DULOXETINE capsule, delayed release

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

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Active ingredient:
DULOXETINE HYDROCHLORIDE (UNII: 9044SC542W) (DULOXETINE - UNII:O5TNM5N07U)
Available from:
St. Mary's Medical Park Pharmacy
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Duloxetine delayed-release capsules are indicated for the treatment of: - Major Depressive Disorder [see Clinical Studies ( 14.1 )] . - Generalized Anxiety Disorder [see Clinical Studies ( 14.2 )] . - Diabetic Peripheral Neuropathy [see Clinical Studies ( 14.3 )] . - Chronic Musculoskeletal Pain [see Clinical Studies ( 14.5 )] .          Monoamine Oxidase Inhibitors (MAOIs)   - The use of MAOIs intended to treat psychiatric disorders with duloxetine or within 5 days of stopping treatment with duloxetine is contraindicated because of an increased risk of serotonin syndrome. The use of duloxetine within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated [see Dosage and Administration ( 2.8) and Warnings and Precautions ( 5.4)].          Starting duloxetine in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is al
Product summary:
Duloxetine delayed-release capsules are available in the following strengths, colors, imprints, and presentations: 60MG Capsule- White/Blue Imprint- ap;LX60 NDC 60760-462-30 BOTTLES OF 30          Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [ see USP Controlled Room Temperature].
Authorization status:
Abbreviated New Drug Application
Authorization number:
60760-462-30

DULOXETINE- duloxetine capsule, delayed release

St. Mary's Medical Park Pharmacy

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Medication Guide

Duloxetine Delayed-Release Capsules

(doo lox’ e teen)

Read this Medication Guide before you start taking duloxetine delayed-release capsules and each time you

get a refill. There may be new information. This information does not take the place of talking to your

healthcare provider about your medical condition or treatment.

Talk to your healthcare provider about:

all risks and benefits of treatment with antidepressant medicines

all treatment choices for depression or other serious mental illness

What is the most important information I should know about antidepressant medicines, depression, other

serious mental illnesses, and suicidal thoughts or actions?

Duloxetine delayed-release capsules and other antidepressant medicines may increase suicidal

thoughts or actions in some children, teenagers, or young adults within the first few months of

treatment or when the dose is changed.

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

actions. Some people may have a particularly high risk of having suicidal thoughts or actions. These

include people who have (or have a family history of) bipolar illness (also called manic-depressive

illness).

How can I watch for and try to prevent suicidal thoughts and actions?

Pay close attention to any changes in mood, behavior, actions, thoughts, or feelings, especially

sudden changes. This is very important when an antidepressant medicine is started or when the

dose is changed.

Call your healthcare provider right away to report new or sudden changes in mood, behavior,

thoughts, or feelings.

Keep all follow-up visits with your healthcare provider as scheduled. Call your

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 or feelings, especially if

they are new, worse, or worry you. In an emergency, call 911.

attempts to commit suicide

acting on dangerous impulses

acting aggressive, being angry, or violent

thoughts about suicide or dying

new or worse depression

new or worse anxiety

panic attacks

feeling very agitated or restless

new or worse irritability

trouble sleeping

an extreme increase in activity or talking (mania)

other unusual changes in behavior or mood

What else do I need to know about antidepressant medicines?

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

antidepressant medicine suddenly can cause other symptoms.

Antidepressants are medicines used to treat depression and other illnesses. It is important to discuss

all the risks of treating depression and also the risks of not treating it. Patients should discuss all

treatment choices with your healthcare provider, not just the use of antidepressants.

Antidepressant medicines have other side effects. Talk to your healthcare provider about the side

effects of the medicine prescribed for you or your family member.

Antidepressant medicines can interact with other medicines. Know all of the medicines that you or

your family member takes. Keep a list of all medicines to show your healthcare provider. Do not start

new medicines without first checking with your healthcare provider.

What are duloxetine delayed-release capsules?

Duloxetine delayed-release capsules are a prescription medicine used to treat a certain type of depression

called Major Depressive Disorder (MDD). Duloxetine delayed-release capsules belongs to a class of

medicines known as SNRIs (or serotonin-norepinephrine reuptake inhibitors).

Duloxetine delayed-release capsules are also used to treat or manage:

Generalized Anxiety Disorder (GAD)

Diabetic Peripheral Neuropathic Pain (DPNP)

Chronic Musculoskeletal Pain

Who should not take duloxetine delayed-release capsules?

Do Not take duloxetine delayed-release capsules if you:

take a Monoamine Oxidase Inhibitor (MAOI). Ask your healthcare provider or pharmacist if

you are not sure if you take an MAOI, including the antibiotic linezolid or intravenous

methylene blue.

Do not take an MAOI within 5 days of stopping duloxetine delayed-release capsules

unless directed to do so by your healthcare provider.

Do not start duloxetine delayed-release capsules if you stopped taking an MAOI in the

last 14 days unless directed to do so by your healthcare provider.

People who take duloxetine delayed-release capsules close in time to an MAOI may have a serious problem

called Serotonin Syndrome (see “What are the possible side effects of duloxetine delayed-release

capsules?”).

What should I tell my healthcare provider before taking duloxetine delayed-release capsules?

Before starting duloxetine delayed-release capsules, tell your healthcare provider if you:

have heart problems or high blood pressure

have diabetes (duloxetine delayed-release capsules treatment makes it harder for some people

with diabetes to control their blood sugar)

have liver problems

have kidney problems

have glaucoma

have or had seizures or convulsions

have bipolar disorder or mania

have low sodium levels in your blood

have delayed stomach emptying

have or had bleeding problems

are pregnant or plan to become pregnant. It is not known if duloxetine delayed-release

capsules will harm your unborn baby. Talk to your healthcare provider about the benefits and

risks of treating depression or other conditions with duloxetine delayed-release capsules

during pregnancy.

are breastfeeding or plan to breastfeed. Duloxetine can pass into your breast milk. Talk to your

healthcare provider about the best way to feed your baby while taking duloxetine delayed-

release capsules.

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

counter medicines, vitamins, and herbal supplements. Duloxetine delayed-release capsules and some

medicines may interact with each other, may not work as well, or may cause serious side effects.

Especially tell your healthcare provider if you take:

triptans used to treat migraine headache

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

tricyclics, lithium, buspirone, SSRIs, SNRIs or MAOIs

tramadol and fentanyl

amphetamines

cimetidine

the antibiotics ciprofloxacin, enoxacin

medicine to treat irregular heart rate (like propafenone, flecainide, quinidine)

theophylline

the blood thinner warfarin (Coumadin, Jantoven)

non-steroidal anti-inflammatory drug (NSAID) (like ibuprofen, naproxen or aspirin).

over-the-counter supplements such as tryptophan or St. John's Wort

thioridazine (Mellaril). Mellaril together with duloxetine delayed-release capsules can

cause serious heart rhythm problems or sudden death.

Ask your healthcare provider for a list of these medicines if you are not sure.

Do not take duloxetine delayed-release capsules with any other medicine that contain duloxetine.

How should I take duloxetine delayed-release capsules?

Take duloxetine delayed-release capsules exactly as your healthcare provider tells you to take it. Your

healthcare provider may need to change the dose of duloxetine delayed-release capsules until it is the

right dose for you.

Swallow duloxetine delayed-release capsules whole. Do not chew or crush duloxetine delayed-release

capsules.

Do not open the capsule and sprinkle on food or mix with liquids. Opening the capsule may affect

how well duloxetine delayed-release capsules works.

Duloxetine delayed-release capsules may be taken with or without food.

If you miss a dose of duloxetine delayed-release capsules, take the missed dose as soon as you

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

regular time. Do not take two doses of duloxetine delayed-release capsules at the same time.

If you take too much duloxetine delayed-release capsules, call your healthcare provider or poison

control center at 1800-222-1222 right away, or get emergency treatment.

When switching from another antidepressant to duloxetine delayed-release capsules your healthcare

provider may want to lower the dose of the initial antidepressant first to potentially avoid side effects.

What should I avoid while taking duloxetine delayed-release capsules?

Duloxetine delayed-release capsules can cause sleepiness or may affect your ability to make

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

dangerous activities until you know how duloxetine delayed-release capsules affects you.

Use of duloxetine delayed-release capsules concomitantly with heavy alcohol intake may be

associated with severe liver injury. Avoid heavy alcohol use while taking duloxetine delayed-release

capsules.

What are the possible side effects of duloxetine delayed-release capsules?

Duloxetine delayed-release capsules may cause serious side effects, including: See “What is the most

important information I should know about duloxetine delayed-release capsules?”

Common possible side effects in people who take duloxetine delayed-release capsules include:

1. liver damage. Symptoms may include:

itching

right upper abdominal pain

dark urine

yellow skin or eyes

enlarged liver

increased liver enzymes

2. changes in blood pressure and falls. Monitor your blood pressure before starting and throughout

treatment. Duloxetine delayed-release capsules may:

increase your blood pressure.

decrease your blood pressure when standing and cause dizziness or fainting, mostly when first

starting duloxetine delayed-release capsules or when increasing the dose.

increase risk of falls, especially in elderly.

3. Serotonin Syndrome: This condition can be life-threatening and symptoms may include:

agitation, hallucinations, coma or other changes in mental status

coordination problems or muscle twitching (overactive reflexes)

racing heartbeat, high or low blood pressure

sweating or fever

nausea, vomiting, or diarrhea

muscle rigidity

dizziness

flushing

tremor

seizures

4. abnormal bleeding: Duloxetine delayed-release capsules and other antidepressant medicines may increase

your risk of bleeding or bruising, especially if you take the blood thinner warfarin (Coumadin, Jantoven), a

non-steroidal anti-inflammatory drug (NSAIDs, like ibuprofen or naproxen), or aspirin.

5. severe skin reactions: Duloxetine delayed-release capsules may cause serious skin reactions that may

require stopping its use. This may need to be treated in a hospital and may be life-threatening. Call your

healthcare provider right away or get emergency help if you have skin blisters, peeling rash, sores in the

mouth, hives or any other allergic reactions.

6. discontinuation symptoms: Do not stop duloxetine delayed-release capsules without first talking to your

healthcare provider. Stopping duloxetine delayed-release capsule stoo quickly or changing from another

antidepressant too quickly may result in serious symptoms including:

anxiety

irritability

feeling tired or problems sleeping

headache

sweating

dizziness

electric shock-like sensations

vomiting or nausea

diarrhea

7. manic episodes:

greatly increased energy

severe trouble sleeping

racing thoughts

reckless behavior

unusually grand ideas

excessive happiness or irritability

talking more or faster than usual

8. v isual problems:

eye pain

changes in vision

swelling or redness in or around the eye

Only some people are at risk for these problems. You may want to undergo an eye examination to see if you

are at risk and receive preventative treatment if you are.

9. seizures or convulsions

10. low salt (sodium) levels in the blood. Elderly people may be at greater risk for this.

Symptoms may include:

headache

weakness or feeling unsteady

confusion, problems concentrating or thinking or memory problems

11. problems with urination. Symptoms may include:

decreased urine flow

unable to pass any urine

The most common side effects of duloxetine delayed-release capsules include:

nausea

dry mouth

sleepiness

fatigue

constipation

loss of appetite

increased sweating

dizziness

Common possible side effects in children and adolescents who take duloxetine delayed-release

capsules include:

nausea

decreased weight

dizziness

Side effects in adults may also occur in children and adolescents who take duloxetine delayed-release

capsules. Children and adolescents should have height and weight monitored during treatment.

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

These are not all the possible side effects of duloxetine delayed-release capsules. For more information, ask

your healthcare provider or pharmacist.

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

How should I store duloxetine delayed-release capsules?

Store duloxetine delayed-release capsules at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [

see USP Controlled Room Temperature].

Keep duloxetine delayed-release capsules and all medicines out of the reach of children.

General information about the safe and effective use of duloxetine delayed-release capsules

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

duloxetine delayed-release capsules for a condition for which it was not prescribed. Do not give duloxetine

delayed-release capsules to other people, even if they have the same symptoms that you have. It may harm

them.

This Medication Guide summarizes the most important information about duloxetine delayed-release

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

healthcare provider or pharmacist for information about duloxetine delayed-release capsules that is written

for healthcare professionals.

For more information, call 1-855-664-7744.

What are the ingredients in duloxetine delayed-release capsules?

Active ingredient: duloxetine hydrochloride, USP

Inactive ingredients:

sugar spheres, hypromellose, sucrose, talc, methacrylic acid copolymer dispersion, and triethyl citrate.

The capsule shell contains gelatin, FD&C Red No. 3 (40 mg), FD&C Blue No. 1 (40 mg), FD&C Blue No. 2

(20 mg, 30 mg, 60 mg), titanium dioxide, and sodium lauryl sulfate.

For 20 mg, 30 mg, 40 mg (body & cap) and 60 mg (body only) strengths, imprinting black ink contains

shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, strong ammonia solution,

black iron oxide, potassium hydroxide, and purified water.

For 60 mg (cap only) strength, imprinting white ink contains shellac, dehydrated alcohol, isopropyl alcohol,

butyl alcohol, propylene glycol, strong ammonia solution, purified water, potassium hydroxide, and titanium

dioxide.

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

All trademarks are the properties of their respective owners.

Medication Guide revised: 03/2019

Marketed by:

Ajanta Pharma USA Inc.

Bridgewater, NJ 08807.

Made un INDIA.

Revised: 9/2019

Document Id: 92218bcb-021b-eaff-e053-2995a90ae620

34391-3

Set id: 9221f3e5-17b8-ea74-e053-2a95a90ad1a8

Version: 1

Effective Time: 20190905

St. Mary's Medical Park Pharmacy

DULOXETINE- duloxetine capsule, delayed release

St. Mary's Medical Park Pharmacy

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use DULOXETINE DELAYED-RELEASE

CAPSULES safely and effectively. See full prescribing information for DULOXETINE DELAYED-RELEASE

CAPSULES.

DULOXETINE delayed-release capsules, for oral use.

Initial U.S. Approval: 2004

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS

See full prescribing information for complete boxed warning.

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

5.1)

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

RECENT MAJOR CHANGES

None .

INDICATIONS AND USAGE

Duloxetine delayed-release capsules are a serotonin and norepinephrine reuptake inhibitor (SNRI) indicated for:

Major Depressive Disorder (MDD) ( 1)

Generalized Anxiety Disorder (GAD) ( 1)

Diabetic Peripheral Neuropathic Pain (DPNP) ( 1)

Chronic Musculoskeletal Pain ( 1)

DOSAGE AND ADMINISTRATION

Take duloxetine delayed-release capsules once daily, with or without food. Swallow duloxetine delayed-release

capsules whole; do not crush or chew, do not open capsule. Take a missed dose as soon as it is remembered. Do not

take two doses of duloxetine delayed-release capsules at the same time. ( 2)

Indication

Starting

Dose

Target Dose

Maximum

Dose

MDD ( 2.1)

40 mg/day

to 60 mg/day

Acute Treatment: 40 mg/day (20 mg twice daily) to

60 mg/day (once daily or as 30 mg twice daily);

Maintenance Treatment: 60 mg/day

120 mg/day

GAD ( 2.2)

Adults

60 mg/day

60 mg/day (once daily)

120 mg/day

Elderly

30 mg/day

60 mg/day (once daily)

120 mg/day

Children and Adolescents (7

to 17 years of age)

30 mg/day

30 to 60 mg/day (once daily)

120 mg/day

DPNP ( 2.3)

60 mg/day

60 mg/day (once daily)

60 mg/day

Chronic

Musculoskeletal

Pain ( 2.5)

30 mg/day

60 mg/day (once daily)

60 mg/day

Some patients may benefit from starting at 30 mg once daily ( 2)

There is no evidence that doses greater than 60 mg/day confers additional benefit, while some adverse reactions were

observed to be dose-dependent ( 2)

Discontinuing duloxetine delayed-release capsules: Gradually reduce dosage to avoid discontinuation symptoms ( 2.7,

5.7)

Hepatic Impairment: Avoid use in patients with chronic liver disease or cirrhosis ( 5.14)

Renal Impairment: Avoid use in patients with severe renal impairment, GFR <30 mL/min ( 5.14)

DOSAGE FORMS AND STRENGTHS

20 mg, 30 mg, 40 mg and 60 mg delayed-release capsules ( 3)

CONTRAINDICATIONS

Serotonin Syndrome and MAOIs: Do not use MAOIs intended to treat psychiatric disorders with duloxetine or within 5

days of stopping treatment with duloxetine. Do not use duloxetine within 14 days of stopping an MAOI intended to treat

psychiatric disorders. In addition, do not start duloxetine in a patient who is being treated with linezolid or intravenous

methylene blue ( 4)

WARNINGS AND PRECAUTIONS

Hepatotoxicity: Hepatic failure, sometimes fatal, has been reported in patients treated with duloxetine. Duloxetine

should be discontinued in patients who develop jaundice or other evidence of clinically significant liver dysfunction and

should not be resumed unless another cause can be established. Duloxetine should not be prescribed to patients with

substantial alcohol use or evidence of chronic liver disease ( 5.2)

Orthostatic Hypotension, Falls and Syncope: Cases have been reported with duloxetine therapy ( 5.3)

Serotonin Syndrome: Serotonin syndrome has been reported with SSRIs and SNRIs, including with duloxetine, both

when taken alone, but especially when co-administered with other serotonergic agents (including triptans, tricyclic

antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. John’s Wort). If such

symptoms occur, discontinue duloxetine and initiate supportive treatment. If concomitant use of duloxetine with other

serotonergic drugs is clinically warranted, patients should be made aware of a potential increased risk for serotonin

syndrome, particularly during treatment initiation and dose increases ( 5.4)

Abnormal Bleeding: Duloxetine may increase the risk of bleeding events. Patients should be cautioned about the risk of

bleeding associated with the concomitant use of duloxetine and NSAIDs, aspirin, or other drugs that affect coagulation (

5.5, 7.4)

Severe Skin Reactions: Severe skin reactions, including erythema multiforme and Stevens-Johnson Syndrome (SJS),

can occur with duloxetine. Duloxetine should be discontinued at the first appearance of blisters, peeling rash, mucosal

erosions, or any other sign of hypersensitivity if no other etiology can be identified. ( 5.6)

Discontinuation: May result in symptoms, including dizziness, headache, nausea, diarrhea, paresthesia, irritability,

vomiting, insomnia, anxiety, hyperhidrosis, and fatigue ( 5.7)

Activation of mania or hypomania has occurred ( 5.8)

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

treated with antidepressants. ( 5.9)

Seizures: Prescribe with care in patients with a history of seizure disorder ( 5.10)

Blood Pressure: Monitor blood pressure prior to initiating treatment and periodically throughout treatment ( 5.11)

Inhibitors of CYP1A2 or Thioridazine: Should not administer with duloxetine ( 5.12)

Hyponatremia: Cases of hyponatremia have been reported ( 5.13)

Glucose Control in Diabetes: In diabetic peripheral neuropathic pain patients, small increases in fasting blood glucose,

and HbA

have been observed ( 5.14)

Conditions that Slow Gastric Emptying: Use cautiously in these patients ( 5.14)

Urinary Hesitation and Retention ( 5.15)

ADVERSE REACTIONS

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

somnolence, constipation, decreased appetite, and hyperhidrosis ( 6.3).

To report SUSPECTED ADVERSE REACTIONS, contact Ajanta Pharma USA Inc. at 1-855-664-7744 or FDA at

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

DRUG INTERACTIONS

Potent inhibitors of CYP1A2 should be avoided ( 7.1).

Potent inhibitors of CYP2D6 may increase duloxetine concentrations ( 7.2).

Duloxetine is a moderate inhibitor of CYP2D6 ( 7.9).

USE IN SPECIFIC POPULATIONS

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

Nursing Mothers: Exercise caution when administered to a nursing woman ( 8.3)

See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

Revised: 5/2019

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Dosage for Treatment of Major Depressive Disorder

2.2 Dosage for Treatment of Generalized Anxiety Disorder

2.3 Dosage for Treatment of Diabetic Peripheral Neuropathic pain

2.5 Dosage for Treatment of Chronic Musculoskeletal Pain

2.6 Dosing in Special Populations

2.7 Discontinuing Duloxetine Delayed-Release Capsules

2.8 Switching a Patient to or from a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat

Psychiatric Disorders

2.9 Use of Duloxetine Delayed-Release Capsules 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 Children, Adolescents and Young Adults

5.2 Hepatotoxicity

5.3 Orthostatic Hypotension, Falls and Syncope

5.4 Serotonin Syndrome

5.5 Abnormal Bleeding

5.6 Severe Skin Reactions

5.7 Discontinuation of Treatment with Duloxetine Delayed-Release Capsules

5.8 Activation of Mania/Hypomania

5.9 Angle-Closure Glaucoma

5.10 Seizures

5.11 Effect on Blood Pressure

5.12 Clinically Important Drug Interactions

5.13 Hyponatremia

5.14 Use in Patients with Concomitant Illness

5.15 Urinary Hesitation and Retention

5.16 Laboratory Tests

6 ADVERSE REACTIONS

6.1 Clinical Trial Data Sources

6.2 Adverse Reactions Reported as Reasons for Discontinuation of Treatment in Adult Placebo-

Controlled Trials

6.3 Most Common Adult Adverse Reactions

6.4 Adverse Reactions Occurring at an Incidence of 5% or More Among Duloxetine-Treated

Patients in Adult Placebo-Controlled Trials

6.5 Adverse Reactions Occurring at an Incidence of 2% or More Among Duloxetine-Treated

Patients in Adult Placebo-Controlled Trials

6.6 Effects on Male and Female Sexual Function in Adults

6.7 Vital Sign Changes in Adults

6.8 Laboratory Changes in Adults

6.9 Electrocardiogram Changes in Adults

6.10 Other Adverse Reactions Observed During the Premarketing and Postmarketing Clinical Trial

Evaluation of Duloxetine in Adults

6.11 Adverse Reactions Observed in Children and Adolescent Placebo-Controlled Clinical Trials

6.12 Postmarketing Spontaneous Reports

7 DRUG INTERACTIONS

7.1 Inhibitors of CYP1A2

7.2 Inhibitors of CYP2D6

7.3 Dual Inhibition of CYP1A2 and CYP2D6

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

7.5 Lorazepam

7.6 Temazepam

7.7 Drugs that Affect Gastric Acidity

7.8 Drugs Metabolized by CYP1A2

7.9 Drugs Metabolized by CYP2D6

7.10 Drugs Metabolized by CYP2C9

7.11 Drugs Metabolized by CYP3A

7.12 Drugs Metabolized by CYP2C19

7.13 Monoamine Oxidase Inhibitors (MAOIs )

7.14 Serotonergic Drugs

7.15 Alcohol

7.16 CNS Drugs

7.17 Drugs Highly Bound to Plasma Protein

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Gender

8.7 Smoking Status

8.8 Race

8.9 Hepatic Impairment

8.10 Severe Renal Impairment

9 DRUG ABUSE AND DEPENDENCE

9.2 Abuse

9.3 Dependence

10 OVERDOSAGE

10.1 Signs and Symptoms

10.2 Management of Overdose

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

14.1 Major Depressive Disorder

14.2 Generalized Anxiety Disorder

14.3 Diabetic Peripheral Neuropathic Pain

14.5 Chronic Musculoskeletal Pain

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

16.2 Storage and Handling

17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

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

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)].

1 INDICATIONS AND USAGE

Duloxetine delayed-release capsules are indicated for the treatment of:

Major Depressive Disorder [see Clinical Studies (14.1)].

Generalized Anxiety Disorder [see Clinical Studies (14.2)].

Diabetic Peripheral Neuropathy [see Clinical Studies (14.3)].

Chronic Musculoskeletal Pain [see Clinical Studies (14.5)].

2 DOSAGE AND ADMINISTRATION

Swallow duloxetine delayed-release capsules whole. Do not chew or crush. Do not open the

capsule and sprinkle its contents on food or mix with liquids. All of these might affect the enteric

coating. Duloxetine delayed-release capsules can be given without regard to meals. If a dose of

duloxetine delayed-release capsules is missed, take the missed dose as soon as it is remembered. If it is

almost time for the next dose, skip the missed dose and take the next dose at the regular time. Do not take

two doses of duloxetine delayed-release capsules at the same time.

2.1 Dosage for Treatment of Major Depressive Disorder

Administer duloxetine delayed-release capsules at a total dose of 40 mg/day (given as 20 mg

twice daily) to 60 mg/day (given either once daily or as 30 mg twice daily). For some patients, it may be

desirable to start at 30 mg once daily for 1 week, to allow patients to adjust to the medication before

increasing to 60 mg once daily. While a 120 mg/day dose was shown to be effective, there is no

evidence that doses greater than 60 mg/day confer any additional benefits. The safety of doses above

120 mg/day has not been adequately evaluated. Periodically reassess to determine the need for

maintenance treatment and the appropriate dose for such treatment [see Clinical Studies ( 14.1)] .

2.2 Dosage for Treatment of Generalized Anxiety Disorder

Adults - For most patients, initiate duloxetine delayed-release capsules 60 mg once daily. For some

patients, it may be desirable to start at 30 mg once daily for 1 week, to allow patients to adjust to the

medication before increasing to 60 mg once daily. While a 120 mg once daily dose was shown to be

effective, there is no evidence that doses greater than 60 mg/day confer additional benefit.

Nevertheless, if a decision is made to increase the dose beyond 60 mg once daily, increase dose in

increments of 30 mg once daily. The safety of doses above 120 mg once daily has not been adequately

evaluated. Periodically reassess to determine the continued need for maintenance treatment and the

appropriate dose for such treatment [see Clinical Studies ( 14.2)].

Elderly - Initiate duloxetine delayed-release capsules at a dose of 30 mg once daily for 2 weeks before

considering an increase to the target dose of 60 mg. Thereafter, patients may benefit from doses above

60 mg once daily. If a decision is made to increase the dose beyond 60 mg once daily, increase dose in

increments of 30 mg once daily. The maximum dose studied was 120 mg per day. Safety of doses above

120 mg once daily has not been adequately evaluated [see Clinical Studies ( 14.2)].

Children and Adolescents (7 to 17 years of age) - Initiate duloxetine delayed-release capsules at a dose

of 30 mg once daily for 2 weeks before considering an increase to 60 mg. The recommended dose

range is 30 to 60 mg once daily. Some patients may benefit from doses above 60 mg once daily. If a

decision is made to increase the dose beyond 60 mg once daily, increase dose in increments of 30 mg

once daily. The maximum dose studied was 120 mg per day. The safety of doses above 120 mg once

daily has not been evaluated [see Clinical Studies ( 14.2)].

2.3 Dosage for Treatment of Diabetic Peripheral Neuropathic pain

Administer duloxetine delayed-release capsules 60 mg once daily. There is no evidence that

doses higher than 60 mg confer additional significant benefit and the higher dose is clearly less well

tolerated [see Clinical Studies ( 14.3)] . For patients for whom tolerability is a concern, a lower starting

dose may be considered.

Since diabetes is frequently complicated by renal disease, consider a lower starting dose and

gradual increase in dose for patients with renal impairment [see Dosage and Administration ( 2.6), Use in

Specific Populations ( 8.10), and Clinical Pharmacology ( 12.3)] .

2.5 Dosage for Treatment of Chronic Musculoskeletal Pain

Administer duloxetine delayed-release capsules 60 mg once daily. Begin treatment at 30 mg for

one week, to allow patients to adjust to the medication before increasing to 60 mg once daily. There is

no evidence that higher doses confer additional benefit, even in patients who do not respond to a 60 mg

dose, and higher doses are associated with a higher rate of adverse reactions [see Clinical Studies (

14.5)] .

2.6 Dosing in Special Populations

Hepatic Impairment - Avoid use in patients with chronic liver disease or cirrhosis [see Warnings

and Precautions ( 5.14) and Use in Specific Populations ( 8.9)] .

Severe Renal Impairment - Avoid use in patients with severe renal impairment, GFR <30 mL/min

[see Warnings and Precautions ( 5.14) and Use in Specific Populations ( 8.10)] .

2.7 Discontinuing Duloxetine Delayed-Release Capsules

Adverse reactions after discontinuation of duloxetine delayed-release capsules, after abrupt or

tapered discontinuation, include: dizziness, headache, nausea, diarrhea, paresthesia, irritability,

vomiting, insomnia, anxiety, hyperhidrosis, and fatigue. A gradual reduction in dosage rather than abrupt

cessation is recommended whenever possible [see Warnings and Precautions ( 5.7)].

2.8 Switching a Patient to or from a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat

Psychiatric Disorders

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

disorders and initiation of therapy with duloxetine delayed-release capsules. Conversely, at least 5 days

should be allowed after stopping duloxetine delayed-release capsules before starting an MAOI

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

2.9 Use of Duloxetine Delayed-Release Capsules with Other MAOIs such as Linezolid or

Methylene Blue

Do not start duloxetine delayed-release capsules in a patient who is being treated with linezolid or

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

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

should be considered [see Contraindications ( 4)].

In some cases, a patient already receiving duloxetine delayed-release capsules 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, duloxetine delayed-release capsules should be stopped promptly, and linezolid or

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

serotonin syndrome for 5 days or until 24 hours after the last dose of linezolid or intravenous methylene

blue, whichever comes first. Therapy with duloxetine delayed-release capsules may be resumed 24

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

5.4)].

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 duloxetine delayed-release

capsules is unclear. The clinician should, nevertheless, be aware of the possibility of emergent

symptoms of serotonin syndrome with such use [see Warnings and Precautions ( 5.4)].

3 DOSAGE FORMS AND STRENGTHS

Duloxetine delayed-release capsules are available as:

20 mg white and blue capsules imprinted with “ap DLX20”

30 mg blue and blue capsules imprinted with “ap DLX30”

40 mg pink and blue capsules imprinted with “ap DLX40”

60 mg white and blue capsules imprinted with “ap DLX60”

4 CONTRAINDICATIONS

Monoamine Oxidase Inhibitors (MAOIs) - The use of MAOIs intended to treat psychiatric

disorders with duloxetine or within 5 days of stopping treatment with duloxetine is contraindicated

because of an increased risk of serotonin syndrome. The use of duloxetine within 14 days of stopping

an MAOI intended to treat psychiatric disorders is also contraindicated [see Dosage and Administration (

2.8) and Warnings and Precautions ( 5.4)].

Starting duloxetine 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 ( 2.9) and Warnings and Precautions ( 5.4)].

5 WARNINGS AND PRECAUTIONS

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

Patients with major depressive disorder (MDD), both adult and pediatric, may experience

worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or

unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may

persist until significant remission occurs. Suicide is a known risk of depression and certain other

psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has

been a long-standing concern, however, that antidepressants may have a role in inducing worsening of

depression and the emergence of suicidality in certain patients during the early phases of treatment.

Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and

others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in

children, adolescents, and young adults (ages 18 to 24) with major depressive disorder (MDD) and

other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with

antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants

compared to placebo in adults aged 65 and older.

The pooled analyses of placebo-controlled trials in children and adolescents with MDD,

obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term

trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials

in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median

duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable

variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients

for almost all drugs studied. There were differences in absolute risk of suicidality across the different

indications, with the highest incidence in MDD. The risk of differences (drug vs placebo), however,

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

difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1.

Table 1

Age Range

Drug-Placebo Difference in Number of Cases of Suicidality

per 1000 Patients Treated

Increases Compared to Placebo

<18

14 additional cases

18-24

5 additional cases

Decreases Compared to Placebo

25-64

1 fewer case

≥65

6 fewer cases

No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the

number was not sufficient to reach any conclusion about drug effect on suicide.

It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months.

However, there is substantial evidence from placebo-controlled maintenance trials in adults with

depression that the use of antidepressants can delay the recurrence of depression.

All patients being treated with antidepressants for any indication should be monitored

appropriately and observed closely for clinical worsening, suicidality, and unusual changes in

behavior, especially during the initial few months of a course of drug therapy, or at times of dose

changes, either increases or decreases.

The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility,

aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been

reported in adult and pediatric patients being treated with antidepressants for major depressive disorder

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

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

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

emerging suicidality.

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

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

experiencing emergent suicidality or symptoms that might be precursors to worsening depression or

suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's

presenting symptoms.

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

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

Dosage and Administration ( 2.7) and Warnings and Precautions ( 5.7) for descriptions of the risks of

discontinuation of duloxetine].

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

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

need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior,

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

such symptoms immediately to health care providers. Such monitoring should include daily

observation by families and caregivers. Prescriptions for duloxetine should be written for the

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

risk of overdose.

Screening Patients for Bipolar Disorder — A major depressive episode may be the initial

presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that

treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a

mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described

above represent such a conversion is unknown. However, prior to initiating treatment with an

antidepressant, patients with depressive symptoms should be adequately screened to determine if they

are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a

family history of suicide, bipolar disorder, and depression. It should be noted that duloxetine is not

approved for use in treating bipolar depression.

5.2 Hepatotoxicity

There have been reports of hepatic failure, sometimes fatal, in patients treated with duloxetine.

These cases have presented as hepatitis with abdominal pain, hepatomegaly, and elevation of

transaminase levels to more than twenty times the upper limit of normal with or without jaundice,

reflecting a mixed or hepatocellular pattern of liver injury. Duloxetine should be discontinued in

patients who develop jaundice or other evidence of clinically significant liver dysfunction and should

not be resumed unless another cause can be established.

Cases of cholestatic jaundice with minimal elevation of transaminase levels have also been

reported. Other postmarketing reports indicate that elevated transaminases, bilirubin, and alkaline

phosphatase have occurred in patients with chronic liver disease or cirrhosis.

Duloxetine increased the risk of elevation of serum transaminase levels in development program

clinical trials. Liver transaminase elevations resulted in the discontinuation of 0.3% (92/34,756) of

duloxetine-treated patients. In most patients, the median time to detection of the transaminase elevation

was about two months. In adult placebo-controlled trials in any indication, for patients with normal and

abnormal baseline ALT values, elevation of ALT >3 times the upper limit of normal occurred in 1.25%

(144/11,496) of duloxetine-treated patients compared to 0.45% (39/8716) of placebo-treated patients.

In adult placebo-controlled studies using a fixed dose design, there was evidence of a dose response

relationship for ALT and AST elevation of >3 times the upper limit of normal and >5 times the upper

limit of normal, respectively.

Because it is possible that duloxetine and alcohol may interact to cause liver injury or that

duloxetine may aggravate pre-existing liver disease, duloxetine delayed release capsules should not be

prescribed to patients with substantial alcohol use or evidence of chronic liver disease.

5.3 Orthostatic Hypotension, Falls and Syncope

Orthostatic hypotension, falls and syncope have been reported with therapeutic doses of

duloxetine. Syncope and orthostatic hypotension tend to occur within the first week of therapy but can

occur at any time during duloxetine treatment, particularly after dose increases. The risk of falling

appears to be related to the degree of orthostatic decrease in blood pressure as well as other factors

that may increase the underlying risk of falls.

In an analysis of patients from all placebo-controlled trials, patients treated with duloxetine

reported a higher rate of falls compared to patients treated with placebo. Risk appears to be related to

the presence of orthostatic decrease in blood pressure. The risk of blood pressure decreases may be

greater in patients taking concomitant medications that induce orthostatic hypotension (such as

antihypertensives) or are potent CYP1A2 inhibitors [see Warnings and Precautions ( 5.12) and Drug

Interactions ( 7.1)] and in patients taking duloxetine at doses above 60 mg daily. Consideration should be

given to dose reduction or discontinuation of duloxetine in patients who experience symptomatic

orthostatic hypotension, falls and/or syncope during duloxetine therapy.

Risk of falling also appeared to be proportional to a patient’s underlying risk for falls and

appeared to increase steadily with age. As elderly patients tend to have a higher underlying risk for

falls due to a higher prevalence of risk factors such as use of multiple medications, medical

comorbidities and gait disturbances, the impact of increasing age by itself is unclear. Falls with serious

consequences including bone fractures and hospitalizations have been reported [see Adverse Reactions (

6.10) and Patient Counseling Information ( 17)] .

5.4 Serotonin Syndrome

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

SNRIs and SSRIs, including duloxetine, alone but particularly with concomitant use of other

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

buspirone, amphetamines, and St. John's Wort) and with drugs that impair metabolism of serotonin (in

particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid

and intravenous methylene blue).

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

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

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

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

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

The concomitant use of duloxetine with MAOIs intended to treat psychiatric disorders is

contraindicated. Duloxetine should also not be started in a patient who is being treated with MAOIs such

as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on

the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg.

No reports involved the administration of methylene blue by other routes (such as oral tablets or local

tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment

with an MAOI such as linezolid or intravenous methylene blue in a patient taking duloxetine. Duloxetine

should be discontinued before initiating treatment with the MAOI [see Dosage and Administration ( 2.8,

2.9), and Contraindications ( 4)].

If concomitant use of duloxetine with other serotonergic drugs including triptans, tricyclic

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

clinically warranted, patients should be made aware of a potential increased risk for serotonin

syndrome, particularly during treatment initiation and dose increases. Treatment with duloxetine and any

concomitant serotonergic agents, should be discontinued immediately if the above events occur and

supportive symptomatic treatment should be initiated.

5.5 Abnormal Bleeding

SSRIs and SNRIs, including duloxetine, may increase the risk of bleeding events. Concomitant use

of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anti-coagulants may add to this risk.

Case reports and epidemiological studies (case-control and cohort design) have demonstrated an

association between use of drugs that interfere with serotonin reuptake and the occurrence of

gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs use have ranged from

ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages.

Patients should be cautioned about the risk of bleeding associated with the concomitant use of

duloxetine and NSAIDs, aspirin, or other drugs that affect coagulation.

5.6 Severe Skin Reactions

Severe skin reactions, including erythema multiforme and Stevens-Johnson Syndrome (SJS), can

occur with duloxetine. The reporting rate of SJS associated with duloxetine use exceeds the general

population background incidence rate for this serious skin reaction (1 to 2 cases per million person

years). The reporting rate is generally accepted to be an underestimate due to underreporting.

Duloxetine should be discontinued at the first appearance of blisters, peeling rash, mucosal

erosions, or any other sign of hypersensitivity if no other etiology can be identified.

5.7 Discontinuation of Treatment with Duloxetine Delayed-Release Capsules

Discontinuation symptoms have been systematically evaluated in patients taking duloxetine.

Following abrupt or tapered discontinuation in adult placebo-controlled clinical trials, the following

symptoms occurred at 1% or greater and at a significantly higher rate in duloxetine-treated patients

compared to those discontinuing from placebo: dizziness, headache, nausea, diarrhea, paresthesia,

irritability, vomiting, insomnia, anxiety, hyperhidrosis, and fatigue.

During marketing of other SSRIs and SNRIs (serotonin and norepinephrine reuptake inhibitors),

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

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

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

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

events are generally self-limiting, some have been reported to be severe.

Patients should be monitored for these symptoms when discontinuing treatment with duloxetine. A

gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If

intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then

resuming the previously prescribed dose may be considered. Subsequently, the physician may continue

decreasing the dose but at a more gradual rate [see Dosage and Administration ( 2.7)] .

5.8 Activation of Mania/Hypomania

In adult placebo-controlled trials in patients with major depressive disorder, activation of mania or

hypomania was reported in 0.1% (4/3779) of duloxetine-treated patients and 0.04% (1/2536) of placebo-

treated patients. No activation of mania or hypomania was reported in DPNP, GAD, or chronic

musculoskeletal pain placebo-controlled trials. Activation of mania or hypomania has been reported in a

small proportion of patients with mood disorders who were treated with other marketed drugs effective

in the treatment of major depressive disorder. As with these other agents, duloxetine should be used

cautiously in patients with a history of mania.

5.9 Angle-Closure Glaucoma

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

may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a

patent iridectomy.

5.10 Seizures

Duloxetine has not been systematically evaluated in patients with a seizure disorder, and such

patients were excluded from clinical studies. In adult placebo-controlled clinical trials,

seizures/convulsions occurred in 0.02% (3/12,722) of patients treated with duloxetine and 0.01%

(1/9513) of patients treated with placebo. Duloxetine should be prescribed with care in patients with a

history of a seizure disorder.

5.11 Effect on Blood Pressure

In adult placebo-controlled clinical trials across indications from baseline to endpoint, duloxetine

treatment was associated with mean increases of 0.5 mm Hg in systolic blood pressure and 0.8 mm Hg

in diastolic blood pressure compared to mean decreases of 0.6 mm Hg systolic and 0.3 mm Hg diastolic

in placebo-treated patients. There was no significant difference in the frequency of sustained (3

consecutive visits) elevated blood pressure. In a clinical pharmacology study designed to evaluate the

effects of duloxetine on various parameters, including blood pressure at supratherapeutic doses with an

accelerated dose titration, there was evidence of increases in supine blood pressure at doses up to 200

mg twice daily. At the highest 200 mg twice daily dose, the increase in mean pulse rate was 5.0 to 6.8

beats and increases in mean blood pressure were 4.7 to 6.8 mm Hg (systolic) and 4.5 to 7 mm Hg

(diastolic) up to 12 hours after dosing.

Blood pressure should be measured prior to initiating treatment and periodically measured

throughout treatment [see Adverse Reactions ( 6.7)] .

5.12 Clinically Important Drug Interactions

Both CYP1A2 and CYP2D6 are responsible for duloxetine metabolism.

Potential for Other Drugs to Affect Duloxetine

CYP1A2 Inhibitors - Co-administration of duloxetine with potent CYP1A2 inhibitors should be

avoided [see Drug Interactions ( 7.1)] .

CYP2D6 Inhibitors - Because CYP2D6 is involved in duloxetine metabolism, concomitant use of

duloxetine with potent inhibitors of CYP2D6 would be expected to, and does, result in higher

concentrations (on average of 60%) of duloxetine [see Drug Interactions ( 7.2)] .

Potential for Duloxetine to Affect Other Drugs

Drugs Metabolized by CYP2D6 - Co-administration of duloxetine with drugs that are extensively

metabolized by CYP2D6 and that have a narrow therapeutic index, including certain antidepressants

(tricyclic antidepressants [TCAs], such as nortriptyline, amitriptyline, and imipramine), phenothiazines

and Type 1C antiarrhythmics (e.g., propafenone, flecainide), should be approached with caution. Plasma

TCA concentrations may need to be monitored and the dose of the TCA may need to be reduced if a

TCA is co-administered with duloxetine. Because of the risk of serious ventricular arrhythmias and

sudden death potentially associated with elevated plasma levels of thioridazine, duloxetine and

thioridazine should not be co-administered [see Drug Interactions ( 7.9)] .

Other Clinically Important Drug Interactions

Alcohol — Use of duloxetine concomitantly with heavy alcohol intake may be associated with

severe liver injury. For this reason, duloxetine should not be prescribed for patients with substantial

alcohol use [see Warnings and Precautions ( 5.2) and Drug Interactions ( 7.15)] .

CNS Acting Drugs — Given the primary CNS effects of duloxetine, it should be used with caution

when it is taken in combination with or substituted for other centrally acting drugs, including those with

a similar mechanism of action [see Warnings and Precautions ( 5.12) and Drug Interactions ( 7.16)] .

5.13 Hyponatremia

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

appeared to be reversible when duloxetine was discontinued. Elderly patients may be at greater risk of

developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise

volume depleted may be at greater risk [see Use in Specific Populations ( 8.5)] . Discontinuation of

duloxetine should be considered in patients with symptomatic hyponatremia and appropriate medical

intervention should be instituted.

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

impairment, confusion, weakness, and unsteadiness, which may lead to falls. More severe and/or acute

cases have been associated with hallucination, syncope, seizure, coma, respiratory arrest, and death.

5.14 Use in Patients with Concomitant Illness

Clinical experience with duloxetine in patients with concomitant systemic illnesses is limited.

There is no information on the effect that alterations in gastric motility may have on the stability of

duloxetine's enteric coating. In extremely acidic conditions, duloxetine, unprotected by the enteric

coating, may undergo hydrolysis to form naphthol. Caution is advised in using duloxetine in patients

with conditions that may slow gastric emptying (e.g., some diabetics).

Duloxetine has not been systematically evaluated in patients with a recent history of myocardial

infarction or unstable coronary artery disease. Patients with these diagnoses were generally excluded

from clinical studies during the product's premarketing testing.

Hepatic Impairment — Avoid use in patients with chronic liver disease or cirrhosis [see Dosage

and Administration ( 2.6), Warnings and Precautions ( 5.2), and Use in Specific Populations ( 8.9)].

Severe Renal Impairment — Avoid use in patients with severe renal impairment, GFR <30 mL/min.

Increased plasma concentration of duloxetine, and especially of its metabolites, occur in patients with

end-stage renal disease (requiring dialysis) [see Dosage and Administration ( 2.6) and Use in Specific

Populations ( 8.10)].

Glycemic Control in Patients with Diabetes — As observed in DPNP trials, duloxetine treatment

worsens glycemic control in some patients with diabetes. In three clinical trials of duloxetine for the

management of neuropathic pain associated with diabetic peripheral neuropathy, the mean duration of

diabetes was approximately 12 years, the mean baseline fasting blood glucose was 176 mg/dL, and the

mean baseline hemoglobin A

(HbA

) was 7.8%. In the 12-week acute treatment phase of these

studies, duloxetine was associated with a small increase in mean fasting blood glucose as compared to

placebo. In the extension phase of these studies, which lasted up to 52 weeks, mean fasting blood

glucose increased by 12 mg/dL in the duloxetine group and decreased by 11.5 mg/dL in the routine care

group. HbA

increased by 0.5% in the duloxetine and by 0.2% in the routine care groups.

5.15 Urinary Hesitation and Retention

Duloxetine is in a class of drugs known to affect urethral resistance. If symptoms of urinary

hesitation develop during treatment with duloxetine, consideration should be given to the possibility that

they might be drug-related.

In post marketing experience, cases of urinary retention have been observed. In some instances of

urinary retention associated with duloxetine use, hospitalization and/or catheterization has been needed.

5.16 Laboratory Tests

No specific laboratory tests are recommended.

6 ADVERSE REACTIONS

The following serious adverse reactions are described below and elsewhere in the labeling:

Suicidal Thoughts and Behaviors in Children, Adolescents and Young Adults [see Boxed Warning

and Warnings and Precautions ( 5.1)]

Hepatotoxicity [see Warnings and Precautions ( 5.2)]

Orthostatic Hypotension, Falls and Syncope [see Warnings and Precautions ( 5.3)]

Serotonin Syndrome [see Warnings and Precautions ( 5.4)]

Abnormal Bleeding [see Warnings and Precautions ( 5.5)]

Severe Skin Reactions [see Warnings and Precautions ( 5.6)]

Discontinuation of Treatment with Duloxetine Delayed-Release Capsules [see Warnings and

Precautions ( 5.7)]

Activation of Mania/Hypomania [see Warnings and Precautions ( 5.8)]

Angle-Closure Glaucoma [see Warnings and Precautions ( 5.9)]

Seizures [see Warnings and Precautions ( 5.10)]

Effect on Blood Pressure [see Warnings and Precautions ( 5.11)]

Clinically Important Drug Interactions [see Warnings and Precautions ( 5.12)]

Hyponatremia [see Warnings and Precautions ( 5.13)]

Urinary Hesitation and Retention [see Warnings and Precautions ( 5.15)]

6.1 Clinical Trial Data Sources

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

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

and may not reflect the rates observed in practice.

The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at

least once, a treatment-emergent adverse reaction of the type listed. A reaction was considered

treatment-emergent if it occurred for the first time or worsened while receiving therapy following

baseline evaluation. Reactions reported during the studies were not necessarily caused by the therapy,

and the frequencies do not reflect investigator impression (assessment) of causality.

Adults — The data described below reflect exposure to duloxetine delayed-release capsules in

placebo-controlled trials for MDD (N=3779), GAD (N=1018), OA (N=503), CLBP (N=600), DPNP

(N=906), and another indication (N=1294). The population studied was 17 to 89 years of age; 65.7%,

60.8%, 60.6%, 42.9%, and 94.4% female; and 81.8%, 72.6%, 85.3%, 74.0% and 85.7% Caucasian for

MDD, GAD, OA and CLBP, DPNP, and another indication, respectively. Most patients received doses

of a total of 60 to 120 mg per day [see Clinical Studies ( 14)]. The data below do not include results of

the trial examining the efficacy of duloxetine delayed-release capsules in patients ≥ 65 years old for the

treatment of generalized anxiety disorder; however, the adverse reactions observed in this geriatric

sample were generally similar to adverse reactions in the overall adult population.

Children and Adolescents — The data described below reflect exposure to duloxetine delayed-release

capsules in pediatric, 10-week, placebo-controlled trials for MDD (N=341) and GAD (N=135). The

population studied (N=476) was 7 to 17 years of age with 42.4% children age 7 to 11 years of age,

50.6% female, and 68.6% white. Patients received 30-120 mg per day during placebo-controlled acute

treatment studies. Additional data come from the overall total of 822 pediatric patients (age 7 to 17 years

of age) with 41.7% children age 7 to 11 years of age and 51.8% female exposed to duloxetine delayed-

release capsules in MDD and GAD clinical trials up to 36-weeks in length, in which most patients

received 30-120 mg per day.

6.2 Adverse Reactions Reported as Reasons for Discontinuation of Treatment in Adult Placebo-

Controlled Trials

Major Depressive Disorder — Approximately 8.4% (319/3779) of the patients who received

duloxetine in placebo-controlled trials for MDD discontinued treatment due to an adverse reaction,

compared with 4.6% (117/2536) of the patients receiving placebo. Nausea (duloxetine 1.1%, placebo

0.4%) was the only common adverse reaction reported as a reason for discontinuation and considered to

be drug-related (i.e., discontinuation occurring in at least 1% of the duloxetine-treated patients and at a

rate of at least twice that of placebo).

Generalized Anxiety Disorder — Approximately 13.7% (139/1018) of the patients who received

duloxetine in placebo-controlled trials for GAD discontinued treatment due to an adverse reaction,

compared with 5.0% (38/767) for placebo. Common adverse reactions reported as a reason for

discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine 3.3%,

placebo 0.4%), and dizziness (duloxetine 1.3%, placebo 0.4%).

Diabetic Peripheral Neuropathic Pain — Approximately 12.9% (117/906) of the patients who

received duloxetine in placebo-controlled trials for DPNP discontinued treatment due to an adverse

reaction, compared with 5.1% (23/448) for placebo. Common adverse reactions reported as a reason for

discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine 3.5%,

placebo 0.7%), dizziness (duloxetine 1.2%, placebo 0.4%), and somnolence (duloxetine 1.1%, placebo

0.0%).

Chronic Pain due to Osteoarthritis — Approximately 15.7% (79/503) of the patients who received

duloxetine in 13-week, placebo-controlled trials for chronic pain due to OA discontinued treatment due

to an adverse reaction, compared with 7.3% (37/508) for placebo. Common adverse reactions reported

as a reason for discontinuation and considered to be drug-related (as defined above) included nausea

(duloxetine 2.2%, placebo 1.0%).

Chronic Low Back Pain — Approximately 16.5% (99/600) of the patients who received

duloxetine in 13-week, placebo-controlled trials for CLBP discontinued treatment due to an adverse

reaction, compared with 6.3% (28/441) for placebo. Common adverse reactions reported as a reason

for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine

3.0%, placebo 0.7%), and somnolence (duloxetine 1.0%, placebo 0.0%).

6.3 Most Common Adult Adverse Reactions

Pooled Trials for all Approved Indications — The most commonly observed adverse reactions in

duloxetine-treated patients (incidence of at least 5% and at least twice the incidence in placebo patients)

were nausea, dry mouth, somnolence, constipation, decreased appetite, and hyperhidrosis.

Diabetic Peripheral Neuropathic Pain — The most commonly observed adverse reactions in

duloxetine-treated patients (as defined above) were nausea, somnolence, decreased appetite,

constipation, hyperhidrosis, and dry mouth.

Chronic Pain due to Osteoarthritis — The most commonly observed adverse reactions in

duloxetine delayed-release capsules-treated patients (as defined above) were nausea, fatigue,

constipation, dry mouth, insomnia, somnolence, and dizziness.

Chronic Low Back Pain — The most commonly observed adverse reactions in duloxetine delayed-

release capsules-treated patients (as defined above) were nausea, dry mouth, insomnia, somnolence,

constipation, dizziness, and fatigue.

6.4 Adverse Reactions Occurring at an Incidence of 5% or More Among Duloxetine-Treated

Patients in Adult Placebo-Controlled Trials

Table 2 gives the incidence of treatment-emergent adverse reactions in placebo-controlled trials

for approved indications that occurred in 5% or more of patients treated with duloxetine and with an

incidence greater than placebo.

Table 2: Treatment-Emergent Adverse Reactions: Incidence of 5% or More and Greater than

Placebo in Placebo-Controlled Trials of Approved Indications

Adverse Reaction

Percentage of Patients Reporting Reaction

Duloxetine

(N=8100)

Placebo

(N=5655)

Nausea

Headache

Dry mouth

Somnolence

Fatigue

Insomnia

Constipation

Dizziness

Diarrhea

Decreased appetite

Hyperhidrosis

Abdominal Pain

a

b, c

The inclusion of an event in the table is determined based on the percentages before rounding;

however, the percentages displayed in the table are rounded to the nearest integer.

Also includes asthenia.

Events for which there was a significant dose-dependent relationship in fixed-dose studies, excluding

three MDD studies which did not have a placebo lead-in period or dose titration.

Also includes initial insomnia, middle insomnia, and early morning awakening.

Also includes hypersomnia and sedation.

Also includes abdominal discomfort, abdominal pain lower, abdominal pain upper, abdominal

tenderness, and gastrointestinal pain.

6.5 Adverse Reactions Occurring at an Incidence of 2% or More Among Duloxetine-Treated

Patients in Adult Placebo-Controlled Trials

Pooled MDD and GAD Trials — Table 3 gives the incidence of treatment-emergent adverse

reactions in MDD and GAD placebo-controlled trials for approved indications that occurred in 2% or

more of patients treated with duloxetine and with an incidence greater than placebo.

Table 3: Treatment-Emergent Adverse Reactions: Incidence of 2% or More and Greater than

Placebo in MDD and GAD Placebo-Controlled Trials

System Organ Class / Adverse Reaction

Percentage of Patients Reporting Reaction

Duloxetine

(N=4797)

Placebo

(N=3303)

Cardiac Disorders

Palpitations

Eye Disorders

Vision blurred

Gastrointestinal Disorders

Nausea

Dry mouth

Constipation

Diarrhea

Abdominal pain

Vomiting

General Disorders and Administration Site

Conditions

Fatigue

Metabolism and Nutrition Disorders

Decreased appetite

Nervous System Disorders

Headache

Dizziness

Somnolence

Tremor

Psychiatric Disorders

Insomnia

Agitation

Anxiety

Reproductive System and Breast Disorders

Erectile dysfunction

Ejaculation delayed

Libido decreased

Orgasm abnormal

<1

a,b

The inclusion of an event in the table is determined based on the percentages before rounding;

however, the percentages displayed in the table are rounded to the nearest integer.

For GAD, there were no adverse events that were significantly different between treatments in adults

≥65 years that were also not significant in the adults <65 years.

Events for which there was a significant dose-dependent relationship in fixed-dose studies, excluding

three MDD studies which did not have a placebo lead-in period or dose titration.

Also includes abdominal pain upper, abdominal pain lower, abdominal tenderness, abdominal

discomfort, and gastrointestinal pain.

Also includes asthenia.

Also includes hypersomnia and sedation

Also includes initial insomnia, middle insomnia, and early morning awakening

Also includes feeling jittery, nervousness, restlessness, tension and psychomotor hyperactivity

Also includes loss of libido

Also includes anorgasmia

Respiratory, Thoracic, and Mediastinal

Disorders

Yawning

<1

Skin and Subcutaneous Tissue Disorders

Hyperhidrosis

DPNP, another indication, OA, and CLBP - Table 4 gives the incidence of treatment-emergent

adverse events that occurred in 2% or more of patients treated with duloxetine (determined prior to

rounding) in the premarketing acute phase of DPNP, another indication, OA, and CLBP placebo-

controlled trials and with an incidence greater than placebo.

Table 4: Treatment-Emergent Adverse Reactions: Incidence of 2% or More and Greater

than Placebo in DPNP, another indication, OA, and CLBP Placebo-Controlled Trials

System Organ Class /

Adverse Reaction

Percentage of Patients Reporting Reaction

Duloxetine

(N=3303)

Placebo

(N=2352)

Gastrointestinal Disorders

Nausea

Dry Mouth

Constipation

Diarrhea

Abdominal Pain

Vomiting

Dyspepsia

General Disorders and

Administration Site

Conditions

Fatigue

Infections and Infestations

Nasopharyngitis

Upper Respiratory Tract

Infection

Influenza

Metabolism and Nutrition

Disorders

Decreased Appetite

Musculoskeletal and

Connective Tissue

a

The inclusion of an event in the table is determined based on the percentages before rounding;

however, the percentages displayed in the table are rounded to the nearest integer.

Incidence of 120 mg/day is significantly greater than the incidence for 60 mg/day.

Also includes abdominal discomfort, abdominal pain lower, abdominal pain upper, abdominal

tenderness and gastrointestinal pain

Also includes asthenia

Also includes myalgia and neck pain

Also includes hypersomnia and sedation

Also includes hypoaesthesia, hypoaesthesia facial, genital hypoaesthesia and paraesthesia

oral

Also includes initial insomnia, middle insomnia, and early morning awakening.

Also includes feeling jittery, nervousness, restlessness, tension and psychomotor

hyperactivity

Also includes ejaculation failure

Also includes hot flush

Also includes blood pressure diastolic increased, blood pressure systolic increased, diastolic

hypertension, essential hypertension, hypertension, hypertensive crisis, labile hypertension,

orthostatic hypertension, secondary hypertension, and systolic hypertension

Musculoskeletal Pain

Muscle Spasms

Nervous System Disorders

Headache

Somnolence

Dizziness

Paraesthesia

Tremor

<1

Psychiatric Disorders

Insomnia

Agitation

Reproductive System and

Breast Disorders

Erectile Dysfunction

<1

Ejaculation Disorder

<1

Respiratory, Thoracic, and

Mediastinal Disorders

Cough

Skin and Subcutaneous

Tissue Disorders

Hyperhidrosis

Vascular Disorders

Flushing

Blood pressure increased

6.6 Effects on Male and Female Sexual Function in Adults

Changes in sexual desire, sexual performance and sexual satisfaction often occur as manifestations

of psychiatric disorders or diabetes, but they may also be a consequence of pharmacologic treatment.

Because adverse sexual reactions are presumed to be voluntarily underreported, the Arizona Sexual

Experience Scale (ASEX), a validated measure designed to identify sexual side effects, was used

prospectively in 4 MDD placebo-controlled trials. In these trials, as shown in Table 5 below, patients

treated with duloxetine experienced significantly more sexual dysfunction, as measured by the total

score on the ASEX, than did patients treated with placebo. Gender analysis showed that this difference

occurred only in males. Males treated with duloxetine experienced more difficulty with ability to reach

orgasm (ASEX Item 4) than males treated with placebo. Females did not experience more sexual

dysfunction on duloxetine than on placebo as measured by ASEX total score. Negative numbers signify

an improvement from a baseline level of dysfunction, which is commonly seen in depressed patients.

Physicians should routinely inquire about possible sexual side effects.

Table 5: Mean Change in ASEX Scores by Gender in MDD Placebo-Controlled Trials

n=Number of patients with non-missing change score for ASEX total

p=0.013 versus placebo

p<0.001 versus placebo

Male Patients

Female Patients

Duloxetine

(n=175)

Placebo

(n=83)

Duloxetine

(n=241)

Placebo

(n=126)

ASEX Total (Items 1 to 5)

0.56

-1.07

-1.15

-1.07

Item 1 — Sex drive

-0.07

-0.12

-0.32

-0.24

Item 2 — Arousal

0.01

-0.26

-0.21

-0.18

Item 3 — Ability to achieve erection

(men); Lubrication (women)

0.03

-0.25

-0.17

-0.18

Item 4 — Ease of reaching orgasm

0.40

-0.24

-0.09

-0.13

Item 5 — Orgasm satisfaction

0.09

-0.13

-0.11

-0.17

6.7 Vital Sign Changes in Adults

In placebo-controlled clinical trials across approved indications for change from baseline to

endpoint, duloxetine treatment was associated with mean increases of 0.23 mm Hg in systolic blood

pressure and 0.73 mm Hg in diastolic blood pressure compared to mean decreases of 1.09 mm Hg

systolic and 0.55 mm Hg diastolic in placebo-treated patients. There was no significant difference in the

frequency of sustained (3 consecutive visits) elevated blood pressure [see Warnings and Precautions (

5.3, 5.11)] .

Duloxetine treatment, for up to 26 weeks in placebo-controlled trials across approved indications,

typically caused a small increase in heart rate for change from baseline to endpoint compared to placebo

of up to 1.37 beats per minute (increase of 1.20 beats per minute in duloxetine-treated patients, decrease

of 0.17 beats per minute in placebo-treated patients).

6.8 Laboratory Changes in Adults

Duloxetine treatment in placebo-controlled clinical trials across approved indications, was

associated with small mean increases from baseline to endpoint in ALT, AST, CPK, and alkaline

phosphatase; infrequent, modest, transient, abnormal values were observed for these analytes in

duloxetine-treated patients when compared with placebo-treated patients [see Warnings and Precautions (

5.2)] . High bicarbonate, cholesterol, and abnormal (high or low) potassium, were observed more

frequently in duloxetine treated patients compared to placebo.

6.9 Electrocardiogram Changes in Adults

The effect of duloxetine 160 mg and 200 mg administered twice daily to steady state was

evaluated in a randomized, double-blinded, two-way crossover study in 117 healthy female subjects. No

QT interval prolongation was detected. Duloxetine appears to be associated with concentration-

dependent but not clinically meaningful QT shortening.

6.10 Other Adverse Reactions Observed During the Premarketing and Postmarketing Clinical

Trial Evaluation of Duloxetine in Adults

Following is a list of treatment-emergent adverse reactions reported by patients treated with

duloxetine in clinical trials. In clinical trials of all indications, 34,756 patients were treated with

a

a

duloxetine. Of these, 26.9% (9337) took duloxetine for at least 6 months, and 12.4% (4317) for at least

one year. The following listing is not intended to include reactions (1) already listed in previous tables

or elsewhere in labeling, (2) for which a drug cause was remote, (3) which were so general as to be

uninformative, (4) which were not considered to have significant clinical implications, or (5) which

occurred at a rate equal to or less than placebo.

Reactions are categorized by body system according to the following definitions: frequent

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

occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in fewer than 1/1000 patients.

Cardiac Disorders Frequent: palpitations; Infrequent: myocardial infarction, tachycardia, and

Takotsubo cardiomyopathy.

Ear and Labyrinth Disorders Frequent: vertigo; Infrequent: ear pain and tinnitus.

Endocrine Disorders Infrequent: hypothyroidism.

Eye Disorders Frequent: vision blurred; Infrequent: diplopia, dry eye, and visual impairment.

Gastrointestinal Disorders Frequent: flatulence; Infrequent: dysphagia , eructation, gastritis,

gastrointestinal hemorrhage, halitosis, and stomatitis; Rare: gastric ulcer.

General Disorders and Administration Site Conditions Frequent: chills/rigors; Infrequent:

falls, feeling abnormal, feeling hot and/or cold, malaise, and thirst; Rare: gait disturbance.

Infections and Infestations Infrequent: gastroenteritis and laryngitis.

Investigations Frequent: weight increased, weight decreased; Infrequent: blood cholesterol

increased.

Metabolism and Nutrition Disorders Infrequent: dehydration and hyperlipidemia; Rare:

dyslipidemia.

Musculoskeletal and Connective Tissue Disorders Frequent: musculoskeletal pain;

Infrequent: muscle tightness and muscle twitching.

Nervous System Disorders Frequent: dysgeusia, lethargy, and paresthesia/hypoesthesia;

Infrequent: disturbance in attention, dyskinesia, myoclonus, and poor quality sleep; Rare: dysarthria.

Psychiatric Disorders Frequent: abnormal dreams and sleep disorder; Infrequent: apathy,

bruxism, disorientation/confusional state, irritability, mood swings, and suicide attempt; Rare: completed

suicide.

Renal and Urinary Disorders Frequent: urinary frequency; Infrequent: dysuria, micturition

urgency, nocturia, polyuria, and urine odor abnormal.

Reproductive System and Breast Disorders Frequent: anorgasmia/orgasm abnormal;

Infrequent: menopausal symptoms, sexual dysfunction, and testicular pain; Rare: menstrual disorder.

Respiratory, Thoracic and Mediastinal Disorders Frequent: yawning, oropharyngeal pain;

Infrequent: throat tightness.

Skin and Subcutaneous Tissue Disorders Frequent: pruritus; Infrequent: cold sweat,

dermatitis contact, erythema, increased tendency to bruise, night sweats, and photosensitivity reaction;

Rare: ecchymosis .

Vascular Disorders Frequent: hot flush; Infrequent: flushing, orthostatic hypotension, and

peripheral coldness.

6.11 Adverse Reactions Observed in Children and Adolescent Placebo-Controlled Clinical Trials

The adverse drug reaction profile observed in pediatric clinical trials (children and adolescents)

was consistent with the adverse drug reaction profile observed in adult clinical trials. The specific

adverse drug reactions observed in adult patients can be expected to be observed in pediatric patients

adverse drug reactions observed in adult patients can be expected to be observed in pediatric patients

(children and adolescents) [see Adverse Reactions ( 6.5)] . The most common (≥5% and twice placebo)

adverse reactions observed in pediatric clinical trials include: nausea, diarrhea, decreased weight, and

dizziness.

Table 6 provides the incidence of treatment-emergent adverse reactions in MDD and GAD

pediatric placebo-controlled trials that occurred in greater than 2% of patients treated with duloxetine

and with an incidence greater than placebo.

Table 6: Treatment-Emergent Adverse Reactions: Incidence of 2% or More and Greater than

Placebo in three 10 week Pediatric Placebo-Controlled Trials

The inclusion of an event in the table is determined based on the percentages before rounding;

however, the percentages displayed in the table are rounded to the nearest integer.

Also includes abdominal pain upper, abdominal pain lower, abdominal tenderness, abdominal

discomfort, and gastrointestinal pain.

Also includes asthenia.

Frequency based on weight measurement meeting potentially clinically significant threshold of ≥3.5%

weight loss (N=467 duloxetine; N=354 Placebo).

Also includes hypersomnia and sedation.

Also includes initial insomnia, insomnia, middle insomnia, and terminal insomnia.

System Organ Class/Adverse Reaction

Percentage of Pediatric Patients Reporting

Reaction

Duloxetine

Placebo

(N=476)

(N=362)

Gastrointestinal Disorders

Nausea

Abdominal Pain

Vomiting

Diarrhea

Dry Mouth

General Disorders and Administration Site

Conditions

Fatigue

Investigations

Decreased Weight

Metabolism and Nutrition Disorders

Decreased Appetite

Nervous System Disorders

Headache

Somnolence

Dizziness

Psychiatric Disorders

Insomnia

Respiratory, Thoracic, and Mediastinal

Disorders

Oropharyngeal Pain

Cough

a

Other adverse reactions that occurred at an incidence of less than 2% but were reported by more

duloxetine treated patients than placebo treated patients and are associated duloxetine treatment:

abnormal dreams (including nightmare), anxiety, flushing (including hot flush), hyperhidrosis,

palpitations, pulse increased, and tremor.

Discontinuation-emergent symptoms have been reported when stopping duloxetine. The most

commonly reported symptoms following discontinuation of duloxetine in pediatric clinical trials have

included headache, dizziness, insomnia, and abdominal pain [see Warnings and Precautions ( 5.7) and

Adverse Reactions ( 6.2)].

Growth (Height and Weight) - Decreased appetite and weight loss have been observed in

association with the use of SSRIs and SNRIs. Pediatric patients treated with duloxetine in clinical trials

experienced a 0.1kg mean decrease in weight at 10 weeks, compared with a mean weight gain of

approximately 0.9 kg in placebo-treated patients. The proportion of patients who experienced a

clinically significant decrease in weight (≥3.5%) was greater in the duloxetine group than in the placebo

group (14% and 6%, respectively). Subsequently, over the 4- to 6-month uncontrolled extension

periods, duloxetine-treated patients on average trended toward recovery to their expected baseline

weight percentile based on population data from age- and sex-matched peers. In studies up to 9 months,

duloxetine-treated pediatric patients experienced an increase in height of 1.7 cm on average (2.2 cm

increase in children [7 to 11 years of age] and 1.3 cm increase in adolescents [12 to 17 years of age]).

While height increase was observed during these studies, a mean decrease of 1% in height percentile

was observed (decrease of 2% in children [7 to 11 years of age] and increase of 0.3% in adolescents

[12 to 17 years of age]). Weight and height should be monitored regularly in children and adolescents

treated with duloxetine.

6.12 Postmarketing Spontaneous Reports

The following adverse reactions have been identified during post approval use of duloxetine.

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.

Adverse reactions reported since market introduction that were temporally related to duloxetine

therapy and not mentioned elsewhere in labeling include: acute pancreatitis, anaphylactic reaction,

aggression and anger (particularly early in treatment or after treatment discontinuation), angioneurotic

edema, angle-closure glaucoma, colitis (microscopic or unspecified), cutaneous vasculitis (sometimes

associated with systemic involvement), extrapyramidal disorder, galactorrhea, gynecological bleeding,

hallucinations, hyperglycemia, hyperprolactinemia, hypersensitivity, hypertensive crisis, muscle spasm,

rash, restless legs syndrome, seizures upon treatment discontinuation, supraventricular arrhythmia,

tinnitus (upon treatment discontinuation), trismus, and urticaria.

7 DRUG INTERACTIONS

Both CYP1A2 and CYP2D6 are responsible for duloxetine metabolism.

7.1 Inhibitors of CYP1A2

When duloxetine 60 mg was co-administered with fluvoxamine 100 mg, a potent CYP1A2

inhibitor, to male subjects (n=14) duloxetine AUC was increased approximately 6-fold, the C

increased about 2.5-fold, and duloxetine t

was increased approximately 3-fold. Other drugs that

inhibit CYP1A2 metabolism include cimetidine and quinolone antimicrobials such as ciprofloxacin and

enoxacin [see Warnings and Precautions ( 5.12)] .

7.2 Inhibitors of CYP2D6

Concomitant use of duloxetine (40 mg once daily) with paroxetine (20 mg once daily) increased

the concentration of duloxetine AUC by about 60%, and greater degrees of inhibition are expected with

higher doses of paroxetine. Similar effects would be expected with other potent CYP2D6 inhibitors

(e.g., fluoxetine, quinidine) [see Warnings and Precautions ( 5.12)] .

7.3 Dual Inhibition of CYP1A2 and CYP2D6

Concomitant administration of duloxetine 40 mg twice daily with fluvoxamine 100 mg, a potent

CYP1A2 inhibitor, to CYP2D6 poor metabolizer subjects (n=14) resulted in a 6-fold increase in

duloxetine AUC and C

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

Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of

the case-control and cohort design that have demonstrated an association between use of psychotropic

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

also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered

anticoagulant effects, including increased bleeding, have been reported when SSRIs or SNRIs are co-

administered with warfarin. Concomitant administration of warfarin (2 to 9 mg once daily) under steady

state conditions with duloxetine 60 or 120 mg once daily for up to 14 days in healthy subjects (n=15) did

not significantly change INR from baseline (mean INR changes ranged from 0.05 to +0.07). The total

warfarin (protein bound plus free drug) pharmacokinetics (AUC

or t

) for both R- and

S-warfarin were not altered by duloxetine. Because of the potential effect of duloxetine on platelets,

patients receiving warfarin therapy should be carefully monitored when duloxetine is initiated or

discontinued [see Warnings and Precautions ( 5.5)] .

7.5 Lorazepam

Under steady-state conditions for duloxetine (60 mg Q 12 hours) and lorazepam (2 mg Q 12 hours),

the pharmacokinetics of duloxetine were not affected by co-administration.

7.6 Temazepam

Under steady-state conditions for duloxetine (20 mg qhs) and temazepam (30 mg qhs), the

pharmacokinetics of duloxetine were not affected by co-administration.

7.7 Drugs that Affect Gastric Acidity

Duloxetine has an enteric coating that resists dissolution until reaching a segment of the

gastrointestinal tract where the pH exceeds 5.5. In extremely acidic conditions, duloxetine, unprotected

by the enteric coating, may undergo hydrolysis to form naphthol. Caution is advised in using duloxetine

in patients with conditions that may slow gastric emptying (e.g., some diabetics). Drugs that raise the

gastrointestinal pH may lead to an earlier release of duloxetine. However, co-administration of

duloxetine with aluminum- and magnesium-containing antacids (51 mEq) or duloxetine with famotidine,

had no significant effect on the rate or extent of duloxetine absorption after administration of a 40 mg

oral dose. It is unknown whether the concomitant administration of proton pump inhibitors affects

duloxetine absorption [see Warnings and Precautions ( 5.14)] .

7.8 Drugs Metabolized by CYP1A2

In vitro drug interaction studies demonstrate that duloxetine does not induce CYP1A2 activity.

Therefore, an increase in the metabolism of CYP1A2 substrates (e.g., theophylline, caffeine) resulting

from induction is not anticipated, although clinical studies of induction have not been performed.

Duloxetine is an inhibitor of the CYP1A2 isoform in in vitro studies, and in two clinical studies the

average (90% confidence interval) increase in theophylline AUC was 7% (1%-15%) and 20% (13%-

27%) when co-administered with duloxetine (60 mg twice daily).

7.9 Drugs Metabolized by CYP2D6

Duloxetine is a moderate inhibitor of CYP2D6. When duloxetine was administered (at a dose of

60 mg twice daily) in conjunction with a single 50 mg dose of desipramine, a CYP2D6 substrate, the

T ,s s ,

max,ss

max,ss

AUC of desipramine increased 3-fold [see Warnings and Precautions ( 5.12)] .

7.10 Drugs Metabolized by CYP2C9

Results of in vitro studies demonstrate that duloxetine does not inhibit activity. In a clinical study,

the pharmacokinetics of S-warfarin, a CYP2C9 substrate, were not significantly affected by duloxetine

[see Drug Interactions ( 7.4)] .

7.11 Drugs Metabolized by CYP3A

Results of in vitro studies demonstrate that duloxetine does not inhibit or induce CYP3A activity.

Therefore, an increase or decrease in the metabolism of CYP3A substrates (e.g., oral contraceptives

and other steroidal agents) resulting from induction or inhibition is not anticipated, although clinical

studies have not been performed.

7.12 Drugs Metabolized by CYP2C19

Results of in vitro studies demonstrate that duloxetine does not inhibit CYP2C19 activity at

therapeutic concentrations. Inhibition of the metabolism of CYP2C19 substrates is therefore not

anticipated, although clinical studies have not been performed.

7.13 Monoamine Oxidase Inhibitors (MAOIs )

[See Dosage and Administration ( 2.8, 2.9), Contraindications ( 4), and Warnings and Precautions (

5.4)] .

7.14 Serotonergic Drugs

[See Dosage and Administration ( 2.8, 2.9), Contraindications ( 4), and Warnings and Precautions (

5.4)].

7.15 Alcohol

When duloxetine and ethanol were administered several hours apart so that peak concentrations of

each would coincide, duloxetine did not increase the impairment of mental and motor skills caused by

alcohol.

In the duloxetine clinical trials database, three duloxetine-treated patients had liver injury as

manifested by ALT and total bilirubin elevations, with evidence of obstruction. Substantial intercurrent

ethanol use was present in each of these cases, and this may have contributed to the abnormalities seen

[see Warnings and Precautions ( 5.2 and 5.12)] .

7.16 CNS Drugs

[See Warnings and Precautions ( 5.12)] .

7.17 Drugs Highly Bound to Plasma Protein

Because duloxetine is highly bound to plasma protein, administration of duloxetine to a patient

taking another drug that is highly protein bound may cause increased free concentrations of the other

drug, potentially resulting in adverse reactions. However, co-administration of duloxetine (60 or 120

mg) with warfarin (2 to 9 mg), a highly protein-bound drug, did not result in significant changes in INR

and in the pharmacokinetics of either total S-or total R-warfarin (protein bound plus free drug) [see

DrugInteractions ( 7.4)] .

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C

Risk Summary — There are no adequate and well-controlled studies of duloxetine administration in

pregnant women. In animal studies with duloxetine, fetal weights were decreased but there was no

evidence of teratogenicity in pregnant rats and rabbits at oral doses administered during the period of

organogenesis up to 4 and 7 times the maximum recommended human dose (MRHD) of 120 mg/day,

respectively. When duloxetine was administered orally to pregnant rats throughout gestation and

lactation, pup weights at birth and pup survival to 1 day postpartum were decreased at a dose 2 times the

MRHD. At this dose, pup behaviors consistent with increased reactivity, such as increased startle

response to noise and decreased habituation of locomotor activity were observed. Post-weaning growth

was not adversely affected. Duloxetine should be used in pregnancy only if the potential benefit

justifies the potential risk to the fetus.

Clinical Considerations

Fetal/Neonatal Adverse Reaction — Neonates exposed during pregnancy to serotonin -

norepinephrine reuptake inhibitors (SNRIs) or selective serotonin reuptake inhibitors (SSRIs) have

developed complications requiring prolonged hospitalization, respiratory support, and tube feeding

which 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 the SNRIs or SSRIs, 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 ( 5.4)] .

Data

Animal Data — In animal reproduction studies, duloxetine has been shown to have adverse effects

on embryo/fetal and postnatal development.

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

organogenesis, there was no evidence of teratogenicity at doses up to 45 mg/kg/day (4 times the

maximum recommended human dose (MRHD) of 120 mg/day on a mg/m

basis, in rat; 7 times the MRHD

in rabbit). However, fetal weights were decreased at this dose, with a no-effect dose of 10 mg/kg/day

approximately equal to the MRHD in rats; 2 times the MRHD in rabbits).

When duloxetine was administered orally to pregnant rats throughout gestation and lactation, the

survival of pups to 1 day postpartum and pup body weights at birth and during the lactation period were

decreased at a dose of 30 mg/kg/day (2 times the MRHD); the no-effect dose was 10 mg/kg/day.

Furthermore, behaviors consistent with increased reactivity, such as increased startle response to noise

and decreased habituation of locomotor activity, were observed in pups following maternal exposure to

30 mg/kg/day. Post-weaning growth and reproductive performance of the progeny were not affected

adversely by maternal duloxetine treatment.

8.3 Nursing Mothers

Risk Summary

Duloxetine is present in human milk. In a published study, lactating women who were weaning their

infants were given duloxetine. At steady state, the concentration of duloxetine in breast milk was

approximately 25% that of maternal plasma. The estimated daily infant dose was approximately 0.14% of

the maternal dose. The developmental and health benefits of human milk feeding should be considered

along with the mother’s clinical need for duloxetine and any potential adverse effects on the milk-fed

child from the drug or from the underlying maternal condition. Exercise caution when duloxetine is

administered to a nursing woman.

Data

The disposition of duloxetine was studied in 6 lactating women who were at least 12 weeks

postpartum and had elected to wean their infants. The women were given 40 mg of duloxetine twice

daily for 3.5 days. The peak concentration measured in breast milk occurred at a median of 3 hours after

the dose. The amount of duloxetine in breast milk was approximately 7 mcg/day while on that dose; the

estimated daily infant dose was approximately 2 mcg/kg/day. The presence of duloxetine metabolites in

breast milk was not examined.

8.4 Pediatric Use

Generalized Anxiety Disorder — In pediatric patients aged 7 to 17 years, efficacy was demonstrated in

one 10 week, placebo-controlled trial. The study included 272 pediatric patients with GAD of which

47% were 7 to 11 years of age. Duloxetine demonstrated superiority over placebo as measured by

greater improvement in the Pediatric Anxiety Rating Scale (PARS) for GAD severity score [see Clinical

Studies ( 14.2)]. The safety and effectiveness in pediatric patients less than 7 years of age have not been

established.

Major Depressive Disorder — Efficacy was not demonstrated in two 10-week, placebo-controlled

trials with 800 pediatric patients with MDD, age 7-17. Neither duloxetine nor an active control

(indicated for treatment of pediatric depression) was superior to placebo. The safety and effectiveness

in pediatric patients less than 7 years of age have not been established.

The most frequently observed adverse reactions in the clinical trials included nausea, headache,

decreased weight, and abdominal pain. Decreased appetite and weight loss have been observed in

association with the use of SSRIs and SNRIs. Perform regular monitoring of weight and growth in

children and adolescents treated with an SNRI such as duloxetine [see Adverse Reactions ( 6.11)].

Use of duloxetine in a child or adolescent must balance the potential risks with the clinical need [see

Boxed Warning and Warnings and Precautions ( 5.1)].

Animal Data — Duloxetine administration to young rats from post-natal day 21 (weaning) through post-

natal day 90 (adult) resulted in decreased body weights that persisted into adulthood, but recovered

when drug treatment was discontinued; slightly delayed (~1.5 days) sexual maturation in females,

without any effect on fertility; and a delay in learning a complex task in adulthood, which was not

observed after drug treatment was discontinued. These effects were observed at the high dose of 45

mg/kg/day (2 times the MRHD, for a child); the no-effect-level was 20 mg/kg/day (≈1 times the MRHD,

for a child).

8.5 Geriatric Use

Of the 2,418 patients in premarketing clinical studies of duloxetine for MDD, 5.9% (143) were 65 years

of age or over. Of the 1041 patients in CLBP premarketing studies, 21.2% (221) were 65 years of age

or over. Of the 487 patients in OA premarketing studies, 40.5% (197) were 65 years of age or over. Of

the 1,074 patients in the DPNP premarketing studies, 33% (357) were 65 years of age or over. In the

MDD, GAD, DPNP, OA, CLBP, and other studies, no overall differences in safety or effectiveness

were generally observed between these subjects and younger subjects, and other reported clinical

experience has not identified differences in responses between the elderly and younger patients, but

greater sensitivity of some older individuals cannot be ruled out. SSRIs and SNRIs, including

duloxetine have been associated with cases of clinically significant hyponatremia in elderly patients,

who may be at greater risk for this adverse event [seeWarnings and Precautions ( 5.13)] .

In an analysis of data from all placebo-controlled-trials, patients treated with duloxetine reported a

higher rate of falls compared to patients treated with placebo. The increased risk appears to be

proportional to a patient’s underlying risk for falls. Underlying risk appears to increase steadily with

age. As elderly patients tend to have a higher prevalence of risk factors for falls such as medications,

medical comorbidities and gait disturbances, the impact of increasing age by itself on falls during

treatment with duloxetine is unclear. Falls with serious consequences including bone fractures and

hospitalizations have been reported [see Warnings and Precautions ( 5.3) and Adverse Reactions ( 6.10)] .

The pharmacokinetics of duloxetine after a single dose of 40 mg were compared in healthy elderly

females (65 to 77 years) and healthy middle-age females (32 to 50 years). There was no difference in

the Cmax, but the AUC of duloxetine was somewhat (about 25%) higher and the half-life about 4 hours

longer in the elderly females. Population pharmacokinetic analyses suggest that the typical values for

clearance decrease by approximately 1% for each year of age between 25 to 75 years of age; but age as

a predictive factor only accounts for a small percentage of between-patient variability. Dosage

adjustment based on the age of the patient is not necessary.

8.6 Gender

Duloxetine's half-life is similar in men and women. Dosage adjustment based on gender is not

necessary.

8.7 Smoking Status

Duloxetine bioavailability (AUC) appears to be reduced by about one-third in smokers. Dosage

modifications are not recommended for smokers.

8.8 Race

No specific pharmacokinetic study was conducted to investigate the effects of race.

8.9 Hepatic Impairment

Patients with clinically evident hepatic impairment have decreased duloxetine metabolism and

elimination. After a single 20 mg dose of duloxetine, 6 cirrhotic patients with moderate liver impairment

(Child-Pugh Class B) had a mean plasma duloxetine clearance about 15% that of age- and gender-

matched healthy subjects, with a 5-fold increase in mean exposure (AUC). Although C

was similar

to normals in the cirrhotic patients, the half-life was about 3 times longer [see Dosage and

Administration ( 2.6) and Warnings and Precautions ( 5.14)] .

8.10 Severe Renal Impairment

Limited data are available on the effects of duloxetine in patients with end-stage renal disease

(ESRD). After a single 60 mg dose of duloxetine, C

and AUC values were approximately 100%

greater in patients with end-stage renal disease receiving chronic intermittent hemodialysis than in

subjects with normal renal function. The elimination half-life, however, was similar in both groups. The

AUCs of the major circulating metabolites, 4-hydroxy duloxetine glucuronide and 5-hydroxy, 6-

methoxy duloxetine sulfate, largely excreted in urine, were approximately 7- to 9-fold higher and

would be expected to increase further with multiple dosing. Population PK analyses suggest that mild to

moderate degrees of renal impairment (estimated CrCl 30 to 80 mL/min) have no significant effect on

duloxetine apparent clearance [see Dosage and Administration ( 2.6) and Warnings and Precautions (

5.14)] .

9 DRUG ABUSE AND DEPENDENCE

9.2 Abuse

In animal studies, duloxetine did not demonstrate barbiturate-like (depressant) abuse potential.

While duloxetine has not been systematically studied in humans for its potential for abuse, there

was no indication of drug-seeking behavior in the clinical trials. However, it is not possible to predict

on the basis of premarketing experience the extent to which a CNS active drug will be misused,

diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for

a history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse

of duloxetine (e.g., development of tolerance, incrementation of dose, drug-seeking behavior).

9.3 Dependence

In drug dependence studies, duloxetine did not demonstrate dependence-producing potential in rats.

10 OVERDOSAGE

10.1 Signs and Symptoms

In postmarketing experience, fatal outcomes have been reported for acute overdoses, primarily

with mixed overdoses, but also with duloxetine only, at doses as low as 1000 mg. Signs and symptoms

of overdose (duloxetine alone or with mixed drugs) included somnolence, coma, serotonin syndrome,

seizures, syncope, tachycardia, hypotension, hypertension, and vomiting.

10.2 Management of Overdose

There is no specific antidote to duloxetine but if serotonin syndrome ensues, specific treatment

(such as with cyproheptadine and/or temperature control) may be considered. In case of acute overdose,

treatment should consist of those general measures employed in the management of overdose with any

drug.

An adequate airway, oxygenation, and ventilation should be assured, and cardiac rhythm and vital

signs should be monitored. Induction of emesis is not recommended. Gastric lavage with a large-bore

orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after

ingestion or in symptomatic patients.

Activated charcoal may be useful in limiting absorption of duloxetine from the gastrointestinal

tract. Administration of activated charcoal has been shown to decrease AUC and C

by an average of

one-third, although some subjects had a limited effect of activated charcoal. Due to the large volume of

distribution of this drug, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are

unlikely to be beneficial.

In managing overdose, the possibility of multiple drug involvement should be considered. A

specific caution involves patients who are taking or have recently taken duloxetine and might ingest

excessive quantities of a TCA. In such a case, decreased clearance of the parent tricyclic and/or its

active metabolite may increase the possibility of clinically significant sequelae and extend the time

needed for close medical observation [see Warnings and Precautions ( 5.4) and Drug Interactions ( 7)] .

The physician should consider contacting a poison control center (1-800-222-1222 or

www.poison.org) for additional information on the treatment of any overdose. Telephone numbers for

certified poison control centers are listed in the Physicians' Desk Reference (PDR).

11 DESCRIPTION

Duloxetine hydrochloride USP is a selective serotonin and norepinephrine reuptake inhibitor

(SSNRI) for oral administration. Its chemical designation is (+)-( S)- N-methyl-γ-(1-naphthyloxy)-2-

thiophenepropylamine hydrochloride. The molecular formula is C

NOSHCl, which corresponds

to a molecular weight of 333.88. The structural formula is:

Duloxetine hydrochloride USP is a white to brownish-white solid, which is slightly soluble in

water.

Each capsule contains enteric-coated pellets of 22.4, 33.7, 44.9 or 67.3 mg of duloxetine

hydrochloride USP equivalent to 20, 30, 40, or 60 mg of duloxetine, respectively. These enteric-

coated pellets are designed to prevent degradation of the drug in the acidic environment of the stomach.

Inactive ingredients include sugar spheres, hypromellose, sucrose, talc, methacrylic acid copolymer

dispersion, and triethyl citrate.

The capsule shell contains gelatin, FD&C Red No. 3 (40 mg), FD&C Blue No. 1 (40 mg), FD&C Blue

No. 2 (20 mg, 30 mg, 60 mg), titanium dioxide, and sodium lauryl sulfate.

For 20 mg, 30 mg, 40 mg (body & cap) and 60 mg (body only) strengths, imprinting black ink contains

shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, strong ammonia

solution, black iron oxide, potassium hydroxide and purified water.

For 60 mg (cap only) strength, imprinting white ink contains shellac, dehydrated alcohol, isopropyl

alcohol, butyl alcohol, propylene glycol, strong ammonia solution, purified water, potassium

hydroxide, and titanium dioxide.

USP Assay & Organic Impurities test pending.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Although the exact mechanisms of the antidepressant, central pain inhibitory and anxiolytic actions

of duloxetine in humans are unknown, these actions are believed to be related to its potentiation of

serotonergic and noradrenergic activity in the CNS.

12.2 Pharmacodynamics

Preclinical studies have shown that duloxetine is a potent inhibitor of neuronal serotonin and

norepinephrine reuptake and a less potent inhibitor of dopamine reuptake. Duloxetine has no significant

affinity for dopaminergic, adrenergic, cholinergic, histaminergic, opioid, glutamate, and GABA

receptors in vitro. Duloxetine does not inhibit monoamine oxidase (MAO).

Duloxetine is in a class of drugs known to affect urethral resistance. If symptoms of urinary

hesitation develop during treatment with duloxetine, consideration should be given to the possibility that

they might be drug-related.

12.3 Pharmacokinetics

Duloxetine has an elimination half-life of about 12 hours (range 8 to 17 hours) and its

pharmacokinetics are dose proportional over the therapeutic range. Steady-state plasma concentrations

are typically achieved after 3 days of dosing. Elimination of duloxetine is mainly through hepatic

metabolism involving two P450 isozymes, CYP1A2 and CYP2D6.

Absorption and Distribution — Orally administered duloxetine hydrochloride is well absorbed.

There is a median 2 hour lag until absorption begins (T

), with maximal plasma concentrations (C

of duloxetine occurring 6 hours post dose. Food does not affect the C

of duloxetine, but delays the

time to reach peak concentration from 6 to 10 hours and it marginally decreases the extent of absorption

(AUC) by about 10%. There is a 3 hour lag in absorption and a one-third increase in apparent clearance

of duloxetine after an evening dose as compared to a morning dose.

The apparent volume of distribution averages about 1640 L. Duloxetine is highly bound (>90%)

to proteins in human plasma, binding primarily to albumin and α

-acid glycoprotein. The interaction

between duloxetine and other highly protein bound drugs has not been fully evaluated. Plasma protein

binding of duloxetine is not affected by renal or hepatic impairment.

Metabolism and Elimination — Biotransformation and disposition of duloxetine in humans have

been determined following oral administration of

C-labeled duloxetine. Duloxetine comprises about

3% of the total radiolabeled material in the plasma, indicating that it undergoes extensive metabolism to

numerous metabolites. The major biotransformation pathways for duloxetine involve oxidation of the

naphthyl ring followed by conjugation and further oxidation. Both CYP1A2 and CYP2D6 catalyze the

oxidation of the naphthyl ring in vitro. Metabolites found in plasma include 4-hydroxy duloxetine

glucuronide and 5-hydroxy, 6-methoxy duloxetine sulfate. Many additional metabolites have been

identified in urine, some representing only minor pathways of elimination. Only trace (<1% of the dose)

amounts of unchanged duloxetine are present in the urine. Most (about 70%) of the duloxetine dose

appears in the urine as metabolites of duloxetine; about 20% is excreted in the feces. Duloxetine

undergoes extensive metabolism, but the major circulating metabolites have not been shown to

contribute significantly to the pharmacologic activity of duloxetine.

Children and Adolescents (ages 7 to 17 years) - Duloxetine steady-state plasma concentration was

comparable in children (7 to 12 years of age), adolescents (13 to 17 years of age) and adults. The

average steady-state duloxetine concentration was approximately 30% lower in the pediatric population

(children and adolescents) relative to the adults. The model-predicted duloxetine steady state plasma

concentrations in children and adolescents were mostly within the concentration range observed in adult

patients and did not exceed the concentration range in adults.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis — Duloxetine was administered in the diet to mice and rats for 2 years.

In female mice receiving duloxetine at 140 mg/kg/day (6 times the maximum recommended human

dose (MRHD) of 120 mg/day on a mg/m

basis), there was an increased incidence of hepatocellular

adenomas and carcinomas. The no-effect dose was 50 mg/kg/day (2 times the MRHD). Tumor incidence

was not increased in male mice receiving duloxetine at doses up to 100 mg/kg/day (4 times the MRHD).

In rats, dietary doses of duloxetine up to 27 mg/kg/day in females (2 times the MRHD) and up to 36

mg/kg/day in males (3 times the MRHD) did not increase the incidence of tumors.

Mutagenesis — Duloxetine was not mutagenic in the in vitro bacterial reverse mutation assay

(Ames test) and was not clastogenic in an in vivo chromosomal aberration test in mouse bone marrow

cells. Additionally, duloxetine was not genotoxic in an in vitro mammalian forward gene mutation assay

in mouse lymphoma cells or in an in vitro unscheduled DNA synthesis (UDS) assay in primary rat

hepatocytes, and did not induce sister chromatid exchange in Chinese hamster bone marrow in vivo.

Impairment of Fertility — Duloxetine administered orally to either male or female rats prior to and

throughout mating at doses up to 45 mg/kg/day (4 times the MRHD) did not alter mating or fertility.

14 CLINICAL STUDIES

The efficacy of duloxetine has been established in the following adequate and well-controlled trials:

Major Depressive Disorder (MDD): 4 short-term and 1 maintenance trial in adults [see Clinical

Studies ( 14.1)] .

Generalized Anxiety Disorder (GAD): 3 short-term trials in adults, 1 maintenance trial in adults, and

1 short-term trial in children and adolescents [see Clinical Studies ( 14.2)] .

Diabetic Peripheral Neuropathic Pain (DPNP): Two 12-week trials in adults, and 1 short-term trial in

children and adolescents [see Clinical Studies ( 14.3)] .

Chronic Musculoskeletal Pain: Two 12- to 13-week trials in adult patients with chronic low back

pain (CLBP) and one 13-week trial in adult patients with chronic pain due to osteoarthritis [see

Clinical Studies ( 14.5)] .

14.1 Major Depressive Disorder

The efficacy of duloxetine as a treatment for depression was established in 4 randomized, double-

blind, placebo-controlled, fixed-dose studies in adult outpatients (18 to 83 years) meeting DSM-IV

criteria for major depression. In 2 studies, patients were randomized to duloxetine 60 mg once daily

(N=123 and N=128, respectively) or placebo (N=122 and N=139, respectively) for 9 weeks; in the third

study, patients were randomized to duloxetine 20 or 40 mg twice daily (N=86 and N=91, respectively)

or placebo (N=89) for 8 weeks; in the fourth study, patients were randomized to duloxetine 40 or 60 mg

twice daily (N=95 and N=93, respectively) or placebo (N=93) for 8 weeks. There is no evidence that

doses greater than 60 mg/day confer additional benefits.

In all 4 studies, duloxetine demonstrated superiority over placebo as measured by improvement in

the 17-item Hamilton Depression Rating Scale (HAMD-17) total score. (Studies 1-4 in Table 7).

In all of these clinical studies, analyses of the relationship between treatment outcome and age,

gender, and race did not suggest any differential responsiveness on the basis of these patient

characteristics.

Table 7: Summary of the Primary Efficacy Results for Studies in Major Depressive Disorder

SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval, not

adjusted for multiplicity in trials where multiple dose groups were included.

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

Doses statistically significantly superior to placebo.

Study

Number

Treatment Group

Primary Efficacy Measure: HAMD-17

Mean Baseline

Score (SD)

LS Mean Change

from Baseline

(SE)

Placebo-Subtracted

Difference

(95%

CI)

Study 1

Duloxetine (60 mg/day)

21.5 (4.10)

-10.9 (0.70)

-4.9 (-6.8, -2.9)

Placebo

21.1 (3.71)

-6.1 (0.69)

Study 2

Duloxetine (60 mg/day)

20.3 (3.32)

-10.5 (0.71)

-2.2 (-4.0, -0.3)

Placebo

20.5 (3.42)

-8.3 (0.67)

Study 3

Duloxetine (20 mg BID)

18.6 (5.85)

-7.4 (0.80)

-2.4 (-4.7, -0.2)

Duloxetine (40 mg BID)

18.1 (4.52)

-8.6 (0.81)

-3.6 (-5.9, -1.4)

Placebo

17.2 (5.11)

-5.0 (0.81)

Study 4

Duloxetine (40 mg BID)

19.9 (3.54)

-11.0 (0.49)

-2.2 (-3.6, -0.9)

Duloxetine (60 mg BID)

20.2 (3.41)

-12.1 (0.49)

-3.3 (-4.7, -1.9)

Placebo

19.9 (3.58)

-8.8 (0.50)

In another study, 533 patients meeting DSM-IV criteria for MDD received duloxetine 60 mg once

daily during an initial 12-week open-label treatment phase. Two hundred and seventy-eight patients who

responded to open label treatment (defined as meeting the following criteria at weeks 10 and 12: a

HAMD-17 total score ≤9, Clinical Global Impressions of Severity (CGI-S) ≤2, and not meeting the

DSM-IV criteria for MDD) were randomly assigned to continuation of duloxetine at the same dose

(N=136) or to placebo (N=142) for 6 months. Patients on duloxetine experienced a statistically

a

(N=136) or to placebo (N=142) for 6 months. Patients on duloxetine experienced a statistically

significantly longer time to relapse of depression than did patients on placebo (Study 5 in Figure 1).

Relapse was defined as an increase in the CGI-S score of ≥2 points compared with that obtained at week

12, as well as meeting the DSM-IV criteria for MDD at 2 consecutive visits at least 2 weeks apart,

where the 2-week temporal criterion had to be satisfied at only the second visit. The effectiveness of

duloxetine in hospitalized patients with major depressive disorder has not been studied.

Figure 1: Kaplan-Meier Estimation of Cumulative Proportion of Patients with Relapse (MDD

Study 5)

14.2 Generalized Anxiety Disorder

The efficacy of duloxetine in the treatment of generalized anxiety disorder (GAD) was established in 1

fixed-dose randomized, double-blind, placebo-controlled trial and 2 flexible-dose randomized, double-

blind, placebo-controlled trials in adult outpatients between 18 and 83 years of age meeting the DSM-IV

criteria for GAD.

In 1 flexible-dose study and in the fixed-dose study, the starting dose was 60 mg once daily where

down titration to 30 mg once daily was allowed for tolerability reasons before increasing it to 60 mg

once daily. Fifteen percent of patients were down titrated. One flexible-dose study had a starting dose

of 30 mg once daily for 1 week before increasing it to 60 mg once daily.

The 2 flexible-dose studies involved dose titration with duloxetine doses ranging from 60 mg once

daily to 120 mg once daily (N=168 and N=162) compared to placebo (N=159 and N=161) over a 10-

week treatment period. The mean dose for completers at endpoint in the flexible-dose studies was

104.75 mg/day. The fixed-dose study evaluated duloxetine doses of 60 mg once daily (N=168) and 120

mg once daily (N=170) compared to placebo (N=175) over a 9-week treatment period. While a 120

mg/day dose was shown to be effective, there is no evidence that doses greater than 60 mg/day confer

additional benefit.

In all 3 studies, duloxetine demonstrated superiority over placebo as measured by greater improvement

in the Hamilton Anxiety Scale (HAM-A) total score (Studies 1-3 in Table 8) and by the Sheehan

Disability Scale (SDS) global functional impairment score. The SDS is a composite measurement of the

extent emotional symptoms disrupt patient functioning in 3 life domains: work/school, social life/leisure

activities, and family life/home responsibilities.

In another study, 887 patients meeting DSM-IV-TR criteria for GAD received duloxetine 60 mg to 120

mg once daily during an initial 26-week open-label treatment phase. Four hundred and twenty-nine

patients who responded to open-label treatment (defined as meeting the following criteria at weeks 24

and 26: a decrease from baseline HAM-A total score by at least 50% to a score no higher than 11, and a

Clinical Global Impressions of Improvement [CGI-Improvement] score of 1 or 2) were randomly

assigned to continuation of duloxetine at the same dose (N=216) or to placebo (N=213) and were

observed for relapse. Of the patients randomized, 73% had been in a responder status for at least 10

weeks. Relapse was defined as an increase in CGI-Severity score at least 2 points to a score ≥4 and a

MINI (Mini-International Neuropsychiatric Interview) diagnosis of GAD (excluding duration), or

discontinuation due to lack of efficacy. Patients taking duloxetine experienced a statistically

significantly longer time to relapse of GAD than did patients taking placebo (Study 4 in Figure 2).

Subgroup analyses did not indicate that there were any differences in treatment outcomes as a function

of age or gender.

The efficacy of duloxetine in the treatment of patients ≥65 years of age with generalized anxiety

disorder was established in one 10-week flexible-dose, randomized, double-blind, placebo-controlled

trial in adults ≥65 years of age meeting the DSM-IV criteria for GAD. In this study, the starting dose

was 30 mg once daily for 2 weeks before further dose increases in 30 mg increments at treatment weeks

2, 4, and 7 up to 120 mg once daily were allowed based on investigator judgment of clinical response

and tolerability. The mean dose for patients completing the 10-week acute treatment phase was 50.95

mg. Patients treated with duloxetine (N=151) demonstrated significantly greater improvement compared

with placebo (N=140) on mean change from baseline to endpoint as measured by the Hamilton Anxiety

Rating Scale total score (Study 5 in Table 8).

The efficacy of duloxetine in the treatment of pediatric patients 7 to 17 years of age with generalized

anxiety disorder (GAD) was established in 1 flexible-dose randomized, double-blind, placebo-

controlled trial in pediatric outpatients with GAD (based on DSM-IV criteria).

In this study, the starting dose was 30 mg once daily for 2 weeks. Further dose increases in 30 mg

increments up to 120 mg once daily were allowed based on investigator judgment of clinical response

and tolerability. The mean dose for patients completing the 10-week treatment phase was 57.6 mg/day. In

this study, duloxetine (N=135) demonstrated superiority over placebo (N=137) from baseline to

endpoint as measured by greater improvement in the Pediatric Anxiety Rating Scale (PARS) for GAD

severity score (Study 6 in Table 8).

Table 8: Summary of the Primary Efficacy Results for Studies in General Anxiety Disorder

Study Number

Treatment Group

Primary Efficacy Measure

Mean Baseline

Score (SD)

LS Mean Change

from Baseline (SE)

Placebo-Subtracted

Difference

(95% CI)

Study 1

(HAM-A)

Duloxetine

(60 mg/day)

25.1 (7.18)

-12.8 (0.68)

-4.4 (-6.2, -2.5)

Duloxetine

(120 mg/day)

25.1 (7.24)

-12.5 (0.67)

-4.1 (-5.9, -2.3)

Placebo

25.8 (7.66)

-8.4 (0.67)

Study 2

Duloxetine

22.5 (7.44)

-8.1 (0.70)

-2.2 (-4.2, -0.3)

a

SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval, not

adjusted for multiplicity in trials where multiple dose groups were included.

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

Dose statistically significantly superior to placebo.

(HAM-A)

(60-120 mg/day)

22.5 (7.44)

-8.1 (0.70)

-2.2 (-4.2, -0.3)

Placebo

23.5 (7.91)

-5.9 (0.70)

Study 3

(HAM-A)

Duloxetine

(60-120 mg/day)

25.8 (5.66)

-11.8 (0.69)

-2.6 (-4.5, -0.7)

Placebo

25.0 (5.82)

-9.2 (0.67)

Study 5

(Elderly) (HAM-

Duloxetine

(60-120 mg/day)

24.6 (6.21)

-15.9 (0.63)

-4.2 (-5.9, -2.5)

Placebo

24.5 (7.05)

-11.7 (0.67)

Study 6

(Pediatric)

(PARS for

GAD)

Duloxetine

(30-120 mg/day)

17.5 (1.98)

-9.7 (0.50)

-2.7 (-4.0, -1.3)

Placebo

17.4 (2.24)

-7.1 (0.50)

Figure 2: Kaplan-Meier Estimation of Cumulative Proportion of Patients with Relapse (GAD

Study 4)

14.3 Diabetic Peripheral Neuropathic Pain

The efficacy of duloxetine for the management of neuropathic pain associated with diabetic

peripheral neuropathy was established in 2 randomized, 12-week, double-blind, placebo-controlled,

fixed-dose studies in adult patients having diabetic peripheral neuropathic pain for at least 6 months.

Study DPNP-1 and Study DPNP-2 enrolled a total of 791 patients of whom 592 (75%) completed the

studies. Patients enrolled had Type I or II diabetes mellitus with a diagnosis of painful distal

symmetrical sensorimotor polyneuropathy for at least 6 months. The patients had a baseline pain score

of ≥4 on an 11-point scale ranging from 0 (no pain) to 10 (worst possible pain). Patients were permitted

up to 4 g of acetaminophen per day as needed for pain, in addition to duloxetine. Patients recorded their

pain daily in a diary.

Both studies compared duloxetine 60 mg once daily or 60 mg twice daily with placebo. DPNP-1

additionally compared duloxetine 20 mg with placebo. A total of 457 patients (342 duloxetine, 115

placebo) were enrolled in DPNP-1 and a total of 334 patients (226 duloxetine, 108 placebo) were

enrolled in DPNP-2. Treatment with duloxetine 60 mg one or two times a day statistically significantly

improved the endpoint mean pain scores from baseline and increased the proportion of patients with at

least a 50% reduction in pain scores from baseline. For various degrees of improvement in pain from

baseline to study endpoint, Figures 3 and 4 show the fraction of patients achieving that degree of

improvement. The figures are cumulative, so that patients whose change from baseline is, for example,

50%, are also included at every level of improvement below 50%. Patients who did not complete the

study were assigned 0% improvement. Some patients experienced a decrease in pain as early as week 1,

which persisted throughout the study.

Figure 3: Percentage of Patients Achieving Various Levels of Pain Relief as Measured by 24-

Hour Average Pain Severity - DPNP-1

Figure 4: Percentage of Patients Achieving Various Levels of Pain Relief as Measured by 24-

Hour Average Pain Severity - DPNP-2

14.5 Chronic Musculoskeletal Pain

Duloxetine delayed-release capsules are indicated for the management of chronic musculoskeletal

pain. This has been established in studies in patients with chronic low back pain and chronic pain due to

osteoarthritis.

Studies in Chronic Low Back Pain

The efficacy of duloxetine delayed-release capsules in chronic low back pain (CLBP) was

assessed in two double-blind, placebo-controlled, randomized clinical trials of 13-weeks duration

(Study CLBP-1 and Study CLBP-2), and one of 12-weeks duration (CLBP- 3). CLBP-1 and CLBP-3

demonstrated efficacy of duloxetine delayed-release capsules in the treatment of chronic low back pain.

Patients in all studies had no signs of radiculopathy or spinal stenosis.

Study CLBP-1: Two hundred thirty-six adult patients (N=115 on duloxetine delayed-release

capsules, N=121 on placebo) enrolled and 182 (77%) completed 13-week treatment phase. After 7

weeks of treatment, duloxetine delayed-release capsules patients with less than 30% reduction in

average daily pain and who were able to tolerate duloxetine 60 mg once daily had their dose of

duloxetine delayed-release capsules, in a double-blinded fashion, increased to 120 mg once daily for

the remainder of the study. Patients had a mean baseline pain rating of 6 on a numerical rating scale

ranging from 0 (no pain) to 10 (worst possible pain). After 13 weeks of treatment, patients taking

duloxetine delayed-release capsules 60 to 120 mg daily had a significantly greater pain reduction

compared to placebo. Randomization was stratified by the patients’ baseline NSAIDs-use status.

Subgroup analyses did not indicate that there were differences in treatment outcomes as a function of

NSAIDs use.

Study CLBP-2: Four hundred and four patients were randomized to receive fixed doses of

duloxetine delayed-release capsules daily or a matching placebo (N=59 on duloxetine delayed-release

capsules 20 mg, N=116 on duloxetine delayed-release capsules 60 mg, N=112 on duloxetine delayed-

release capsules 120 mg, N=117 on placebo) and 267 (66%) completed the entire 13-week study. After

13 weeks of treatment, none of the three duloxetine delayed-release capsules doses showed a

statistically significant difference in pain reduction compared to placebo.

Study CLBP-3: Four hundred and one patients were randomized to receive fixed doses of

duloxetine delayed-release capsules 60 mg daily or placebo (N=198 on duloxetine delayed-release

capsules, N=203 on placebo), and 303 (76%) completed the study. Patients had a mean baseline pain

rating of 6 on a numerical rating scale ranging from 0 (no pain) to 10 (worst possible pain). After 12

weeks of treatment, patients taking duloxetine delayed-release capsules 60 mg daily had significantly

greater pain reduction compared to placebo.

For various degrees of improvement in pain from baseline to study endpoint, Figures 7 and 8 show

the fraction of patients in CLBP-1 and CLBP-3 achieving that degree of improvement. The figures are

cumulative, so that patients whose change from baseline is, for example, 50%, are also included at

every level of improvement below 50%. Patients who did not complete the study were assigned the

value of 0% improvement.

Figure 7: Percentage of Patients Achieving Various Levels of Pain Relief as Measured by 24-

Hour Average Pain Severity – CLBP-1

Figure 8: Percentage of Patients Achieving Various Levels of Pain Relief as Measured by 24-

Hour Average Pain Severity – CLBP-3

Studies in Chronic Pain Due to Osteoarthritis

The efficacy of duloxetine delayed-release capsules in chronic pain due to osteoarthritis was

assessed in 2 double-blind, placebo-controlled, randomized clinical trials of 13-weeks duration (Study

OA-1 and Study OA-2). All patients in both studies fulfilled the ACR clinical and radiographic criteria

for classification of idiopathic osteoarthritis of the knee. Randomization was stratified by the patients’

baseline NSAIDs-use status. Patients assigned to duloxetine delayed-release capsules started treatment

in both studies at a dose of 30 mg once daily for one week. After the first week, the dose of duloxetine

delayed-release capsules was increased to 60 mg once daily. After 7 weeks of treatment with

duloxetine delayed-release capsules 60 mg once daily, in OA-1 patients with sub-optimal response to

treatment (<30% pain reduction) and tolerated duloxetine 60 mg once daily had their dose increased to

120 mg. However, in OA-2, all patients, regardless of their response to treatment after 7 weeks, were

re-randomized to either continue receiving duloxetine delayed-release capsules 60 mg once daily or

have their dose increased to 120 mg once daily for the remainder of the study. Patients in the placebo

treatment groups in both studies received a matching placebo for the entire duration of studies. For both

studies, efficacy analyses were conducted using 13-week data from the combined duloxetine delayed-

release capsules 60 mg and 120 mg once daily treatment groups compared to the placebo group.

Study OA-1: Two hundred fifty-six patients (N=128 on duloxetine delayed-release capsules,

N=128 on placebo) enrolled and 204 (80%) completed the study. Patients had a mean baseline pain

rating of 6 on a numerical rating scale ranging from 0 (no pain) to 10 (worst possible pain). After 13

weeks of treatment, patients taking duloxetine delayed-release capsules had significantly greater pain

reduction. Subgroup analyses did not indicate that there were differences in treatment outcomes as a

function of NSAIDs use.

Study OA-2: Two hundred thirty-one patients (N=111 on duloxetine delayed-release capsules,

N=120 on placebo) enrolled and 173 (75%) completed the study. Patients had a mean baseline pain of 6

on a numerical rating scale ranging from 0 (no pain) to 10 (worst possible pain). After 13 weeks of

treatment, patients taking duloxetine delayed-release capsules did not show a significantly greater pain

reduction.

In Study OA-1, for various degrees of improvement in pain from baseline to study endpoint,

Figure 9 shows the fraction of patients achieving that degree of improvement. The figure is cumulative,

so that patients whose change from baseline is, for example, 50%, are also included at every level of

improvement below 50%. Patients who did not complete the study were assigned the value of 0%

improvement.

Figure 9: Percentage of Patients Achieving Various Levels of Pain Relief as Measured by 24-

Hour Average Pain Severity – OA-1

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

Duloxetine delayed-release capsules are available in the following strengths, colors, imprints, and

presentations:

60MG Capsule- White/Blue Imprint- ap;LX60

60760-462-30 BOTTLES OF 30

16.2 Storage and Handling

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [ see USP Controlled

Room Temperature].

17 PATIENT COUNSELING INFORMATION

See FDA-approved patient labeling (Medication Guide).

Information on Medication Guide - Inform patients, their families, and their caregivers about the

benefits and risks associated with treatment with duloxetine delayed-release capsules and

counsel them in its appropriate use. A patient Medication Guide is available for duloxetine

delayed-release capsules. Instruct patients, their families, and their caregivers to read the

Medication Guide before starting duloxetine delayed-release capsules and each time their

prescription is renewed, and assist them in understanding its contents. Give patients the

opportunity to discuss the contents of the Medication Guide and to obtain answers to any

questions they may have. The complete text of the Medication Guide is reprinted at the end of

this document.

Advise patients of the following issues and ask them to alert their prescriber if these occur while taking

duloxetine delayed-release capsules.

Suicidal Thoughts and Behaviors - Encourage patients, their families, and their caregivers to be

alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility,

aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other

unusual changes in behavior, worsening of depression, and suicidal ideation, especially early

during antidepressant treatment and when the dose is adjusted up or down.

Advise families and caregivers of patients to observe for the emergence of such symptoms on a day-to-

day basis, since changes may be abrupt. Such symptoms should be reported to the patient’s prescriber or

health professional, especially if they are severe, abrupt in onset, or were not part of the patient’s

presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal

thinking and behavior and indicate a need for very close monitoring and possibly changes in the

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

Duloxetine delayed-release capsules should be swallowed whole and should not be chewed or

crushed, nor should the capsule be opened and its contents be sprinkled on food or mixed with

liquids. All of these might affect the enteric coating.

Continuing the Therapy Prescribed - While patients may notice improvement with duloxetine

delayed-release capsules therapy in 1 to 4 weeks, advise patients to continue therapy as directed.

Hepatotoxicity – Inform patients that severe liver problems, sometimes fatal, have been reported

in patients treated with duloxetine delayed-release capsules. Instruct patients to talk to their

healthcare provider if they develop itching, right upper belly pain, dark urine, or yellow

skin/eyes while taking duloxetine delayed-release capsules, which may be signs of liver

problems. Instruct patients to talk to their healthcare provider about their alcohol consumption.

Use of duloxetine with heavy alcohol intake may be associated with severe liver injury [see

Warnings and Precautions ( 5.2)].

Alcohol - Although duloxetine does not increase the impairment of mental and motor skills

caused by alcohol, use of duloxetine concomitantly with heavy alcohol intake may be associated

with severe liver injury. For this reason, duloxetine delayed-release capsules should not be

prescribed for patients with substantial alcohol use [see Warnings and Precautions ( 5.2) and

Drug Interactions ( 7.15)] .

Orthostatic Hypotension, Falls and Syncope - Advise patients of the risk of orthostatic

hypotension, falls and syncope, especially during the period of initial use and subsequent dose

escalation, and in association with the use of concomitant drugs that might potentiate the

orthostatic effect of duloxetine [see Warnings and Precautions ( 5.3)] .

Serotonin Syndrome - Caution patients about the risk of serotonin syndrome with the concomitant

use of duloxetine delayed-release capsules and other serotonergic agents including triptans,

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

St. John’s Wort [see Contraindications ( 4), Warnings and Precautions ( 5.4), and Drug Interactions

( 7.14)] .

Advise patients of the signs and symptoms associated with serotonin syndrome that 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

changes (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or

gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Caution patients to seek medical care

immediately if they experience these symptoms.

Abnormal Bleeding - Caution patients about the concomitant use of duloxetine and NSAIDs,

aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic

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

increased risk of bleeding [see Warnings and Precautions ( 5.5)].

Severe Skin Reactions - Caution patients that duloxetine may cause serious skin reactions. This

may need to be treated in a hospital and may be life-threatening. Counsel patients to call their

doctor right away or get emergency help if they have skin blisters, peeling rash, sores in their

mouth, hives, or any other allergic reactions [see Warnings and Precautions ( 5.6)] .

Discontinuation of Treatment - Instruct patients that discontinuation of duloxetine delayed-

release capsules may be associated with symptoms such as dizziness, headache, nausea,

diarrhea, paresthesia, irritability, vomiting, insomnia, anxiety, hyperhidrosis, and fatigue, and

should be advised not to alter their dosing regimen, or stop taking duloxetine delayed-release

capsules without consulting their physician [see Warnings and Precautions ( 5.7)] .

Activation of Mania or Hypomania - Adequately screen patients with depressive symptoms for

risk of bipolar disorder (e.g. family history of suicide, bipolar disorder, and depression) prior

to initiating treatment with duloxetine delayed-release capsules. Advise patients to report any

signs or symptoms of a manic reaction such as greatly increased energy, severe trouble

sleeping, racing thoughts, reckless behavior, talking more or faster than usual, unusually grand

ideas, and excessive happiness or irritability [see Warnings and Precautions ( 5.8)] .

Angle-Closure GlaucomaAdvise patients that taking duloxetine delayed-release capsules can

cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle-

closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle-

closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle

glaucoma is not a risk factor for angle-closure glaucoma. Patients may wish to be examined to

determine whether they are susceptible to angle-closure, and have a prophylactic procedure

(e.g., iridectomy), if they are susceptible [See Warnings and Precautions ( 5.9)].

Seizures – Advise patients to inform their physician if they have a history of seizure disorder

[see Warnings and Precautions ( 5.10)] .

Effects on Blood Pressure – Caution patients that duloxetine delayed-release capsules may

cause an increase in blood pressure [see Warnings and Precautions ( 5.11)] .

Concomitant Medications – Advise patients to inform their physicians if they are taking, or plan

to take, any prescription or over-the-counter medications, since there is a potential for

interactions [see Dosage and Administration ( 2.8, 2.9), Contraindications ( 4), Warnings and

Precautions ( 5.4, 5.12), and Drug Interactions ( 7)] .

HyponatremiaAdvise patients that hyponatremia has been reported as a result of treatment with

SNRIs and SSRIs, including duloxetine delayed-release capsules. Advise patients of the signs

and symptoms of hyponatremia [see Warnings and Precautions ( 5.13)].

Concomitant IllnessesAdvise patients to inform their physicians about all of their medical

conditions [see Warnings and Precautions ( 5.14)].

Duloxetine is in a class of medicines that may affect urination. Instruct patients to consult with

their healthcare provider if they develop any problems with urine flow [see Warnings and

Precautions ( 5.15)] .

Pregnancy and Nursing Mothers

Advise patients to notify their physician if they:

become pregnant during therapy

intend to become pregnant during therapy

are nursing [see Use in Specific Populations ( 8.1, 8.3)] .

Pediatric Use – Safety and efficacy of duloxetine in patients 7 to 17 years of age have been

established for the treatment of GAD. The types of adverse reactions observed with duloxetine

in children and adolescents were generally similar to those observed in adults.

The safety and effectiveness of duloxetine have not been established in pediatric patients less

than 18 years of age with other indications. [See Use in Specific Populations (8.4)].

Interference with Psychomotor Performance - Any psychoactive drug may impair judgment,

thinking, or motor skills. Although in controlled studies duloxetine has not been shown to impair

psychomotor performance, cognitive function, or memory, it may be associated with sedation and

dizziness. Therefore, caution patients about operating hazardous machinery including

automobiles, until they are reasonably certain that duloxetine therapy does not affect their ability

to engage in such activities.

Literature revised 03/2019

Marketed by:

Ajanta Pharma USA Inc.

Bridgewater, NJ 08807.

Made in INDIA.

Medication Guide

Duloxetine Delayed-Release Capsules

(doo lox’ e teen)

Read this Medication Guide before you start taking duloxetine delayed-release capsules and each time

you get a refill. There may be new information. This information does not take the place of talking to

your healthcare provider about your medical condition or treatment.

Talk to your healthcare provider about:

all risks and benefits of treatment with antidepressant medicines

all treatment choices for depression or other serious mental illness

What is the most important information I should know about antidepressant medicines,

depression, other serious mental illnesses, and suicidal thoughts or actions?

1. Duloxetine delayed-release capsules and other antidepressant medicines may increase

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

months of treatment or when the dose is changed.

2. Depression and other serious mental illnesses are the most important causes of suicidal

thoughts or actions. Some people may have a particularly high risk of having suicidal thoughts

or actions. These include people who have (or have a family history of) bipolar illness (also called

manic-depressive illness).

3. How can I watch for and try to prevent suicidal thoughts and actions?

Pay close attention to any changes in mood, behavior, actions, thoughts, or feelings, especially

sudden changes. This is very important when an antidepressant medicine is started or when the

dose is changed.

Call your healthcare provider right away to report new or sudden changes in mood, behavior,

thoughts, or feelings.

Keep all follow-up visits with your healthcare provider as scheduled. Call your 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 or feelings,

especially if they are new, worse, or worry you. In an emergency, call 911.

attempts to commit suicide

acting on dangerous impulses

acting aggressive, being angry, or violent

thoughts about suicide or dying

new or worse depression

new or worse anxiety

panic attacks

feeling very agitated or restless

new or worse irritability

trouble sleeping

an extreme increase in activity or talking (mania)

other unusual changes in behavior or mood

What else do I need to know about antidepressant medicines?

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

antidepressant medicine suddenly can cause other symptoms.

Antidepressants are medicines used to treat depression and other illnesses. It is important to discuss

all the risks of treating depression and also the risks of not treating it. Patients should discuss all

treatment choices with your healthcare provider, not just the use of antidepressants.

Antidepressant medicines have other side effects. Talk to your healthcare provider about the side

effects of the medicine prescribed for you or your family member.

Antidepressant medicines can interact with other medicines. Know all of the medicines that you or

your family member takes. Keep a list of all medicines to show your healthcare provider. Do not

start new medicines without first checking with your healthcare provider.

What are duloxetine delayed-release capsules?

Duloxetine delayed-release capsules are a prescription medicine used to treat a certain type of

depression called Major Depressive Disorder (MDD). Duloxetine delayed-release capsules belongs to

a class of medicines known as SNRIs (or serotonin-norepinephrine reuptake inhibitors).

Duloxetine delayed-release capsules are also used to treat or manage:

Generalized Anxiety Disorder (GAD)

Diabetic Peripheral Neuropathic Pain (DPNP)

Chronic Musculoskeletal Pain

Who should not take duloxetine delayed-release capsules?

Do Not take duloxetine delayed-release capsules if you:

take a Monoamine Oxidase Inhibitor (MAOI). Ask your healthcare provider or pharmacist if

you are not sure if you take an MAOI, including the antibiotic linezolid or intravenous methylene

blue.

Do not take an MAOI within 5 days of stopping duloxetine delayed-release capsules unless

directed to do so by your healthcare provider.

Do not start duloxetine delayed-release capsules if you stopped taking an MAOI in the last

14 days unless directed to do so by your healthcare provider.

People who take duloxetine delayed-release capsules close in time to an MAOI may have a

serious problem called Serotonin Syndrome (see “What are the possible side effects of duloxetine

delayed-release capsules?”).

What should I tell my healthcare provider before taking duloxetine delayed-release capsules?

Before starting duloxetine delayed-release capsules, tell your healthcare provider if you:

have heart problems or high blood pressure

have diabetes (duloxetine delayed-release capsules treatment makes it harder for some people

with diabetes to control their blood sugar)

have liver problems

have kidney problems

have glaucoma

have or had seizures or convulsions

have bipolar disorder or mania

have low sodium levels in your blood

have delayed stomach emptying

have or had bleeding problems

are pregnant or plan to become pregnant. It is not known if duloxetine delayed-release capsules

will harm your unborn baby. Talk to your healthcare provider about the benefits and risks of

treating depression or other conditions with duloxetine delayed-release capsules during

pregnancy.

are breastfeeding or plan to breastfeed. Duloxetine can pass into your breast milk. Talk to your

healthcare provider about the best way to feed your baby while taking duloxetine delayed-

release capsules.

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

over-the-counter medicines, vitamins, and herbal supplements. Duloxetine delayed-release capsules and

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

Especially tell your healthcare provider if you take:

triptans used to treat migraine headache

medicines used to treat mood, anxiety, psychotic or thought disorders, including tricyclics,

lithium, buspirone, SSRIs, SNRIs or MAOIs

tramadol and fentanyl

amphetamines

cimetidine

the antibiotics ciprofloxacin, enoxacin

medicine to treat irregular heart rate (like propafenone, flecainide, quinidine)

theophylline

the blood thinner warfarin (Coumadin, Jantoven)

non-steroidal anti-inflammatory drug (NSAID) (like ibuprofen, naproxen or aspirin).

over-the-counter supplements such as tryptophan or St. John's Wort

thioridazine (Mellaril). Mellaril together with duloxetine delayed-release capsules can cause

serious heart rhythm problems or sudden death.

Ask your healthcare provider for a list of these medicines if you are not sure.

Do not take duloxetine delayed-release capsules with any other medicine that contain duloxetine.

How should I take duloxetine delayed-release capsules?

Take duloxetine delayed-release capsules exactly as your healthcare provider tells you to take it.

Your healthcare provider may need to change the dose of duloxetine delayed-release capsules until

it is the right dose for you.

Swallow duloxetine delayed-release capsules whole. Do not chew or crush duloxetine delayed-

release capsules.

Do not open the capsule and sprinkle on food or mix with liquids. Opening the capsule may affect

how well duloxetine delayed-release capsules works.

Duloxetine delayed-release capsules may be taken with or without food.

If you miss a dose of duloxetine delayed-release capsules, take the missed dose as soon as you

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

regular time. Do not take two doses of duloxetine delayed-release capsules at the same time.

If you take too much duloxetine delayed-release capsules, call your healthcare provider or poison

control center at 1800-222-1222 right away, or get emergency treatment.

When switching from another antidepressant to duloxetine delayed-release capsules your healthcare

provider may want to lower the dose of the initial antidepressant first to potentially avoid side

effects.

What should I avoid while taking duloxetine delayed-release capsules?

Duloxetine delayed-release capsules can cause sleepiness or may affect your ability to make

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

other dangerous activities until you know how duloxetine delayed-release capsules affects you.

Use of duloxetine delayed-release capsules concomitantly with heavy alcohol intake may be

associated with severe liver injury. Avoid heavy alcohol use while taking duloxetine delayed-

release capsules.

What are the possible side effects of duloxetine delayed-release capsules?

Duloxetine delayed-release capsules may cause serious side effects, including: See “What is the most

important information I should know about duloxetine delayed-release capsules?”

Common possible side effects in people who take duloxetine delayed-release capsules include:

1. liver damage. Symptoms may include:

itching

right upper abdominal pain

dark urine

yellow skin or eyes

enlarged liver

increased liver enzymes

2. changes in blood pressure and falls. Monitor your blood pressure before starting and throughout

treatment. Duloxetine delayed-release capsules may:

increase your blood pressure.

decrease your blood pressure when standing and cause dizziness or fainting, mostly when first

starting duloxetine delayed-release capsules or when increasing the dose.

increase risk of falls, especially in elderly.

3. Serotonin Syndrome: This condition can be life-threatening and symptoms may include:

agitation, hallucinations, coma or other changes in mental status

coordination problems or muscle twitching (overactive reflexes)

racing heartbeat, high or low blood pressure

sweating or fever

nausea, vomiting, or diarrhea

muscle rigidity

dizziness

flushing

tremor

seizures

4. abnormal bleeding: Duloxetine delayed-release capsules and other antidepressant medicines may

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

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

5. severe skin reactions: Duloxetine delayed-release capsules may cause serious skin reactions that

may require stopping its use. This may need to be treated in a hospital and may be life-threatening. Call

your healthcare provider right away or get emergency help if you have skin blisters, peeling rash,

sores in the mouth, hives or any other allergic reactions.

6. discontinuation symptoms: Do not stop duloxetine delayed-release capsules without first talking

to your healthcare provider. Stopping duloxetine delayed-release capsule stoo quickly or changing

from another antidepressant too quickly may result in serious symptoms including:

anxiety

irritability

feeling tired or problems sleeping

headache

sweating

dizziness

electric shock-like sensations

vomiting or nausea

diarrhea

7. manic episodes:

greatly increased energy

severe trouble sleeping

racing thoughts

reckless behavior

unusually grand ideas

excessive happiness or irritability

talking more or faster than usual

8. v isual problems:

eye pain

changes in vision

swelling or redness in or around the eye

Only some people are at risk for these problems. You may want to undergo an eye examination to see if

you are at risk and receive preventative treatment if you are.

9. seizures or convulsions

10. low salt (sodium) levels in the blood. Elderly people may be at greater risk for this.

Symptoms may include:

headache

weakness or feeling unsteady

confusion, problems concentrating or thinking or memory problems

11. problems with urination. Symptoms may include:

decreased urine flow

unable to pass any urine

The most common side effects of duloxetine delayed-release capsules include:

nausea

dry mouth

sleepiness

fatigue

constipation

loss of appetite

increased sweating

dizziness

Common possible side effects in children and adolescents who take duloxetine delayed-release

capsules include:

nausea

decreased weight

dizziness

Side effects in adults may also occur in children and adolescents who take duloxetine delayed-release

capsules. Children and adolescents should have height and weight monitored during treatment.

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

These are not all the possible side effects of duloxetine delayed-release capsules. For more

information, ask your healthcare provider or pharmacist.

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

1088.

How should I store duloxetine delayed-release capsules?

Store duloxetine delayed-release capsules at 25°C (77°F); excursions permitted to 15° to 30°C (59° to

86°F) [ see USP Controlled Room Temperature].

Keep duloxetine delayed-release capsules and all medicines out of the reach of children.

General information about the safe and effective use of duloxetine delayed-release capsules

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

use duloxetine delayed-release capsules for a condition for which it was not prescribed. Do not give

duloxetine delayed-release capsules to other people, even if they have the same symptoms that you

have. It may harm them.

This Medication Guide summarizes the most important information about duloxetine delayed-release

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

healthcare provider or pharmacist for information about duloxetine delayed-release capsules that is

written for healthcare professionals.

For more information, call 1-855-664-7744.

What are the ingredients in duloxetine delayed-release capsules?

Active ingredient: duloxetine hydrochloride, USP

Inactive ingredients:

sugar spheres, hypromellose, sucrose, talc, methacrylic acid copolymer dispersion, and triethyl citrate.

The capsule shell contains gelatin, FD&C Red No. 3 (40 mg), FD&C Blue No. 1 (40 mg), FD&C Blue

No. 2 (20 mg, 30 mg, 60 mg), titanium dioxide, and sodium lauryl sulfate.

For 20 mg, 30 mg, 40 mg (body & cap) and 60 mg (body only) strengths, imprinting black ink contains

shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, strong ammonia

solution, black iron oxide, potassium hydroxide, and purified water.

For 60 mg (cap only) strength, imprinting white ink contains shellac, dehydrated alcohol, isopropyl

alcohol, butyl alcohol, propylene glycol, strong ammonia solution, purified water, potassium

hydroxide, and titanium dioxide.

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

All trademarks are the properties of their respective owners.

Medication Guide revised: 03/2019

Marketed by:

Ajanta Pharma USA Inc.

Bridgewater, NJ 08807.

Made un INDIA.

DULOXETINE

duloxetine capsule, delayed release

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:6 0 76 0 -46 2(NDC:27241-0 9 9 )

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

DULO XETINE HYDRO CHLO RIDE (UNII: 9 0 44SC542W) (DULOXETINE - UNII:O5TNM5N0 7U)

DULOXETINE

6 0 mg

Inactive Ingredients

Ingredient Name

Stre ng th

HYPRO MELLO SES (UNII: 3NXW29 V3WO)

SUCRO SE (UNII: C151H8 M554)

TALC (UNII: 7SEV7J4R1U)

METHACRYLIC ACID - ETHYL ACRYLATE CO PO LYMER ( 1:1) TYPE A (UNII: NX76 LV5T8 J)

TRIETHYL CITRATE (UNII: 8 Z9 6 QXD6 UM)

FD&C BLUE NO . 2 (UNII: L0 6 K8 R7DQK)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

SO DIUM LAURYL SULFATE (UNII: 36 8 GB5141J)

SHELLAC (UNII: 46 N10 7B71O)

ALCO HO L (UNII: 3K9 9 58 V9 0 M)

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

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

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

AMMO NIA (UNII: 5138 Q19 F1X)

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

PO TASSIUM HYDRO XIDE (UNII: WZH3C48 M4T)

WATER (UNII: 0 59 QF0 KO0 R)

St. Mary's Medical Park Pharmacy

Product Characteristics

Color

white, blue

S core

no sco re

S hap e

CAPSULE

S iz e

19 mm

Flavor

Imprint Code

DLX6 0 ;ap

Contains

Packag ing

#

Item Code

Package Description

Marketing Start

Date

Marketing End

Date

1

NDC:6 0 76 0 -46 2-

30 in 1 BOTTLE, PLASTIC; Type 0 : No t a Co mbinatio n

Pro duc t

0 9 /0 5/20 19

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA20 8 70 6

0 9 /0 5/20 19

Labeler -

St. Mary's Medical Park Pharmacy (063050751)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

St. Mary's Medical Park Pharmacy

0 6 30 50 751

re la be l(6 0 76 0 -46 2)

Revised: 9/2019

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