PAXIL CR- paroxetine hydrochloride tablet, film coated, extended release PAXIL CR- paroxetine hydrochloride tablet, film coated

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

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Active ingredient:
PAROXETINE HYDROCHLORIDE HEMIHYDRATE (UNII: X2ELS050D8) (PAROXETINE - UNII:41VRH5220H)
Available from:
Apotex Corp
INN (International Name):
PAROXETINE HYDROCHLORIDE HEMIHYDRATE
Composition:
PAROXETINE 12.5 mg
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
PAXIL CR is indicated in adults for the treatment of: - Major depressive disorder (MDD) - Panic disorder (PD) - Social anxiety disorder (SAD) - Premenstrual dysphoric disorder (PMDD) PAXIL CR is contraindicated in patients with a hypersensitivity (e.g., anaphylaxis, angioedema, Stevens-Johnson syndrome) to paroxetine or to any of the inactive ingredients in PAXIL CR.   - 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)]. - Taking thioridazine because of risk of QT prolongation [see Warnings and Precautions (5.3), Drug Interactions (7)].  - Taking pimozide because of risk of QT prolongation [see Warnings and Precautions (5.3), Drug Interactions (7)]. - With known hypersensitivity (e.g., anaphylaxis, angioedema, Stevens-Johnson syndrome) to paroxetine or to any of the inactive ingredients in PAXIL CR [see Adverse Reactions (6.1, 6.2)]. Pre
Product summary:
PAXIL CR is supplied as an enteric film-coated, controlled-release, round tablet, as follows: 12.5 mg yellow tablets NDC 60505-4377-3 Bottles of 30 (one face is plain and the other is engraved with 12.5) 25 mg pink tablets NDC 60505-4378-3 Bottles of 30 (one face is plain and the other is engraved with 25) 37.5 mg blue tablets NDC 60505-4379-3 Bottles of 30 (one face is plain and the other is engraved with 37.5) 12.5-mg yellow tablets NDC 60505-3668-3 Bottles of 30 (engraved with GSK and 12.5) 25-mg pink tablets NDC 60505-3669-3 Bottles of 30 (engraved with GSK and 25) 37.5 mg blue tablets NDC 60505-3670-3 Bottles of 30 (engraved with GSK and 37.5) Store at or below 25° C (77° F) [see USP].
Authorization status:
New Drug Application
Authorization number:
60505-3668-3, 60505-3669-3, 60505-3670-3, 60505-4377-3, 60505-4378-3, 60505-4379-3

PAXIL CR- paroxetine hydrochloride tablet, film coated, extended release

PAXIL CR- paroxetine hydrochloride tablet, film coated, extended release

Apotex Corp

----------

MEDICATION GUIDE

PAXIL CR® (PAX-il) (paroxetine hydrochloride) estended-release tablets

What is the most important information I should know about PAXIL CR?

PAXIL CR can cause serious side effects, including:

Increased risk of suicidal thoughts or actions. Antidepressant medicines may increase suicidal

thoughts and actions in some children and young adults within the first few months of treatment or

when the dose is changed. PAXIL CR is not for use in people younger than 18 years of age.

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

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

actions.

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

or if you develop suicidal thoughts or actions. This is very important when an antidepressant medicine

is started or when the dose is changed.

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

or feelings or if you develop suicidal thoughts or actions.

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

between visits as needed, especially if you have concerns about symptoms.

Call your healthcare provider or get emergency medical help right away if you have any of the following

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

attempts to commit suicide

acting aggressive or violent

new or worse depression

feeling agitated, restless, angry, or irritable

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

acting on dangerous impulses

thoughts about suicide or dying

new or worse anxiety or panic attacks

trouble sleeping

other unusual changes in behavior or mood

What is PAXIL CR?

PAXIL CR is a prescription medicine used in adults to treat:

A certain type of depression called Major Depressive Disorder (MDD)

Panic Disorder

Social Anxiety Disorder (SAD)

Premenstrual Dysphoric Disorder (PMDD)

Do not take PAXIL CR if you:

take a monoamine oxidase inhibitor (MAOI)

have stopped taking an MAOI in the last 14 days

are being treated with the antibiotic linezolid or intravenous methylene blue

are taking thioridazine

are taking pimozide

are allergic to paroxetine or any of the ingredients in PAXIL CR. See the end of this Medication

Guide for a complete list of ingredients in PAXIL CR.

Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI or one of these

medicines, including intravenous methylene blue.

Do not start taking an MAOI for at least 14 days after you stop treatment with PAXIL CR.

Before taking PAXIL CR, tell your healthcare provider about all your medical conditions, including if you:

have heart problems

have or had bleeding problems

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

have or had seizures or convulsions

have glaucoma (high pressure in the eye)

have low sodium levels in your blood

have bone problems

have kidney or liver problems

are pregnant or plan to become pregnant. PAXIL CR may harm your unborn baby. Talk to your

healthcare provider about the risks to your unborn baby if you take PAXIL CR during pregnancy. Tell

your healthcare provider right away if you become pregnant or think you are pregnant during

treatment with PAXIL CR.

are breastfeeding or plan to breastfeed. PAXIL CR passes into your breast milk. Talk to your

healthcare provider about the best way to feed your baby during treatment with PAXIL CR.

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

medicines, vitamins, and herbal supplements.

PAXIL CR and some other medicines may affect each other causing possible serious side effects. PAXIL CR

may affect the way other medicines work and other medicines may affect the way PAXIL CR works.

Especially tell your healthcare provider if you take:

medicines used to treat migraine headaches called triptans

tricyclic antidepressants

fentanyl

lithium

tramadol

tryptophan

buspirone

amphetamines

St. John’s Wort

medicines that can affect blood clotting such as aspirin, nonsteroidal anti-inflammatory drugs

(NSAIDs), or warfarin

diuretics

tamoxifen

Ask your healthcare provider if you are not sure if you are taking any of these medicines. Your healthcare

provider can tell you if it is safe to take PAXIL CR with your other medicines.

Do not start or stop any other medicines during treatment with PAXIL CR without talking to your healthcare

provider first. Stopping PAXIL CR suddenly may cause you to have serious side effects. See, “What are the

possible side effects of PAXIL CR?”

Know the medicines you take. Keep a list of them to show to your healthcare provider and pharmacist when

you get a new medicine.

How should I take PAXIL CR?

Take PAXIL CR exactly as your healthcare provider tell you to. Your healthcare provider may need

to change the dose of PAXIL CR until it is the right dose for you.

Take PAXIL CR 1 time each day in the morning.

PAXIL CR may be taken with or without food.

Swallow PAXIL CR tablets whole. Do not chew or crush PAXIL CR tablets.

If you take too much PAXIL CR, call your poison control center at 1-800-222-1222 or got to the

nearest hospital emergency room right away.

What are possible side effects of PAXIL CR?

PAXIL CR may cause serious side effects, including:

See, “What is the most important information I should know about PAXIL CR?”

Serotonin syndrome. A potentially life-threatening problem called serotonin syndrome can happen

when you take PAXIL CR with certain other medicines. See, “Who should not take PAXIL CR?”

Call your healthcare provider or go to the nearest hospital emergency room right away if you have

any of the following signs and symptoms of serotonin syndrome:

agitation

seeing or hearing things that are not real (hallucinations)

confusion

coma

fast heart beat

changes in blood pressure

dizziness

sweating

flushing

high body temperature (hyperthermia)

shaking (tremors), stiff muscles, or muscle twitching

loss of coordination

seizures

nausea, vomiting, diarrhea

Medicine interactions. Taking PAXIL CR with certain other medicines including thioridazine and

pimozide may increase the risk of developing a serious heart problem called QT prolongation.

Abnormal bleeding. Taking PAXIL CR with aspirin, NSAIDs, or blood thinners may add to this risk.

Tell your healthcare provider about any unusual bleeding or bruising.

Manic episodes. Manic episodes may happen in people with bipolar disorder who take PAXIL CR.

Symptoms may include:

greatly increased energy

racing thoughts

unusually grand ideas

talking more or faster than usual

severe problems sleeping

reckless behavior

excessive happiness or irritability

Discontinuation syndrome. Suddenly stopping PAXIL CR may cause you to have serious side effects.

Your healthcare provider may want to decrease your dose slowly. Symptoms may include:

nausea

sweating

changes in mood

irritability and agitation

dizziness

electric shock feeling (paresthesia)

tremor

anxiety

confusion

headache

tiredness

problems sleeping

ringing in your ears (tinnitus)

seizures

Seizures (convulsions).

Eye problems (angle-closure glaucoma). PAXIL CR may cause a type of eye problem called angle-

closure glaucoma in people with certain other eye conditions. You may want to undergo an eye

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

Low sodium levels in your blood (hyponatremia). Low sodium levels in your blood that may be

serious and may cause death, can happen during treatment with PAXIL CR. Elderly people and

people who take certain medicines may be at a greater risk for developing low sodium levels in your

blood. Signs and symptoms may include:

headache

difficulty concentrating

memory changes

confusion

weakness and unsteadiness on your feet which can lead to falls

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

seeing or hearing things that are not real (hallucinations)

fainting

seizures

coma

stopping breathing (respiratory arrest)

Bone fractures.

The most common side effects PAXIL CR include:

male and female sexual function problems

blurred vision

weakness (asthenia)

constipation

decreased appetite

diarrhea

dizziness

dry mouth

problems sleeping

nausea

sleepiness

sweating

tremor

These are not all the possible side effects of PAXIL CR.

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

1088.

How should I store PAXIL CR?

Store PAXIL CR at room temperature between 68°F to 77°F (20°C to 25°C).

Keep PAXIL CR and all medicines out of the reach of children.

General information about the safe and effective use of PAXIL CR.

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

PAXIL CR for a condition for which it was not prescribed. Do not give PAXIL CR to other people, even if

they have the same symptoms that you have. It may harm them. You may ask your healthcare provider or

pharmacist for information about PAXIL CR that is written for healthcare professionals.

What are the ingredients in PAXIL CR?

Active ingredient: paroxetine hydrochloride

Inactive ingredients: glyceryl behenate, hypromellose, lactose monohydrate, magnesium stearate, methacrylic

acid copolymer type C, polyethylene glycols, polysorbate 80, polyvinylpyrrolidone, silicon dioxide, sodium

lauryl sulfate, talc, titanium dioxide, triethyl citrate and the following colorants: D&C Red No. 30 aluminum

lake (25 mg), D&C Yellow No. 10 aluminum lake (12.5 mg), FD&C Blue No. 2 aluminum lake (37.5 mg),

FD&C Yellow No. 6 aluminum lake (12.5 mg), red ferric oxide (25 mg) and Yellow ferric oxide (12.5 mg

and 37.5 mg).

All registered trademarks in this document are the property of their respective owners.

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

Manufactured by:

ApotexInc.

Toronto, Ontario

M9L 1T9

Manufactured by:

GlaxoSmithKline

Research Triangle Park, NC 27709

Manufactured for:

Apotex Corp.

Weston, FL 33326

February 2020

Revised: 6/2020

Document Id: 36a6feaf-9711-551a-bdfa-4769d2834439

34391-3

Set id: 483bd97f-c4d0-4e23-aaa8-6334f4471e0c

Version: 20

Effective Time: 20200626

Apotex Corp

PAXIL CR- paroxetine hydrochloride tablet, film coated, extended release

PAXIL CR- paroxetine hydrochloride tablet, film coated, extended release

Apotex Corp

----------

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use PAXIL CR safely and effectively. See full

prescribing information for PAXIL CR.

PAXIL CR (paroxetine) extended-release Tablets, for oral use

Initial U.S. Approval: 1992

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS

See full prescribing information for complete boxed warning.

Increased risk of suicidal thoughts and behavior in pediatric and young adult patients taking

antidepressants. Closely monitor all antidepressant-treated patients for clinical worsening and

emergence of suicidal thoughts and behaviors. PAXIL CR is not approved for use in pediatric patients.

(5.1, 8.4)

INDICATIONS AND USAGE

PAXIL CR is a selective serotonin reuptake inhibitor (SSRI) indicated for use in adults for the treatment of (1):

Major Depressive Disorder (MDD)

Panic Disorder (PD)

Social Anxiety Disorder (SAD)

Premenstrual Dysphoric Disorder (PMDD)

DOSAGE AND ADMINISTRATION

Swallow tablet whole; do not chew or crush. (2.1)

Recommended starting and maximum daily dosage: (2.2, 2.3)

Indication Starting Dose Maximum Dose

25 mg/day

62.5 mg/day

12.5 mg/day

75 mg/day

12.5 mg/day

37.5 mg/day

PMDD

12.5 mg/day

25 mg/day

For PMDD, dose continuously or intermittently (luteal phase only). (2.3)

If inadequate response to starting dosage, titrate in 12.5 mg per day increments once weekly. (2.2, 2.3)

Elderly patients, patients with severe renal impairment or severe hepatic impairment: Starting dose is 12.5 mg per day.

Do not exceed 50 mg per day for treatment of MDD and PD and 37.5 mg per day for treatment of SAD. (2.5)

When discontinuing PAXIL CR, reduce dose gradually. (2.7)

DOSAGE FORMS AND STRENGTHS

Extended-release tablets:12.5 mg, 25 mg, and 37.5 mg tablets. (3)

CONTRAINDICATIONS

Concomitant use of monoamine oxidase inhibitors (MAOIs) or use within 14 days of discontinuing a MAOIs. (4, 5.2, 7)

Concomitant use of pimozide or thioridazine. (4, 5.3, 7)

Known hypersensitivity to paroxetine or to any of the inactive ingredients in PAXIL CR. (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 occurs, discontinue PAXIL CR and initiate supportive measures. (5.2)

Embryofetal and Neonatal Toxicity: Can cause fetal and neonatal harm. Increased risk of cardiovascular malformations

for exposure during the first trimester. Exposure in late pregnancy may lead to an increased risk for persistent

pulmonary hypertension (PPNH) of the newborn. (5.4, 8.1)

Increased Risk of Bleeding: Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, other antiplatelet drugs,

warfarin, and other anticoagulant drugs may increase risk. (5.5)

Activation of Mania/Hypomania: Screen patients for bipolar disorder. (5.6)

Seizures: Use with caution in patients with seizure disorders. (5.8)

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

treated with antidepressants (5.9)

ADVERSE REACTIONS

Most common adverse reactions (≥5% and at least twice placebo) in placebo-controlled MDD, PD, SAD, and PMDD clinical

trials :

abnormal ejaculation, abnormal vision, asthenia, constipation, decreased appetite, diarrhea, dizziness, dry mouth, female

genital disorder, impotence, insomnia, libido decreased, nausea, somnolence, sweating, tremor. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Apotex Corp.at 1-800-706-5575 or FDA at 1-800-FDA-

1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

Drugs Highly Bound to Plasma Protein: Monitor for adverse reactions and reduce dosage of PAXIL CR or other

protein-bound drugs (e.g., warfarin) as warranted. (7)

Drugs Metabolized by CYP2D6: Reduce dosage of drugs metabolized by CYP2D6 as warranted. (7)

Concomitant use with Tamoxifen: Consider use of an alternative antidepressant with little or no CYP2D6 inhibition.

(5.11, 7)

USE IN SPECIFIC POPULATIONS

Pregnancy: Can cause fetal and neonatal harm. Advise women of potential risk to the fetus. (5.4, 8.1)

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

See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

Revised: 2/2020

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Important Administrative Instructions

2.2 Dosage in Patients with Major Depressive Disporder, Panic Disorder, and Social Anxiety

Disporder

2.3 Dosage in Patients with Prementrual Dysphoric Disorder

2.4 Screen for Bipolar Disorder Prior to Starting Paxil CR

2.5 Dosage Modifications for Elderly Patients, Patients with Severe Renal Impairment and Patients

with Severe Hepatic Impairment

2.6 Switching Patients to or From a Monoamine Oxidase Inhibitor Antidepressant

2.7 Discontinuation of Treatment with Paxil CR

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Suicidal Thoughts and Behaviors in Adolescents and Young Adults

5.2 Serotonin Syndrome

5.3 Drug Interactions Leading to QT Prolongation

5.4 Embryofetal and Neonatal Toxicity

5.5 Increased Risk of Bleeding

5.6 Activation of Mania or Hypomania

5.7 Discontinuation Syndrome

5.8 Seizures

5.9 Angle-Closure Glaucoma

5.10 Hyponatremia

5.11 Reduction of Efficacy of Tamoxifen

5.12 Bone Fracture

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

7.1 Clinically Significant Drug Interactions

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Renal and/or Hepatic Impairment

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 Panic Disorder

14.3 Social Anxiety Disorder

14.4 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 compared to placebo of suicidal thinking and behavior

(suicidality) in children, adolescents, and young adults in short-term studies of major

depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of

PAXIL CR or any other antidepressant in a child, adolescent, or young adult must balance

this risk with the clinical need. Short-term studies did not show an increase in the risk of

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

reduction in risk with antidepressants compared to placebo in adults aged 65 and older.

Depression and certain other psychiatric disorders are themselves associated with

increases in the risk of suicide. Patients of all ages who are started on antidepressant

therapy should be monitored appropriately and observed closely for clinical worsening,

suicidality, or unusual changes in behavior. Families and caregivers should be advised of

the need for close observation and communication with the prescriber. PAXIL CR is not

approved for use in pediatric patients. [See Warnings and Precautions (5.1)]

1 INDICATIONS AND USAGE

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

PAXIL CR is indicated in adults for the treatment of:

Major depressive disorder (MDD)

Panic disorder (PD)

Social anxiety disorder (SAD)

Premenstrual dysphoric disorder (PMDD)

2 DOSAGE AND ADMINISTRATION

2.1 Important Administrative Instructions

Administer PAXIL CR as a single daily dose in the morning, with or without food. Swallow tablets

whole and do not chew or crush.

2.2 Dosage in Patients with Major Depressive Disporder, Panic Disorder, and Social Anxiety

Dis porder

The recommended initial dosage and maximum dosage of PAXIL CR in patients with MDD, PD, and

SAD are presented in Table 1.

In patients with an inadequate response, dosage may be increased inincrements of 12.5 mg per day at

intervals of at least 1 week, depending on tolerability.

Table 1: Recommended Daily Dosage of PAXIL CR in Patients with MDD, PD, and SAD

Indication

Starting Dose

Maximum Dose

25 mg

62.5 mg

12.5 mg

75 mg

12.5 mg

37.5 mg

2.3 Dosage in Patients with Prementrual Dysphoric Disorder

The recommended starting dosage in women with PMDD is 12.5 mg per day. PAXIL CR 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 is

repeated with each new cycle.

In patients with an inadequate response, the dosage may be increased to the maximum recommended

dosage of 25 mg per day, depending on tolerability. Institute dosage adjustments at intervals of at least 1

week.

2.4 Screen for Bipolar Disorder Prior to Starting Paxil CR

Prior to initiating treatment with Paxil CR or another antidepressant, screen patients for a personal or

family history of bipolar disorder, mania, or hypomania [see Warnings and Precautions (5.6)].

2.5 Dosage Modifications for Elderly Patients, Patients with Severe Renal Impairment and

Patients with Severe Hepatic Impairment

The recommended initial dose of PAXIL CR is 12.5 mg per day for elderly patients, patients with

severe renal impairment, and patients with severe hepatic impairment. Reduce initial dose and increase

up-titration intervals if necessary. Dosage should not exceed 50 mg per day for MDD or PD and should

not exceed 37.5 mg per day for SAD [see Use in Specific Populations (8.5, 8.6)].

2.6 Switching Patients to or From a Monoamine Oxidase Inhibitor Antidepressant

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

antidepressant and initiation of PAXIL CR. In addition, at least 14 days must elapse after

stopping PAXIL CR before starting an MAOI antidepressant [see Contraindications (4), Warnings and

Precautions (5.2)].

2.7 Discontinuation of Treatment with Paxil CR

Adverse reactions may occur upon discontinuation of PAXIL CR [see Warnings and Precautions (5.6)].

Gradually reduce the dosage rather than stopping Paxil CR abruptly whenever possible.

3 DOSAGE FORMS AND STRENGTHS

PAXIL CR is supplied as an enteric film-coated, controlled-release, round tablet, as follows:

12.5-mg yellow tablets, (One face is plain and the other is engraved 12.5)

25-mg pink tablets, (One face is plain and the other is engraved 25)

37.5 mg blue tablets, (One face is plain and the other is engraved 37.5)

4 CONTRAINDICATIONS

PAXIL CR is contraindicated in patients with a hypersensitivity (e.g., anaphylaxis, angioedema, Stevens-

Johnson syndrome) to paroxetine or to any of the inactive ingredients in PAXIL CR.

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)].

Taking thioridazine because of risk of QT prolongation [see Warnings and Precautions (5.3), Drug

Interactions (7)].

Taking pimozide because of risk of QT prolongation [see Warnings and Precautions (5.3), Drug

Interactions (7)].

With known hypersensitivity (e.g., anaphylaxis, angioedema, Stevens-Johnson syndrome) to

paroxetine or to any of the inactive ingredients in PAXIL CR [see Adverse Reactions(6.1, 6.2)].

5 WARNINGS AND PRECAUTIONS

5.1 Suicidal Thoughts and Behaviors in Adolescents and Young Adults

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

classes) that included approximately 77,000 adult patients and 4,500 pediatric patients, the incidence of

suicidal thoughts and behaviors in antidepressant-treated patients age 24 years and younger was greater

than in placebo-treated patients. There was considerable variation in risk of suicidal thoughts and

behaviors among drugs, but there was an increased risk identified in young patients for most drugs

studied. There were differences in absolute risk of suicidal thoughts and behaviors across the different

indications, with the highest incidence in patients with MDD. The drug-placebo differences in the

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

Table 2: Risk Differences of the Number of Patients of Suicidal Thoughts and Behaviors in the

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

Age Range

Drug-Placebo Difference in Number of Patients of Suicidal Thoughts and Behaviors

per 1,000 Patients Treated

Increases Compared to Placebo

<18 years

14 additional cases

18-24 years

5 additional cases

Decreases Compared to Placebo

25-64 years

1 fewer case

≥65 years

6 fewer cases

It is unknown whether the risk of suicidal thoughts and behaviors in children, adolescents, and young

adults 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 and that depression itself is a risk factor for suicidal thoughts and behaviors.

Monitor all antidepressant-treated patients for any indication 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 PAXIL CR, 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 PAXIL CR, 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 PAXIL CR with MAOIs is contraindicated. In addition, do not initiate PAXIL

CR 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 PAXIL CR, discontinue PAXIL CR before initiating treatment with the

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

Monitor all patients taking PAXIL CR for the emergence of serotonin syndrome. Discontinue treatment

with PAXIL CR and any concomitant serotonergic agents immediately if the above symptoms occur, and

initiate supportive symptomatic treatment. If concomitant use of PAXIL CR with other serotonergic

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

for symptoms.

5.3 Drug Interactions Leading to QT Prolongation

The CYP2D6 inhibitory properties of paroxetine can elevate plasma levels of thioridazine and

pimozide. Since thioridazine and pimozide given alone produce prolongation of the QTc interval and

increase the risk of serious ventricular arrhythmias, the use of PAXIL CR is contraindicated in

combination with thioridazine and pimozide [see Contraindications (4), Drug Interactions (7), Clinical

Pharmacology (12.3)].

5.4 Embryofetal and Neonatal Toxicity

PAXIL CR can cause fetal harm when administered to a pregnant woman. Epidemiological studies have

shown that infants exposed to paroxetine in the first trimester of pregnancy have an increased risk of

cardiovascular malformations. Exposure to paroxetine in late pregnancy may lead to an increased risk

for persistent pulmonary hypertension of the newborn (PPNH) and/or neonatal complications requiring

prolonged hospitalization, respiratory support, and tube feeding.

If PAXIL CR is used during pregnancy, or if the patient becomes pregnant while taking PAXIL CR, the

patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations (8.1)].

5.5 Increased Risk of Bleeding

Drugs that interfere with serotonin reuptake inhibition, including PAXIL CR, 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 ecchymoses, hematomas,

epistaxis, and petechiae to life-threatening hemorrhages.

Inform patients about the increased risk of bleeding associated with the concomitant use of PAXIL CR

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

normalized ratio.

5.6 Activation of Mania or Hypomania

In patients with bipolar disorder, treating a depressive episode with PAXIL CR or another

antidepressant may precipitate a mixed/manic episode. During controlled clinical trials of

immediate release paroxetine hydrochloride, hypomania or mania occurred in approximately 1% of

paroxetine treated unipolar patients compared to 1.1% of active control and 0.3% of placebo treated

unipolar patients. Prior to initiating treatment with PAXIL CR, screen patients for any personal or family

history of bipolar disorder, mania, or hypomania.

5.7 Discontinuation Syndrome

Adverse reactions after discontinuation of serotonergic antidepressants, particularly after abrupt

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

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

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

rather than abrupt cessation is recommended whenever possible [See Dosage and Administration (2.7)].

Adverse reactions have been reported upon discontinuation of treatment with paroxetine in pediatric

patients. The safety and effectiveness of PAXIL CR in pediatric patients have not been established [see

Boxed Warning, Warnings and Precautions (5.1), Use in Specific Populations (8.4)].

5.8 Seizures

PAXIL CR has not been systematically evaluated in patients with seizure disorders. Patients with history

of seizures were excluded from clinical studies. PAXIL CR should be prescribed with caution in

patients with a seizure disorder and should be discontinued in any patient who develops seizures.

5.9 Angle-Closure Glaucoma

The pupillary dilation that occurs following use of many antidepressant drugs including PAXIL CR may

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

iridectomy. Cases of angle-closure glaucoma associated with use of paroxetine hydrochloride tablets

have been reported. Avoid use of antidepressants, including PAXIL CR, in patients with untreated

anatomically narrow angles.

5.10 Hyponatremia

Hyponatremia may occur as a result of treatment with SNRIs and SSRIs, including PAXIL CR. 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 and/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 PAXIL CR 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 SNRIs and SSRIs. [see Use in Specific Populations (8.5)].

5.11 Reduction of Efficacy of Tamoxifen

Some studies have shown that the efficacy of tamoxifen, as measured by the risk of breast cancer

relapse/mortality, may be reduced with concomitant use of paroxetine as a result of paroxetine’s

irreversible inhibition of CYP2D6 and lower blood levels of tamoxifen [see Drug Interactions (7.3)].

One study suggests that the risk may increase with longer duration of coadministration. However, other

studies have failed to demonstrate such a risk. When tamoxifen is used for the treatment or prevention of

breast cancer, prescribers should consider using an alternative antidepressant with little or no CYP2D6

inhibition.

5.12 Bone Fracture

Epidemiological studies on bone fracture risk during exposure to some antidepressants, including

SSRIs, have reported an association between antidepressant treatment and fractures. There are multiple

possible causes for this observation and it is unknown to what extent fracture risk is directly attributable

to SSRI treatment.

6 ADVERSE REACTIONS

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

information:

Hypersensitivity reactions to paroxetine [see Contraindications (4)]

Suicidal Thoughts and Behaviors [see Warnings and Precautions (5.1)]

Serotonin Syndrome [see Warnings and Precautions (5.2)]

Embryofetal and Neonatal Toxicity [see Warnings and Precautions (5.4)]

Increased Risk of Bleeding [see Warnings and Precautions (5.5)]

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

Discontinuation Syndrome [see Warnings and Precautions (5.7)]

Seizures [see Warnings and Precautions (5.8)]

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

Hyponatremia [see Warnings and Precautions (5.10)]

Bone Fracture [see Warnings and Precautions (5.12)]

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.

Safety data for PAXIL CR is from 11 short-term, placebo controlled clinical trials including 3 studies

in patients with major depressive disorder (MDD) (Studies 1, 2, and 3), 3 studies in patients with panic

disorder (PD) (Studies 4, 5, and 6), 1 study in patients with social anxiety disorder (SAD) (Study 7), and

4 studies in female patients with premenstrual dysphoric disorder (PMDD) (Studies 8, 9, 10, and 11)

[see Clinical Studies (14)]. These 11 trials included 1627 We acknowledge the Agency’s

comment.patients treated with Paxil CR.

Studies 1 and 2 were 12-week studies that enrolled patients 18 to 65 years old who received PAXIL

CR at doses ranging from 25 mg to 62.5 mg once daily. Study 3 was a 12-week study in patients 60

to 88 years old who received PAXIL CR at doses ranging from 12.5 mg to 50 mg once daily.

Studies 4, 5, and 6 were 10-week studies in patients 19 to 72 years old who received PAXIL CR at

doses ranging from 12.5 mg to 75 mg once daily.

Study 7 was a 12-week study that enrolled adult patients who received PAXIL CR at doses ranging

from 12.5 mg to 37.5 mg once daily.

Studies 8, 9, and 10 were 12 week, placebo controlled trials in female patients 18 to 46 years old

who received PAXIL CR at doses of 12.5 mg or 25 mg once daily. Study 11 was a 12-week

placebo controlled trial in patients 18 to 46 years old who received PAXIL CR 2 weeks prior to the

onset of menses (luteal phase dosing) at doses of 12.5 mg or 25 mg once daily.

Adverse Reactions Leading to Discontinuation in Patients with MDD, PD, SAD, and PMDD

In pooled studies in patients with MDD, PD and SAD, the most common adverse reactions leading to

study withdrawal were: nausea (up to 4% of patients), asthenia, headache, depression, insomnia, and

abnormal liver function tests (each occurring in up to 2% of patients), and dizziness, somnolence, and

diarrhea (each occurring in up to 1% of patients).

In pooled studies for PMDD, the most common adverse reactions leading to study withdrawal were:

nausea (occurring in up to 6% of patients), asthenia (occurring in up to 5% of patients), somnolence

(occurring in up to 4% of patients), insomnia (occurring in approximately 2% of patients); and impaired

concentration, dry mouth, dizziness, decreased appetite, sweating, tremor, yawn and diarrhea (occurring

in less than or equal to 2% of patients).

Adverse Reactions in MDD, PD, and SAD

Table 3 presents the most common adverse reactions in PAXIL CR-treated patients (incidence ≥5% and

greater than placebo within at least 1 of the indications) in controlled trials in patients with MDD, PD,

and SAD

Table 3. Adverse Reactions (³5% of Patients Treated with PAXIL CR and Greater than Placebo)

in 10 to 12 Week Studies of MDD, PD, and SAD

MDD

18 to 65 year olds

MDD

≥60 years old

Panic Disorder

Social Anxiety

Dis order

Body System/

Adverse

Reaction

PAXIL

(N=212)

Placebo

(N=211)

PAXIL

(N=104)

Placebo

(N=109)

PAXIL CR

(N=444)

Placebo

(N=445)

PAXIL CR

(N=186)

Placebo

(N=184)

Body as a

Whole

Headache

Asthenia

Abdominal Pain

Back Pain

Diges tive

Sys tem

Nausea

Diarrhea

Dry Mouth

Dry Mouth

Constipation

Flatulence

Decreased

Appetite

<1

Dyspepsia

<1

Mus culos keletal

Sys tem

Myalgia

Nervous

Sys tem

Somnolence

Insomnia

Dizziness

Libido

Decreased

<1

Nervousness

Tremor

Anxiety

Res piratory

Sys tem

Sinusitis

Yawn

Skin and

Appendages

Sweating

<1

Special Senses

Abnormal

Vision

<1

Urogenital

Sys tem

Abnormal

Ejaculation

Female Genital

Disorder

<1

Impotence

Hyphen = the reaction listed occurred in <5% of patients treated with PAXIL CR

NA = the adverse reaction listed did not occur in this group of patients

Mostly blurred vision

Based on the number of males or females

Mostly anorgasmia or delayed ejaculation

Mostly anorgasmia or delayed orgasm

Other Adverse Reactions Observed During the Premarketing Evaluation of PAXIL CR

Adverse reactions from studies in MDD (not including Study 3 in elderly patients), PD, and SAD that

occurred between 1% and 5% of patients treated with PAXIL CR and at a rate greater than in placebo-

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