibitor (MAOI)

have stopped taking an MAOI in the last 14 days.

Ask your healthcare provider or pharmacist if you

are not sure if you take an MAOI.

are being treated with the antibiotic linezolid or the

intravenous methylene blue

Do not start taking an MAOI for at least 7 days after

you stop treatment with desvenlafaxine extended-

release tablets.

Before taking desvenlafaxine extended-release

tablets tell your healthcare provider about all your

medical conditions, including if you:

have high blood pressure

have heart problems

have cerebrovascular problems or had a stroke

have or had bleeding problems

have, or have a family history of, bipolar disorder,

mania or hypomania

have high cholesterol or high triglycerides

have or had depression, suicidal thoughts or

behavior

have kidney or liver problems

have or had seizures or convulsions

have low sodium levels in your blood

are pregnant or plan to become pregnant. Talk to

your healthcare provider about the risk to your

unborn baby if you take desvenlafaxine extended-

release tablets during pregnancy.

Tell your healthcare provider if you become

pregnant or think you are pregnant during treatment

with desvenlafaxine extended-release tablets.

are breastfeeding or plan to breastfeed.

Desvenlafaxine extended-release tablets can pass

into your breast milk. Talk to your healthcare

provider about the best way to feed your baby

during treatment with desvenlafaxine extended-

release tablets.

Tell your healthcare provider about all the

medicines you take, including prescription and over-

the-counter

medicines, vitamins, and herbal supplements.

Desvenlafaxine extended-release tablets and other

medicines may affect each other causing possible

serious side effects. Desvenlafaxine extended-

release tablets may affect the way other medicines

work and other medicines may affect the way

desvenlafaxine extended-release tablets work.

Especially tell your healthcare provider if you take:

·other MAOIs

medicines to treat migraine headaches known as

triptans

tricyclic antidepressants

fentanyl

lithium

tramadol

tryptophan

buspirone

amphetamines

St. John’s Wort

other medicines containing desvenlafaxine or

venlafaxine

medicines that can affect blood clotting such as

aspirin, nonsteroidal anti-inflammatory drugs

(NSAIDs), warfarin

medicines used to treat mood, anxiety, psychotic, or

thought disorders, including selective serotonin

reuptake inhibitors (SSRIs) and serotonin

norepinephrine reuptake inhibitors (SNRIs)

Ask your healthcare provider if you are not sure if you

are taking any of these medicines. Your healthcare

provider can tell you if it is safe to take desvenlafaxine

extended-release tablets with your other medicines.

Do not start or stop any other medicines during

treatment with desvenlafaxine extended-release tablets

without talking to your healthcare provider first.

Stopping desvenlafaxine extended-release tablets

suddenly may cause you to have serious side effects.

See, “What are the possible side effects of

desvenlafaxine extended-release tablets?”

Know the medicines you take. Keep a list of them to

show to your healthcare providers when you get a new

medicine.

How should I take desvenlafaxine extended-release

tablets ?

Take desvenlafaxine extended-release tablets

exactly as your healthcare provider tells you to.

Take desvenlafaxine extended-release tablets 1 time

a day at about the same time each day.

Desvenlafaxine extended-release tablets may be

taken either with or without food.

Swallow desvenlafaxine extended-release tablets

whole, with fluid. Do not divide, crush, chew, or

dissolve desvenlafaxine extended-release tablets.

When you take desvenlafaxine extended-release

tablets, you may see something in your stool that

looks like a tablet. This is the empty shell from the

tablet after the medicine has been absorbed by your

body.

If over-exposure occurs, call your Poison Control

Center at 1-800-222-1222 or go to the nearest

hospital emergency room right away.

What should I avoid while taking desvenlafaxine

extended-release tablets?

Do not drive a car or operate heavy machinery until

you know how desvenlafaxine extended-release

tablets affects you.

You should not drink alcohol while taking

desvenlafaxine extended-release tablets.

What are the possible side effects of desvenlafaxine

extended-release tablets?

Desvenlafaxine extended-release tablets can cause

serious side effects, including:

See, What is the most important information I

should know about desvenlafaxine extended-

release tablets?”

Serotonin syndrome. A potentially life-threatening

problem called serotonin syndrome can happen when

you take desvenlafaxine extended-release tablets with

certain other medicines. See, “Who should not take

desvenlafaxine extended-release tablets?” Call your

healthcare provider or go to the nearest hospital

emergency room right away if you have any of the

following signs and symptoms of serotonin syndrome:

agitation

confusion

fast heart beat

dizziness

flushing

tremors, stiff

muscles, or

muscle twitching

seizures

seeing or hearing things that

are not real (hallucinations)

coma

changes in blood pressure

sweating

high body temperature

(hyperthermia)

loss of coordination

nausea, vomiting, diarrhea

New or worsened high blood pressure

(hypertension). Your healthcare provider should

check your blood pressure before and during

treatment with desvenlafaxine extended-release

tablets. If you have high blood pressure, it should

be controlled before you start treatment with

desvenlafaxine extended-release tablets.

Increased chance of bleeding or bruising. Taking

desvenlafaxine extended-release tablets with

aspirin, NSAIDs, or blood thinners may add to this

risk. Tell your healthcare provider right away about

any unusual bleeding or bruising.

Eye problems (angle closure glaucoma). Many

antidepressant medicines, including desvenlafaxine

extended-release tablets, may cause a certain type of

eye problem called angle-closure glaucoma. Call

your healthcare provider if you have changes in

your vision or eye pain.

Discontinuation syndrome. Suddenly stopping

desvenlafaxine extended-release tablets when you

take higher doses may cause you to have serious

side effects. Your healthcare provider may want to

decrease your dose slowly. Symptoms may include:

dizziness

irritability

agitation

anxiety

sweating

seizures

ringing in

your ears

(tinnitus)

nausea

problems

sleeping

tiredness

confusion

electric

shock

sensation

(paresthesia)

headache

diarrhea

abnormal dreams

changes in your mood

hypomania

Seizures (convulsions).

Low sodium levels in your blood (hyponatremia).

Low sodium levels can happen during treatment with

desvenlafaxine extended-release tablets. Low

sodium levels in your blood may be serious and may

cause death. Signs and Symptoms of low sodium

levels in your blood may include:

headache

difficulty concentrating

memory changes

confusion

weakness and unsteadiness on your feet which can

lead to falls

In severe or more sudden cases, signs and

symptoms include:

hallucinations (seeing or hearing things that are not

real)

fainting

seizures

coma

Lung problems. Some people who have taken the

medicine venlafaxine which is the same kind of

medicine as the medicine in desvenlafaxine

extended-release tablets have had lung problems.

Symptoms of lung problems include difficulty

breathing, cough, or chest discomfort. Tell your

healthcare provider right away if you have any of

these symptoms.

The most common side effects of desvenlafaxine

extended-release tablets include:

nausea

problems sleeping

constipation

decreased

appetite

sexual function

problems

dizziness

sweating

feeling sleepy

anxiety

These are not all the possible side effects of

desvenlafaxine extended-release tablets.

Call your doctor for medical advice about side effects.

You may report side effects to FDA at 1-800-FDA-

1088.

How should I store desvenlafaxine extended-release

tablets ?

Store desvenlafaxine extended-release tablets at

room temperature between 68° to 77°F (20° to

25°C).

Keep desvenlafaxine extended-release tablets

and all medicines out of the reach of children.

General Information about the safe and effective use

of desvenlafaxine extended-release tablets

Medicines are sometimes prescribed for purposes

other than those listed in a Medication Guide. Do not

take desvenlafaxine extended-release tablets for a

condition for which they were not prescribed. Do not

give desvenlafaxine extended-release tablets to other

people, even if they have the same symptoms that you

have. They may harm them. You can ask your pharmacist

or healthcare provider for information about

desvenlafaxine extended-release tablets that is written

for healthcare professionals.

What are the ingredients in desvenlafaxine

extended-release tablets?

Active ingredient: desvenlafaxine

Inactive ingredients: Inactive ingredients for the 25

mg, 50 mg and 100 mg tablet consist of hypromellose,

microcrystalline cellulose, talc, magnesium stearate,

polyethylene oxide and colloidal silicon dioxide and

film coating, which consists of polyvinyl alcohol,

polyethylene glycol, talc, titanium dioxide, and iron

oxide yellow and iron oxide red. The imprinting ink

contains hypromellose, propylene glycol and iron oxide

black.

Manufactured by:

Actavis Laboratories FL, Inc.

Fort Lauderdale, FL 33314 USA

Distributed by:

Actavis Pharma, Inc.

Parsippany, NJ 07054 USA

For more information, go to www.actavis.com or call 1-

800-272-5525.

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

Revised: 2/ 2018

Des venlafaxine

DESVENLAFAXINE

desvenlafaxine tablet, extended release

Product Information

Product T ype

HUMAN PRESCRIPTION

DRUG

Ite m Code

(S ource )

NDC:50 0 9 0 -438 8 (NDC:0 59 1-40 6 0 )

Route of Administration

ORAL

A-S Medication Solutions

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength Strength

DESVENLAFAXINE SUCCINATE (UNII: ZB22ENF0 XR) (DESVENLAFAXINE - UNII:NG9 9 554ANW)

DESVENLAFAXINE

25 mg

Inactive Ingredients

Ingredient Name

Stre ng th

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

MICRO CRYSTALLINE CELLULO SE (UNII: OP1R32D6 1U)

TALC (UNII: 7SEV7J4R1U)

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

PO LYETHYLENE O XIDE 9 0 0 0 0 0 (UNII: 16 P9 29 5IIL)

SILICO N DIO XIDE (UNII: ETJ7Z6 XBU4)

PO LYVINYL ALCO HO L, UNSPECIFIED (UNII: 532B59 J9 9 0 )

PO LYETHYLENE GLYCO L, UNSPECIFIED (UNII: 3WJQ0 SDW1A)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

FERRIC O XIDE YELLO W (UNII: EX438 O2MRT)

FERRIC O XIDE RED (UNII: 1K0 9 F3G6 75)

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

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

Product Characteristics

Color

PINK (light pink)

S core

no sco re

S hap e

SQUARE (square pyramid)

S iz e

9 mm

Flavor

Imprint Code

A112

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:50 0 9 0 -438 8 -0

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

0 6 /25/20 19

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA20 40 6 5

0 3/0 1/20 17

Labeler -

A-S Medication Solutions (830016429)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

A-S Medicatio n So lutio ns

8 30 0 16 429

RELABEL(50 0 9 0 -438 8 )

Revised: 7/2019

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