SERTRALINE HYDROCHLORIDE solution, concentrate

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Prospect Prospect (PIL)

21-01-2020

Ingredient activ:
SERTRALINE HYDROCHLORIDE (UNII: UTI8907Y6X) (SERTRALINE - UNII:QUC7NX6WMB)
Disponibil de la:
Rising Pharmaceuticals, Inc.
INN (nume internaţional):
SERTRALINE HYDROCHLORIDE
Compoziție:
SERTRALINE 20 mg in 1 mL
Calea de administrare:
ORAL
Tip de prescriptie medicala:
PRESCRIPTION DRUG
Indicații terapeutice:
Sertraline hydrochloride oral solution is indicated for the treatment of the following [See Clinical Studies (14)] : - Major depressive disorder (MDD) - Obsessive-compulsive disorder (OCD) - Panic disorder (PD) - Posttraumatic stress disorder (PTSD) - Social anxiety disorder (SAD) - Premenstrual dysphoric disorder (PMDD) Sertraline hydrochloride oral solution is contraindicated in patients: - Taking, or within 14 days of stopping, MAOIs, (including the MAOIs linezolid and intravenous methylene blue) because of an increased risk of serotonin syndrome [See Warnings and Precautions (5.2), Drug Interactions (7.1)] . - Taking pimozide [See Drug Interactions (7.1)] . - With known hypersensitivity to sertraline (e.g., anaphylaxis, angioedema) [See Adverse Reactions (6.1, 6.2)]. In addition to the contraindications for all sertraline hydrochloride oral solution formulations listed above, sertraline hydrochloride oral solution is contraindicated in patients: - Taking disulfiram. Sertraline hydrochloride oral solution
Rezumat produs:
Sertraline Hydrochloride Oral Solution USP is a clear, colorless peppermint flavored liquid in 60 mL amber colored round PET bottle with Child-Resistant closure having induction sealing liner.              Bottles of 60 mL                      NDC 64980-409-06 Store at 20º to 25ºC (68º to 77ºF); excursions permitted to 15º to 30ºC (59° to 86°F) [see USP Controlled Room Temperature].
Statutul autorizaţiei:
Abbreviated New Drug Application
Numărul autorizaţiei:
64980-409-06

SERTRALINE HYDROCHLORIDE - sertraline hydrochloride solution, concentrate

Rising Pharmaceuticals, Inc.

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Medication Guide

Sertraline Hydrochloride Oral Solution USP

(ser' tra leen hye'' droe klor' ide)

What is the most important information I should know about sertraline hydrochloride oral solution?

Sertraline hydrochloride oral solution and other antidepressant medicines may cause serious side effects. Call

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

emergency.

1. Suicidal thoughts or actions:

Sertraline hydrochloride oral solution and other antidepressant medicines may increase suicidal

thoughts or actions in some people 24 years of age and younger, especially within the first few

months of treatment or when the dose is changed.

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

actions.

Watch for these changes and call your healthcare provider right away if you notice new or sudden

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

Pay particular attention to such changes when sertraline hydrochloride oral solution is started

or when the dose is changed.

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

worried about symptoms.

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

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

attempts to commit suicide

acting on dangerous impulses

acting aggressive or violent

thoughts about suicide or dying

new or worse depression

new or worse anxiety or panic attacks

feeling agitated, restless, angry or irritable

trouble sleeping

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

other unusual changes in behavior or mood

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

agitation, hallucinations, coma, or other changes in mental status

nausea, vomiting, or diarrhea

racing heartbeat, high or low blood pressure

sweating or fever

coordination problems or muscle twitching (overactive reflexes)

muscle rigidity

3. Increased chance of bleeding: sertraline hydrochloride oral solution 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.

4. Manic episodes. Symptoms may include:

greatly increased energy

severe trouble sleeping

excessive happiness or irritability

racing thoughts

reckless behavior

talking more or faster than usual

unusually grand ideas

5. Seizures or convulsions.

6. Glaucoma (angle-closure glaucoma). Many antidepressant medicines including sertraline hydrochloride

oral solution may cause a certain type of eye problem

called angle-closure glaucoma. Call your healthcare provider if you have eye pain, changes in your vision,

or 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.

7. Changes in appetite or weight. Children and adolescents should have height and weight monitored during

treatment.

8. Low salt (sodium) levels in the blood. Elderly people may be at greater risk for this. Symptoms may

include:

Headache

weakness or feeling unsteady

confusion, problems concentrating or thinking, or memory problems

Do not stop sertraline hydrochloride oral solution without first talking to your healthcare provider. Stopping

sertraline hydrochloride oral solution too quickly may cause serious symptoms including:

anxiety, irritability, high or low mood, feeling restless or changes in sleep habits

headache, sweating, nausea, dizziness

electric shock-like sensations, shaking, confusion

What is Sertraline Hydrochloride Oral Solution?

Sertraline hydrochloride oral solution is a prescription medicine used to treat:

Major Depressive Disorder (MDD)

Obsessive Compulsive Disorder (OCD)

Panic Disorder

Posttraumatic Stress Disorder (PTSD)

Social Anxiety Disorder

Premenstrual Dysphoric Disorder (PMDD)

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

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

Sertraline hydrochloride oral solution is safe and effective in treating children with OCD age 6 to 17 years.

It is not known if sertraline hydrochloride oral solution is safe and effective for use in children under 6 years

of age with OCD or children with other behavior health conditions.

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

hydrochloride oral solution treatment.

Who should not take sertraline hydrochloride oral solution?

Do not take sertraline hydrochloride oral solution 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.

have taken an MAOI within 2 weeks of stopping sertraline hydrochloride oral solution unless directed

to do so by your healthcare provider.

have stopped taking an MAOI in the last 2 weeks unless directed to do so by your healthcare provider.

take any other medicines that contain sertraline (such as sertraline HCl or sertraline hydrochloride).

take the antipsychotic medicine pimozide (Orap®) because this can cause serious heart problems.

are allergic to sertraline or any of the ingredients in sertraline hydrochloride oral solution. See the end

of this Medication Guide for a complete list of ingredients in sertraline hydrochloride oral solution.

take Antabuse® (disulfiram) (if you are taking the liquid form of sertraline hydrochloride oral

solution) due to the alcohol content.

People who take sertraline hydrochloride oral solution close in time to an MAOI may have serious or even

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

high fever

uncontrolled muscle spasms

stiff muscles

rapid changes in heart rate or blood pressure

confusion

loss of consciousness (pass out)

What should I tell my healthcare provider before taking sertraline hydrochloride oral solution?

Before starting sertraline hydrochloride oral solution, tell your healthcare provider:

if you have:

liver problems

kidney problems

a history of a stroke

heart problems

or have had seizures or convulsions

high blood pressure

bipolar disorder or mania

low sodium levels in your blood

or have had bleeding problems

are pregnant or plan to become pregnant. Your baby may have withdrawal symptoms after birth or

may be at increased risk for a serious lung problem at birth. Talk to your healthcare provider about the

benefits and risks of taking sertraline hydrochloride oral solution during pregnancy.

are breastfeeding or plan to breastfeed. A small amount of sertraline hydrochloride oral solution may

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

while taking sertraline hydrochloride oral solution.

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

counter medicines, vitamins, and herbal supplements.

Sertraline hydrochloride oral solution and some medicines may interact with each other, may not work as

well, or may cause serious side effects.

Your healthcare provider or pharmacist can tell you if it is safe to take sertraline hydrochloride oral solution

with your other medicines. Do not start or stop any medicine while taking sertraline hydrochloride oral

solution without talking to your healthcare provider first.

How should I take sertraline hydrochloride oral solution?

Take sertraline hydrochloride oral solution exactly as prescribed. Your healthcare provider may need

to change the dose of sertraline hydrochloride oral solution until it is the right dose for you.

Sertraline hydrochloride oral solution may look cloudy or hazy after mixing, this is normal.

Sertraline hydrochloride oral solution must be diluted before use:

Do not mix sertraline hydrochloride oral solution until you are ready to take it.

When diluting sertraline hydrochloride oral solution, use only water, ginger ale, lemon/lime

soda, lemonade, or orange juice.

If you miss a dose of sertraline hydrochloride oral solution, 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 sertraline hydrochloride oral solution at the same time.

If you take too much sertraline hydrochloride oral solution, call your healthcare provider or poison control

center right away, or go to the nearest hospital emergency room right away.

What should I avoid while taking sertraline hydrochloride oral solution?

Sertraline hydrochloride oral solution 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 sertraline hydrochloride oral solution affects you. Do not drink alcohol while you take

sertraline hydrochloride oral solution.

What are the possible side effects of sertraline hydrochloride oral solution?

Sertraline hydrochloride oral solution may cause serious side effects, including:

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

solution?”

The most common side effects in adults who take sertraline hydrochloride oral solution include:

nausea, loss of appetite, diarrhea, or indigestion

change in sleep habits including increased sleepiness or insomnia

increased sweating

sexual problems including decreased libido and ejaculation failure

tremor or shaking

feeling tired or fatigued

agitation

anxiety

The most common side effects in children and adolescents who take include abnormal increase in muscle

movement or agitation, nose bleeds, urinary incontinence, aggressive reaction, possible slowed growth rate,

and weight change. Your child’s height and weight should be monitored during treatment with sertraline

hydrochloride oral solution.

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 sertraline hydrochloride oral solution. For more information, ask

your healthcare provider or pharmacist.

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

FDA-1088.

How should I store sertraline hydrochloride oral solution?

Store sertraline hydrochloride oral solution at room temperature, 68° to 77°F (20° to 25°C).

Keep sertraline hydrochloride oral solution bottle closed tightly.

Keep sertraline hydrochloride oral solution and all medicines out of the reach of children.

General information about the safe and effective use of sertraline hydrochloride oral solution

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

sertraline hydrochloride oral solution for a condition for which it was not prescribed. Do not give sertraline

hydrochloride oral solution to other people, even if they have the same condition. It may harm them.

This Medication Guide summarizes the most important information about sertraline hydrochloride oral

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

healthcare provider or pharmacist for information about sertraline hydrochloride oral solution that is written

for healthcare professionals.

For more information call 1-866-562-4597.

What are the ingredients in sertraline hydrochloride oral solution?

Active ingredient: sertraline hydrochloride

Inactive ingredients: alcohol (12%), natural peppermint flavor, propylene glycol and purified water.

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

All brands listed are the trademarks of their respective owners and are not trademarks of Aurobindo Pharma

Limited.

Dispense with Medication Guide available at: http://www.risingpharma.com/med-guides.html

Distributed by:

Rising Pharmaceuticals, Inc.

Saddle Brook, NJ 07663

Made in India

Code: TS/DRUGS/19/1993

Revised: 03/2018

Revised: 1/2020

Document Id: 96aab609-1fd1-4880-87ce-5b8cf4fc560f

34391-3

Set id: af2c75a3-131e-4bde-83fd-310fd2c01161

Version: 7

Effective Time: 20200121

Rising Pharmaceuticals, Inc.

SERTRALINE HYDROCHLORIDE - sertraline hydrochloride solution, concentrate

Rising Pharmaceuticals, Inc.

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HIGHLIGHTS OF PRESCRIBING INFORMATION

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

SOLUTION safely and effectively. See full prescribing information for SERTRALINE HYDROCHLORIDE ORAL

SOLUTION.

SERTRALINE HYDROCHLORIDE oral solution

Initial U.S. Approval: 1991

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS

See full prescribing information for complete boxed warning.

Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric and young adult

patients (5.1)

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

RECENT MAJOR CHANGES

Warnings and Precautions, QTc Prolongation (5.10) 12/2017

INDICATIONS AND USAGE

Sertraline hydrochloride oral solution is a selective serotonin reuptake inhibitor (SSRI) indicated for the treatment of (1):

Major depressive disorder (MDD)

Obsessive-compulsive disorder (OCD)

Panic disorder (PD)

Post-traumatic stress disorder (PTSD)

Social anxiety disorder (SAD)

Premenstrual dysphoric disorder (PMDD)

DOSAGE AND ADMINISTRATION

Indication

Starting Dosage

Maximum Dosage

MDD (2.1)

50 mg per day

200 mg per day

OCD (2.1)

25 mg per day (ages 6 to 12) 50 mg per

day (ages ≥ 13)

200 mg per day

PD, PTSD, SAD (2.1)

25 mg per day

200 mg per day

PMDD (2.2) continuous dosing

50 mg per day

150 mg per day

PMDD (2.2) intermittent dosing

50 mg per day during luteal phase only

100 mg per day during luteal phase only

If inadequate response to starting dosage, titrate in 25 to 50 mg per day increments once weekly in MDD, OCD, PD,

PTSD, and SAD (2.1)

See Full Prescribing Information for titration in PMDD (2.2)

Hepatic impairment:

Mild: Recommended starting and maximum dosage is half recommended dosage (2.4)

Moderate or severe: Not recommended (2.4)

When discontinuing sertraline hydrochloride oral solution, reduce dose gradually (2.6, 5.4)

Oral solution: Must be diluted before administration (2.7)

DOSAGE FORMS AND STRENGTHS

Oral solution: 20 mg/mL (3)

CONTRAINDICATIONS

Concomitant use of monoamine oxidase inhibitors (MAOIs), or use within 14 days of stopping MAOIs (4, 7.1)

Concomitant use of pimozide (4, 7.1)

Known hypersensitivity to sertraline or excipients (4, 5.4)

Sertraline hydrochloride oral solution only: Concomitant use of disulfiram (4)

WARNINGS AND PRECAUTIONS

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

but also when taken alone. If it occurs, discontinue sertraline hydrochloride and initiate supportive treatment. (5.2)

Increased Risk of Bleeding: Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), other

antiplatelet drugs, warfarin, and other anticoagulants may increase this risk. (5.3)

Activation of Mania/Hypomania: Screen patients for bipolar disorder. (5.4)

Seizures: Use with caution in patients with seizure disorders. (5.6)

Angle Closure Glaucoma: Avoid use of antidepressants, including sertraline hydrochloride, in patients with untreated

anatomically narrow angles. (5.7)

QTc Prolongation: Sertraline hydrochloride should be used with caution in patients with risk factors for QTc

prolongation. (5.10)

ADVERSE REACTIONS

Most common adverse reactions (≥5% and twice placebo) in pooled placebo-controlled MDD, OCD, PD, PTSD, SAD and

PMDD clinical trials were nausea, diarrhea/loose stool, tremor, dyspepsia, decreased appetite, hyperhidrosis, ejaculation

failure, and decreased libido (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Rising Pharmaceuticals, Inc. at 1-866-562-4597 or FDA

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

DRUG INTERACTIONS

Protein-bound drugs: Monitor for adverse reactions and reduce dosage of sertraline hydrochloride or other protein-

bound drugs (e.g., warfarin) as warranted. (7.1, 12.3)

CYP2D6 substrates: Reduce dosage of drugs metabolized by CYP2D6 (7.1, 12.3)

USE IN SPECIFIC POPULATIONS

Pregnancy: Third trimester use may increase risk for persistent pulmonary hypertension and withdrawal in the neonate

(8.1)

Pediatric use: Safety and effectiveness of sertraline hydrochloride in pediatric patients other than those with OCD have

not been established (8.4)

See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

Revised: 3/2018

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Dosage in Patients with MDD, OCD, PD, PTSD, and SAD

2.2 Dosage in Patients with PMDD

2.3 Screen for Bipolar Disorder Prior to Starting Sertraline Hydrochloride Oral Solution

2.4 Dosage Modifications in Patients with Hepatic Impairment

2.5 Switching Patients to or from a Monoamine Oxidase Inhibitor Antidepressant

2.6 Discontinuation of Treatment with Sertraline Hydrochloride Oral Solution

2.7 Preparation of Sertraline Hydrochloride Oral Solution

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Suicidal Thoughts and Behaviors in Pediatric and Young Adult Patients

5.2 Serotonin Syndrome

5.3 Increased Risk of Bleeding

5.4 Activation of Mania or Hypomania

5.5 Discontinuation Syndrome

5.6 Seizures

5.7 Angle-Closure Glaucoma

5.8 Hyponatremia

5.9 False-Positive Effects on Screening Tests for Benzodiazepines

5.10 QTc Prolongation

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Post-marketing Experience

7 DRUG INTERACTIONS

7.1 Clinically Significant Drug Interactions

7.2 Drugs Having No Clinically Important Interactions with Sertraline Hydrochloride

7.3 False-Positive Screening Tests for Benzodiazepines

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Hepatic Impairment

8.7 Renal Impairment

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

9.2 Abuse

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

14.1 Major Depressive Disorder

14.2 Obsessive-Compulsive Disorder

14.3 Panic Disorder

14.4 Posttraumatic Stress Disorder

14.5 Social Anxiety Disorder

14.6 Premenstrual Dysphoric Disorder

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS

Antidepressants increased the risk of suicidal thoughts and behavior in pediatric and young

adult patients in short-term studies. Closely monitor all antidepressant-treated patients for

clinical worsening, and for emergence of suicidal thoughts and behaviors [See Warnings and

Precautions (5.1)].

1 INDICATIONS AND USAGE

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

Sertraline hydrochloride oral solution is indicated for the treatment of the following [See Clinical

Studies (14)]:

Major depressive disorder (MDD)

Obsessive-compulsive disorder (OCD)

Panic disorder (PD)

Posttraumatic stress disorder (PTSD)

Social anxiety disorder (SAD)

Premenstrual dysphoric disorder (PMDD)

2 DOSAGE AND ADMINISTRATION

2.1 Dosage in Patients with MDD, OCD, PD, PTSD, and SAD

The recommended initial dosage and maximum sertraline hydrochloride oral solution dosage in patients

with MDD, OCD, PD, PTSD, and SAD are displayed in Table 1 below. A dosage of 25 mg or 50 mg

per day is the initial therapeutic dosage.

For adults and pediatric patients, subsequent dosages may be increased in case of an inadequate

response in 25 to 50 mg per day increments once a week, depending on tolerability, up to a maximum of

200 mg per day. Given the 24-hour elimination half-life of sertraline hydrochloride oral solution, the

recommended interval between dose changes is one week.

Table 1: Recommended Daily Dosage of Sertraline Hydrochloride Oral Solution in Patients with

MDD, OCD, PD, PTSD, and SAD

Indication

Starting Dose

Therapeutic Range

Adults

50 mg

50 to 200 mg

50 mg

PD, PTSD, SAD

25 mg

Pediatric Patients

OCD (ages 6 to 12 years old)

25 mg

50 to 200 mg

OCD (ages 13 to 17 years old)

50 mg

2.2 Dosage in Patients with PMDD

The recommended starting sertraline hydrochloride oral solution dosage in adult women with PMDD is

50 mg per day. Sertraline hydrochloride oral solution may be administered either continuously (every

day throughout the menstrual cycle) or intermittently (only during the luteal phase of the menstrual

cycle, i.e., starting the daily dosage 14 days prior to the anticipated onset of menstruation and continuing

through the onset of menses). Intermittent dosing would be repeated with each new cycle.

When dosing continuously, patients not responding to a 50 mg dosage may benefit from dosage

increases at 50 mg increments per menstrual cycle up to 150 mg per day.

When dosing intermittently, patients not responding to a 50 mg dosage may benefit from increasing

the dosage up to a maximum of 100 mg per day during the next menstrual cycle (and subsequent

cycles) as follows: 50 mg per day during the first 3 days of dosing followed by 100 mg per day

during the remaining days in the dosing cycle.

2.3 Screen for Bipolar Disorder Prior to Starting Sertraline Hydrochloride Oral Solution

Prior to initiating treatment with sertraline hydrochloride oral solution or another antidepressant, screen

patients for a personal or family history of bipolar disorder, mania, or hypomania [See Warnings and

Precautions (5.4)].

2.4 Dosage Modifications in Patients with Hepatic Impairment

Both the recommended starting dosage and therapeutic range in patients with mild hepatic impairment

(Child Pugh scores 5 or 6) are half the recommended daily dosage [See Dosage and Administration (2.1,

2.2)]. The use of sertraline hydrochloride oral solution in patients with moderate (Child Pugh scores 7

to 9) or severe hepatic impairment (Child Pugh scores 10 to 15) is not recommended [See Use in Specific

Populations (8.6), Clinical Pharmacology (12.3)].

2.5 Switching Patients to or from a Monoamine Oxidase Inhibitor Antidepressant

At least 14 days must elapse between discontinuation of a monoamine oxidase inhibitor (MAOI)

antidepressant and initiation of sertraline hydrochloride oral solution. In addition, at least 14 days must

elapse after stopping sertraline hydrochloride oral solution before starting an MAOI antidepressant [See

Contraindications (4), Warnings and Precautions (5.2)].

2.6 Discontinuation of Treatment with Sertraline Hydrochloride Oral Solution

Adverse reactions may occur upon discontinuation of sertraline hydrochloride oral solution [See

Warnings and Precautions (5.5)]. Gradually reduce the dosage rather than stopping sertraline

hydrochloride oral solution abruptly whenever possible.

2.7 Preparation of Sertraline Hydrochloride Oral Solution

Sertraline hydrochloride oral solution must be diluted before use.

Use the supplied calibrated dispensing syringe to measure the amount of sertraline hydrochloride

oral solution needed

Note: The supplied calibrated dispensing syringe has 25 mg and 50 mg graduation marks only

Mix with 4 ounces (1/2 cup) of water, ginger ale, lemon/lime soda, lemonade or orange juice

ONLY. After mixing, a slight haze may appear, which is normal.

Instruct patients or caregivers to immediately take the dose after mixing.

3 DOSAGE FORMS AND STRENGTHS

Sertraline Hydrochloride Oral Solution USP is a clear, colorless peppermint flavored liquid containing

sertraline hydrochloride equivalent to 20 mg of sertraline per mL and 12% alcohol. It is supplied as a

60 mL amber colored round PET bottle with an accompanying calibrated dispensing syringe that has 25

mg and 50 mg graduation marks.

4 CONTRAINDICATIONS

Sertraline hydrochloride oral solution is contraindicated in patients:

Taking, or within 14 days of stopping, MAOIs, (including the MAOIs linezolid and intravenous

methylene blue) because of an increased risk of serotonin syndrome [See Warnings and Precautions

(5.2), Drug Interactions (7.1)].

Taking pimozide [See Drug Interactions (7.1)].

With known hypersensitivity to sertraline (e.g., anaphylaxis, angioedema) [See Adverse Reactions

(6.1, 6.2)].

In addition to the contraindications for all sertraline hydrochloride oral solution formulations listed

above, sertraline hydrochloride oral solution is contraindicated in patients:

Taking disulfiram. Sertraline hydrochloride oral solution contains alcohol, and concomitant use of

sertraline hydrochloride oral solution and disulfiram may result in a disulfiram-alcohol reaction.

5 WARNINGS AND PRECAUTIONS

5.1 Suicidal Thoughts and Behaviors in Pediatric and Young Adult Patients

In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant

classes) that included approximately 77,000 adult patients and over 4,400 pediatric patients, the

incidence of suicidal thoughts and behaviors in pediatric and young adult patients was greater in

antidepressant-treated patients than in placebo-treated patients. The drug-placebo differences in the

number of cases of suicidal thoughts and behaviors per 1000 patients treated are provided in Table 2.

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

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

Table 2: Risk Differences of the Number of Cases of Suicidal Thoughts or Behaviors in the

Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Patients

Age

Range

(years)

Drug-Placebo Difference in Number of Patients of Suicidal Thoughts or Behaviors per

1000 Patients Treated

Increases Compared to Placebo

<18

14 additional patients

18 to 24

5 additional patients

Decreases Compared to Placebo

25 to 64

1 fewer patient

≥65

6 fewer patients

It is unknown whether the risk of suicidal thoughts and behaviors in pediatric and young adult patients

extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from

placebo-controlled maintenance trials in adults with MDD that antidepressants delay the recurrence of

depression.

Monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts

and behaviors, especially during the initial few months of drug therapy and at times of dosage changes.

Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the

healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing

sertraline hydrochloride, in patients whose depression is persistently worse, or who are experiencing

emergent suicidal thoughts or behaviors.

5.2 Serotonin Syndrome

Serotonin-norepinephrine reuptake inhibitors (SNRIs) and SSRIs, including sertraline hydrochloride,

can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased with

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

lithium, tramadol, tryptophan, buspirone, amphetamines, and St. John’s Wort) and with drugs that impair

metabolism of serotonin, i.e., MAOIs [See Contraindications (4), Drug Interactions (7.1)]. Serotonin

syndrome can also occur when these drugs are used alone.

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

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

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

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

vomiting, diarrhea).

The concomitant use of sertraline hydrochloride with MAOIs is contraindicated. In addition, do not

initiate sertraline hydrochloride in a patient being treated with MAOIs such as linezolid or intravenous

methylene blue. No reports involved the administration of methylene blue by other routes (such as oral

tablets or local tissue injection). If it is necessary to initiate treatment with an MAOI such as linezolid or

intravenous methylene blue in a patient taking sertraline hydrochloride, discontinue sertraline

hydrochloride before initiating treatment with the MAOI [See Contraindications (4), Drug Interactions

(7.1)].

Monitor all patients taking sertraline hydrochloride for the emergence of serotonin syndrome.

Discontinue treatment with sertraline hydrochloride and any concomitant serotonergic agents

immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant

use of sertraline hydrochloride with other serotonergic drugs is clinically warranted, inform patients of

the increased risk for serotonin syndrome and monitor for symptoms.

5.3 Increased Risk of Bleeding

Drugs that interfere with serotonin reuptake inhibition, including sertraline hydrochloride, increase the

risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs),

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

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

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

events related to drugs that interfere with serotonin reuptake have ranged from ecchymosis, hematoma,

epistaxis, and petechiae to life-threatening hemorrhages.

Inform patients of the increased risk of bleeding associated with the concomitant use of sertraline

hydrochloride and antiplatelet agents or anticoagulants. For patients taking warfarin, carefully monitor

the international normalized ratio.

5.4 Activation of Mania or Hypomania

In patients with bipolar disorder, treating a depressive episode with sertraline hydrochloride or another

antidepressant may precipitate a mixed/manic episode. In controlled clinical trials, patients with bipolar

disorder were generally excluded; however, symptoms of mania or hypomania were reported in 0.4%

of patients treated with sertraline hydrochloride. Prior to initiating treatment with sertraline

hydrochloride, screen patients for any personal or family history of bipolar disorder, mania, or

hypomania.

5.5 Discontinuation Syndrome

Adverse reactions after discontinuation of serotonergic antidepressants, particularly after abrupt

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

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

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

rather than abrupt cessation is recommended whenever possible [See Dosage and Administration (2.6)].

5.6 Seizures

Sertraline hydrochloride has not been systematically evaluated in patients with seizure disorders.

Patients with a history of seizures were excluded from clinical studies. Sertraline hydrochloride should

be prescribed with caution in patients with a seizure disorder.

5.7 Angle-Closure Glaucoma

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

hydrochloride may trigger an angle closure attack in a patient with anatomically narrow angles who

does not have a patent iridectomy. Avoid use of antidepressants, including sertraline hydrochloride, in

patients with untreated anatomically narrow angles.

5.8 Hyponatremia

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

hydrochloride. Cases with serum sodium lower than 110 mmol/L have been reported. Signs and

symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion,

weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe

or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death. In

many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic

hormone secretion (SIADH).

In patients with symptomatic hyponatremia, discontinue sertraline hydrochloride and institute appropriate

medical intervention. Elderly patients, patients taking diuretics, and those who are volume-depleted may

be at greater risk of developing hyponatremia with SSRIs and SNRIs [See Use in Specific Populations

(8.5)].

5.9 False-Positive Effects on Screening Tests for Benzodiazepines

False-positive urine immunoassay screening tests for benzodiazepines have been reported in patients

taking sertraline hydrochloride. This finding is due to lack of specificity of the screening tests. False-

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

hydrochloride. Confirmatory tests, such as gas chromatography/mass spectrometry, will help

distinguish sertraline hydrochloride from benzodiazepines [See Drug Interactions (7.3)].

5.10 QTc Prolongation

During post-marketing use of sertraline, cases of QTc prolongation and Torsade de Pointes (TdP) have

been reported. Most reports were confounded by other risk factors. In a randomized, double-blind,

placebo- and positive-controlled three-period crossover thorough QTc study in 54 healthy adult

subjects, there was a positive relationship between the length of the rate-adjusted QTc interval and

serum sertraline concentration. Therefore, sertraline hydrochloride should be used with caution in

patients with risk factors for QTc prolongation [See Drug Interactions (7.1), Clinical Pharmacology

(12.2)].

6 ADVERSE REACTIONS

The following adverse reactions are described in more detail in other sections of the prescribing

information:

Hypersensitivity reactions to sertraline [See Contraindications (4)]

Disulfiram-alcohol reaction when sertraline hydrochloride oral solution is taken with disulfiram

[See Contraindications (4)]

QTc prolongation and ventricular arrhythmias when taken with pimozide [See Contraindications

(4), Clinical Pharmacology (12.2) ]

Suicidal thoughts and behaviors [See Warnings and Precautions (5.1)]

Serotonin syndrome [See Contraindications (4), Warnings and Precautions (5.2), Drug Interactions

(7.1)]

Increased risk of bleeding [See Warnings and Precautions (5.3)]

Activation of mania/hypomania [See Warnings and Precautions (5.4)]

Discontinuation syndrome [See Warnings and Precautions (5.5)]

Seizures [See Warnings and Precautions (5.6)]

Angle-closure glaucoma [See Warnings and Precautions (5.7)]

Hyponatremia [See Warnings and Precautions (5.8)]

6.1 Clinical Trials Experience

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

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

and may not reflect the rates observed in practice.

The data described below are from randomized, double-blind, placebo-controlled trials of sertraline

hydrochloride (mostly 50 mg to 200 mg per day) in 3066 adults diagnosed with MDD, OCD, PD,

PTSD, SAD, and PMDD. These 3066 patients exposed to sertraline hydrochloride for 8 to 12 weeks

represent 568 patient-years of exposure. The mean age was 40 years; 57% were females and 43% were

males.

The most common adverse reactions (≥5% and twice placebo) in all pooled placebo-controlled clinical

trials of all sertraline hydrochloride-treated patients with MDD, OCD, PD, PTSD, SAD and PMDD

were nausea, diarrhea/loose stool, tremor, dyspepsia, decreased appetite, hyperhidrosis, ejaculation

failure, and decreased libido (see Table 3). The following are the most common adverse reactions in

trials of sertraline hydrochloride (≥5% and twice placebo) by indication that were not mentioned

previously.

MDD: somnolence;

OCD: insomnia, agitation;

PD: constipation, agitation;

PTSD: fatigue;

PMDD: somnolence, dry mouth, dizziness, fatigue, and abdominal pain;

SAD: insomnia, dizziness, fatigue, dry mouth, malaise.

Table 3: Common Adverse Reactions in Pooled Placebo-Controlled Trials in Adults with MDD,

OCD, PD, PTSD, SAD, and PMDD*

Sertraline

hydrochloride

(N=3066)

Placebo

(N=2293)

Cardiac disorders

Palpitations

Eye disorders

Visual impairment

Gastrointestinal Disorders

Nausea

Diarrhea/Loose Stools

Dry mouth

Dyspepsia

Constipation

Vomiting

General disorders and administration site conditions

Fatigue

Metabolism and nutrition disorders

Decreased appetite

Nervous system disorders

Dizziness

Somnolence

Tremor

Psychiatric Disorders

Insomnia

Agitation

Libido Decreased

Reproductive system and breast disorders

Ejaculation failure

Erectile dysfunction

Ejaculation disorder

Male sexual dysfunction

Skin and subcutaneous tissue disorders

Hyperhidrosis

Denominator used was for male patients only (n=1316 sertraline hydrochloride; n=973 placebo).

* Adverse reactions that occurred greater than 2% in sertraline hydrochloride-treated patients and at

least 2% greater in sertraline hydrochloride-treated patients than placebo-treated patients.

Adverse Reactions Leading to Discontinuation in Placebo-Controlled Clinical Trials

In all placebo-controlled studies in patients with MDD, OCD, PD, PTSD, SAD and PMDD, 368 (12%)

of the 3066 patients who received sertraline hydrochloride discontinued treatment due to an adverse

reaction, compared with 93 (4%) of the 2293 placebo-treated patients. In placebo-controlled studies, the

following were the common adverse reactions leading to discontinuation in sertraline hydrochloride-

treated patients:

MDD, OCD, PD, PTSD, SAD and PMDD: nausea (3%), diarrhea (2%), agitation (2%), and insomnia

(2%).

MDD (>2% and twice placebo): decreased appetite, dizziness, fatigue, headache, somnolence,

tremor, and vomiting.

OCD: somnolence.

PD: nervousness and somnolence.

Male and Female Sexual Dysfunction

Although changes in sexual desire, sexual performance and sexual satisfaction often occur as

manifestations of a psychiatric disorder, they may also be a consequence of SSRI treatment. However,

reliable estimates of the incidence and severity of untoward experiences involving sexual desire,

performance and satisfaction are difficult to obtain, in part because patients and healthcare providers

may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual

experience and performance cited in labeling may underestimate their actual incidence.

Table 4 below displays the incidence of sexual adverse reactions reported by at least 2% of sertraline

hydrochloride-treated patients and twice placebo from pooled placebo-controlled trials. For men and all

indications, the most common adverse reactions (>2% and twice placebo) included: ejaculation failure,

decreased libido, erectile dysfunction, ejaculation disorder, and male sexual dysfunction. For women,

the most common adverse reaction (≥2% and twice placebo) was decreased libido.

Table 4: Most Common Sexual Adverse Reactions (≥2% and twice placebo) in Men or Women

from Sertraline Hydrochloride Pooled Controlled Trials in Adults with MDD, OCD, PD, PTSD,

SAD, and PMDD

Sertraline

hydrochloride

Placebo

Men only

(N=1316)

(N=973)

Ejaculation failure

Libido decreased

Erectile dysfunction

Ejaculation disorder

Male sexual dysfunction

Women only

(N=1750)

(N=1320)

Libido decreased

Adverse Reactions in Pediatric Patients

In 281 pediatric patients treated with sertraline hydrochloride in placebo-controlled studies, the overall

profile of adverse reactions was generally similar to that seen in adult studies. Adverse reactions that

do not appear in Table 3 (most common adverse reactions in adults) yet were reported in at least 2% of

pediatric patients and at a rate of at least twice the placebo rate include fever, hyperkinesia, urinary

incontinence, aggression, epistaxis, purpura, arthralgia, decreased weight, muscle twitching, and

anxiety.

Other Adverse Reactions Observed During the Premarketing Evaluation of Sertraline Hydrochloride

Other infrequent adverse reactions, not described elsewhere in the prescribing information, occurring

at an incidence of < 2% in patients treated with sertraline hydrochloride were:

Cardiac disorders – tachycardia

Ear and labyrinth disorders – tinnitus

Endocrine disorders - hypothyroidism

Eye disorders - mydriasis, blurred vision

Gastrointestinal disorders - hematochezia, melena, rectal hemorrhage

General disorders and administration site conditions - edema, gait disturbance, irritability, pyrexia

Hepatobiliary disorders - elevated liver enzymes

Immune system disorders - anaphylaxis

Metabolism and nutrition disorders - diabetes mellitus, hypercholesterolemia, hypoglycemia, increased

appetite

Musculoskeletal and connective tissue disorders – arthralgia, muscle spasms, tightness, or twitching

Nervous system disorders - ataxia, coma, convulsion, decreased alertness, hypoesthesia, lethargy,

psychomotor hyperactivity, syncope

Psychiatric disorders - aggression, bruxism, confusional state, euphoric mood, hallucination

Renal and urinary disorders - hematuria

Reproductive system and breast disorders - galactorrhea, priapism, vaginal hemorrhage

Respiratory, thoracic and mediastinal disorders - bronchospasm, epistaxis, yawning

Skin and subcutaneous tissue disorders - alopecia; cold sweat; dermatitis; dermatitis bullous; pruritus;

purpura; erythematous, follicular, or maculopapular rash; urticaria

Vascular disorders - hemorrhage, hypertension, vasodilation

6.2 Post-marketing Experience

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

hydrochloride. 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.

Bleeding or clotting disorders - increased coagulation times (altered platelet function)

Cardiac disorders – AV block, bradycardia, atrial arrhythmias, QTc-interval prolongation, ventricular

tachycardia (including Torsade de Pointes) [See Clinical Pharmacology (12.2)]

Endocrine disorders - gynecomastia, hyperprolactinemia, menstrual irregularities, SIADH

Eye disorders - blindness, optic neuritis, cataract

Hepatobiliary disorders – severe liver events (including hepatitis, jaundice, liver failure with some fatal

outcomes), pancreatitis

Hemic and lymphatic disorders – agranulocytosis, aplastic anemia and pancytopenia, leukopenia,

thrombocytopenia, lupus-like syndrome, serum sickness

Immune system disorders - angioedema

Metabolism and nutrition disorders – hyponatremia, hyperglycemia

Musculoskeletal and connective tissue disorders – rhabdomyolysis, trismus

Nervous system disorders -serotonin syndrome, extrapyramidal symptoms (including akathisia and

dystonia), oculogyric crisis

Psychiatric disorders – psychosis, enuresis, paroniria

Renal and urinary disorders - acute renal failure

Respiratory, thoracic and mediastinal

disorders - pulmonary hypertension

Skin and subcutaneous tissue disorders - photosensitivity skin reaction and other severe cutaneous

reactions, which potentially can be fatal, such as Stevens-Johnson syndrome (SJS) and toxic epidermal

necrolysis (TEN)

Vascular disorders - cerebrovascular spasm (including reversible cerebral vasoconstriction syndrome

and Call-Fleming syndrome), vasculitis

7 DRUG INTERACTIONS

7.1 Clinically Significant Drug Interactions

Table 5 includes clinically significant drug interactions with sertraline hydrochloride [See Clinical

Pharmacology (12.3)].

Table 5: Clinically-Significant Drug Interactions with Sertraline Hydrochloride

Monoamine Oxidase Inhibitors (MAOIs)

Clinical Impact:

The concomitant use of SSRIs including sertraline hydrochloride and MAOIs

increases the risk of serotonin syndrome.

Intervention:

Sertraline hydrochloride is contraindicated in patients taking MAOIs, including

MAOIs such as linezolid or intravenous methylene blue [See Dosage and

Administration (2.5), Contraindications (4), Warnings and Precautions (5.2)].

Examples:

selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue

Pimozide

Clinical Impact:

Increased plasma concentrations of pimozide, a drug with a narrow therapeutic

index, may increase the risk of QTc prolongation and ventricular arrhythmias.

Intervention:

Concomitant use of pimozide and sertraline hydrochloride is contraindicated [See

Contraindications (4)].

Other Serotonergic Drugs

Clinical Impact:

The concomitant use of serotonergic drugs with sertraline hydrochloride increases

the risk of serotonin syndrome.

Intervention:

Monitor patients for signs and symptoms of serotonin syndrome, particularly during

treatment initiation and dosage increases. If serotonin syndrome occurs, consider

discontinuation of sertraline hydrochloride and/or concomitant serotonergic drugs

[See Warnings and Precautions (5.2)].

Examples:

other SSRIs, SNRIs, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol,

tryptophan, buspirone, St. John’s Wort

Drugs that Interfere with Hemostasis (antiplatelet agents and anticoagulants)

Clinical Impact:

The concurrent use of an antiplatelet agent or anticoagulant with sertraline

hydrochloride may potentiate the risk of bleeding.

Intervention:

Inform patients of the increased risk of bleeding associated with the concomitant use

of sertraline hydrochloride and antiplatelet agents and anticoagulants. For patients

taking warfarin, carefully monitor the international normalized ratio [See Warnings

and Precautions (5.3)].

Examples:

aspirin, clopidogrel, heparin, warfarin

Drugs Highly Bound to Plasma Protein

Sertraline hydrochloride is highly bound to plasma protein. The concomitant use of

sertraline hydrochloride with another drug that is highly bound to plasma protein

Clinical Impact:

sertraline hydrochloride with another drug that is highly bound to plasma protein

may increase free concentrations of sertraline hydrochloride or other tightly-bound

drugs in plasma [See Clinical Pharmacology (12.3)].

Intervention:

Monitor for adverse reactions and reduce dosage of sertraline hydrochloride or

other protein-bound drugs as warranted.

Examples:

warfarin

Drugs Metabolized by CYP2D6

Clinical Impact:

Sertraline hydrochloride is a CYP2D6 inhibitor [See Clinical Pharmacology (12.3)].

The concomitant use of sertraline hydrochloride with a CYP2D6 substrate may

increase the exposure of the CYP2D6 substrate.

Intervention:

Decrease the dosage of a CYP2D6 substrate if needed with concomitant sertraline

hydrochloride use. Conversely, an increase in dosage of a CYP2D6 substrate may

be needed if sertraline hydrochloride is discontinued.

Examples:

propafenone, flecainide, atomoxetine, desipramine, dextromethorphan, metoprolol,

nebivolol, perphenazine, thoridazine, tolterodine, venlafaxine

Phenytoin

Clinical Impact:

Phenytoin is a narrow therapeutic index drug. sertraline hydrochloride may increase

phenytoin concentrations.

Intervention:

Monitor phenytoin levels when initiating or titrating sertraline hydrochloride.

Reduce phenytoin dosage if needed.

Examples:

phenytoin, fosphenytoin

Drugs that Prolong the QTc Interval

Clinical Impact:

The risk of QTc prolongation and/or ventricular arrhythmias (e.g., TdP) is increased

with concomitant use of other drugs which prolong the QTc interval [See Warnings

and Precautions (5.10), Clinical Pharmacology (12.2)].

Intervention:

Pimozide is contraindicated for use with sertraline. Avoid the concomitant use of

drugs known to prolong the QTc interval.

Examples:

Specific

antipsychotics

(e.g.,

ziprasidone,

iloperidone,

chlorpromazine,

mesoridazine,

droperidol);

specific

antibiotics

(e.g.,

erythromycin,

gatifloxacin,

moxifloxacin, sparfloxacin); Class 1A antiarrhythmic medications (e.g., quinidine,

procainamide); Class III antiarrhythmics (e.g., amiodarone, sotalol); and others (e.g.,

pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron

mesylate, probucol or tacrolimus).

7.2 Drugs Having No Clinically Important Interactions with Sertraline Hydrochloride

Based on pharmacokinetic studies, no dosage adjustment of sertraline hydrochloride is necessary when

used in combination with cimetidine. Additionally, no dosage adjustment is required for diazepam,

lithium, atenolol, tolbutamide, digoxin, and drugs metabolized by CYP3A4, when sertraline

hydrochloride is administered concomitantly [See Clinical Pharmacology (12.3)].

7.3 False-Positive Screening Tests for Benzodiazepines

False-positive urine immunoassay screening tests for benzodiazepines have been reported in patients

taking sertraline hydrochloride. This finding is due to lack of specificity of the screening tests. False-

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

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

sertraline from benzodiazepines.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Overall, available published epidemiologic studies of pregnant women exposed to sertraline in the first

trimester suggest no difference in major birth defect risk compared to the background rate for major

birth defects in comparator populations. Some studies have reported increases for specific major birth

defects; however, these study results are inconclusive [See Data]. There are clinical considerations

regarding neonates exposed to SSRIs and SNRIs, including sertraline hydrochloride, during the third

trimester of pregnancy [See Clinical Considerations].

Although no teratogenicity was observed in animal reproduction studies, delayed fetal ossification was

observed when sertraline was administered during the period of organogenesis at doses less than the

maximum recommended human dose (MRHD) in rats and doses 3.1 times the MRHD in rabbits on a

mg/m basis in adolescents. When sertraline was administered to female rats during the last third of

gestation, there was an increase in the number of stillborn pups and pup deaths during the first four days

after birth at the MRHD [See Data].

The background risk of major birth defects and miscarriage for the indicated population are unknown. In

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

clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Advise a pregnant woman of

possible risks to the fetus when prescribing sertraline hydrochloride.

Sertraline hydrochloride oral solution contains 12% alcohol and is not recommended during pregnancy

because there is no known safe level of alcohol exposure during pregnancy.

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

A prospective longitudinal study followed 201 pregnant women with a history of major depression who

were euthymic taking antidepressants at the beginning of pregnancy. The women who discontinued

antidepressants during pregnancy were more likely to experience a relapse of major depression than

women who continued antidepressants. Consider the risks of untreated depression when discontinuing

or changing treatment with antidepressant medication during pregnancy and postpartum.

Fetal/Neonatal adverse reactions

Exposure to SSRIs and SNRIs, including sertraline hydrochloride in late pregnancy may lead to an

increased risk for neonatal complications requiring prolonged hospitalization, respiratory support, and

tube feeding, and/or persistent pulmonary hypertension of the newborn (PPHN).

When treating a pregnant woman with sertraline hydrochloride during the third trimester, carefully

consider both the potential risks and benefits of treatment. Monitor neonates who were exposed to

sertraline hydrochloride in the third trimester of pregnancy for PPHN and drug discontinuation

syndrome [See Data].

Data

Human Data

Third Trimester Exposure

Neonates exposed to sertraline hydrochloride and other SSRIs or SNRIs late in the third trimester have

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

These findings are based on post-marketing reports. Such complications can arise immediately upon

delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures,

temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia,

hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with

either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. In some

cases, the clinical picture was consistent with serotonin syndrome [See Warnings and Precautions (5.2)].

Exposure during late pregnancy to SSRIs may have an increased risk for persistent pulmonary

hypertension of the newborn (PPHN). PPHN occurs in 1 to 2 per 1,000 live births in the general

population and is associated with substantial neonatal morbidity and mortality. In a retrospective case-

control study of 377 women whose infants were born with PPHN and 836 women whose infants were

born healthy, the risk for developing PPHN was approximately six-fold higher for infants exposed to

SSRIs after the 20

week of gestation compared to infants who had not been exposed to antidepressants

during pregnancy. A study of 831,324 infants born in Sweden in 1997 to 2005 found a PPHN risk ratio

of 2.4 (95% CI 1.2-4.3) associated with patient-reported maternal use of SSRIs “in early pregnancy” and

a PPHN risk ratio of 3.6 (95% CI 1.2 to 8.3) associated with a combination of patient-reported maternal

use of SSRIs “in early pregnancy” and an antenatal SSRI prescription “in later pregnancy”.

First Trimester Exposure

The weight of evidence from epidemiologic studies of pregnant women exposed to sertraline in the

first trimester suggest no difference in major birth defect risk compared to the background rate for

major birth defects in pregnant women who were not exposed to sertraline. A meta-analysis of studies

suggest no increase in the risk of total malformations (summary odds ratio=1.01, 95% CI=0.88 to 1.17)

or cardiac malformations (summary odds ratio=0.93, 95% CI=0.70 to 1.23) among offspring of women

with first trimester exposure to sertraline. An increased risk of congenital cardiac defects, specifically

septal defects, the most common type of congenital heart defect, was observed in some published

epidemiologic studies with first trimester sertraline exposure; however, most of these studies were

limited by the use of comparison populations that did not allow for the control of confounders such as

the underlying depression and associated conditions and behaviors, which may be factors associated

with increased risk of these malformations.

Animal Data

Reproduction studies have been performed in rats and rabbits at doses up to 80 mg/kg/day and 40

mg/kg/day, respectively. These doses correspond to approximately 3.1 times the maximum

recommended human dose (MRHD) of 200 mg/day on a mg/m basis in adolescents. There was no

evidence of teratogenicity at any dose level. When pregnant rats and rabbits were given sertraline

during the period of organogenesis, delayed ossification was observed in fetuses at doses of 10 mg/kg

(0.4 times the MRHD on a mg/m basis) in rats and 40 mg/kg (3.1 times the MRHD on a mg/m basis) in

rabbits. When female rats received sertraline during the last third of gestation and throughout lactation,

there was an increase in stillborn pups and pup deaths during the first 4 days after birth. Pup body

weights were also decreased during the first four days after birth. These effects occurred at a dose of

20 mg/kg (0.8 times the MRHD on a mg/m basis). The no effect dose for rat pup mortality was 10

mg/kg (0.4 times the MRHD on a mg/m basis). The decrease in pup survival was shown to be due to in

utero exposure to sertraline. The clinical significance of these effects is unknown.

8.2 Lactation

Risk Summary

Available data from published literature demonstrate low levels of sertraline and its metabolites in

human milk [See Data]. There are no data on the effects of sertraline on milk production. The

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

clinical need for sertraline hydrochloride and any potential adverse effects on the breastfed infant from

the drug or from the underlying maternal condition.

Data

In a published pooled analysis of 53 mother-infant pairs, exclusively human milk-fed infants had an

average of 2% (range 0% to 15%) of the sertraline serum levels measured in their mothers. No adverse

reactions were observed in these infants.

8.4 Pediatric Use

The safety and efficacy of sertraline hydrochloride have been established in the treatment of OCD in

pediatric patients aged 6 to 17 [See Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies

(14.2)]. Safety and effectiveness in pediatric patients in patients with OCD below the age of 6 have not

been established. Safety and effectiveness have not been established in pediatric patients for indications

other than OCD. Two placebo-controlled trials were conducted in pediatric patients with MDD, but the

data were not sufficient to support an indication for use in pediatric patients.

Monitoring Pediatric Patients Treated with Sertraline Hydrochloride

Monitor all patients being treated with antidepressants for clinical worsening, suicidal thoughts, and

unusual changes in behavior, especially during the initial few months of treatment, or at times of dose

increases or decreases [See Boxed Warning, Warnings and Precautions (5.1)]. Decreased appetite and

weight loss have been observed with the use of SSRIs. Monitor weight and growth in pediatric patients

treated with an SSRI such as sertraline hydrochloride.

Weight Loss in Studies in Pediatric Patients with MDD

In a pooled analysis of two 10-week, double-blind, placebo-controlled, flexible dose (50 to 200 mg)

outpatient trials for MDD (n=373), there was a difference in weight change between sertraline

hydrochloride and placebo of roughly 1 kg, for both children (ages 6 to 11) and adolescents (ages 12 to

17), in both age groups representing a slight weight loss for the sertraline hydrochloride group

compared to a slight gain for the placebo group. For children, about 7% of the sertraline

hydrochloride-treated patients had a weight loss greater than 7% of body weight compared to 0% of the

placebo-treated patients; for adolescents, about 2% of sertraline hydrochloride-treated patients had a

weight loss > 7% of body weight compared to about 1% of placebo-treated patients.

A subset of patients who completed the randomized controlled trials in patients with MDD (sertraline

hydrochloride n=99, placebo n=122) were continued into a 24-week, flexible-dose, open-label,

extension study. Those subjects who completed 34 weeks of sertraline hydrochloride treatment (10

weeks in a placebo-controlled trial + 24 weeks open-label, n=68) had weight gain that was similar to

that expected using data from age-adjusted peers. However, there are no studies that directly evaluate

the long-term effects of sertraline hydrochloride on the growth, development, and maturation in

pediatric patients.

Alcohol Content in sertraline hydrochloride oral solution

Sertraline hydrochloride oral solution contains 12% alcohol.

Juvenile Animal Data

A study conducted in juvenile rats at clinically relevant doses showed delay in sexual maturation, but

there was no effect on fertility in either males or females.

In this study in which juvenile rats were treated with oral doses of sertraline at 0, 10, 40 or 80

mg/kg/day from postnatal day 21 to 56, a delay in sexual maturation was observed in males treated with

80 mg/kg/day and females treated with doses ≥10 mg/kg/day. There was no effect on male and female

reproductive endpoints or neurobehavioral development up to the highest dose tested (80 mg/kg/day),

except a decrease in auditory startle response in females at 40 and 80 mg/kg/day at the end of treatment

but not at the end of the drug –free period. The highest dose of 80 mg/kg/day produced plasma levels

(AUC) of sertraline 5 times those seen in pediatric patients (6 to 17 years of age) receiving the

maximum recommended dose of sertraline (200 mg/day).

8.5 Geriatric Use

Of the total number of patients in clinical studies of sertraline hydrochloride in patients with MDD,

OCD, PD, PTSD, SAD and PMDD, 797 (17%) were ≥ 65 years old, while 197 (4%) were ≥ 75 years

old.

No overall differences in safety or effectiveness were observed between these subjects and younger

subjects, and other reported clinical experience has not identified differences in responses between the

elderly and younger patients. In general, dose selection for an elderly patient should be conservative,

usually starting at the low end of the dosing range, reflecting the greater frequency of decreased

hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

In 354 geriatric subjects treated with sertraline hydrochloride in MDD placebo-controlled trials, the

overall profile of adverse reactions was generally similar to that shown in Table 3 [See Adverse

Reactions (6.1)], except for tinnitus, arthralgia with an incidence of at least 2% and at a rate greater than

placebo in geriatric patients.

SNRIs and SSRIs, including sertraline hydrochloride, have been associated with cases of clinically

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

Warnings and Precautions (5.8)].

8.6 Hepatic Impairment

The recommended dosage in patients with mild hepatic impairment (Child-Pugh score 5 or 6) is half the

recommended dosage due to increased exposure in this patient population. The use of sertraline

hydrochloride in patients with moderate (Child-Pugh score 7 to 10) or severe hepatic impairment

(Child-Pugh score 10 to 15) is not recommended, because sertraline hydrochloride is extensively

metabolized, and the effects of sertraline hydrochloride in patients with moderate and severe hepatic

impairment have not been studied [See Dosage and Administration (2.4), Clinical Pharmacology (12.3)].

8.7 Renal Impairment

No dose adjustment is needed in patients with mild to severe renal impairment. Sertraline exposure does

not appear to be affected by renal impairment [See Clinical Pharmacology (12.3)].

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

Sertraline hydrochloride oral solution contains sertraline, which is not a controlled substance.

9.2 Abuse

In a placebo-controlled, double-blind, randomized study of the comparative abuse liability of sertraline

hydrochloride oral solution, alprazolam, and d-amphetamine in humans, sertraline hydrochloride oral

solution did not produce the positive subjective effects indicative of abuse potential, such as euphoria

or drug liking, that were observed with the other two drugs.

10 OVERDOSAGE

Human Experience

The most common signs and symptoms associated with non-fatal sertraline hydrochloride overdosage

were somnolence, vomiting, tachycardia, nausea, dizziness, agitation and tremor. No cases of fatal

overdosage with only sertraline have been reported.

Other important adverse events reported with sertraline hydrochloride overdose (single or multiple

drugs) include bradycardia, bundle branch block, coma, convulsions, delirium, hallucinations,

hypertension, hypotension, manic reaction, pancreatitis, QTc-interval prolongation, Torsade de Pointes,

serotonin syndrome, stupor, and syncope [See Clinical Pharmacology (12.2)].

Overdose Management

No specific antidotes for sertraline hydrochloride are known. Contact Poison Control (1-800-222-

1222) for latest recommendations.

11 DESCRIPTION

Sertraline hydrochloride oral solution USP contains sertraline hydrochloride, an SSRI. Sertraline

hydrochloride has a molecular weight of 342.7 and has the following chemical name: (1S-cis)-4-(3,4-

dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine hydrochloride. The molecular formula

H NCl

HCl is represented by the following structural formula:

2

Sertraline hydrochloride USP is a white crystalline powder that is slightly soluble in water and

isopropyl alcohol, and sparingly soluble in ethanol.

Sertraline hydrochloride oral solution USP is available in a multidose 60 mL bottle. Each mL of

solution contains sertraline hydrochloride USP equivalent to 20 mg of sertraline. The solution contains

the following inactive ingredients: alcohol (12%), natural peppermint flavor, propylene glycol and

purified water. The oral solution must be diluted prior to administration [See Dosage and Administration

(2.7)].

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Sertraline potentiates serotonergic activity in the central nervous system through inhibition of neuronal

reuptake of serotonin (5-HT).

12.2 Pharmacodynamics

Studies at clinically relevant doses have demonstrated that sertraline blocks the uptake of serotonin into

human platelets. In vitro studies in animals also suggest that sertraline is a potent and selective inhibitor

of neuronal serotonin reuptake and has only very weak effects on norepinephrine and dopamine neuronal

reuptake. In vitro studies have shown that sertraline has no significant affinity for adrenergic (alpha1,

alpha2, beta), cholinergic, GABA, dopaminergic, histaminergic, serotonergic (5HT1A, 5HT1B, 5HT2),

or benzodiazepine receptors. The chronic administration of sertraline was found in animals to down

regulate brain norepinephrine receptors. Sertraline does not inhibit monoamine oxidase.

Alcohol

In healthy subjects, the acute cognitive and psychomotor effects of alcohol were not potentiated by

sertraline hydrochloride oral solution.

Cardiac Electrophysiology

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

positive-controlled three-period crossover thorough QTc study in 54 healthy adult subjects. At 2-fold

the maximum recommended daily dose (~3-fold the steady-state exposure for sertraline and N-

desmethylsertraline), the largest mean ΔΔQTc was 10 ms with upper bound of two-sided 90%

confidence interval of 12 ms. The length of the QTc interval was also positively correlated with serum

concentrations of sertraline and N-desmethylsertraline concentrations. These concentration-based

analyses, however, indicated a lesser effect on QTc at maximally observed concentration than in the

primary analysis [See Warnings and Precautions (5), Adverse Reactions (6), Drug Interactions (7),

Overdosage (10)].

12.3 Pharmacokinetics

Absorption

Following oral once-daily sertraline hydrochloride dosing over the range of 50 to 200 mg for 14 days,

mean peak plasma concentrations (C

) of sertraline occurred between 4.5 to 8.4 hours post-dosing.

The average terminal elimination half-life of plasma sertraline is about 26 hours. Consistent with the

terminal elimination half-life, there is an approximately two-fold accumulation up to steady-state

concentrations, which are achieved after one week of once-daily dosing. Linear dose-proportional

pharmacokinetics were demonstrated in a single dose study in which the C

and area under the plasma

concentration time curve (AUC) of sertraline were proportional to dose over a range of 50 to 200 mg.

The single dose bioavailability of sertraline hydrochloride tablets is approximately equal to an

equivalent dose of sertraline hydrochloride oral solution. Administration with food causes a small

increase in C

and AUC.

Metabolism

Sertraline undergoes extensive first pass metabolism. The principal initial pathway of metabolism for

sertraline is N-demethylation. N-desmethylsertraline has a plasma terminal elimination half-life of 62 to

104 hours. Both in vitro biochemical and in vivo pharmacological testing have shown N-

desmethylsertraline to be substantially less active than sertraline. Both sertraline and N-

desmethylsertraline undergo oxidative deamination and subsequent reduction, hydroxylation, and

glucuronide conjugation. In a study of radiolabeled sertraline involving two healthy male subjects,

sertraline accounted for less than 5% of the plasma radioactivity. About 40 to 45% of the administered

radioactivity was recovered in urine in 9 days. Unchanged sertraline was not detectable in the urine. For

the same period, about 40 to 45% of the administered radioactivity was accounted for in feces,

including 12 to 14% unchanged sertraline.

Desmethylsertraline exhibits time-related, dose dependent increases in AUC (0 to 24-hour), C

, with about a 5- to 9-fold increase in these pharmacokinetic parameters between day 1 and day 14.

Protein Binding

In vitro protein binding studies performed with radiolabeled 3H-sertraline showed that sertraline is

highly bound to serum proteins (98%) in the range of 20 to 500 ng/mL. However, at up to 300 and 200

ng/mL concentrations, respectively, sertraline and N-desmethylsertraline did not alter the plasma protein

binding of two other highly protein bound drugs, warfarin and propranolol.

Studies in Specific Populations

Pediatric Patients

Sertraline pharmacokinetics were evaluated in a group of 61 pediatric patients (29 aged 6 to 12 years,

32 aged 13 to 17 years) including both males (N=28) and females (N=33). Relative to the adults,

pediatric patients aged 6 to 12 years and 13 to 17 years showed about 22% lower AUC (0 to 24 hr) and

values when plasma concentration was adjusted for weight. The half-life was similar to that in

values when plasma concentration was adjusted for weight. The half-life was similar to that in

adults, and no gender-associated differences were observed [See Dosage and Administration (2.1), Use

in Specific Populations (8.4)].

Geriatric Patients

Sertraline plasma clearance in a group of 16 (8 male, 8 female) elderly patients treated with 100

mg/day of sertraline hydrochloride for 14 days was approximately 40% lower than in a similarly

studied group of younger (25 to 32 year old) individuals. Steady-state, therefore, was achieved after 2

to 3 weeks in older patients. The same study showed a decreased clearance of desmethylsertraline in

older males, but not in older females [See Use in Specific Populations (8.5)].

Hepatic Impairment

In patients with chronic mild liver impairment (N=10: 8 patients with Child-Pugh scores of 5 to 6; and 2

patients with Child-Pugh scores of 7 to 8) who received 50 mg of sertraline hydrochloride per day for

21 days, sertraline clearance was reduced, resulting in approximately 3-fold greater exposure compared

to age-matched volunteers with normal hepatic function (N=10). The exposure to desmethylsertraline

was approximately 2-fold greater in patients with mild hepatic impairment compared to age-matched

volunteers with normal hepatic function. There were no significant differences in plasma protein

binding observed between the two groups. The effects of sertraline hydrochloride in patients with

moderate and severe hepatic impairment have not been studied [See Dosage and Administration (2.4), Use

in Specific Populations (8.6)].

Renal Impairment

Sertraline is extensively metabolized and excretion of unchanged drug in urine is a minor route of

elimination. In volunteers with mild to moderate (CLcr=30 to 60 mL/min), moderate to severe (CLcr=10

to 29 mL/min) or severe (receiving hemodialysis) renal impairment (N=10 each group), the

pharmacokinetics and protein binding of 200 mg sertraline per day maintained for 21 days were not

altered compared to age-matched volunteers (N=12) with no renal impairment. Thus sertraline multiple

dose pharmacokinetics appear to be unaffected by renal impairment [See Use in Specific Populations

(8.7)].

Drug Interaction Studies

Pimozide

In a controlled study of a single dose (2 mg) of pimozide, 200 mg sertraline hydrochloride (once daily)

co-administration to steady state was associated with a mean increase in pimozide AUC and C

about 40%, but was not associated with any changes in ECG. The highest recommended pimozide dose

(10 mg) has not been evaluated in combination with sertraline hydrochloride. The effect on QTc interval

and PK parameters at doses higher than 2 mg of pimozide are not known [See Drug Interactions (7.1)].

Drugs Metabolized by CYP2D6

Many antidepressant drugs (e.g., SSRIs, including sertraline hydrochloride, and most tricyclic

antidepressant drugs) inhibit the biochemical activity of the drug metabolizing isozyme CYP2D6

(debrisoquin hydroxylase), and, thus, may increase the plasma concentrations of co-administered drugs

that are metabolized by CYP2D6. The drugs for which this potential interaction is of greatest concern

are those metabolized primarily by CYP2D6 and that have a narrow therapeutic index (e.g., tricyclic

antidepressant drugs and the Type 1C antiarrhythmics propafenone and flecainide). The extent to which

this interaction is an important clinical problem depends on the extent of the inhibition of CYP2D6 by

the antidepressant and the therapeutic index of the co-administered drug. There is variability among the

drugs effective in the treatment of MDD in the extent of clinically important 2D6 inhibition, and in fact

sertraline hydrochloride at lower doses has a less prominent inhibitory effect on 2D6 than some others

in the class. Nevertheless, even sertraline hydrochloride has the potential for clinically important 2D6

inhibition [See Drug Interactions (7.1)].

Phenytoin

Clinical trial data suggested that sertraline hydrochloride may increase phenytoin concentrations [See

Drug Interactions (7.1)].

Cimetidine

In a study assessing disposition of sertraline hydrochloride (100 mg) on the second of 8 days of

cimetidine administration (800 mg daily), there were increases in sertraline hydrochloride mean AUC

(50%), C

(24%) and half-life (26%) compared to the placebo group [See Drug Interactions (7.2)].

Diazepam

In a study comparing the disposition of intravenously administered diazepam before and after 21 days of

dosing with either sertraline hydrochloride (50 to 200 mg/day escalating dose) or placebo, there was a

32% decrease relative to baseline in diazepam clearance for the sertraline hydrochloride group

compared to a 19% decrease relative to baseline for the placebo group (p<0.03). There was a 23%

increase in T

for desmethyldiazepam in the sertraline hydrochloride group compared to a 20%

decrease in the placebo group (p<0.03) [See Drug Interactions (7.2)].

Lithium

In a placebo-controlled trial in normal volunteers, the administration of two doses of sertraline

hydrochloride did not significantly alter steady-state lithium levels or the renal clearance of lithium

[See Drug Interactions (7.2)].

Tolbutamide

In a placebo-controlled trial in normal volunteers, administration of sertraline hydrochloride for 22 days

(including 200 mg/day for the final 13 days) caused a statistically significant 16% decrease from

baseline in the clearance of tolbutamide following an intravenous 1000 mg dose. Sertraline

hydrochloride administration did not noticeably change either the plasma protein binding or the apparent

volume of distribution of tolbutamide, suggesting that the decreased clearance was due to a change in

the metabolism of the drug [See Drug Interactions (7.2)].

Atenolol

Sertraline hydrochloride (100 mg) when administered to 10 healthy male subjects had no effect on the

beta-adrenergic blocking ability of atenolol [See Drug Interactions (7.2)].

Digoxin

In a placebo-controlled trial in normal volunteers, administration of sertraline hydrochloride for 17 days

(including 200 mg/day for the last 10 days) did not change serum digoxin levels or digoxin renal

clearance [See Drug Interactions (7.2)].

Drugs Metabolized by CYP3A4

In three separate in vivo interaction studies, sertraline hydrochloride was co-administered with CYP3A4

substrates, terfenadine, carbamazepine, or cisapride under steady-state conditions. The results of these

studies indicated that sertraline hydrochloride did not increase plasma concentrations of terfenadine,

carbamazepine, or cisapride. These data indicate that sertraline hydrochloride’s extent of inhibition of

CYP3A4 activity is not likely to be of clinical significance. Results of the interaction study with

cisapride indicate that sertraline hydrochloride 200 mg (once daily) induces the metabolism of

cisapride (cisapride AUC and C

were reduced by about 35%) [See Drug Interactions (7.2)].

Microsomal Enzyme Induction

Preclinical studies have shown sertraline hydrochloride to induce hepatic microsomal enzymes. In

clinical studies, sertraline hydrochloride was shown to induce hepatic enzymes minimally as determined

by a small (5%) but statistically significant decrease in antipyrine half-life following administration of

200 mg of sertraline hydrochloride per day for 21 days. This small change in antipyrine half-life

reflects a clinically insignificant change in hepatic metabolism.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Lifetime carcinogenicity studies were carried out in CD-1 mice and Long-Evans rats at doses up to 40

mg/kg/day. These doses correspond to 1 times (mice) and 2 times (rats) the maximum recommended

human dose (MRHD) of 200 mg/day on a mg/m basis. There was a dose-related increase of liver

adenomas in male mice receiving sertraline at 10 to 40 mg/kg (0.25 to 1.0 times the MRHD on a mg/m

basis). No increase was seen in female mice or in rats of either sex receiving the same treatments, nor

was there an increase in hepatocellular carcinomas. Liver adenomas have a variable rate of spontaneous

occurrence in the CD-1 mouse and are of unknown significance to humans. There was an increase in

follicular adenomas of the thyroid in female rats receiving sertraline at 40 mg/kg (2 times the MRHD on

a mg/m basis); this was not accompanied by thyroid hyperplasia. While there was an increase in uterine

adenocarcinomas in rats receiving sertraline at 10 to 40 mg/kg (0.5 to 2.0 times the MRHD on a mg/m

basis) compared to placebo controls, this effect was not clearly drug related.

Mutagenesis

Sertraline had no genotoxic effects, with or without metabolic activation, based on the following

assays: bacterial mutation assay; mouse lymphoma mutation assay; and tests for cytogenetic aberrations

in vivo in mouse bone marrow and in vitro in human lymphocytes.

Impairment of Fertility

A decrease in fertility was seen in one of two rat studies at a dose of 80 mg/kg (3.1 times the maximum

recommended human dose on a mg/m basis in adolescents).

14 CLINICAL STUDIES

Efficacy of sertraline hydrochloride was established in the following trials:

MDD: two short-term trials and one maintenance trials in adults [See Clinical Studies (14.1)].

OCD: three short-term trials in adults and one short-term trial in pediatric patients [See Clinical

Studies (14.2)].

PD: three short-term trials and one maintenance trial in adults [See Clinical Studies (14.3)].

PTSD: two short-term trials and one maintenance trial in adults [See Clinical Studies (14.4)].

SAD: two short-term trials and one maintenance trial in adults [See Clinical Studies (14.5)].

PMDD: two short-term trials in adult female patients [See Clinical Studies (14.6)].

14.1 Major Depressive Disorder

The efficacy of sertraline hydrochloride as a treatment for MDD was established in two randomized,

double-blind, placebo-controlled studies and one double-blind, randomized-withdrawal study following

an open label study in adult (ages 18 to 65) outpatients who met the Diagnostic and Statistical Manual of

Mental Disorders (DSM-III) criteria for MDD (studies MDD-1 and MDD-2).

Study MDD-1 was an 8-week, 3-arm study with flexible dosing of sertraline hydrochloride,

amitriptyline, and placebo. Adult patients received sertraline hydrochloride (N=126, in a daily dose

titrated weekly to 50 mg, 100 mg, or 200 mg), amitriptyline (N=123, in a daily dose titrated weekly

to 50 mg, 100 mg, or 150 mg), or placebo (N= 130).

Study MDD-2 was a 6-week, multicenter parallel study of three fixed doses of sertraline

hydrochloride administered once daily at 50 mg (N=82), 100 mg (N=75), and 200 mg (N=56) doses

and placebo (N=76) in the treatment of adult outpatients with MDD.

Overall, these studies demonstrated sertraline hydrochloride to be superior to placebo on the Hamilton

Rating Scale for Depression (HAMD-17) and the Clinical Global Impression Severity (CGI-S) of

Illness and Global Improvement (CGI-I) scores. Study MDD-2 was not readily interpretable regarding a

dose response relationship for effectiveness.

A third study (Study MDD-3) involved adult outpatients meeting the DSM-III criteria for MDD who had

responded by the end of an initial 8-week open treatment phase on sertraline hydrochloride 50 to 200

mg/day. These patients (n=295) were randomized to continuation on double-blind sertraline

hydrochloride 50 to 200 mg/day or placebo for 44 weeks. A statistically significantly lower relapse

rate was observed for patients taking sertraline hydrochloride compared to those on placebo: sertraline

hydrochloride [n=11 (8%)] and placebo [n=31 (39%)]. The mean sertraline hydrochloride dose for

completers was 70 mg/day.

Analyses for gender effects on outcome did not suggest any differential responsiveness on the basis of

sex.

14.2 Obsessive-Compulsive Disorder

Adults with OCD

The effectiveness of sertraline hydrochloride in the treatment of OCD was demonstrated in three

multicenter placebo-controlled studies of adult (age 18 to 65) non-depressed outpatients (Studies OCD-

1, OCD-2, and OCD-3). Patients in all three studies had moderate to severe OCD (DSM-III or DSM-III-

R) with mean baseline ratings on the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) total score

ranging from 23 to 25.

Study OCD-1 was an 8-week randomized, placebo-controlled study with flexible dosing of

sertraline hydrochloride in a range of 50 to 200 mg/day, titrated in 50 mg increments every 4 days to

a maximally tolerated dose; the mean dose for completers was 186 mg/day. Patients receiving

sertraline hydrochloride (N=43) experienced a mean reduction of approximately 4 points on the Y-

BOCS total score which was statistically significantly greater than the mean reduction of 2 points in

placebo-treated patients (N=44). The mean change in Y-BOCS from baseline to last visit (the

primary efficacy endpoint) was -3.79 (sertraline hydrochloride) and -1.48 (placebo).

Study OCD-2 was a 12-week randomized, placebo-controlled fixed-dose study, including sertraline

hydrochloride doses of 50, 100, and 200 mg/day. Sertraline hydrochloride (N=240) was titrated to

the assigned dose over two weeks in 50 mg increments every 4 days. Patients receiving sertraline

hydrochloride doses of 50 and 200 mg/day experienced mean reductions of approximately 6 points

on the Y-BOCS total score, which were statistically significantly greater than the approximately 3

point reduction in placebo-treated patients (N=84). The mean change in Y-BOCS from baseline to

last visit (the primary efficacy endpoint) was -5.7 (pooled results from sertraline hydrochloride 50

mg, 100 mg, and 150 mg) and -2.85 (placebo).

Study OCD-3 was a 12-week randomized, placebo controlled study with flexible dosing of

sertraline hydrochloride in a range of 50 to 200 mg/day; the mean dose for completers was 185

mg/day. Sertraline hydrochloride (N=241) was titrated to the assigned dose over two weeks in 50

mg increments every 4 days. Patients receiving sertraline hydrochloride experienced a mean

reduction of approximately 7 points on the Y-BOCS total score which was statistically significantly

greater than the mean reduction of approximately 4 points in placebo-treated patients (N=84). The

mean change in Y-BOCS from baseline to last visit (the primary efficacy endpoint) was -6.5

(sertraline hydrochloride) and -3.6 (placebo).

Analyses for age and gender effects on outcome did not suggest any differential responsiveness on the

basis of age or sex.

The effectiveness of sertraline hydrochloride was studied in the risk reduction of OCD relapse. In

Study OCD-4, patients ranging in age from 18 to 79 meeting DSM-III-R criteria for OCD who had

responded during a 52-week single-blind trial on sertraline hydrochloride 50 to 200 mg/day (n=224)

were randomized to continuation of sertraline hydrochloride or to substitution of placebo for up to 28

weeks of observation for analysis of discontinuation due to relapse or insufficient clinical response.

Response during the single-blind phase was defined as a decrease in the Y-BOCS score of ≥ 25%

compared to baseline and a CGI-I of 1 (very much improved), 2 (much improved) or 3 (minimally

improved). Insufficient clinical response during the double-blind phase indicated a worsening of the

patient’s condition that resulted in study discontinuation, as assessed by the investigator. Relapse during

the double-blind phase was defined as the following conditions being met (on three consecutive visits

for 1 and 2, and condition 3 being met at visit 3):

Condition 1: Y-BOCS score increased by ≥ 5 points, to a minimum of 20, relative to baseline;

Condition 2: CGI-I increased by ≥ one point; and

Condition 3: Worsening of the patient’s condition in the investigator’s judgment, to justify

alternative treatment.

Patients receiving continued sertraline hydrochloride treatment experienced a statistically significantly

lower rate of discontinuation due to relapse or insufficient clinical response over the subsequent 28

weeks compared to those receiving placebo. This pattern was demonstrated in male and female subjects.

Pediatric Patients with OCD

The effectiveness of sertraline hydrochloride for the treatment of OCD was demonstrated in a 12-week,

multicenter, placebo-controlled, parallel group study in a pediatric outpatient population (ages 6 to 17)

(Study OCD-5). Sertraline hydrochloride (N=92) was initiated at doses of either 25 mg/day (pediatric

patients ages 6 to 12) or 50 mg/day (adolescents, ages 13 to 17), and then titrated at 3 and 4 day intervals

(25 mg incremental dose for pediatric patients ages 6 to 12) or 1 week intervals (50 mg incremental dose

adolescents ages 13 to 17) over the next four weeks to a maximum dose of 200 mg/day, as tolerated.

The mean dose for completers was 178 mg/day. Dosing was once a day in the morning or evening.

Patients in this study had moderate to severe OCD (DSM-III-R) with mean baseline ratings on the

Children’s Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) total score of 22. Patients receiving

sertraline hydrochloride experienced a mean reduction of approximately 7 units on the CY-BOCS total

score which was statistically significantly greater than the 3 unit reduction for placebo patients (n=95).

Analyses for age and gender effects on outcome did not suggest any differential responsiveness on the

basis of age or sex.

14.3 Panic Disorder

The effectiveness of sertraline hydrochloride in the treatment of PD was demonstrated in three double-

blind, placebo-controlled studies (Studies PD-1, PD-2, and PD-3) of adult outpatients who had a primary

diagnosis of PD (DSM-III-R), with or without agoraphobia.

Studies PD-1 and PD-2 were 10-week flexible dose studies of sertraline hydrochloride (N=80

study PD-1 and N=88 study PD-2) compared to placebo (N=176 study PD-1 and PD-2). In both

studies, sertraline hydrochloride was initiated at 25 mg/day for the first week, then titrated in weekly

increments of 50 mg per day to a maximum dose of 200 mg/day on the basis of clinical response and

toleration. The mean sertraline hydrochloride doses for completers to 10 weeks were 131 mg/day

and 144 mg/day, respectively, for Studies PD-1 and PD-2. In these studies, sertraline hydrochloride

was shown to be statistically significantly more effective than placebo on change from baseline in

panic attack frequency and on the Clinical Global Impression Severity (CGI-S) of Illness and Global

Improvement (CGI-I) scores. The difference between sertraline hydrochloride and placebo in

reduction from baseline in the number of full panic attacks was approximately 2 panic attacks per

week in both studies.

Study PD-3 was a 12-week randomized, double-blind fixed-dose study, including sertraline

hydrochloride doses of 50, 100, and 200 mg/day. Patients receiving sertraline hydrochloride (50

mg N=43, 100 mg N=44, 200 mg N=45) experienced a statistically significantly greater reduction in

panic attack frequency than patients receiving placebo (N=45). Study PD-3 was not readily

interpretable regarding a dose response relationship for effectiveness.

Subgroup analyses did not indicate that there were any differences in treatment outcomes as a function

of age, race, or gender.

In Study PD-4, patients meeting DSM-III-R criteria for PD who had responded during a 52-week open

trial on sertraline hydrochloride 50 to 200 mg/day (n=183) were randomized to continuation of

sertraline hydrochloride or to substitution of placebo for up to 28 weeks of observation for

discontinuation due to relapse or insufficient clinical response. Response during the open phase was

defined as a CGI-I score of 1(very much improved) or 2 (much improved). Insufficient clinical response

in the double-blind phase indicated a worsening of the patient’s condition that resulted in study

discontinuation, as assessed by the investigator. Relapse during the double-blind phase was defined as

the following conditions being met on three consecutive visits:

(1) CGI-I ≥ 3;

(2) meets DSM-III-R criteria for PD;

(3) number of panic attacks greater than at baseline.

Patients receiving continued sertraline hydrochloride treatment experienced a statistically significantly

lower rate of discontinuation due to relapse or insufficient clinical response over the subsequent 28

weeks compared to those receiving placebo. This pattern was demonstrated in male and female subjects.

14.4 Posttraumatic Stress Disorder

The effectiveness of sertraline hydrochloride in the treatment of PTSD was established in two

multicenter placebo-controlled studies (Studies PSTD-1 and PSTD-2) of adult outpatients who met

DSM-III-R criteria for PTSD. The mean duration of PTSD for these patients was 12 years (Studies

PSTD-1 and PSTD-2 combined) and 44% of patients (169 of the 385 patients treated) had secondary

depressive disorder.

Studies PSTD-1 and PSTD-2 were 12-week flexible dose studies. Sertraline hydrochloride was

initiated at 25 mg/day for the first week, and titrated in weekly increments of 50 mg per day to a

maximum dose of 200 mg/day on the basis of clinical response and tolerability. The mean sertraline

hydrochloride dose for completers was 146 mg/day and 151 mg/day, respectively, for Studies PSTD-1

and PSTD-2. Study outcome was assessed by the Clinician-Administered PTSD Scale Part 2 (CAPS),

which is a multi-item instrument that measures the three PTSD diagnostic symptom clusters of

reexperiencing/intrusion, avoidance/numbing, and hyperarousal as well as the patient-rated Impact of

Event Scale (IES), which measures intrusion and avoidance symptoms. Patients receiving sertraline

hydrochloride (N=99 and N=94, respectively) showed statistically significant improvement compared

to placebo (N=83 and N=92) on change from baseline to endpoint on the CAPS, IES, and on the Clinical

Global Impressions (CGI-S) Severity of Illness and Global Improvement (CGI-I) scores.

In two additional placebo-controlled PTSD trials (Studies PSTD-3 and PSTD-4), the difference in

response to treatment between patients receiving sertraline hydrochloride and patients receiving

placebo was not statistically significant. One of these additional studies was conducted in patients

similar to those recruited for Studies PSTD-1 and PSTD-2, while the second additional study was

conducted in predominantly male veterans.

As PTSD is a more common disorder in women than men, the majority (76%) of patients in Studies

PSTD-1 and PSTD-2 described above were women. Post hoc exploratory analyses revealed a

statistically significant difference between sertraline hydrochloride and placebo on the CAPS, IES and

CGI in women, regardless of baseline diagnosis of comorbid major depressive disorder, but essentially

no effect in the relatively smaller number of men in these studies. The clinical significance of this

apparent gender effect is unknown at this time. There was insufficient information to determine the

effect of race or age on outcome.

In Study PSTD-5, patients meeting DSM-III-R criteria for PTSD who had responded during a 24-week

open trial on sertraline hydrochloride 50 to 200 mg/day (n=96) were randomized to continuation of

sertraline hydrochloride or to substitution of placebo for up to 28 weeks of observation for relapse.

Response during the open phase was defined as a CGI-I of 1 (very much improved) or 2 (much

improved), and a decrease in the CAPS-2 score of > 30% compared to baseline. Relapse during the

double-blind phase was defined as the following conditions being met on two consecutive visits:

(1) CGI-I ≥ 3;

(2) CAPS-2 score increased by ≥ 30% and by ≥ 15 points relative to baseline; and

(3) worsening of the patient's condition in the investigator's judgment.

Patients receiving continued sertraline hydrochloride treatment experienced statistically significantly

lower relapse rates over the subsequent 28 weeks compared to those receiving placebo. This pattern

was demonstrated in male and female subjects.

14.5 Social Anxiety Disorder

The effectiveness of sertraline hydrochloride in the treatment of SAD (also known as social phobia)

was established in two multicenter, randomized, placebo-controlled studies (Study SAD-1 and SAD-2)

of adult outpatients who met DSM-IV criteria for SAD.

Study SAD-1 was a 12-week, flexible dose study comparing sertraline hydrochloride (50 to 200

mg/day), n=211, to placebo, n=204, in which sertraline hydrochloride was initiated at 25 mg/day for the

first week, then titrated to the maximum tolerated dose in 50 mg increments biweekly. Study outcomes

were assessed by the:

(1) Liebowitz Social Anxiety Scale (LSAS), a 24-item clinician administered instrument that

measures fear, anxiety, and avoidance of social and performance situations, and

(2) Proportion of responders as defined by the Clinical Global Impression of Improvement (CGI-I)

criterion of CGI-I ≤ 2 (very much or much improved).

Sertraline hydrochloride was statistically significantly more effective than placebo as measured by the

LSAS and the percentage of responders.

Study SAD-2 was a 20-week, flexible dose study that compared sertraline hydrochloride (50 to 200

mg/day), n=135, to placebo, n=69. Sertraline hydrochloride was titrated to the maximum tolerated dose

in 50 mg increments every 3 weeks. Study outcome was assessed by the:

(1) Duke Brief Social Phobia Scale (BSPS), a multi-item clinician-rated instrument that measures

fear, avoidance and physiologic response to social or performance situations,

(2) Marks Fear Questionnaire Social Phobia Subscale (FQ-SPS), a 5-item patient-rated instrument

that measures change in the severity of phobic avoidance and distress, and

(3) CGI-I responder criterion of ≤ 2.

Sertraline hydrochloride was shown to be statistically significantly more effective than placebo as

measured by the BSPS total score and fear, avoidance and physiologic factor scores, as well as the FQ-

SPS total score, and to have statistically significantly more responders than placebo as defined by the

CGI-I. Subgroup analyses did not suggest differences in treatment outcome on the basis of gender.

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

In Study SAD-3, patients meeting DSM-IV criteria for SAD who had responded while assigned to

sertraline hydrochloride (CGI-I of 1 or 2) during a 20-week placebo-controlled trial on sertraline

hydrochloride 50 to 200 mg/day were randomized to continuation of sertraline hydrochloride or to

substitution of placebo for up to 24 weeks of observation for relapse. Relapse was defined as ≥ 2 point

increase in the Clinical Global Impression Severity of Illness (CGI-S) score compared to baseline or

study discontinuation due to lack of efficacy. Patients receiving sertraline hydrochloride continuation

treatment experienced a statistically significantly lower relapse rate during this 24-week period than

patients randomized to placebo substitution.

14.6 Premenstrual Dysphoric Disorder

The effectiveness of sertraline hydrochloride for the treatment of PMDD was established in two

double-blind, parallel group, placebo-controlled flexible dose trials (Studies PMDD-1 and PMDD-2)

conducted over 3 menstrual cycles in adult female patients. The effectiveness of sertraline

hydrochloride for PMDD for more than 3 menstrual cycles has not been systematically evaluated in

controlled trials.

Patients in Study PMDD-1 met DSM-III-R criteria for Late Luteal Phase Dysphoric Disorder (LLPDD),

the clinical entity referred to as PMDD in DSM-IV. Patients in Study PMDD-2 met DSM-IV criteria for

PMDD. Study PMDD-1 utilized continuous daily dosing throughout the study, while Study PMDD-2

utilized luteal phase dosing (intermittent dosing) for the 2 weeks prior to the onset of menses. The mean

duration of PMDD symptoms was approximately 10.5 years in both studies. Patients taking oral

contraceptives were excluded from these trials; therefore, the efficacy of sertraline hydrochloride in

combination with oral contraceptives for the treatment of PMDD is unknown.

Efficacy was assessed with the Daily Record of Severity of Problems (DRSP), a patient-rated

instrument that mirrors the diagnostic criteria for PMDD as identified in the DSM-IV, and includes

assessments for mood, physical symptoms, and other symptoms. Other efficacy assessments included

the Hamilton Rating Scale for Depression (HAMD-17), and the Clinical Global Impression Severity of

Illness (CGI-S) and Improvement (CGI-I) scores.

In Study PMDD-1, involving 251 randomized patients, (n=125 on sertraline hydrochloride and n=126

on placebo), sertraline hydrochloride treatment was initiated at 50 mg/day and administered daily

throughout the menstrual cycle. In subsequent cycles, sertraline hydrochloride was titrated in 50 mg

increments at the beginning of each menstrual cycle up to a maximum of 150 mg/day on the basis of

clinical response and tolerability. The mean dose for completers was 102 mg/day. Sertraline

hydrochloride administered daily throughout the menstrual cycle was statistically significantly more

effective than placebo on change from baseline to endpoint on the DRSP total score, the HAMD-17

total score, and the CGI-S score, as well as the CGI-I score at endpoint.

In Study PMDD-2, involving 281 randomized patients, (n=142 on sertraline hydrochloride and

n=139 on placebo), sertraline hydrochloride treatment was initiated at 50 mg/day in the late luteal

phase (last 2 weeks) of each menstrual cycle and then discontinued at the onset of menses

(intermittent dosing). In subsequent cycles, patients were dosed in the range of 50 to 100 mg/day in

the luteal phase of each cycle, on the basis of clinical response and tolerability. Patients who

received 100 mg/day started with 50 mg/day for the first 3 days of the cycle, then 100 mg/day for

the remainder of the cycle. The mean sertraline hydrochloride dose for completers was 74 mg/day.

Sertraline hydrochloride administered in the late luteal phase of the menstrual cycle was statistically

significantly more effective than placebo on change from baseline to endpoint on the DRSP total

score and the CGI-S score, as well as the CGI-I score at endpoint (Week 12).

There was insufficient information to determine the effect of race or age on outcome in these studies.

16 HOW SUPPLIED/STORAGE AND HANDLING

Sertraline Hydrochloride Oral Solution USP is a clear, colorless peppermint flavored liquid in 60 mL

amber colored round PET bottle with Child-Resistant closure having induction sealing liner.

Bottles of 60 mL NDC 64980-409-06

Store at 20º to 25ºC (68º to 77ºF); excursions permitted to 15º to 30ºC (59° to 86°F) [see USP

Controlled Room Temperature].

17 PATIENT COUNSELING INFORMATION

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

Suicidal Thoughts and Behaviors

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

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

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

Important Administration Instructions for Oral Solution

For patients prescribed sertraline hydrochloride oral solution, inform them that:

Sertraline hydrochloride oral solution must be diluted before use. Do not mix in advance.

Use the dispensing syringe to remove the required amount of sertraline hydrochloride oral solution

and mix with 4 ounces (1/2 cup) of water, ginger ale, lemon/lime soda, lemonade or orange juice

ONLY. Do not mix sertraline hydrochloride oral solution with anything other than the liquids listed.

Take the dose immediately after mixing. At times, a slight haze may appear after mixing; this is

normal.

Disulfiram Contraindication for Sertraline Hydrochloride Oral Solution

Inform patients not to take disulfiram when taking sertraline hydrochloride oral solution. Concomitant

use is contraindicated due the alcohol content of the oral solution [See Contraindication (4)].

Serotonin Syndrome

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

hydrochloride with other serotonergic drugs including triptans, tricyclic antidepressants, fentanyl,

lithium, tramadol, tryptophan, buspirone, amphetamines, 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). Patients should contact their health care provider or report to the

emergency room if they experience signs or symptoms of serotonin syndrome [See Warnings and

Precautions (5.2), Drug Interactions (7.1)].

Increased Risk of Bleeding

Inform patients about the concomitant use of sertraline hydrochloride with aspirin, NSAIDs, other

antiplatelet drugs, warfarin, or other anticoagulants because the combined use has been associated with

an increased risk of bleeding. Advise patients to inform their health care providers if they are taking or

planning to take any prescription or over-the-counter medications that increase the risk of bleeding [See

Warnings and Precautions (5.3)].

Activation of Mania/Hypomania

Advise patients and their caregivers to observe for signs of activation of mania/hypomania and instruct

them to report such symptoms to the healthcare provider [See Warnings and Precautions (5.4)].

Discontinuation Syndrome

Advise patients not to abruptly discontinue sertraline hydrochloride and to discuss any tapering regimen

with their healthcare provider. Adverse reactions can occur when sertraline hydrochloride is

discontinued [See Warnings and Precautions (5.5)].

Allergic Reactions

Advise patients to notify their healthcare provider if they develop an allergic reaction such as rash,

hives, swelling, or difficulty breathing [See Adverse Reactions (6.2)].

Pregnancy

Inform pregnant women that sertraline hydrochloride may cause withdrawal symptoms in the newborn or

persistent pulmonary hypertension of the newborn (PPHN) [See Use in Specific Populations (8.1)].

Dispense with Medication Guide available at: http://www.risingpharma.com/med-guides.html

PATIENT

INSTRUCTIONS

USING YOUR SERTRALINE HYDROCHLORIDE DISPENSING SYRINGE AND BOTTLE

Use this product as indicated below, unless directed otherwise by your Physician.

IMPORTANT: Please read these instructions before using Sertraline hydrochloride oral

s olution.

1. Push the plastic screw-cap on the bottle down while turning it counter clockwise. Remove the

unscrewed cap (see Figure 1).

2. Hold the pull tab of the seal and remove (see Figure 2).

3. Insert the adaptor into the mouth of the bottle and push down until it is completely seated in

the neck of the bottle (leave adaptor inserted in the bottle after use) (see Figure 3).

4. Remove the secure tip from orifice of the dispensing syringe (see Figure 4).

5. Insert the dispensing syringe into the adaptor fixed to the bottle neck (see Figure 5).

6. After inserting the syringe into the adaptor, make the bottle upside down and pull the plunger

up to the level (see markings on side) that equals the dosage prescribed by your physician

(see Figure 6).

7. Turn the bottle to original position and remove the dispensing syringe from the bottle (see

Figure 7) and then empty the entire contents of the dispensing syringe and mix with 4 oz (1/2

cup) of water, ginger ale, lemon/lime soda, lemonade or orange juice ONLY. Do not mix

sertraline hydrochloride oral solution with anything other than the liquids listed. The dose

should be taken immediately after mixing. Do not mix in advance. At times, a slight haze may

appear after mixing; this is normal.

8. Replace the plastic cap on the bottle by screwing it clockwise; rinse the empty dispensing

syringe with water. And close the orifice of the dispensing syringe by fixing the secure tip (see

Figure 8).

Medication Guide

Sertraline Hydrochloride Oral Solution USP

(ser' tra leen hye'' droe klor' ide)

What is the most important information I should know about sertraline hydrochloride oral

s olution?

Sertraline hydrochloride oral solution and other antidepressant medicines may cause serious

side effects. Call your healthcare provider right away if you have any of the following symptoms,

or call 911 if there is an emergency.

1. Suicidal thoughts or actions:

Sertraline hydrochloride oral solution and other antidepressant medicines may increase

suicidal thoughts or actions in some people 24 years of age and younger, especially within the

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

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

actions.

Watch for these changes and call your healthcare provider right away if you notice new or sudden

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

Pay particular attention to such changes when sertraline hydrochloride oral solution is started or

when the dose is changed.

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

worried about symptoms.

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

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

attempts to commit suicide

acting on dangerous impulses

acting aggressive or violent

thoughts about suicide or dying

new or worse depression

new or worse anxiety or panic attacks

feeling agitated, restless, angry or irritable

trouble sleeping

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

other unusual changes in behavior or mood

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

agitation, hallucinations, coma, or other changes in mental status

nausea, vomiting, or diarrhea

racing heartbeat, high or low blood pressure

sweating or fever

coordination problems or muscle twitching (overactive reflexes)

muscle rigidity

3. Increased chance of bleeding: sertraline hydrochloride oral solution 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.

4. Manic episodes. Symptoms may include:

greatly increased energy

severe trouble sleeping

excessive happiness or irritability

racing thoughts

reckless behavior

talking more or faster than usual

unusually grand ideas

5. Seizures or convulsions.

6. Glaucoma (angle-closure glaucoma). Many antidepressant medicines including sertraline

hydrochloride oral solution may cause a certain type of eye problem

called angle-closure glaucoma. Call your healthcare provider if you have eye pain, changes in your

vision, or 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.

7. Changes in appetite or weight. Children and adolescents should have height and weight monitored

during treatment.

8. Low salt (sodium) levels in the blood. Elderly people may be at greater risk for this. Symptoms may

include:

Headache

weakness or feeling unsteady

confusion, problems concentrating or thinking, or memory problems

Do not stop sertraline hydrochloride oral solution without first talking to your healthcare

provider. Stopping sertraline hydrochloride oral solution too quickly may cause serious symptoms

including:

anxiety, irritability, high or low mood, feeling restless or changes in sleep habits

headache, sweating, nausea, dizziness

electric shock-like sensations, shaking, confusion

What is Sertraline Hydrochloride Oral Solution?

Sertraline hydrochloride oral solution is a prescription medicine used to treat:

Major Depressive Disorder (MDD)

Obsessive Compulsive Disorder (OCD)

Panic Disorder

Posttraumatic Stress Disorder (PTSD)

Social Anxiety Disorder

Premenstrual Dysphoric Disorder (PMDD)

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

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

Sertraline hydrochloride oral solution is safe and effective in treating children with OCD age 6 to 17

years.

It is not known if sertraline hydrochloride oral solution is safe and effective for use in children under 6

years of age with OCD or children with other behavior health conditions.

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

hydrochloride oral solution treatment.

Who should not take sertraline hydrochloride oral solution?

Do not take sertraline hydrochloride oral solution 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.

have taken an MAOI within 2 weeks of stopping sertraline hydrochloride oral solution unless

directed to do so by your healthcare provider.

have stopped taking an MAOI in the last 2 weeks unless directed to do so by your healthcare

provider.

take any other medicines that contain sertraline (such as sertraline HCl or sertraline hydrochloride).

take the antipsychotic medicine pimozide (Orap

) because this can cause serious heart problems.

are allergic to sertraline or any of the ingredients in sertraline hydrochloride oral solution. See the

end of this Medication Guide for a complete list of ingredients in sertraline hydrochloride oral

solution.

take Antabuse

(disulfiram) (if you are taking the liquid form of sertraline hydrochloride oral

solution) due to the alcohol content.

People who take sertraline hydrochloride oral solution close in time to an MAOI may have

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

s ymptoms :

high fever

uncontrolled muscle spasms

stiff muscles

rapid changes in heart rate or blood pressure

confusion

loss of consciousness (pass out)

What should I tell my healthcare provider before taking sertraline hydrochloride oral solution?

Before starting sertraline hydrochloride oral solution, tell your healthcare provider:

if you have:

liver problems

kidney problems

a history of a stroke

heart problems

or have had seizures or convulsions

high blood pressure

bipolar disorder or mania

low sodium levels in your blood

or have had bleeding problems

are pregnant or plan to become pregnant. Your baby may have withdrawal symptoms after birth

or may be at increased risk for a serious lung problem at birth. Talk to your healthcare provider

about the benefits and risks of taking sertraline hydrochloride oral solution during pregnancy.

are breastfeeding or plan to breastfeed. A small amount of sertraline hydrochloride oral solution

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

baby while taking sertraline hydrochloride oral solution.

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

over-the-counter medicines, vitamins, and herbal supplements.

Sertraline hydrochloride oral solution and some medicines may interact with each other, may not work

as well, or may cause serious side effects.

Your healthcare provider or pharmacist can tell you if it is safe to take sertraline hydrochloride oral

solution with your other medicines. Do not start or stop any medicine while taking sertraline

hydrochloride oral solution without talking to your healthcare provider first.

How should I take sertraline hydrochloride oral solution?

Take sertraline hydrochloride oral solution exactly as prescribed. Your healthcare provider may

need to change the dose of sertraline hydrochloride oral solution until it is the right dose for you.

Sertraline hydrochloride oral solution may look cloudy or hazy after mixing, this is normal.

Sertraline hydrochloride oral solution must be diluted before use:

Do not mix sertraline hydrochloride oral solution until you are ready to take it.

When diluting sertraline hydrochloride oral solution, use only water, ginger ale, lemon/lime

soda, lemonade, or orange juice.

If you miss a dose of sertraline hydrochloride oral solution, 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 sertraline hydrochloride oral solution at the same time.

If you take too much sertraline hydrochloride oral solution, call your healthcare provider or

poison control center right away, or go to the nearest hospital emergency room right away.

What should I avoid while taking sertraline hydrochloride oral solution?

Sertraline hydrochloride oral solution 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 sertraline hydrochloride oral solution affects you. Do not

drink alcohol while you take sertraline hydrochloride oral solution.

What are the possible side effects of sertraline hydrochloride oral solution?

Sertraline hydrochloride oral solution may cause serious side effects, including:

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

oral solution?”

The most common side effects in adults who take sertraline hydrochloride oral solution include:

nausea, loss of appetite, diarrhea, or indigestion

change in sleep habits including increased sleepiness or insomnia

increased sweating

sexual problems including decreased libido and ejaculation failure

tremor or shaking

feeling tired or fatigued

agitation

anxiety

The most common side effects in children and adolescents who take include abnormal increase in

muscle movement or agitation, nose bleeds, urinary incontinence, aggressive reaction, possible slowed

growth rate, and weight change. Your child’s height and weight should be monitored during treatment

with sertraline hydrochloride oral solution.

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 sertraline hydrochloride oral solution. For more

information, ask your healthcare provider or pharmacist.

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

800-FDA-1088.

How should I store sertraline hydrochloride oral solution?

Store sertraline hydrochloride oral solution at room temperature, 68° to 77°F (20° to 25°C).

Keep sertraline hydrochloride oral solution bottle closed tightly.

Keep sertraline hydrochloride oral solution and all medicines out of the reach of children.

General information about the safe and effective use of sertraline hydrochloride oral solution

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

use sertraline hydrochloride oral solution for a condition for which it was not prescribed. Do not give

sertraline hydrochloride oral solution to other people, even if they have the same condition. It may harm

them.

This Medication Guide summarizes the most important information about sertraline hydrochloride oral

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

healthcare provider or pharmacist for information about sertraline hydrochloride oral solution that is

written for healthcare professionals.

For more information call 1-866-562-4597.

What are the ingredients in sertraline hydrochloride oral solution?

Active ingredient: sertraline hydrochloride

Inactive ingredients: alcohol (12%), natural peppermint flavor, propylene glycol and purified water.

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

All brands listed are the trademarks of their respective owners and are not trademarks of Aurobindo

Pharma Limited.

Dispense with Medication Guide available at: http://www.risingpharma.com/med-guides.html

Distributed by:

Rising Pharmaceuticals, Inc.

Saddle Brook, NJ 07663

Made in India

Code: TS/DRUGS/19/1993

Revised: 03/2018

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - 20 mg/mL (60 mL Bottle)

Rising® NDC 64980-409-06

Sertraline Hydrochloride

Oral Solution USP

20 mg/mL*

Contains 12% alcohol.

Must Be Diluted Before Use

(see side panel for instructions)

PHARMACIST: PLEASE DISPENSE WITH

MEDICATION GUIDE PROVIDED SEPARATELY

60 mL Rx only

PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 20 mg/mL Carton Label

Rising® NDC 64980-409-06

Sertraline

Hydrochloride

Oral Solution USP

20 mg/mL*

ADAPTOR AND DISPENSING

SYRINGE ENCLOSED

Must Be Diluted Before Use

(see side panel for instructions)

PHARMACIST: PLEASE DISPENSE

WITH MEDICATION GUIDE PROVIDED

SEPARATELY

60 mL Rx Only

SERTRALINE HYDROCHLORIDE

sertraline hydrochloride solution, concentrate

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:6 49 8 0 -40 9

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

SERTRALINE HYDRO CHLO RIDE (UNII: UTI8 9 0 7Y6 X) (SERTRALINE - UNII:QUC7NX6 WMB)

SERTRALINE

20 mg in 1 mL

Inactive Ingredients

Ingredient Name

Stre ng th

ALCO HO L (UNII: 3K9 9 58 V9 0 M)

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

WATER (UNII: 0 59 QF0 KO0 R)

Rising Pharmaceuticals, Inc.

Product Characteristics

Color

S core

S hap e

S iz e

Flavor

PEPPERMINT (Natural Peppermint)

Imprint Code

Contains

Packag ing

#

Item Code

Package Description

Marketing Start

Date

Marketing End

Date

1

NDC:6 49 8 0 -40 9 -

1 in 1 CARTON

10 /31/20 0 8

1

6 0 mL in 1 BOTTLE, PLASTIC; Type 1: Co nvenience Kit o f Co -

Pa c ka ge

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 78 8 6 1

10 /31/20 0 8

Labeler -

Rising Pharmaceuticals, Inc. (041241766)

Registrant -

Aurobindo Pharma Limited (650082092)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Auro bindo Pharma Limited

9 18 9 176 42

ANALYSIS(6 49 8 0 -40 9 ) , MANUFACTURE(6 49 8 0 -40 9 )

Revised: 1/2020

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