PAROXETINE- paroxetine 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:
NuCare Pharmaceuticals,Inc.
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Paroxetine tablets, USP are indicated for the treatment of major depressive disorder. The efficacy of paroxetine tablets, USP in the treatment of a major depressive episode was established in 6-week controlled trials of outpatients whose diagnoses corresponded most closely to the DSM-III category of major depressive disorder (see CLINICAL PHARMACOLOGY —Clinical Trials ). A major depressive episode implies a prominent and relatively persistent depressed or dysphoric mood that usually interferes with daily functioning (nearly every day for at least 2 weeks); it should include at least 4 of the following 8 symptoms: Change in appetite, change in sleep, psychomotor agitation or retardation, loss of interest in usual activities or decrease in sexual drive, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, and a suicide attempt or suicidal ideation. The effects of paroxetine tablets, USP in hospitalized depressed patients have not been adequately studied. The efficacy
Product summary:
Paroxetine Tablets USP, 40 mg are white to off-white, round-shaped, biconvex, film- coated tablets debossed with the logo of ZC18 on one side and plain on other side. NDC 68071-4997-3 BOTTLES OF 30 Store at 20° to 25° C (68° to 77° F) [See USP Controlled Room Temperature]. Manufactured by: Cadila Healthcare Ltd. India Distributed by: Zydus Pharmaceuticals (USA) Inc. Pennington, NJ 08534 Rev.: 08/17
Authorization status:
Abbreviated New Drug Application
Authorization number:
68071-4997-3

PAROXETINE- paroxetine tablet, film coated

NuCare Pharmaceuticals,Inc.

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Medication Guide

Paroxetine

(pa-ROX-a-teen)

Tablets, USP

Read the Medication Guide that comes with paroxetine tablets before you start taking it and each time you

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

healthcare provider about your medical condition or treatment. Talk with your healthcare provider if there is

something you do not understand or want to learn more about.

What is the most important information I should know about paroxetine?

Paroxetine and other antidepressant medicines may cause serious side effects, including:

1. Suicidal thoughts or actions:

Paroxetine and other antidepressant medicines may increase suicidal thoughts or actions in some

children, teenagers, or young adults within the first few months of treatment or when the dose is

changed .

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

actions.

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

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

Pay particular attention to such changes when paroxetine 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

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

emergency.

Paroxetine may be associated with these serious side effects:

2. Serotonin Syndrome or Neuroleptic Malignant Syndrome-like reactions. This condition can be life-

threatening and may include:

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

coordination problems or muscle twitching (overactive reflexes)

racing heartbeat, high or low blood pressure

sweating or fever

nausea, vomiting, or diarrhea

muscle rigidity

3. Visual problems

eye pain

changes in vision

swelling or redness in or around the eye

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

are at risk and receive preventative treatment if you are.

4. Severe allergic reactions:

trouble breathing

swelling of the face, tongue, eyes, or mouth

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

5. Abnormal bleeding:

Paroxetine 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 antiinflammatory drug

(NSAIDs, like ibuprofen or naproxen), or aspirin.

6. Seizures or convulsions

7. Manic episodes:

greatly increased energy

severe trouble sleeping

racing thoughts

reckless behavior

unusually grand ideas

excessive happiness or irritability

talking more or faster than usual

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

treatment.

9. 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 paroxetine without first talking to your healthcare provider. Stopping paroxetine 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 paroxetine ?

Paroxetine is a prescription medicine used to treat depression . It is important to talk with your healthcare

provider about the risks of treating depression and also the risks of not treating it. You should discuss all

treatment choices with your healthcare provider.

Paroxetine is also used to treat:

Major Depressive Disorder (MDD)

Obsessive Compulsive Disorder (OCD)

Panic Disorder

Social Anxiety Disorder

Generalized Anxiety Disorder (GAD)

Posttraumatic Stress Disorder (PTSD)

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

paroxetine.

Who should not take paroxetine tablets?

Do not take paroxetine tablets if you:

are allergic to paroxetine hydrochloride or any of the ingredients in paroxetine tablets. See the end of

this Medication Guide for a complete list of ingredients in paroxetine tablets.

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

not sure if you take an MAOI, including the antibiotic linezolid.

Do not take an MAOI within 2 weeks of stopping paroxetine tablets unless directed to do so by your

physician.

Do not start paroxetine tablets if you stopped taking an MAOI in the last 2 weeks unless directed to

do so by your physician.

People who take paroxetine tablets 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)

take MELLARIL®* (thioridazine). Do not take MELLARIL ®* together with paroxetine tablets

because this can cause serious heart rhythm problems or sudden death.

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

What should I tell my healthcare provider before taking paroxetine tablets? Ask if you are not sure.

Before starting paroxetine tablets, tell your healthcare provider if you:

are pregnant, may be pregnant, or plan to become pregnant. There is a possibility that paroxetine

tablets may harm your unborn baby, including an increased risk of birth defects, particularly heart

defects. Other risks may include a serious condition in which there is not enough oxygen in the baby's

blood. Your baby may also have certain other symptoms shortly after birth. Premature births have

also been reported in some women who used paroxetine tablets during pregnancy.

are breastfeeding. Paroxetine passes into your milk. Talk to your healthcare provider about the best

way to feed your baby while taking paroxetine.

are taking certain drugs such as:

triptans used to treat migraine headache

other antidepressants (SSRIs, SNRIs, tricyclics, or lithium) or antipsychotics

drugs that affect serotonin, such as lithium, tramadol, tryptophan, St. John's wort

certain drugs used to treat irregular heart beats

certain drugs used to treat schizophrenia

certain drugs used to treat HIV infection

certain drugs that affect the blood, such as warfarin, aspirin, and ibuprofen

certain drugs used to treat epilepsy

atomoxetine

cimetidine

fentanyl

metoprolol

pimozide

procyclidine

tamoxifen

have liver problems

have kidney problems

have heart problems

have or had seizures or convulsions

have bipolar disorder or mania

have low sodium levels in your blood

have a history of a stroke

have high blood pressure

have or had bleeding problems

have glaucoma (high pressure in the eye)

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

medicines, vitamins, and herbal supplements. Paroxetine 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 paroxetine tablets with your other

medicines. Do not start or stop any medicine while taking paroxetine tablets without talking to your

healthcare provider first.

If you take paroxetine tablets, you should not take any other medicines that contain paroxetine hydrochlorid

How should I take paroxetine tablets?

Take paroxetine tablets exactly as prescribed. Your healthcare provider may need to change the dose

of paroxetine tablets until it is the right dose for you.

Paroxetine tablets may be taken with or without food.

If you miss a dose of paroxetine tablets, 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 paroxetine tablets at the same time.

If you take too much paroxetine tablets, call your healthcare provider or poison control center right

away, or get emergency treatment.

Do not stop taking paroxetine tablets suddenly without talking to your doctor (unless you have

symptoms of a severe allergic reaction). If you need to stop taking paroxetine tablets, your healthcare

provider can tell you how to safely stop taking it.

What should I avoid while taking paroxetine?

Paroxetine 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

paroxetine affects you. Do not drink alcohol while using paroxetine.

What are possible side effects of paroxetine?

Paroxetine may cause serious side effects, including all of those described in the section entitled "What is the

most important information I should know about paroxetine?"

Common possible side effects in people who take paroxetine include:

nausea

sleepiness

weakness

dizziness

feeling anxious or trouble sleeping

sexual problems

sweating

shaking

not feeling hungry

dry mouth

constipation

infection

yawning

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 paroxetine. 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 or 1-800-332-1088.

How should I store paroxetine tablets?

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

Keep paroxetine tablets away from light.

Keep bottle of paroxetine tablets closed tightly.

Keep paroxetine tablets and all medicines out of the reach of children.

General information about paroxetine tablets

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

paroxetine tablets for a condition for which they were not prescribed. Do not give paroxetine tablets to other

people, even if they have the same condition. It may harm them.

This Medication Guide summarizes the most important information about paroxetine. If you would like more

information, talk with your healthcare provider. You may ask your healthcare provider or pharmacist for

information about paroxetine that is written for healthcare professionals.

Address medical inquiries to, Telephone: 1-877-993-8779 or MedicalAffairs@zydususa.com.

What are the ingredients in paroxetine tablets, USP?

Active ingredient: paroxetine hydrochloride, USP

Inactive ingredients: dibasic calcium phosphate anhydrous, hypromellose 6 cP, lactose anhydrous,

magnesium stearate, polyethylene glycol 6000, povidone, sodium starch glycolate, talc, and titanium dioxide.

* are the registered trademarks of their respective owners.

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

This product's package insert may have been updated. For current package insert, please visit

www.zydususa.com

Revised: 7/2019

Document Id: 8e97d598-9f08-0220-e053-2a95a90afc1a

34391-3

Set id: 8e97c132-5740-adba-e053-2a95a90a094a

Version: 1

Effective Time: 20190726

NuCare Pharmaceuticals,Inc.

PAROXETINE- paroxetine tablet, film coated

NuCare Pharmaceuticals,Inc.

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Paroxetine Tablets, USP

Suicidality and Antidepressant Drugs

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 paroxetine tablets 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.

Paroxetine tablets are not approved for use in pediatric patients (see WARNINGS: Clinical

Worsening and Suicide Risk, PRECAUTIONS: Information for Patients, and

PRECAUTIONS: Pediatric Use).

DESCRIPTION

Paroxetine tablets, USP are an orally administered psychotropic drug. It is the hydrochloride salt of a

phenylpiperidine compound identified chemically as (-)-trans- 4R-(4' -fluorophenyl)- 3S-[(3',4'-

methylenedioxyphenoxy) methyl] piperidine hydrochloride hemihydrate and has the molecular formula

of C

HCl1/2H

O. The molecular weight is 374.8 (329.4 as free base). The structural

formula of paroxetine hydrochloride hemihydrate is:

Paroxetine hydrochloride, USP is an odorless, white to off-white crystalline powder, having a melting

point range of 120° to 138°C. It is freely soluble in methanol, soluble in ethanol, sparingly soluble in

dichloromethane and slightly soluble in water.

Each paroxetine tablet, USP intended for oral administration contains paroxetine hydrochloride

hemihydrate equivalent to 10 mg or 20 mg or 30 mg or 40 mg of paroxetine. In addition, each tablet

contains the following inactive ingredients: dibasic calcium phosphate anhydrous, hypromellose 6 cP,

lactose anhydrous, magnesium stearate, polyethylene glycol 6000, povidone, sodium starch glycolate,

talc, and titanium dioxide.

CLINICAL PHARMACOLOGY

Pharmacodynamics :

The efficacy of paroxetine in the treatment of major depressive disorder, social anxiety disorder,

obsessive compulsive disorder (OCD), panic disorder (PD), generalized anxiety disorder (GAD) and

posttraumatic stress disorder (PTSD) is presumed to be linked to potentiation of serotonergic activity in

the central nervous system resulting from inhibition of neuronal reuptake of serotonin (5-hydroxy-

tryptamine, 5-HT). Studies at clinically relevant doses in humans have demonstrated that paroxetine

blocks the uptake of serotonin into human platelets. In vitro studies in animals also suggest that

paroxetine is a potent and highly selective inhibitor of neuronal serotonin reuptake and has only very

weak effects on norepinephrine and dopamine neuronal reuptake. In vitro radioligand binding studies

indicate that paroxetine has little affinity for muscarinic, alpha

-, alpha

-, beta-adrenergic-, dopamine

)-, 5-HT

-, 5-HT

-, and histamine (H

)-receptors; antagonism of muscarinic, histaminergic, and

alpha

-adrenergic receptors has been associated with various anticholinergic, sedative, and

cardiovascular effects for other psychotropic drugs.

Because the relative potencies of paroxetine's major metabolites are at most 1/50 of the parent

compound, they are essentially inactive.

Pharmacokinetics :

Paroxetine hydrochloride is completely absorbed after oral dosing of a solution of the hydrochloride

salt. The mean elimination half-life is approximately 21 hours (CV 32%) after oral dosing of paroxetine

tablets, 30 mg daily for 30 days. Paroxetine is extensively metabolized and the metabolites are

considered to be inactive. Nonlinearity in pharmacokinetics is observed with increasing doses.

Paroxetine metabolism is mediated in part by CYP2D6, and the metabolites are primarily excreted in the

urine and to some extent in the feces. Pharmacokinetic behavior of paroxetine has not been evaluated in

subjects who are deficient in CYP2D6 (poor metabolizers).

In a meta analysis of paroxetine from 4 studies done in healthy volunteers following multiple dosing of

20 mg/day to 40 mg/day, males did not exhibit a significantly lower C

or AUC than females.

Absorption and Distribution:

Paroxetine hydrochloride hemihydrate is completely absorbed after oral dosing of a solution of the

hydrochloride salt. In a study in which normal male subjects (n = 15) received 30 mg tablets daily for 30

days, steady-state paroxetine concentrations were achieved by approximately 10 days for most subjects,

although it may take substantially longer in an occasional patient. At steady state, mean values of C

, and T

were 61.7 ng/mL (CV 45%), 5.2 hr. (CV 10%), 30.7 ng/mL (CV 67%), and 21.0

hours (CV 32%), respectively. The steady-state C

and C

values were about 6 and 14 times what

would be predicted from single-dose studies. Steady-state drug exposure based on AUC

was about

8 times greater than would have been predicted from single-dose data in these subjects. The excess

accumulation is a consequence of the fact that 1 of the enzymes that metabolizes paroxetine is readily

saturable.

The effects of food on the bioavailability of paroxetine were studied in subjects administered a single

dose with and without food. AUC was only slightly increased (6%) when drug was administered with

food but the C

was 29% greater, while the time to reach peak plasma concentration decreased from

6.4 hours post-dosing to 4.9 hours.

Paroxetine distributes throughout the body, including the CNS, with only 1% remaining in the plasma.

Approximately 95% and 93% of paroxetine is bound to plasma protein at 100 ng/mL and 400 ng/mL,

respectively. Under clinical conditions, paroxetine concentrations would normally be less than 400

ng/mL. Paroxetine does not alter the in vitro protein binding of phenytoin or warfarin.

Metabolism and Excretion:

The mean elimination half-life is approximately 21 hours (CV 32%) after oral dosing of paroxetine

tablets, 30 mg tablets daily for 30 days. In steady-state dose proportionality studies involving elderly

and nonelderly patients, at doses of 20 mg to 40 mg daily for the elderly and 20 mg to 50 mg daily for

the nonelderly, some nonlinearity was observed in both populations, again reflecting a saturable

metabolic pathway. In comparison to C

values after 20 mg daily, values after 40 mg daily were only

about 2 to 3 times greater than doubled.

Paroxetine is extensively metabolized after oral administration. The principal metabolites are polar and

conjugated products of oxidation and methylation, which are readily cleared. Conjugates with

glucuronic acid and sulfate predominate, and major metabolites have been isolated and identified. Data

indicate that the metabolites have no more than 1/50 the potency of the parent compound at inhibiting

serotonin uptake. The metabolism of paroxetine is accomplished in part by CYP2D6. Saturation of this

enzyme at clinical doses appears to account for the nonlinearity of paroxetine kinetics with increasing

dose and increasing duration of treatment. The role of this enzyme in paroxetine metabolism also

suggests potential drug-drug interactions (see PRECAUTIONS: Drugs Metabolized by CYP2D6).

Approximately 64% of a 30-mg oral solution dose of paroxetine was excreted in the urine with 2% as

the parent compound and 62% as metabolites over a 10-day post-dosing period. About 36% was

excreted in the feces (probably via the bile), mostly as metabolites and less than 1% as the parent

compound over the 10-day post-dosing period.

Other Clinical Pharmacology Information

Specific Populations

Renal and Liver Disease:

Increased plasma concentrations of paroxetine occur in subjects with renal and hepatic impairment. The

mean plasma concentrations in patients with creatinine clearance below 30 mL/min. were approximately

4 times greater than seen in normal volunteers. Patients with creatinine clearance of 30 to 60 mL/min.

and patients with hepatic functional impairment had about a 2-fold increase in plasma concentrations

(AUC, C

The initial dosage should therefore be reduced in patients with severe renal or hepatic impairment, and

upward titration, if necessary, should be at increased intervals (see DOSAGE AND

ADMINISTRATION).

Elderly Patients:

In a multiple-dose study in the elderly at daily paroxetine doses of 20, 30, and 40 mg, C

0-24

concentrations were about 70% to 80% greater than the respective C

concentrations in nonelderly

subjects. Therefore the initial dosage in the elderly should be reduced (see DOSAGE AND

ADMINISTRATION).

Drug-Drug Interactions:

In vitro drug interaction studies reveal that paroxetine inhibits CYP2D6. Clinical drug interaction studies

have been performed with substrates of CYP2D6 and show that paroxetine can inhibit the metabolism of

drugs metabolized by CYP2D6 including desipramine, risperidone, and atomoxetine (see

PRECAUTIONS ─ Drug Interactions).

Clinical Trials

Major Depressive Disorder:

The efficacy of paroxetine tablets as a treatment for major depressive disorder has been established in

6 placebo-controlled studies of patients with major depressive disorder (aged 18 to 73). In these

studies, paroxetine tablets were shown to be significantly more effective than placebo in treating major

depressive disorder by at least 2 of the following measures: Hamilton Depression Rating Scale

(HDRS), the Hamilton depressed mood item, and the Clinical Global Impression (CGI)-Severity of

Illness. Paroxetine tablets were significantly better than placebo in improvement of the HDRS sub-

factor scores, including the depressed mood item, sleep disturbance factor, and anxiety factor.

A study of outpatients with major depressive disorder who had responded to paroxetine tablets (HDRS

total score <8) during an initial 8-week open-treatment phase and were then randomized to continuation

on paroxetine tablets or placebo for 1 year demonstrated a significantly lower relapse rate for patients

taking paroxetine tablets (15%) compared to those on placebo (39%). Effectiveness was similar for

male and female patients.

Obsessive Compulsive Disorder:

The effectiveness of paroxetine tablets in the treatment of obsessive compulsive disorder (OCD) was

demonstrated in two 12-week multicenter placebo-controlled studies of adult outpatients (Studies 1 and

2). Patients in all studies had moderate to severe OCD (DSM-IIIR) with mean baseline ratings on the

Yale Brown Obsessive Compulsive Scale (YBOCS) total score ranging from 23 to 26. Study 1, a dose-

range finding study where patients were treated with fixed doses of 20, 40, or 60 mg of paroxetine/day

demonstrated that daily doses of paroxetine 40 and 60 mg are effective in the treatment of OCD. Patients

receiving doses of 40 and 60 mg paroxetine experienced a mean reduction of approximately 6 and 7

points, respectively, on the YBOCS total score which was significantly greater than the approximate 4-

point reduction at 20 mg and a 3-point reduction in the placebo-treated patients. Study 2 was a flexible-

dose study comparing paroxetine (20 to 60 mg daily) with clomipramine (25 to 250 mg daily). In this

study, patients receiving paroxetine experienced a mean reduction of approximately 7 points on the

YBOCS total score, which was significantly greater than the mean reduction of approximately 4 points

in placebo-treated patients.

The following table provides the outcome classification by treatment group on Global Improvement

items of the Clinical Global Impression (CGI) scale for Study 1.

Outcome Classification (%) on CGI-Global Improvement Item for Completers in Study 1

Outcome Classification

Placebo

(n = 74)

Paroxetine

Tablets USP,

20 mg

(n = 75)

Paroxetine

Tablets USP,

40 mg

(n = 66)

Paroxetine

Tablets USP,

60 mg

(n = 66)

Worse

No Change

Minimally Improved

Much Improved

Very Much Improved

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

of age or gender.

The long-term maintenance effects of paroxetine tablets in OCD were demonstrated in a long-term

extension to Study 1. Patients who were responders on paroxetine during the 3-month double-blind

phase and a 6-month extension on open-label paroxetine (20 to 60 mg/day) were randomized to either

paroxetine or placebo in a 6-month double-blind relapse prevention phase. Patients randomized to

paroxetine were significantly less likely to relapse than comparably treated patients who were

randomized to placebo.

Panic Disorder:

The effectiveness of paroxetine tablets in the treatment of panic disorder was demonstrated in three 10-

to 12-week multicenter, placebo-controlled studies of adult outpatients (Studies 1-3). Patients in all

studies had panic disorder (DSM-IIIR), with or without agoraphobia. In these studies, paroxetine tablets

were shown to be significantly more effective than placebo in treating panic disorder by at least 2 out of

3 measures of panic attack frequency and on the Clinical Global Impression Severity of Illness score.

Study 1 was a 10-week dose-range finding study; patients were treated with fixed paroxetine doses of

10, 20, or 40 mg/day or placebo. A significant difference from placebo was observed only for the 40

mg/day group. At endpoint, 76% of patients receiving paroxetine 40 mg/day were free of panic attacks,

compared to 44% of placebo-treated patients.

Study 2 was a 12-week flexible-dose study comparing paroxetine (10 to 60 mg daily) and placebo. At

endpoint, 51% of paroxetine patients were free of panic attacks compared to 32% of placebo-treated

patients.

Study 3 was a 12-week flexible-dose study comparing paroxetine (10 to 60 mg daily) to placebo in

patients concurrently receiving standardized cognitive behavioral therapy. At endpoint, 33% of the

paroxetine-treated patients showed a reduction to 0 or 1 panic attacks compared to 14% of placebo

patients.

In both Studies 2 and 3, the mean paroxetine dose for completers at endpoint was approximately 40

mg/day of paroxetine.

Long-term maintenance effects of paroxetine tablets in panic disorder were demonstrated in an extension

to Study 1. Patients who were responders during the 10-week double-blind phase and during a 3-month

double-blind extension phase were randomized to either paroxetine (10, 20, or 40 mg/day) or placebo in

a 3-month double-blind relapse prevention phase. Patients randomized to paroxetine were significantly

less likely to relapse than comparably treated patients who were randomized to placebo.

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

of age or gender.

Social Anxiety Disorder:

The effectiveness of paroxetine tablets in the treatment of social anxiety disorder was demonstrated in

three 12-week, multicenter, placebo-controlled studies (Studies 1, 2, and 3) of adult outpatients with

social anxiety disorder (DSM-IV). In these studies, the effectiveness of paroxetine tablets compared to

placebo was evaluated on the basis of (1) the proportion of responders, as defined by a Clinical Global

Impression (CGI) Improvement score of 1 (very much improved) or 2 (much improved), and (2) change

from baseline in the Liebowitz Social Anxiety Scale (LSAS).

Studies 1 and 2 were flexible-dose studies comparing paroxetine (20 to 50 mg daily) and placebo.

Paroxetine demonstrated statistically significant superiority over placebo on both the CGI Improvement

responder criterion and the Liebowitz Social Anxiety Scale (LSAS). In Study 1, for patients who

completed to week 12, 69% of paroxetine-treated patients compared to 29% of placebo-treated patients

were CGI Improvement responders. In Study 2, CGI Improvement responders were 77% and 42% for the

paroxetine- and placebo-treated patients, respectively.

Study 3 was a 12-week study comparing fixed paroxetine doses of 20, 40, or 60 mg/day with placebo.

Paroxetine 20 mg was demonstrated to be significantly superior to placebo on both the LSAS Total

Score and the CGI Improvement responder criterion; there were trends for superiority over placebo for

the 40 mg and 60 mg/day dose groups. There was no indication in this study of any additional benefit

for doses higher than 20 mg/day.

Subgroup analyses generally did not indicate differences in treatment outcomes as a function of age,

race, or gender.

Generalized Anxiety Disorder:

The effectiveness of paroxetine tablets in the treatment of Generalized Anxiety Disorder (GAD) was

demonstrated in two 8-week, multicenter, placebo-controlled studies (Studies 1 and 2) of adult

outpatients with Generalized Anxiety Disorder (DSM-IV).

Study 1 was an 8-week study comparing fixed paroxetine doses of 20 mg or 40 mg/day with placebo.

Doses of 20 mg or 40 mg of paroxetine tablets were both demonstrated to be significantly superior to

placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score. There was not sufficient

evidence in this study to suggest a greater benefit for the 40 mg/day dose compared to the 20 mg/day

dose.

Study 2 was a flexible-dose study comparing paroxetine (20 mg to 50 mg daily) and placebo. Paroxetine

tablets demonstrated statistically significant superiority over placebo on the Hamilton Rating Scale for

Anxiety (HAM-A) total score. A third study, also flexible-dose comparing paroxetine (20 mg to 50 mg

daily), did not demonstrate statistically significant superiority of paroxetine tablets over placebo on the

Hamilton Rating Scale for Anxiety (HAM-A) total score, the primary outcome.

Subgroup analyses did not indicate differences in treatment outcomes as a function of race or gender.

There were insufficient elderly patients to conduct subgroup analyses on the basis of age.

In a longer-term trial, 566 patients meeting DSM-IV criteria for Generalized Anxiety Disorder, who had

responded during a single-blind, 8-week acute treatment phase with 20 to 50 mg/day of paroxetine

tablets, were randomized to continuation of paroxetine tablets at their same dose, or to placebo, for up

to 24 weeks of observation for relapse. Response during the single-blind phase was defined by having

a decrease of ≥ 2 points compared to baseline on the CGI-Severity of Illness scale, to a score of ≤ 3.

Relapse during the double-blind phase was defined as an increase of ≥ 2 points compared to baseline on

the CGI-Severity of Illness scale to a score of ≥ 4, or withdrawal due to lack of efficacy. Patients

receiving continued paroxetine tablets experienced a significantly lower relapse rate over the

subsequent 24 weeks compared to those receiving placebo.

Posttraumatic Stress Disorder:

The effectiveness of paroxetine tablets in the treatment of Posttraumatic Stress Disorder (PTSD) was

demonstrated in two 12-week, multicenter, placebo-controlled studies (Studies 1 and 2) of adult

outpatients who met DSM-IV criteria for PTSD. The mean duration of PTSD symptoms for the 2 studies

combined was 13 years (ranging from .1 year to 57 years). The percentage of patients with secondary

major depressive disorder or non-PTSD anxiety disorders in the combined 2 studies was 41% (356 out

of 858 patients) and 40% (345 out of 858 patients), respectively. Study outcome was assessed by (i) the

Clinician-Administered PTSD Scale Part 2 (CAPS-2) score and (ii) the Clinical Global Impression-

Global Improvement Scale (CGI-I). The CAPS-2 is a multi-item instrument that measures 3 aspects of

PTSD with the following symptom clusters: Reexperiencing/intrusion, avoidance/numbing and

hyperarousal. The 2 primary outcomes for each trial were (i) change from baseline to endpoint on the

CAPS-2 total score (17 items), and (ii) proportion of responders on the CGI-I, where responders were

defined as patients having a score of 1 (very much improved) or 2 (much improved).

Study 1 was a 12-week study comparing fixed paroxetine doses of 20 mg or 40 mg/day to placebo.

Doses of 20 mg and 40 mg of paroxetine tablets were demonstrated to be significantly superior to

placebo on change from baseline for the CAPS-2 total score and on proportion of responders on the

CGI-I. There was not sufficient evidence in this study to suggest a greater benefit for the 40 mg/day

dose compared to the 20 mg/day dose.

Study 2 was a 12-week flexible-dose study comparing paroxetine (20 to 50 mg daily) to placebo.

Paroxetine tablets were demonstrated to be significantly superior to placebo on change from baseline

for the CAPS-2 total score and on proportion of responders on the CGI-I.

A third study, also a flexible-dose study comparing paroxetine (20 to 50 mg daily) to placebo,

demonstrated paroxetine tablets to be significantly superior to placebo on change from baseline for

CAPS2 total score, but not on proportion of responders on the CGI-I.

The majority of patients in these trials were women (68% women: 377 out of 551 subjects in Study 1 and

66% women: 202 out of 303 subjects in Study 2). Subgroup analyses did not indicate differences in

treatment outcomes as a function of gender. There were an insufficient number of patients who were 65

years and older or were non-Caucasian to conduct subgroup analyses on the basis of age or race,

respectively.

INDICATIONS AND USAGE

Major Depressive Disorder:

Paroxetine tablets, USP are indicated for the treatment of major depressive disorder.

The efficacy of paroxetine tablets, USP in the treatment of a major depressive episode was established

in 6-week controlled trials of outpatients whose diagnoses corresponded most closely to the DSM-III

category of major depressive disorder (see CLINICAL PHARMACOLOGY —Clinical Trials). A

major depressive episode implies a prominent and relatively persistent depressed or dysphoric mood

that usually interferes with daily functioning (nearly every day for at least 2 weeks); it should include at

least 4 of the following 8 symptoms: Change in appetite, change in sleep, psychomotor agitation or

retardation, loss of interest in usual activities or decrease in sexual drive, increased fatigue, feelings of

guilt or worthlessness, slowed thinking or impaired concentration, and a suicide attempt or suicidal

ideation.

The effects of paroxetine tablets, USP in hospitalized depressed patients have not been adequately

studied.

The efficacy of paroxetine tablets, USP in maintaining a response in major depressive disorder for up to

1 year was demonstrated in a placebo-controlled trial (see CLINICAL PHARMACOLOGY —

Clinical Trials). Nevertheless, the physician who elects to use paroxetine tablets, USP for extended

periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

Obsessive Compulsive Disorder:

Paroxetine tablets, USP are indicated for the treatment of obsessions and compulsions in patients with

obsessive compulsive disorder (OCD) as defined in the DSM-IV. The obsessions or compulsions

cause marked distress, are time-consuming, or significantly interfere with social or occupational

functioning.

The efficacy of paroxetine tablets, USP were established in two 12-week trials with obsessive

compulsive outpatients whose diagnoses corresponded most closely to the DSM-IIIR category of

obsessive compulsive disorder (see CLINICAL PHARMACOLOGY —Clinical Trials).

Obsessive compulsive disorder is characterized by recurrent and persistent ideas, thoughts, impulses,

or images (obsessions) that are ego-dystonic and/or repetitive, purposeful, and intentional behaviors

(compulsions) that are recognized by the person as excessive or unreasonable.

Long-term maintenance of efficacy was demonstrated in a 6-month relapse prevention trial. In this trial,

patients assigned to paroxetine showed a lower relapse rate compared to patients on placebo (see

CLINICAL PHARMACOLOGY — Clinical Trials). Nevertheless, the physician who elects to use

paroxetine tablets, USP for extended periods should periodically re-evaluate the long-term usefulness

of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).

Panic Disorder:

Paroxetine tablets, USP are indicated for the treatment of panic disorder, with or without agoraphobia,

as defined in DSM-IV. Panic disorder is characterized by the occurrence of unexpected panic attacks

and associated concern about having additional attacks, worry about the implications or consequences of

the attacks, and/or a significant change in behavior related to the attacks.

The efficacy of paroxetine tablets, USP were established in three 10- to 12-week trials in panic

disorder patients whose diagnoses corresponded to the DSM-IIIR category of panic disorder (see

CLINICAL PHARMACOLOGY —Clinical Trials).

Panic disorder (DSM-IV) is characterized by recurrent unexpected panic attacks, i.e., a discrete period

of intense fear or discomfort in which 4 (or more) of the following symptoms develop abruptly and

reach a peak within 10 minutes: (1) palpitations, pounding heart, or accelerated heart rate; (2) sweating;

(3) trembling or shaking; (4) sensations of shortness of breath or smothering; (5) feeling of choking; (6)

chest pain or discomfort; (7) nausea or abdominal distress; (8) feeling dizzy, unsteady, lightheaded, or

faint; (9) derealization (feelings of unreality) or depersonalization (being detached from oneself); (10)

fear of losing control; (11) fear of dying; (12) paresthesias (numbness or tingling sensations); (13) chills

or hot flushes.

Long-term maintenance of efficacy was demonstrated in a 3-month relapse prevention trial. In this trial,

patients with panic disorder assigned to paroxetine demonstrated a lower relapse rate compared to

patients on placebo (see CLINICAL PHARMACOLOGY —Clinical Trials). Nevertheless, the

physician who prescribes paroxetine tablets, USP for extended periods should periodically re-evaluate

the long-term usefulness of the drug for the individual patient (see DOSAGE AND

ADMINISTRATION).

Social Anxiety Disorder:

Paroxetine tablets, USP are indicated for the treatment of social anxiety disorder, also known as social

phobia, as defined in DSM-IV (300.23). Social anxiety disorder is characterized by a marked and

persistent fear of 1 or more social or performance situations in which the person is exposed to

unfamiliar people or to possible scrutiny by others. Exposure to the feared situation almost invariably

provokes anxiety, which may approach the intensity of a panic attack. The feared situations are avoided

or endured with intense anxiety or distress. The avoidance, anxious anticipation, or distress in the

feared situation(s) interferes significantly with the person's normal routine, occupational or academic

functioning, or social activities or relationships, or there is marked distress about having the phobias.

Lesser degrees of performance anxiety or shyness generally do not require psychopharmacological

treatment.

The efficacy of paroxetine tablets, USP were established in three 12-week trials in adult patients with

social anxiety disorder (DSM-IV). Paroxetine tablets, USP have not been studied in children or

adolescents with social phobia (see CLINICAL PHARMACOLOGY — Clinical Trials).

The effectiveness of paroxetine tablets, USP in long-term treatment of social anxiety disorder, i.e., for

more than 12 weeks, has not been systematically evaluated in adequate and well-controlled trials.

Therefore, the physician who elects to prescribe paroxetine tablets, USP for extended periods should

periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE

AND ADMINISTRATION).

Generalized Anxiety Disorder:

Paroxetine tablets, USP are indicated for the treatment of Generalized Anxiety Disorder (GAD), as

defined in DSM-IV. Anxiety or tension associated with the stress of everyday life usually does not

require treatment with an anxiolytic.

The efficacy of paroxetine tablets, USP in the treatment of GAD was established in two 8-week

placebo-controlled trials in adults with GAD. Paroxetine tablets, USP have not been studied in children

or adolescents with Generalized Anxiety Disorder (see CLINICAL PHARMACOLOGY— Clinical

T rials ).

Generalized Anxiety Disorder (DSM-IV) is characterized by excessive anxiety and worry

(apprehensive expectation) that is persistent for at least 6 months and which the person finds difficult to

control. It must be associated with at least 3 of the following 6 symptoms: Restlessness or feeling

keyed up or on edge, being easily fatigued, difficulty concentrating or mind going blank, irritability,

muscle tension, sleep disturbance.

The efficacy of paroxetine tablets, USP in maintaining a response in patients with Generalized Anxiety

Disorder, who responded during an 8-week acute treatment phase while taking paroxetine tablets, USP

and were then observed for relapse during a period of up to 24 weeks, was demonstrated in a placebo-

controlled trial (see CLINICAL PHARMACOLOGY —Clinical Trials). Nevertheless, the physician

who elects to use paroxetine tablets, USP for extended periods should periodically re-evaluate the

long-term usefulness of the drug for the individual patient (see DOSAGE AND

ADMINISTRATION).

Posttraumatic Stress Disorder:

Paroxetine tablets, USP are indicated for the treatment of Posttraumatic Stress Disorder (PTSD).

The efficacy of paroxetine tablets, USP in the treatment of PTSD was established in two 12-week

placebo-controlled trials in adults with PTSD (DSM-IV) (see CLINICAL PHARMACOLOGY:

Clinical Trials).

PTSD, as defined by DSM-IV, requires exposure to a traumatic event that involved actual or threatened

death or serious injury, or threat to the physical integrity of self or others, and a response that involves

intense fear, helplessness, or horror. Symptoms that occur as a result of exposure to the traumatic event

include re-experiencing of the event in the form of intrusive thoughts, flashbacks, or dreams, and

intense psychological distress and physiological reactivity on exposure to cues to the event; avoidance

of situations reminiscent of the traumatic event, inability to recall details of the event, and/or numbing of

general responsiveness manifested as diminished interest in significant activities, estrangement from

others, restricted range of affect, or sense of foreshortened future; and symptoms of autonomic arousal

including hypervigilance, exaggerated startle response, sleep disturbance, impaired concentration, and

irritability or outbursts of anger. A PTSD diagnosis requires that the symptoms are present for at least a

month and that they cause clinically significant distress or impairment in social, occupational, or other

important areas of functioning.

The efficacy of paroxetine tablets, USP in longer-term treatment of PTSD, i.e., for more than 12 weeks,

has not been systematically evaluated in placebo-controlled trials. Therefore, the physician who elects

to prescribe paroxetine tablets, USP for extended periods should periodically re-evaluate the long-term

usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).

CONTRAINDICATIONS

The use of MAOIs intended to treat psychiatric disorders with paroxetine tablets or within 14 days of

stopping treatment with paroxetine tablets is contraindicated because of an increased risk of serotonin

syndrome. The use of paroxetine tablets within 14 days of stopping an MAOI intended to treat

psychiatric disorders is also contraindicated (see WARNINGS and DOSAGE AND

ADMINISTRATION).

Starting paroxetine tablets in a patient who is being treated with MAOIs such as linezolid or intravenous

methylene blue is also contraindicated because of an increased risk of serotonin syndrome (see

WARNINGS and DOSAGE AND ADMINISTRATION).

Concomitant use with thioridazine is contraindicated (see WARNINGS and PRECAUTIONS).

Concomitant use in patients taking pimozide is contraindicated (see PRECAUTIONS).

Paroxetine tablets are contraindicated in patients with a hypersensitivity to paroxetine or any of the

inactive ingredients in paroxetine tablets.

WARNINGS

Clinical Worsening and Suicide Risk:

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

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

in behavior, whether or not they are taking antidepressant medications, and this risk may persist until

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

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

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

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

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

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

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

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

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

compared to placebo in adults aged 65 and older.

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

compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9

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

with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2

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

suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs

studied. There were differences in absolute risk of suicidality across the different indications, with the

highest incidence in MDD. The risk differences (drug vs placebo), however, were relatively stable

within age strata and across indications. These risk differences (drug-placebo difference in the number

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

Table 1

Age Range

Drug-Placebo Difference in Number of Cases of

Suicidality per 1,000 Patients Treated

Increases Compared to Placebo

<18

14 additional cases

18-24

5 additional cases

Decreases Compared to Placebo

25-64

1 fewer case

≥65

6 fewer cases

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

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

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

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

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

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

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

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

changes, either increases or decreases.

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

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

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

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

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

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

emerging suicidality.

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

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

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

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

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

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

PRECAUTIONS and DOSAGE AND ADMINISTRATION: Discontinuation of Treatment With

Paroxetine), for a description of the risks of discontinuation of paroxetine).

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

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

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

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

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

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

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

overdose.

Screening Patients for Bipolar Disorder:

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

(though not established in controlled trials) that treating such an episode with an antidepressant alone

may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar

disorder. Whether any of the symptoms described above represent such a conversion is unknown.

However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should

be adequately screened to determine if they are at risk for bipolar disorder; such screening should

include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and

depression. It should be noted that paroxetine tablets are not approved for use in treating bipolar

depression.

Serotonin Syndrome

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

SSRIs, including paroxetine, alone but particularly with concomitant use of other serotonergic drugs

(including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone,

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

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

intravenous methylene blue).

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

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

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

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

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

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

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

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

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

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

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

with an MAOI such as linezolid or intravenous methylene blue in a patient taking paroxetine. Paroxetine

should be discontinued before initiating treatment with the MAOI (see CONTRAINDICATIONS and

DOSAGE AND ADMINISTRATION).

If concomitant use of paroxetine with certain other serotonergic drugs, i.e., triptans, tricyclic

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

clinically warranted, be aware of a potential increased risk for serotonin syndrome, particularly during

treatment initiation and dose increases.

Treatment with paroxetine and any concomitant serotonergic agents should be discontinued immediately

if the above events occur and supportive symptomatic treatment should be initiated.

Angle-Closure Glaucoma: The pupillary dilation that occurs following use of many antidepressant

drugs including paroxetine may trigger an angle closure attack in a patient with anatomically narrow

angles who does not have a patent iridectomy.

Potential Interaction with Thioridazine:

Thioridazine administration alone produces prolongation of the QTc interval, which is associated

with serious ventricular arrhythmias, such as torsade de pointes-type arrhythmias, and sudden

death. This effect appears to be dose related.

An in vivo study suggests that drugs which inhibit CYP2D6, such as paroxetine, will elevate

plasma levels of thioridazine. Therefore, it is recommended that paroxetine not be used in

combination with thioridazine (see CONTRAINDICATIONS and PRECAUTIONS).

Usage in Pregnancy

Teratogenic Effects:

Epidemiological studies have shown that infants exposed to paroxetine in the first trimester of

pregnancy have an increased risk of congenital malformations, particularly cardiovascular

malformations. The findings from these studies are summarized below:

A study based on Swedish national registry data demonstrated that infants exposed to paroxetine

during pregnancy (n = 815) had an increased risk of cardiovascular malformations (2% risk in

paroxetine-exposed infants) compared to the entire registry population (1% risk), for an odds ratio

(OR) of 1.8 (95% confidence interval 1.1 to 2.8). No increase in the risk of overall congenital

malformations was seen in the paroxetine-exposed infants. The cardiac malformations in the

paroxetine-exposed infants were primarily ventricular septal defects (VSDs) and atrial septal

defects (ASDs). Septal defects range in severity from those that resolve spontaneously to those

which require surgery.

A separate retrospective cohort study from the United States (United Healthcare data) evaluated

5,956 infants of mothers dispensed antidepressants during the first trimester (n = 815 for paroxetine).

This study showed a trend towards an increased risk for cardiovascular malformations for

paroxetine (risk of 1.5%) compared to other antidepressants (risk of 1%), for an OR of 1.5 (95%

confidence interval 0.8 to 2.9). Of the 12 paroxetine-exposed infants with cardiovascular

malformations, 9 had VSDs. This study also suggested an increased risk of overall major congenital

malformations including cardiovascular defects for paroxetine (4% risk) compared to other (2%

risk) antidepressants (OR 1.8; 95% confidence interval 1.2 to 2.8).

Two large case-control studies using separate databases, each with > 9,000 birth defect cases and >

4,000 controls, found that maternal use of paroxetine during the first trimester of pregnancy was

associated with a 2- to 3-fold increased risk of right ventricular outflow tract obstructions. In one

study the odds ratio was 2.5 (95% confidence interval, 1 to 6, 7 exposed infants) and in the other

study the odds ratio was 3.3 (95% confidence interval, 1.3 to 8.8, 6 exposed infants).

Other studies have found varying results as to whether there was an increased risk of overall,

cardiovascular, or specific congenital malformations. A meta-analysis of epidemiological data over a

16-year period (1992 to 2008) on first trimester paroxetine use in pregnancy and congenital

malformations included the above-noted studies in addition to others (n = 17 studies that included

overall malformations and n = 14 studies that included cardiovascular malformations; n = 20 distinct

studies). While subject to limitations, this meta-analysis suggested an increased occurrence of

cardiovascular malformations (prevalence odds ratio [POR] 1.5; 95% confidence interval 1.2 to 1.9) and

overall malformations (POR 1.2; 95% confidence interval 1.1 to 1.4) with paroxetine use during the first

trimester. It was not possible in this meta-analysis to determine the extent to which the observed

prevalence of cardiovascular malformations might have contributed to that of overall malformations, nor

was it possible to determine whether any specific types of cardiovascular malformations might have

contributed to the observed prevalence of all cardiovascular malformations.

If a patient becomes pregnant while taking paroxetine, she should be advised of the potential harm to the

fetus. Unless the benefits of paroxetine to the mother justify continuing treatment, consideration should

be given to either discontinuing paroxetine therapy or switching to another antidepressant (see

PRECAUTIONS: Discontinuation of Treatment With Paroxetine Tablets). For women who intend

to become pregnant or are in their first trimester of pregnancy, paroxetine should only be initiated after

consideration of the other available treatment options.

Animal Findings:

Reproduction studies were performed at doses up to 50 mg/kg/day in rats and 6 mg/kg/day in rabbits

administered during organogenesis. These doses are approximately 8 (rat) and 2 (rabbit) times the

maximum recommended human dose (MRHD) on an mg/m

basis. These studies have revealed no

evidence of teratogenic effects. However, in rats, there was an increase in pup deaths during the first 4

days of lactation when dosing occurred during the last trimester of gestation and continued throughout

lactation. This effect occurred at a dose of 1 mg/kg/day or approximately one-sixth of the MRHD on an

mg/m

basis. The no-effect dose for rat pup mortality was not determined. The cause of these deaths is

not known.

Nonteratogenic Effects:

Neonates exposed to paroxetine tablets and other SSRIs or serotonin and norepinephrine reuptake

inhibitors (SNRIs), late in the third trimester have developed complications requiring prolonged

hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon

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

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

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

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

be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see

WARNINGS— Serotonin Syndrome).

Infants exposed to SSRIs in pregnancy may have an increased risk for persistent pulmonary hypertension

of the newborn (PPHN). PPHN occurs in 1 – 2 per 1,000 live births in the general population and is

associated with substantial neonatal morbidity and mortality. Several recent epidemiologic studies

suggest a positive statistical association between SSRI use (including paroxetine) in pregnancy and

PPHN. Other studies do not show a significant statistical association.

Physicians should also note the results of a prospective longitudinal study of 201 pregnant women with

a history of major depression, who were either on antidepressants or had received antidepressants less

than 12 weeks prior to their last menstrual period, and were in remission. Women who discontinued

antidepressant medication during pregnancy showed a significant increase in relapse of their major

depression compared to those women who remained on antidepressant medication throughout

pregnancy.

When treating a pregnant woman with paroxetine, the physician should carefully consider both the

potential risks of taking an SSRI, along with the established benefits of treating depression with an

antidepressant. This decision can only be made on a case by case basis (see DOSAGE AND

ADMINISTRATION and ADVERSE REACTIONS: Postmarketing Reports).

PRECAUTIONS

General

Activation of Mania Hypomania

During premarketing testing, hypomania or mania occurred in approximately 1.0% of unipolar patients

treated with paroxetine tablets compared to 1.1% of active-control and 0.3% of placebo-treated unipolar

patients. In a subset of patients classified as bipolar, the rate of manic episodes was 2.2% for paroxetine

tablets and 11.6% for the combined active-control groups. As with all drugs effective in the treatment

of major depressive disorder, paroxetine tablets should be used cautiously in patients with a history of

mania.

Seizures :

During premarketing testing, seizures occurred in 0.1% of patients treated with paroxetine tablets, a rate

similar to that associated with other drugs effective in the treatment of major depressive disorder.

Paroxetine tablets should be used cautiously in patients with a history of seizures. It should be

discontinued in any patient who develops seizures.

Discontinuation of Treatment with Paroxetine Tablets:

Recent clinical trials supporting the various approved indications for paroxetine tablets employed a

taper-phase regimen, rather than an abrupt discontinuation of treatment. The taper-phase regimen used in

GAD and PTSD clinical trials involved an incremental decrease in the daily dose by 10 mg/day at

weekly intervals. When a daily dose of 20 mg/day was reached, patients were continued on this dose for

1 week before treatment was stopped.

With this regimen in those studies, the following adverse events were reported at an incidence of 2% or

greater for paroxetine tablets and were at least twice that reported for placebo: Abnormal dreams,

paresthesia, and dizziness. In the majority of patients, these events were mild to moderate and were self

limiting and did not require medical intervention.

During marketing of paroxetine tablets and other SSRIs and SNRIs, there have been spontaneous reports

of adverse events occurring upon the discontinuation of these drugs (particularly when abrupt),

including the following: Dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g.,

paresthesias such as electric shock sensations and tinnitus), anxiety, confusion, headache, lethargy,

emotional lability, insomnia, and hypomania. While these events are generally selflimiting, there have

been reports of serious discontinuation symptoms.

Patients should be monitored for these symptoms when discontinuing treatment with paroxetine tablets.

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

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

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

decreasing the dose but at a more gradual rate (see DOSAGE AND ADMINISTRATION).

See also PRECAUTIONS— Pediatric Use, for adverse events reported upon discontinuation of

treatment with paroxetine tablets in pediatric patients.

Tamoxifen:

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

relapse/mortality, may be reduced when co-prescribed with paroxetine as a result of paroxetine's

irreversible inhibition of CYP2D6 (see DRUG INTERACTIONS). However, other studies have

failed to demonstrate such a risk. It is uncertain whether the coadministration of paroxetine and

tamoxifen has a significant adverse effect on the efficacy of tamoxifen. One study suggests that the risk

may increase with longer duration of coadministration. 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.

Akathis ia:

The use of paroxetine or other SSRIs has been associated with the development of akathisia, which is

characterized by an inner sense of restlessness and psychomotor agitation such as an inability to sit or

stand still usually associated with subjective distress. This is most likely to occur within the first few

weeks of treatment.

Hyponatremia:

Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including paroxetine. In many

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

secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported. Elderly

patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking

diuretics or who are otherwise volume depleted may be at greater risk (see PRECAUTIONS:

Geriatric Use). Discontinuation of paroxetine should be considered in patients with symptomatic

hyponatremia and appropriate medical intervention should be instituted.

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

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

more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest,

and death.

Abnormal Bleeding:

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

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

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

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

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

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

cautioned about the risk of bleeding associated with the concomitant use of paroxetine and NSAIDs,

aspirin, or other drugs that affect coagulation.

Bone Fracture:

Epidemiological studies on bone fracture risk following 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. The possibility of a pathological fracture, that is, a fracture produced by minimal

trauma in a patient with decreased bone mineral density, should be considered in patients treated with

paroxetine who present with unexplained bone pain, point tenderness, swelling, or bruising.

Use in Patients with Concomitant Illness:

Clinical experience with paroxetine tablets in patients with certain concomitant systemic illness is

limited. Caution is advisable in using paroxetine tablets in patients with diseases or conditions that could

affect metabolism or hemodynamic responses.

As with other SSRIs, mydriasis has been infrequently reported in premarketing studies with paroxetine

tablets. A few cases of acute angle closure glaucoma associated with paroxetine therapy have been

reported in the literature. As mydriasis can cause acute angle closure in patients with narrow angle

glaucoma, caution should be used when paroxetine tablets are prescribed for patients with narrow angle

glaucoma.

Paroxetine tablets have not been evaluated or used to any appreciable extent in patients with a recent

history of myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded

from clinical studies during the product's premarket testing. Evaluation of electrocardiograms of 682

patients who received paroxetine tablets in double-blind, placebo-controlled trials, however, did not

indicate that paroxetine tablets are associated with the development of significant ECG abnormalities.

Similarly, paroxetine tablets do not cause any clinically important changes in heart rate or blood

pressure.

Increased plasma concentrations of paroxetine occur in patients with severe renal impairment (creatinine

clearance < 30 mL/min.) or severe hepatic impairment. A lower starting dose should be used in such

patients (see DOSAGE AND ADMINISTRATION).

Information for Patients:

Paroxetine should not be chewed or crushed, and should be swallowed whole.

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

paroxetine and triptans, tramadol, or other serotonergic agents.

Patients should be advised that taking paroxetine tablets can cause mild pupillary dilation, which in

susceptible individuals, can lead to an episode of angle closure glaucoma. Pre-existing glaucoma is

almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated

definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle closure glaucoma.

Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a

prophylactic procedure (e.g., iridectomy), if they are susceptible.

Prescribers or other health professionals should inform patients, their families, and their caregivers

about the benefits and risks associated with treatment with paroxetine tablets and should counsel them in

its appropriate use. A patient Medication Guide is available for paroxetine tablets. The prescriber or

health professional should instruct patients, their families, and their caregivers to read the Medication

Guide and should assist them in understanding its contents. Patients should be given the opportunity to

discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The

complete text of the Medication Guide is reprinted at the end of this document.

Patients should be advised of the following issues and asked to alert their prescriber if these occur

while taking paroxetine.

Clinical Worsening and Suicide Risk:

Patients, their families, and their caregivers should be encouraged to be alert to the emergence of

anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia

(psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of

depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is

adjusted up or down. Families and caregivers of patients should be advised to look for the emergence

of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be

reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset,

or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an

increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and

possibly changes in the medication.

Drugs That Interfere with Hemostasis (e.g.,NSAIDs, Aspirin and Warfarin):

Patients should be cautioned about the concomitant use of paroxetine and NSAIDs, aspirin, warfarin, or

other drugs that affect coagulation since combined use of psychotropic drugs that interfere with

serotonin reuptake and these agents has been associated with an increased risk of bleeding.

Interference with Cognitive and Motor Performance:

Any psychoactive drug may impair judgment, thinking, or motor skills. Although in controlled studies

paroxetine tablets have not been shown to impair psychomotor performance, patients should be

cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain

that therapy with paroxetine tablets does not affect their ability to engage in such activities.

Completing Course of Therapy:

While patients may notice improvement with treatment with paroxetine tablets in 1 to 4 weeks, they

should be advised to continue therapy as directed.

Concomitant Medication:

Patients should be advised to inform their physician if they are taking, or plan to take, any prescription

or over-the-counter drugs, since there is a potential for interactions.

Alcohol:

Although paroxetine tablets have not been shown to increase the impairment of mental and motor skills

caused by alcohol, patients should be advised to avoid alcohol while taking paroxetine tablets.

Pregnancy:

Patients should be advised to notify their physician if they become pregnant or intend to become

pregnant during therapy (see WARNINGS — Usage in Pregnancy: Teratogenic Effectsand

Nonteratogenic Effects).

Nurs ing:

Patients should be advised to notify their physician if they are breastfeeding an infant (see

PRECAUTIONS — Nursing Mothers).

Laboratory Tests:

There are no specific laboratory tests recommended.

Drug Interactions

Tryptophan:

As with other serotonin reuptake inhibitors, an interaction between paroxetine and tryptophan may occur

when they are coadministered. Adverse experiences, consisting primarily of headache, nausea,

sweating, and dizziness, have been reported when tryptophan was administered to patients taking

paroxetine tablets. Consequently, concomitant use of paroxetine tablets with tryptophan is not

recommended (see WARNINGS- Serotonin Syndrome).

Monoamine Oxidase Inhibitors:

See CONTRAINDICATIONS and WARNINGS.

Pimozide:

In a controlled study of healthy volunteers, after paroxetine tablets were titrated to 60 mg daily, co-

administration of a single dose of 2 mg pimozide was associated with mean increases in pimozide AUC

of 151% and C

of 62%, compared to pimozide administered alone. The increase in pimozide AUC

and C

is due to the CYP2D6 inhibitory properties of paroxetine. Due to the narrow therapeutic

index of pimozide and its known ability to prolong the QT interval, concomitant use of pimozide and

paroxetine tablets is contraindicated (see CONTRAINDICATIONS).

Serotonergic Drugs:

Based on the mechanism of action of SNRIs and SSRIs, including paroxetine hydrochloride, and the

potential for serotonin syndrome, caution is advised when paroxetine is coadministered with other

drugs that may affect the serotonergic neurotransmitter systems, such as triptans, lithium, fentanyl,

tramadol, amphetamines, or St. John's Wort (see WARNINGSSerotonin Syndrome).

The concomitant use of paroxetine with MAOIs (including linezolid and intravenous methylene blue) is

contraindicated (see CONTRAINDICATIONS). The concomitant use of paroxetine with other SSRIs,

SNRIs or tryptophan is not recommended (see PRECAUTIONS Drug Interactions Tryptophan).

Thioridazine:

See CONTRAINDICATIONS and WARNINGS.

Warfarin:

Preliminary data suggest that there may be a pharmacodynamic interaction (that causes an increased

bleeding diathesis in the face of unaltered prothrombin time) between paroxetine and warfarin. Since

there is little clinical experience, the concomitant administration of paroxetine tablets and warfarin

should be undertaken with caution (see PRECAUTIONS: Drugs That Interfere with Hemostasis).

Triptans :

There have been rare postmarketing reports of serotonin syndrome with the use of an SSRI and a triptan.

If concomitant use of paroxetine with a triptan is clinically warranted, careful observation of the patient

is advised, particularly during treatment initiation and dose increases (see WARNINGSSerotonin

Syndrome).

Drugs Affecting Hepatic Metabolism:

The metabolism and pharmacokinetics of paroxetine may be affected by the induction or inhibition of

drug-metabolizing enzymes.

Cimetidine:

Cimetidine inhibits many cytochrome P

(oxidative) enzymes. In a study where paroxetine tablets (30

mg once daily) were dosed orally for 4 weeks, steady-state plasma concentrations of paroxetine were

increased by approximately 50% during coadministration with oral cimetidine (300 mg three times

daily) for the final week. Therefore, when these drugs are administered concurrently, dosage adjustment

of paroxetine tablets after the 20-mg starting dose should be guided by clinical effect. The effect of

paroxetine on cimetidine's pharmacokinetics was not studied.

Phenobarbital:

Phenobarbital induces many cytochrome P

(oxidative) enzymes. When a single oral 30-mg dose of

paroxetine tablets was administered at phenobarbital steady state (100 mg once daily for 14 days),

paroxetine AUC and T

were reduced (by an average of 25% and 38%, respectively) compared to

paroxetine administered alone. The effect of paroxetine on phenobarbital pharmacokinetics was not

studied. Since paroxetine tablets exhibits nonlinear pharmacokinetics, the results of this study may not

address the case where the 2 drugs are both being chronically dosed. No initial dosage adjustment of

paroxetine tablets is considered necessary when coadministered with phenobarbital; any subsequent

adjustment should be guided by clinical effect.

Phenytoin:

When a single oral 30-mg dose of paroxetine tablets was administered at phenytoin steady state (300 mg

once daily for 14 days), paroxetine AUC and T

were reduced (by an average of 50% and 35%,

respectively) compared to paroxetine tablets administered alone. In a separate study, when a single oral

300-mg dose of phenytoin was administered at paroxetine steady state (30 mg once daily for 14 days),

phenytoin AUC was slightly reduced (12% on average) compared to phenytoin administered alone.

Since both drugs exhibit nonlinear pharmacokinetics, the above studies may not address the case where

the 2 drugs are both being chronically dosed. No initial dosage adjustments are considered necessary

when these drugs are coadministered; any subsequent adjustments should be guided by clinical effect

(see ADVERSE REACTIONS Postmarketing Reports).

Drugs Metabolized by CYP2D6:

Many drugs, including most drugs effective in the treatment of major depressive disorder (paroxetine,

other SSRIs and many tricyclics), are metabolized by the cytochrome P

isozyme CYP2D6. Like

other agents that are metabolized by CYP2D6, paroxetine may significantly inhibit the activity of this

isozyme. In most patients (> 90%), this CYP2D6 isozyme is saturated early during dosing with

paroxetine tablets. In 1 study, daily dosing of paroxetine tablets (20 mg once daily) under steady-state

conditions increased single dose desipramine (100 mg) C

, AUC, and T

by an average of

approximately 2-, 5-, and 3- fold, respectively. Concomitant use of paroxetine with risperidone, a

CYP2D6 substrate has also been evaluated. In 1 study, daily dosing of paroxetine 20 mg in patients

stabilized on risperidone (4 to 8 mg/day) increased mean plasma concentrations of risperidone

approximately 4-fold, decreased 9-hydroxyrisperidone concentrations approximately 10%, and

increased concentrations of the active moiety (the sum of risperidone plus 9-hydroxyrisperidone)

approximately 1.4-fold. The effect of paroxetine on the pharmacokinetics of atomoxetine has been

evaluated when both drugs were at steady state. In healthy volunteers who were extensive metabolizers

of CYP2D6, paroxetine 20 mg daily was given in combination with 20 mg atomoxetine every 12 hours.

This resulted in increases in steady state atomoxetine AUC values that were 6- to 8-fold greater and in

atomoxetine Cmax values that were 3- to 4-fold greater than when atomoxetine was given alone. Dosage

adjustment of atomoxetine may be necessary and it is recommended that atomoxetine be initiated at a

reduced dose when it is given with paroxetine.

Concomitant use of paroxetine tablets with other drugs metabolized by cytochrome CYP2D6 has not

been formally studied but may require lower doses than usually prescribed for either paroxetine tablets

or the other drug.

Therefore, coadministration of paroxetine tablets with other drugs that are metabolized by this isozyme,

including certain drugs effective in the treatment of major depressive disorder (e.g., nortriptyline,

amitriptyline, imipramine, desipramine, and fluoxetine), phenothiazines, risperidone, and Type 1C

antiarrhythmics (e.g., propafenone, flecainide, and encainide), or that inhibit this enzyme (e.g.,

quinidine), should be approached with caution.

However, due to the risk of serious ventricular arrhythmias and sudden death potentially associated with

elevated plasma levels of thioridazine, paroxetine and thioridazine should not be coadministered (see

CONTRAINDICATIONS and WARNINGS).

Tamoxifen is a pro-drug requiring metabolic activation by CYP2D6. Inhibition of CYP2D6 by

paroxetine may lead to reduced plasma concentrations of an active metabolite (endoxifen) and hence

reduced efficacy of tamoxifen (see PRECAUTIONS).

At steady state, when the CYP2D6 pathway is essentially saturated, paroxetine clearance is governed by

alternative P450 isozymes that, unlike CYP2D6, show no evidence of saturation (see PRECAUTIONS

– Tricyclic Antidepressants [TCAs]).

Drugs Metabolized by Cytochrome CYP3A4:

An in vivo interaction study involving the coadministration under steady-state conditions of paroxetine

and terfenadine, a substrate for cytochrome CYP3A4, revealed no effect of paroxetine on terfenadine

pharmacokinetics. In addition, in vitro studies have shown ketoconazole, a potent inhibitor of CYP3A4

activity, to be at least 100 times more potent than paroxetine as an inhibitor of the metabolism of several

substrates for this enzyme, including terfenadine, astemizole, cisapride, triazolam, and cyclosporine.

Based on the assumption that the relationship between paroxetine's in vitro K

and its lack of effect on

terfenadine's in vivo clearance predicts its effect on other CYP3A4 substrates, paroxetine's extent of

inhibition of CYP3A4 activity is not likely to be of clinical significance.

Tricyclic Antidepressants (TCAs):

Caution is indicated in the coadministration of tricyclic antidepressants (TCAs) with paroxetine tablets,

because paroxetine may inhibit TCA metabolism. Plasma TCA concentrations may need to be monitored,

and the dose of TCA may need to be reduced, if a TCA is coadministered with paroxetine tablets (see

PRECAUTIONS— Drugs Metabolized by Cytochrome CYP2D6).

Drugs Highly Bound to Plasma Protein:

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

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

drug, potentially resulting in adverse events. Conversely, adverse effects could result from

displacement of paroxetine by other highly bound drugs.

Drugs That Interfere with Hemostasis (e.g., NSAIDs, Aspirin and Warfarin):

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

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

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

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

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

coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when

paroxetine is initiated or discontinued.

Alcohol:

Although paroxetine tablets do not increase the impairment of mental and motor skills caused by

alcohol, patients should be advised to avoid alcohol while taking paroxetine tablets.

Lithium:

A multiple-dose study has shown that there is no pharmacokinetic interaction between paroxetine tablets

and lithium carbonate. However, due to the potential for serotonin syndrome, caution is advised when

paroxetine tablets are coadministered with lithium.

Digoxin:

The steady-state pharmacokinetics of paroxetine was not altered when administered with digoxin at

steady state. Mean digoxin AUC at steady state decreased by 15% in the presence of paroxetine. Since

there is little clinical experience, the concurrent administration of paroxetine and digoxin should be

undertaken with caution.

Diazepam:

Under steady-state conditions, diazepam does not appear to affect paroxetine kinetics. The effects of

paroxetine on diazepam were not evaluated.

Procyclidine:

Daily oral dosing of paroxetine tablets (30 mg once daily) increased steady-state AUC

, and

values of procyclidine (5 mg oral once daily) by 35%, 37%, and 67%, respectively, compared to

procyclidine alone at steady state. If anticholinergic effects are seen, the dose of procyclidine should

be reduced.

Beta-Blockers :

In a study where propranolol (80 mg twice daily) was dosed orally for 18 days, the established steady-

state plasma concentrations of propranolol were unaltered during coadministration with paroxetine

tablets (30 mg once daily) for the final 10 days. The effects of propranolol on paroxetine have not been

evaluated (see ADVERSE REACTIONS Postmarketing Reports).

Theophylline:

Reports of elevated theophylline levels associated with treatment with paroxetine tablets have been

reported. While this interaction has not been formally studied, it is recommended that theophylline

levels be monitored when these drugs are concurrently administered.

Fos amprenavir/Ritonavir:

Co-administration of fosamprenavir/ritonavir with paroxetine significantly decreased plasma levels of

paroxetine. Any dose adjustment should be guided by clinical effect (tolerability and efficacy).

Electroconvulsive Therapy (ECT):

There are no clinical studies of the combined use of ECT and paroxetine tablets.

Carcinogenesis, Mutagenesis, Impairment of Fertility:

Carcinogenesis:

Two-year carcinogenicity studies were conducted in rodents given paroxetine in the diet at 1, 5, and 25

mg/kg/day (mice) and 1, 5, and 20 mg/kg/day (rats). These doses are up to 2.4 (mouse) and 3.9 (rat) times

the MRHD for major depressive disorder, social anxiety disorder, GAD and PTSD on a mg/m

basis.

Because the MRHD for major depressive disorder is slightly less than that for OCD (50 mg versus 60

mg), the doses used in these carcinogenicity studies were only 2.0 (mouse) and 3.2 (rat) times the

MRHD for OCD. There was a significantly greater number of male rats in the high-dose group with

reticulum cell sarcomas (1/100, 0/50, 0/50, and 4/50 for control, low-, middle-, and high-dose groups,

respectively) and a significantly increased linear trend across dose groups for the occurrence of

lymphoreticular tumors in male rats. Female rats were not affected. Although there was a dose-related

increase in the number of tumors in mice, there was no drug-related increase in the number of mice with

tumors. The relevance of these findings to humans is unknown.

Mutagenes is :

Paroxetine produced no genotoxic effects in a battery of 5 in vitro and 2 in vivo assays that included the

following: Bacterial mutation assay, mouse lymphoma mutation assay, unscheduled DNA synthesis

assay, and tests for cytogenetic aberrations in vivo in mouse bone marrow and in vitro in human

lymphocytes and in a dominant lethal test in rats.

Impairment of Fertility:

Some clinical studies have shown that SSRIs (including paroxetine) may affect sperm quality during

SSRI treatment, which may affect fertility in some men.

A reduced pregnancy rate was found in reproduction studies in rats at a dose of paroxetine of 15

mg/kg/day, which is 2.9 times the MRHD for major depressive disorder, social anxiety disorder, GAD

and PTSD or 2.4 times the MRHD for OCD on a mg/m

basis. Irreversible lesions occurred in the

reproductive tract of male rats after dosing in toxicity studies for 2 to 52 weeks. These lesions

consisted of vacuolation of epididymal tubular epithelium at 50 mg/kg/day and atrophic changes in the

seminiferous tubules of the testes with arrested spermatogenesis at 25 mg/kg/day (9.8 and 4.9 times the

MRHD for major depressive disorder, social anxiety disorder, and GAD; 8.2 and 4.1 times the MRHD

for OCD and PD on a mg/m

basis).

Pregnancy:

Pregnancy Category D. see WARNINGS ─ Usage in Pregnancy: Teratogenic Effectsand

Nonteratogenic Effects.

Labor and Delivery:

The effect of paroxetine on labor and delivery in humans is unknown.

Nursing Mothers:

Like many other drugs, paroxetine is secreted in human milk, and caution should be exercised when

paroxetine tablets are administered to a nursing woman.

Pediatric Use:

Safety and effectiveness in the pediatric population have not been established (see BOX WARNING

and WARNINGSClinical Worsening and Suicide Risk). Three placebo-controlled trials in 752

0-24

pediatric patients with MDD have been conducted with paroxetine tablets, and the data were not

sufficient to support a claim for use in pediatric patients. Anyone considering the use of paroxetine

tablets in a child or adolescent must balance the potential risks with the clinical need. Decreased

appetite and weight loss have been observed in association with the use of SSRIs.

Consequently, regular monitoring of weight and growth should be performed in children and

adolescents treated with an SSRI such as paroxetine. In placebo-controlled clinical trials conducted

with pediatric patients, the following adverse events were reported in at least 2% of pediatric patients

treated with paroxetine tablets and occurred at a rate at least twice that for pediatric patients receiving

placebo: emotional lability (including self-harm, suicidal thoughts, attempted suicide, crying, and mood

fluctuations), hostility, decreased appetite, tremor, sweating, hyperkinesia, and agitation.

Events reported upon discontinuation of treatment with paroxetine tablets in the pediatric clinical trials

that included a taper phase regimen, which occurred in at least 2% of patients who received paroxetine

tablets and which occurred at a rate at least twice that of placebo, were: emotional lability (including

suicidal ideation, suicide attempt, mood changes, and tearfulness), nervousness, dizziness, nausea, and

abdominal pain (see DOSAGE AND ADMINISTRATION: Discontinuation of Treatment with

Paroxetine Tablets).

Geriatric Use:

SSRIs and SNRIs, including paroxetine, have been associated with cases of clinically significant

hyponatremia in elderly patients, who may be at greater risk for this adverse event (see

PRECAUTIONS, Hyponatremia).

In worldwide premarketing clinical trials with paroxetine tablets, 17% of patients treated with

paroxetine tablets (approximately 700) were 65 years of age or older. Pharmacokinetic studies revealed

a decreased clearance in the elderly, and a lower starting dose is recommended; there were, however,

no overall differences in the adverse event profile between elderly and younger patients, and

effectiveness was similar in younger and older patients (see CLINICAL PHARMACOLOGY and

DOSAGE AND ADMINISTRATION).

ADVERSE REACTIONS

Associated with Discontinuation of Treatment:

Twenty percent (1,199/6,145) of patients treated with paroxetine tablets in worldwide clinical trials in

major depressive disorder and 16.1% (84/522), 11.8% (64/542), 9.4% (44/469), 10.7% (79/735) and

11.7% (79/676) of patients treated with paroxetine tablets in worldwide trials in social anxiety disorder,

OCD, panic disorder, GAD and PTSD, respectively, discontinued treatment due to an adverse event.

The most common events (≥1%) associated with discontinuation and considered to be drug related (i.e.,

those events associated with dropout at a rate approximately twice or greater for paroxetine tablets

compared to placebo) included the following:

Where numbers are not provided the incidence of the adverse events in patients treated with paroxetine tablets were not

>1% or were not greater than or equal to 2 times the incidence of placebo.

Major Depressive

Disorder

OCD

Panic Disorder

Social Anxiety

Disorder

Generalized Anxiety

Disorder

PTSD

Paroxetine

Tablets

Placebo

Paroxetine

Tablets

Placebo

Paroxetine

Tablets

Placebo

Paroxetine

Tablets

Placebo

Paroxetine

Tablets

Placebo

Paroxetine

Tablets

Placebo

CNS

Somnolence

2.3%

0.7%

1.9%

0.3%

3.4%

0.3%

2.0%

0.2%

2.8%

0.6%

Insomnia

1.7%

1.3%

0.3%

3.1%

Agitation

1.1%

0.5%

Tremor

1.1%

0.3%

1.7%

1.0%

0.2%

Anxiety

1.1%

Dizziness

1.5%

1.9%

1.0%

0.2%

Gastrointestinal

Constipation

1.1%

Nausea

3.2%

1.1%

1.9%

3.2%

1.2%

4.0%

0.3%

2.0%

0.2%

2.2%

0.6%

Diarrhea

1.0%

0.3%

Dry Mouth

1.0%

0.3%

Vomiting

1.0%

0.3%

1.0%

Flatulence

1.0%

0.3%

Other

Asthenia

1.6%

0.4%

1.9%

0.4%

2.5%

0.6%

1.8%

0.2%

1.6%

0.2%

Abnormal

ejaculation

1.6%

2.1%

4.9%

0.6%

2.5%

0.5%

Sweating

1.0%

0.3%

1.1%

1.1%

0.2%

Impotence

1.5%

Libido

Decreased

1.0%

Commonly Observed Adverse Events:

Incidence corrected for gender.

Major Depressive Disorder:

The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or

greater and incidence for paroxetine tablets at least twice that for placebo, derived from Table 2) were:

Asthenia, sweating, nausea, decreased appetite, somnolence, dizziness, insomnia, tremor, nervousness,

ejaculatory disturbance, and other male genital disorders.

Obsessive Compulsive Disorder:

The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or

greater and incidence for paroxetine tablets at least twice that of placebo, derived from Table 3) were:

Nausea, dry mouth, decreased appetite, constipation, dizziness, somnolence, tremor, sweating,

impotence, and abnormal ejaculation.

Panic Disorder:

The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or

greater and incidence for paroxetine tablets at least twice that for placebo, derived from Table 3) were:

Asthenia, sweating, decreased appetite, libido decreased, tremor, abnormal ejaculation, female genital

disorders, and impotence.

Social Anxiety Disorder:

The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or

greater and incidence for paroxetine tablets at least twice that for placebo, derived from Table 3) were:

Sweating, nausea, dry mouth, constipation, decreased appetite, somnolence, tremor, libido decreased,

yawn, abnormal ejaculation, female genital disorders, and impotence.

Generalized Anxiety Disorder:

The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or

greater and incidence for paroxetine tablets at least twice that for placebo, derived from Table 4) were:

Asthenia, infection, constipation, decreased appetite, dry mouth, nausea, libido decreased, somnolence,

tremor, sweating, and abnormal ejaculation.

Posttraumatic Stress Disorder:

The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or

greater and incidence for paroxetine tablets at least twice that for placebo, derived from Table 4) were:

Asthenia, sweating, nausea, dry mouth, diarrhea, decreased appetite, somnolence, libido decreased,

abnormal ejaculation, female genital disorders, and impotence.

Incidence in Controlled Clinical Trials:

The prescriber should be aware that the figures in the tables following cannot be used to predict the

incidence of side effects in the course of usual medical practice where patient characteristics and other

factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be

compared with figures obtained from other clinical investigations involving different treatments, uses,

and investigators. The cited figures, however, do provide the prescribing physician with some basis

for estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in

the populations studied.

Major Depressive Disorder:

Table 2 enumerates adverse events that occurred at an incidence of 1% or more among paroxetine-

treated patients who participated in short-term (6-week) placebo-controlled trials in which patients were

dosed in a range of 20 mg to 50 mg/day. Reported adverse events were classified using a standard

COSTART-based Dictionary terminology.

Table 2 Treatment-Emergent Adverse Experience Incidence in Placebo-Controlled

Clinical Trials for Major Depressive Disorder

Body System

Preferred Term

Paroxetine Tablets

Placebo

(n = 421)

(n = 421)

Body as a Whole

Headache

Asthenia

Cardiovascular

Palpitation

Vasodilation

Dermatologic

Sweating

Rash

Gastrointestinal

Nausea

Dry Mouth

Constipation

Diarrhea

Decreased Appetite

Flatulence

Oropharynx Disorder

Dyspepsia

Musculoskeletal

Myopathy

*

Events reported by at least 1% of patients treated with paroxetine tablets are included, except the

following events which had an incidence on placebo ≥ paroxetine tablets: Abdominal pain, agitation,

back pain, chest pain, CNS stimulation, fever, increased appetite, myoclonus, pharyngitis, postural

hypotension, respiratory disorder (includes mostly "cold symptoms" or "URI"), trauma, and vomiting.

Includes mostly "lump in throat" and "tightness in throat."

Percentage corrected for gender.

Mostly "ejaculatory delay."

Includes "anorgasmia," "erectile difficulties," "delayed ejaculation/orgasm," and "sexual dysfunction,"

and "impotence."

Includes mostly "difficulty with micturition" and "urinary hesitancy."

Includes mostly "anorgasmia" and "difficulty reaching climax/orgasm."

Myalgia

Myasthenia

Nervous System

Somnolence

Dizziness

Insomnia

Tremor

Nervousness

Anxiety

Paresthesia

Libido Decreased

Drugged Feeling

Confusion

Respiration

Yawn

Special Senses

Blurred Vision

Taste Perversion

Urogenital System

Ejaculatory Disturbance

Other Male Genital Disorders

Urinary Frequency

Urination Disorder

Female Genital Disorders

Obsessive Compulsive Disorder, Panic Disorder, and Social Anxiety Disorder:

Table 3 enumerates adverse events that occurred at a frequency of 2% or more among OCD patients on

paroxetine tablets who participated in placebo-controlled trials of 12-weeks duration in which patients

were dosed in a range of 20 mg to 60 mg/day or among patients with panic disorder on paroxetine

tablets who participated in placebo-controlled trials of 10- to 12-weeks duration in which patients were

dosed in a range of 10 mg to 60 mg/day or among patients with social anxiety disorder on paroxetine

tablets who participated in placebo-controlled trials of 12-weeks duration in which patients were dosed

in a range of 20 mg to 50 mg/day.

Table 3 Treatment-Emergent Adverse Experience Incidence in Placebo-

Controlled Clinical Trials for Obsessive

Compulsive Disorder, Panic Disorder, and Social Anxiety Disorder

Obsessive

Compulsive

Disorder

Panic Disorder

Social Anxiety

Disorder

Paroxetine

Tablets

Placebo

Paroxetine

Tablets

Placebo

Paroxetine

Tablets

Placebo

Body System

Preferred Term

(n = 542)

(n = 265) (n = 469)

(n = 324) (n = 425)

(n = 339)

Body as a Whole

Asthenia

Abdominal Pain

Chest Pain

Back Pain

Chills

Trauma

Cardiovascular

Vasodilation

Palpitation

Dermatologic

Sweating

Rash

Gastrointestinal

Nausea

Dry Mouth

Constipation

Diarrhea

Decreased

Appetite

Dyspepsia

Flatulence

Increased

‡,§

‡,¶

‡,Þ

*

Events reported by at least 2% of OCD, panic disorder, and social anxiety disorder in patients treated with

paroxetine tablets are included, except the following events which had an incidence on placebo ≥ paroxetine

tablets: [OCD]: Abdominal pain, agitation, anxiety, back pain, cough increased, depression, headache,

hyperkinesia, infection, paresthesia, pharyngitis, respiratory disorder, rhinitis, and sinusitis. [panic disorder]:

Abnormal dreams, abnormal vision, chest pain, cough increased, depersonalization, depression, dysmenorrhea,

dyspepsia, flu syndrome, headache, infection, myalgia, nervousness, palpitation, paresthesia, pharyngitis, rash,

respiratory disorder, sinusitis, taste perversion, trauma, urination impaired, and vasodilation. [social anxiety

disorder]: Abdominal pain, depression, headache, infection, respiratory disorder, and sinusitis.

Percentage corrected for gender.

Appetite

Vomiting

Musculoskeletal

Myalgia

Nervous System

Insomnia

Somnolence

Dizziness

Tremor

Nervousness

Libido Decreased

Agitation

Anxiety

Abnormal

Dreams

Concentration

Impaired

Depersonalization

Myoclonus

Amnesia

Respiratory

System

Rhinitis

Pharyngitis

Yawn

Special Senses

Abnormal Vision

Taste Perversion

Urogenital SystemAbnormal

Ejaculation

Dysmenorrhea

Female Genital

Disorder

Impotence

Urinary

Frequency

Urination

Impaired

Urinary Tract

Infection

Generalized Anxiety Disorderand and Posttraumatic Stress Disorder:

Table 4 enumerates adverse events that occurred at a frequency of 2% or more among GAD patients on

paroxetine tablets who participated in placebo-controlled trials of 8-weeks duration in which patients

were dosed in a range of 10 mg/day to 50 mg/day or among PTSD patients on paroxetine tablets who

participated in placebo-controlled trials of 12-weeks duration in which patients were dosed in a range

of 20 mg/day to 50 mg/day.

Table 4 Treatment-Emergent Adverse Experience Incidence in Placebo Controlled

Clinical Trials for Generalized Anxiety Disorder and Posttraumatic Stress Disorder

Generalized Anxiety Disorder

Posttraumatic Stress

Disorder

Body System

Preferred Term

Paroxetine

Tablets

Placebo

Paroxetine

Tablets

Placebo

(n = 735)

(n = 529)

(n = 676)

(n =

504)

Body as a Whole

Asthenia

Headache

Infection

Abdominal Pain

Trauma

Cardiovascular

Vasodilation

*

Events reported by at least 2% of GAD and PTSD in patients treated with paroxetine tablets are included,

except the following events which had an incidence on placebo ≥ paroxetine tablets [GAD]: Abdominal pain,

back pain, trauma, dyspepsia, myalgia, and pharyngitis. [PTSD]: Back pain, headache, anxiety, depression,

nervousness, respiratory disorder, pharyngitis, and sinusitis.

Percentage corrected for gender.

Dermatologic

Sweating

Gastrointestinal

Nausea

Dry Mouth

Constipation

Diarrhea

Decreased Appetite

Vomiting

Dyspepsia

Nervous System

Insomnia

Somnolence

Dizziness

Tremor

Nervousness

Libido Decreased

Abnormal Dreams

Respiratory SystemRespiratory Disorder

Sinusitis

Yawn

<1%

Special Senses

Abnormal Vision

Urogenital System Abnormal

Ejaculation

Female Genital

Disorder

Impotence

Dose Dependency of Adverse Events:

A comparison of adverse event rates in a fixed-dose study comparing 10, 20, 30, and 40 mg/day of

paroxetine tablets with placebo in the treatment of major depressive disorder revealed a clear dose

dependency for some of the more common adverse events associated with use of paroxetine tablets, as

shown in Table 5:

Table 5 Treatment-Emergent Adverse Experience Incidence in a Dose-

Comparison Trial in the Treatment of Major Depressive Disorder

Rule for including adverse events in table: Incidence at least 5% for 1 of paroxetine groups and ≥

twice the placebo incidence for at least 1 paroxetine group.

Body System/Preferred Term

Placebo

Paroxetine Tablets

n=51

10 mg

n=102

20 mg

n=104

30 mg

n=101

40 mg

n=102

Body As A Whole

Asthenia

0.0%

2.9%

10.6%

13.9%

12.7%

Dermatology

Sweating

2.0%

1.0%

6.7%

8.9%

11.8%

Gastrointestinal

Constipation

5.9%

4.9%

7.7%

9.9%

12.7%

Decreased Appetite

2.0%

2.0%

5.8%

4.0%

4.9%

Diarrhea

7.8%

9.8%

19.2%

7.9%

14.7%

Dry Mouth

2.0%

10.8%

18.3%

15.8%

20.6%

Nausea

13.7%

14.7%

26.9%

34.7%

36.3%

Nervous System

Anxiety

0.0%

2.0%

5.8%

5.9%

5.9%

Dizziness

3.9%

6.9%

6.7%

8.9%

12.7%

Nervousness

0.0%

5.9%

5.8%

4.0%

2.9%

Paresthesia

0.0%

2.9%

1.0%

5.0%

5.9%

Somnolence

7.8%

12.7%

18.3%

20.8%

21.6%

Tremor

0.0%

0.0%

7.7%

7.9%

14.7%

Special Senses

Blurred Vision

2.0%

2.9%

2.9%

2.0%

7.8%

Urogenital System

Abnormal Ejaculation

0.0%

5.8%

6.5%

10.6%

13.0%

Impotence

0.0%

1.9%

4.3%

6.4%

1.9%

Male Genital Disorders

0.0%

3.8%

8.7%

6.4%

3.7%

In a fixed-dose study comparing placebo and 20, 40, and 60 mg of paroxetine tablets in the treatment of

OCD, there was no clear relationship between adverse events and the dose of paroxetine tablets to

*

which patients were assigned. No new adverse events were observed in the group treated with 60 mg

of paroxetine tablets compared to any of the other treatment groups.

In a fixed-dose study comparing placebo and 10, 20, and 40 mg of paroxetine tablets in the treatment of

panic disorder, there was no clear relationship between adverse events and the dose of paroxetine

tablets to which patients were assigned, except for asthenia, dry mouth, anxiety, libido decreased,

tremor, and abnormal ejaculation. In flexible-dose studies, no new adverse events were observed in

patients receiving 60 mg of paroxetine tablets compared to any of the other treatment groups.

In a fixed-dose study comparing placebo and 20, 40, and 60 mg of paroxetine tablets in the treatment of

social anxiety disorder, for most of the adverse events, there was no clear relationship between adverse

events and the dose of paroxetine tablets to which patients were assigned.

In a fixed-dose study comparing placebo and 20 and 40 mg of paroxetine tablets in the treatment of

generalized anxiety disorder, for most of the adverse events, there was no clear relationship between

adverse events and the dose of paroxetine tablets to which patients were assigned, except for the

following adverse events: Asthenia, constipation, and abnormal ejaculation.

In a fixed-dose study comparing placebo and 20 and 40 mg of paroxetine tablets in the treatment of

posttraumatic stress disorder, for most of the adverse events, there was no clear relationship between

adverse events and the dose of paroxetine tablets to which patients were assigned, except for impotence

and abnormal ejaculation.

Adaptation to Certain Adverse Events:

Over a 4- to 6-week period, there was evidence of adaptation to some adverse events with continued

therapy (e.g., nausea and dizziness), but less to other effects (e.g., dry mouth, somnolence, and asthenia).

Male and Female Sexual Dysfunction with SSRIs:

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 pharmacologic treatment. In

particular, some evidence suggests that selective serotonin reuptake inhibitors (SSRIs) can cause such

untoward sexual experiences.

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

performance, and satisfaction are difficult to obtain, however, in part because patients and physicians

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

experience and performance cited in product labeling are likely to underestimate their actual incidence.

In placebo-controlled clinical trials involving more than 3,200 patients, the ranges for the reported

incidence of sexual side effects in males and females with major depressive disorder, OCD, panic

disorder, social anxiety disorder, GAD and PTSD are displayed in Table 6.

Table 6 Incidence of Sexual Adverse Events in Controlled Clinical Trials

Paroxetine Tablets

Placebo

n (males)

1446

1042

Decreased Libido

6-15%

0-5%

Ejaculatory Disturbance

13-28%

0-2%

Impotence

2-9%

0-3%

n (females)

1822

1340

Decreased Libido

0-9%

0-2%

Orgasmic Disturbance

2-9%

0-1%

There are no adequate and well-controlled studies examining sexual dysfunction with paroxetine

treatment.

Paroxetine treatment has been associated with several cases of priapism. In those cases with a known

outcome, patients recovered without sequelae.

While it is difficult to know the precise risk of sexual dysfunction associated with the use of SSRIs,

physicians should routinely inquire about such possible side effects.

Weight and Vital Sign Changes:

Significant weight loss may be an undesirable result of treatment with paroxetine tablets for some

patients but, on average, patients in controlled trials had minimal (about 1 pound) weight loss versus

smaller changes on placebo and active control. No significant changes in vital signs (systolic and

diastolic blood pressure, pulse and temperature) were observed in patients treated with paroxetine

tablets in controlled clinical trials.

ECG Changes:

In an analysis of ECGs obtained in 682 patients treated with paroxetine tablets and 415 patients treated

with placebo in controlled clinical trials, no clinically significant changes were seen in the ECGs of

either group.

Liver Function Tests:

In placebo-controlled clinical trials, patients treated with paroxetine tablets exhibited abnormal values

on liver function tests at no greater rate than that seen in placebo-treated patients. In particular, the

paroxetine tablets-versus-placebo comparisons for alkaline phosphatase, SGOT, SGPT, and bilirubin

revealed no differences in the percentage of patients with marked abnormalities.

Hallucinations :

In pooled clinical trials of immediate-release paroxetine hydrochloride, hallucinations were observed

in 22 of 9089 patients receiving drug and 4 of 3187 patients receiving placebo.

Other Events Observed During the Premarketing Evaluation of Paroxetine Tablets:

During its premarketing assessment in major depressive disorder, multiple doses of paroxetine tablets

were administered to 6,145 patients in phase 2 and 3 studies. The conditions and duration of exposure to

paroxetine tablets varied greatly and included (in overlapping categories) open and double-blind

studies, uncontrolled and controlled studies, inpatient and outpatient studies, and fixed-dose, and titration

studies. During premarketing clinical trials in OCD, panic disorder, social anxiety disorder, generalized

anxiety disorder, and posttraumatic stress disorder 542, 469, 522, 735 and 676 patients, respectively,

received multiple doses of paroxetine tablets. Untoward events associated with this exposure were

recorded by clinical investigators using terminology of their own choosing. Consequently, it is not

possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events

without first grouping similar types of untoward events into a smaller number of standardized event

categories.

In the tabulations that follow, reported adverse events were classified using a standard COSTART-

based Dictionary terminology. The frequencies presented, therefore, represent the proportion of the

9,089 patients exposed to multiple doses of paroxetine tablets who experienced an event of the type

cited on at least 1 occasion while receiving paroxetine tablets. All reported events are included except

those already listed in Tables 2 to 5, those reported in terms so general as to be uninformative and those

events where a drug cause was remote. It is important to emphasize that although the events reported

occurred during treatment with paroxetine, they were not necessarily caused by it.

Events are further categorized by body system and listed in order of decreasing frequency according to

the following definitions: Frequent adverse events are those occurring on 1 or more occasions in at

least 1/100 patients (only those not already listed in the tabulated results from placebo-controlled trials

appear in this listing); infrequent adverse events are those occurring in 1/100 to 1/1,000 patients; rare

events are those occurring in fewer than 1/1,000 patients. Events of major clinical importance are also

described in the PRECAUTIONS section.

Body as a Whole:

Infrequent: Allergic reaction, chills, face edema, malaise, neck pain; rare: Adrenergic syndrome,

cellulitis, moniliasis, neck rigidity, pelvic pain, peritonitis, sepsis, ulcer.

Cardiovascular System:

Frequent: Hypertension, tachycardia; infrequent: Bradycardia, hematoma, hypotension, migraine, postural

hypotension, syncope; rare: Angina pectoris, arrhythmia nodal, atrial fibrillation, bundle branch block,

cerebral ischemia, cerebrovascular accident, congestive heart failure, heart block, low cardiac output,

myocardial infarct, myocardial ischemia, pallor, phlebitis, pulmonary embolus, supraventricular

extrasystoles, thrombophlebitis, thrombosis, varicose vein, vascular headache, ventricular

extrasystoles.

Digestive System:

Infrequent: Bruxism, colitis, dysphagia, eructation, gastritis, gastroenteritis, gingivitis, glossitis,

increased salivation, liver function tests abnormal, rectal hemorrhage, ulcerative stomatitis; rare:

Aphthous stomatitis, bloody diarrhea, bulimia, cardiospasm, cholelithiasis, duodenitis, enteritis,

esophagitis, fecal impactions, fecal incontinence, gum hemorrhage, hematemesis, hepatitis, ileitis, ileus,

intestinal obstruction, jaundice, melena, mouth ulceration, peptic ulcer, salivary gland enlargement,

sialadenitis, stomach ulcer, stomatitis, tongue discoloration, tongue edema, tooth caries.

Endocrine System:

Rare: Diabetes mellitus, goiter, hyperthyroidism, hypothyroidism, thyroiditis.

Hemic and Lymphatic Systems:

Infrequent: Anemia, leukopenia, lymphadenopathy, purpura; rare: Abnormal erythrocytes, basophilia,

bleeding time increased, eosinophilia, hypochromic anemia, iron deficiency anemia, leukocytosis,

lymphedema, abnormal lymphocytes, lymphocytosis, microcytic anemia, monocytosis, normocytic

anemia, thrombocythemia, thrombocytopenia.

Metabolic and Nutritional:

Frequent: Weight gain; infrequent: Edema, peripheral edema, SGOT increased, SGPT increased, thirst,

weight loss; rare: Alkaline phosphatase increased, bilirubinemia, BUN increased, creatinine

phosphokinase increased, dehydration, gamma globulins increased, gout, hypercalcemia,

hypercholesteremia, hyperglycemia, hyperkalemia, hyperphosphatemia, hypocalcemia, hypoglycemia,

hypokalemia, hyponatremia, ketosis, lactic dehydrogenase increased, non-protein nitrogen (NPN)

increased.

Musculoskeletal System:

Frequent: Arthralgia; infrequent: Arthritis, arthrosis; rare: Bursitis, myositis, osteoporosis, generalized

spasm, tenosynovitis, tetany.

Nervous System:

Frequent: Emotional lability, vertigo; infrequent: Abnormal thinking, alcohol abuse, ataxia, dystonia,

dyskinesia, euphoria, hallucinations, hostility, hypertonia, hypesthesia, hypokinesia, incoordination, lack

of emotion, libido increased, manic reaction, neurosis, paralysis, paranoid reaction; rare: Abnormal gait,

akinesia, antisocial reaction, aphasia, choreoathetosis, circumoral paresthesias, convulsion, delirium,

delusions, diplopia, drug dependence, dysarthria, extrapyramidal syndrome, fasciculations, grand mal

convulsion, hyperalgesia, hysteria, manic-depressive reaction, meningitis, myelitis, neuralgia,

neuropathy, nystagmus, peripheral neuritis, psychotic depression, psychosis, reflexes decreased,

reflexes increased, stupor, torticollis, trismus, withdrawal syndrome.

Respiratory System:

Infrequent: Asthma, bronchitis, dyspnea, epistaxis, hyperventilation, pneumonia, respiratory flu; rare:

Emphysema, hemoptysis, hiccups, lung fibrosis, pulmonary edema, sputum increased, stridor, voice

alteration.

Skin and Appendages:

Frequent: Pruritus; infrequent: Acne, alopecia, contact dermatitis, dry skin, ecchymosis, eczema, herpes

simplex, photosensitivity, urticaria; rare: Angioedema, erythema nodosum, erythema multiforme,

exfoliative dermatitis, fungal dermatitis, furunculosis; herpes zoster, hirsutism, maculopapular rash,

seborrhea, skin discoloration, skin hypertrophy, skin ulcer, sweating decreased, vesiculobullous rash.

Special Senses:

Frequent: Tinnitus; infrequent: Abnormality of accommodation, conjunctivitis, ear pain, eye pain,

keratoconjunctivitis, mydriasis, otitis media; rare: Amblyopia, anisocoria, blepharitis, cataract,

conjunctival edema, corneal ulcer, deafness, exophthalmos, eye hemorrhage, glaucoma, hyperacusis,

night blindness, otitis externa, parosmia, photophobia, ptosis, retinal hemorrhage, taste loss, visual field

defect.

Urogenital System:

Infrequent: Amenorrhea, breast pain, cystitis, dysuria, hematuria, menorrhagia, nocturia, polyuria, pyuria,

urinary incontinence, urinary retention, urinary urgency, vaginitis; rare: Abortion, breast atrophy, breast

enlargement, endometrial disorder, epididymitis, female lactation, fibrocystic breast, kidney calculus,

kidney pain, leukorrhea, mastitis, metrorrhagia, nephritis, oliguria, salpingitis, urethritis, urinary casts,

uterine spasm, urolith, vaginal hemorrhage, vaginal moniliasis.

Postmarketing Reports:

Voluntary reports of adverse events in patients taking paroxetine tablets that have been received since

market introduction and not listed above that may have no causal relationship with the drug include acute

pancreatitis, elevated liver function tests (the most severe cases were deaths due to liver necrosis, and

grossly elevated transaminases associated with severe liver dysfunction), Guillain-Barre syndrome,

Stevens-Johnson syndrome, toxic epidermal necrolysis, priapism, syndrome of inappropriate ADH

secretion, symptoms suggestive of prolactinemia and galactorrhea, extrapyramidal symptoms which

have included akathisia, bradykinesia, cogwheel rigidity, dystonia, hypertonia, oculogyric crisis which

has been associated with concomitant use of pimozide; tremor and trismus; status epilepticus, acute renal

failure, pulmonary hypertension, allergic alveolitis, anaphylaxis, eclampsia, laryngismus, optic neuritis,

porphyria, restless legs syndrome (RLS), ventricular fibrillation, ventricular tachycardia (including

torsade de pointes), thrombocytopenia, hemolytic anemia, events related to impaired hematopoiesis

(including aplastic anemia, pancytopenia, bone marrow aplasia, and agranulocytosis), vasculitic

syndromes (such as Henoch-Schonlein purpura), and premature births in pregnant women. There has

been a case report of an elevated phenytoin level after 4 weeks of paroxetine tablets and phenytoin

coadministration. There has been a case report of severe hypotension when paroxetine tablets were

added to chronic metoprolol treatment.

DRUG ABUSE AND DEPENDENCE

Controlled Substance Class:

Paroxetine tablets are not controlled substance.

Physical and Psychologic Dependence:

Paroxetine tablets have not been systematically studied in animals or humans for its potential for abuse,

tolerance or physical dependence. While the clinical trials did not reveal any tendency for any drug-

seeking behavior, these observations were not systematic and it is not possible to predict on the basis of

this limited experience the extent to which a CNS-active drug will be misused, diverted, and/or abused

once marketed. Consequently, patients should be evaluated carefully for history of drug abuse, and such

patients should be observed closely for signs of misuse or abuse of paroxetine tablets (e.g.,

development of tolerance, incrementations of dose, drug-seeking behavior).

OVERDOSAGE

Human Experience:

Since the introduction of paroxetine tablets in the United States, 342 spontaneous cases of deliberate or

accidental overdosage during paroxetine treatment have been reported worldwide (circa 1999). These

include overdoses with paroxetine alone and in combination with other substances. Of these, 48 cases

were fatal and of the fatalities, 17 appeared to involve paroxetine alone. Eight fatal cases that

documented the amount of paroxetine ingested were generally confounded by the ingestion of other

drugs or alcohol or the presence of significant comorbid conditions. Of 145 non-fatal cases with known

outcome, most recovered without sequelae. The largest known ingestion involved 2,000 mg of

paroxetine (33 times the maximum recommended daily dose) in a patient who recovered.

Commonly reported adverse events associated with paroxetine overdosage include somnolence, coma,

nausea, tremor, tachycardia, confusion, vomiting, and dizziness. Other notable signs and symptoms

observed with overdoses involving paroxetine (alone or with other substances) include mydriasis,

convulsions (including status epilepticus), ventricular dysrhythmias (including torsade de pointes),

hypertension, aggressive reactions, syncope, hypotension, stupor, bradycardia, dystonia,

rhabdomyolysis, symptoms of hepatic dysfunction (including hepatic failure, hepatic necrosis, jaundice,

hepatitis, and hepatic steatosis), serotonin syndrome, manic reactions, myoclonus, acute renal failure,

and urinary retention.

Overdosage Management:

No specific antidotes for paroxetine are known.Treatment should consist of those general measures

employed in the management of overdosage with any drugs effective in the treatment of major

depressive disorder.

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

supportive and symptomatic measures are also recommended. Induction of emesis is not recommended.

Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion, or

exchange transfusion are unlikely to be of benefit.

A specific caution involves patients who are taking or have recently taken paroxetine who might ingest

excessive quantities of a tricyclic antidepressant. In such a case, accumulation of the parent tricyclic

and/or an active metabolite may increase the possibility of clinically significant sequelae and extend the

time needed for close medical observation (see PRECAUTIONSDrugs Metabolized by Cytochrome

CYP2D6).

In managing overdosage, consider the possibility of multiple drug involvement. The physician should

consider contacting a poison control center for additional information on the treatment of any overdose.

Telephone numbers for certified poison control centers are listed in the Physicians' Desk Reference

(PDR).

DOSAGE AND ADMINISTRATION

Major Depressive Disorder:

Usual Initial Dosage:

Paroxetine tablets should be administered as a single daily dose with or without food, usually in the

morning. The recommended initial dose is 20 mg/day. Patients were dosed in a range of 20 to 50 mg/day

in the clinical trials demonstrating the effectiveness of paroxetine tablets in the treatment of major

depressive disorder. As with all drugs effective in the treatment of major depressive disorder, the full

effect may be delayed. Some patients not responding to a 20-mg dose may benefit from dose increases,

in 10-mg/day increments, up to a maximum of 50 mg/day. Dose changes should occur at intervals of at

least 1 week.

Maintenance Therapy:

There is no body of evidence available to answer the question of how long the patient treated with

paroxetine tablets should remain on it. It is generally agreed that acute episodes of major depressive

disorder require several months or longer of sustained pharmacologic therapy. Whether the dose

needed to induce remission is identical to the dose needed to maintain and/or sustain euthymia is

unknown.

Systematic evaluation of the efficacy of paroxetine tablets has shown that efficacy is maintained for

periods of up to 1 year with doses that averaged about 30 mg.

Obsessive Compulsive Disorder:

Usual Initial Dosage:

Paroxetine tablets should be administered as a single daily dose with or without food, usually in the

morning. The recommended dose of paroxetine tablets in the treatment of OCD is 40 mg daily. Patients

should be started on 20 mg/day and the dose can be increased in 10-mg/day increments. Dose changes

should occur at intervals of at least 1 week. Patients were dosed in a range of 20 to 60 mg/day in the

clinical trials demonstrating the effectiveness of paroxetine tablets in the treatment of OCD. The

maximum dosage should not exceed 60 mg/day.

Maintenance Therapy:

Long-term maintenance of efficacy was demonstrated in a 6-month relapse prevention trial. In this trial,

patients with OCD assigned to paroxetine demonstrated a lower relapse rate compared to patients on

placebo (see CLINICAL PHARMACOLOGY — Clinical Trials). OCD is a chronic condition, and it

is reasonable to consider continuation for a responding patient. Dosage adjustments should be made to

maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to

determine the need for continued treatment.

Panic Disorder:

Usual Initial Dosage:

Paroxetine tablets should be administered as a single daily dose with or without food, usually in the

morning. The target dose of paroxetine tablets in the treatment of panic disorder is 40 mg/day. Patients

should be started on 10 mg/day. Dose changes should occur in 10-mg/day increments and at intervals of

at least 1 week. Patients were dosed in a range of 10 to 60 mg/day in the clinical trials demonstrating the

effectiveness of paroxetine tablets. The maximum dosage should not exceed 60 mg/day.

Maintenance Therapy:

Long-term maintenance of efficacy was demonstrated in a 3-month relapse prevention trial. In this trial,

patients with panic disorder assigned to paroxetine demonstrated a lower relapse rate compared to

patients on placebo (see CLINICAL PHARMACOLOGY — Clinical Trials). Panic disorder is a

chronic condition, and it is reasonable to consider continuation for a responding patient. Dosage

adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be

periodically reassessed to determine the need for continued treatment.

Social Anxiety Disorder:

Usual Initial Dosage:

Paroxetine tablets should be administered as a single daily dose with or without food, usually in the

morning. The recommended and initial dosage is 20 mg/day. In clinical trials the effectiveness of

paroxetine tablets was demonstrated in patients dosed in a range of 20 to 60 mg/day. While the safety of

paroxetine tablets has been evaluated in patients with social anxiety disorder at doses up to 60 mg/day,

available information does not suggest any additional benefit for doses above 20 mg/day (see

CLINICAL PHARMACOLOGY — Clinical Trials).

Maintenance Therapy:

There is no body of evidence available to answer the question of how long the patient treated with

paroxetine tablets should remain on it. Although the efficacy of paroxetine tablets beyond 12 weeks of

dosing has not been demonstrated in controlled clinical trials, social anxiety disorder is recognized as a

chronic condition, and it is reasonable to consider continuation of treatment for a responding patient.

Dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients

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

Generalized Anxiety Disorder:

Usual Initial Dosage:

Paroxetine tablets should be administered as a single daily dose with or without food, usually in the

morning. In clinical trials the effectiveness of paroxetine tablets was demonstrated in patients dosed in a

range of 20 to 50 mg/day. The recommended starting dosage and the established effective dosage is 20

mg/day. There is not sufficient evidence to suggest a greater benefit to doses higher than 20 mg/day.

Dose changes should occur in 10 mg/day increments and at intervals of at least 1 week.

Maintenance Therapy:

Systematic evaluation of continuing paroxetine tablets for periods of up to 24 weeks in patients with

Generalized Anxiety Disorder who had responded while taking paroxetine tablets during an 8-week

acute treatment phase has demonstrated a benefit of such maintenance (see CLINICAL

PHARMACOLOGY — Clinical Trials). Nevertheless, patients should be periodically reassessed to

determine the need for maintenance treatment.

Posttraumatic Stress Disorder:

Usual Initial Dosage:

Paroxetine tablets should be administered as a single daily dose with or without food, usually in the

morning. The recommended starting dosage and the established effective dosage is 20 mg/day. In 1

clinical trial, the effectiveness of paroxetine tablets was demonstrated in patients dosed in a range of 20

to 50 mg/day. However, in a fixed dose study, there was not sufficient evidence to suggest a greater

benefit for a dose of 40 mg/day compared to 20 mg/day. Dose changes, if indicated, should occur in 10

mg/day increments and at intervals of at least 1 week.

Maintenance Therapy:

There is no body of evidence available to answer the question of how long the patient treated with

paroxetine tablets should remain on it. Although the efficacy of paroxetine tablets beyond 12 weeks of

dosing has not been demonstrated in controlled clinical trials, PTSD is recognized as a chronic

condition, and it is reasonable to consider continuation of treatment for a responding patient. Dosage

adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be

periodically reassessed to determine the need for continued treatment.

Special Populations:

Treatment of Pregnant Women During the Third Trimester:

Neonates exposed to paroxetine tablets and other SSRIs or SNRIs, late in the third trimester have

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

(see WARNINGS: Usage in Pregnancy). When treating pregnant women with paroxetine during the

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

Dosage for Elderly or Debilitated Patients, and Patients with Severe Renal or Hepatic

Impairment:

The recommended initial dose is 10 mg/day for elderly patients, debilitated patients, and/or patients with

severe renal or hepatic impairment. Increases may be made if indicated. Dosage should not exceed 40

mg/day.

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

Psychiatric Disorders:

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

disorders and initiation of therapy with paroxetine tablets. Conversely, at least 14 days should be

allowed after stopping paroxetine tablets before starting an MAOI intended to treat psychiatric

disorders (see CONTRAINDICATIONS).

Use of Paroxetine Tablets With Other MAOIs Such as Linezolid or Methylene Blue:

Do not start paroxetine tablets in a patient who is being treated with linezolid or intravenous methylene

blue because there is increased risk of serotonin syndrome. In a patient who requires more urgent

treatment of a psychiatric condition, other interventions, including hospitalization, should be considered

(see CONTRAINDICATIONS).

In some cases, a patient already receiving therapy with paroxetine tablets may require urgent treatment

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

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

methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient,

paroxetine tablets should be stopped promptly, and linezolid or methylene blue can be administered. The

patient should be monitored for symptoms of serotonin syndrome for 2 weeks or until 24 hours after the

last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with paroxetine

tablets may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue (see

WARNINGS).

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

injection) or in intravenous doses much lower than 1 mg/kg with paroxetine is unclear. The clinician

should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with

such use (see WARNINGS).

Discontinuation of Treatment with Paroxetine Tablets:

Symptoms associated with discontinuation of paroxetine tablets have been reported(see

PRECAUTIONS: Discontinuation of Treatment With Paroxetine Tablets). Patients should be

monitored for these symptoms when discontinuing treatment, regardless of the indication for which

paroxetine tablets are being prescribed. A gradual reduction in the dose rather than abrupt cessation is

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

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

Subsequently, the physician may continue decreasing the dose but at a more gradual rate.

HOW SUPPLIED

Paroxetine Tablets USP, 40 mg are white to off-white, round-shaped, biconvex, film- coated tablets

debossed with the logo of ZC18 on one side and plain on other side.

NDC 68071-4997-3 BOTTLES OF 30

Storage

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

Manufactured by:

Cadila Healthcare Ltd.

India

Distributed by:

Zydus Pharmaceuticals (USA) Inc.

Pennington, NJ 08534

Rev.: 08/17

Medication Guide

Paroxetine

(pa-ROX-a-teen)

Tablets, USP

Read the Medication Guide that comes with paroxetine tablets before you start taking it and each time

you get a refill. There may be new information. This Medication Guide does not take the place of

talking to your healthcare provider about your medical condition or treatment. Talk with your healthcare

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

What is the most important information I should know about paroxetine?

Paroxetine and other antidepressant medicines may cause serious side effects, including:

1. Suicidal thoughts or actions:

Paroxetine and other antidepressant medicines may increase suicidal thoughts or actions in

some children, teenagers, or young adults within the first few months of treatment or when the

dose is changed .

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

actions.

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

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

Pay particular attention to such changes when paroxetine 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

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

an emergency.

Paroxetine may be associated with these serious side effects:

2. Serotonin Syndrome or Neuroleptic Malignant Syndrome-like reactions. This condition can be

life-threatening and may include:

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

coordination problems or muscle twitching (overactive reflexes)

racing heartbeat, high or low blood pressure

sweating or fever

nausea, vomiting, or diarrhea

muscle rigidity

3. Visual problems

eye pain

changes in vision

swelling or redness in or around the eye

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

you are at risk and receive preventative treatment if you are.

4. Severe allergic reactions:

trouble breathing

swelling of the face, tongue, eyes, or mouth

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

5. Abnormal bleeding:

Paroxetine 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

antiinflammatory drug (NSAIDs, like ibuprofen or naproxen), or aspirin.

6. Seizures or convulsions

7. Manic episodes:

greatly increased energy

severe trouble sleeping

racing thoughts

reckless behavior

unusually grand ideas

excessive happiness or irritability

talking more or faster than usual

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

during treatment.

9. 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 paroxetine without first talking to your healthcare provider. Stopping paroxetine 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 paroxetine ?

Paroxetine is a prescription medicine used to treat depression . It is important to talk with your

healthcare provider about the risks of treating depression and also the risks of not treating it. You

should discuss all treatment choices with your healthcare provider.

Paroxetine is also used to treat:

Major Depressive Disorder (MDD)

Obsessive Compulsive Disorder (OCD)

Panic Disorder

Social Anxiety Disorder

Generalized Anxiety Disorder (GAD)

Posttraumatic Stress Disorder (PTSD)

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

using paroxetine.

Who should not take paroxetine tablets?

Do not take paroxetine tablets if you:

are allergic to paroxetine hydrochloride or any of the ingredients in paroxetine tablets. See the end

of this Medication Guide for a complete list of ingredients in paroxetine tablets.

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

not sure if you take an MAOI, including the antibiotic linezolid.

Do not take an MAOI within 2 weeks of stopping paroxetine tablets unless directed to do so by your

physician.

Do not start paroxetine tablets if you stopped taking an MAOI in the last 2 weeks unless directed to

do so by your physician.

People who take paroxetine tablets 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)

take MELLARIL

(thioridazine). Do not take MELLARIL

together with paroxetine

tablets because this can cause serious heart rhythm problems or sudden death.

take the antipsychotic medicine pimozide (ORAP

) because this can cause serious heart

problems .

What should I tell my healthcare provider before taking paroxetine tablets? Ask if you are not

s ure.

Before starting paroxetine tablets, tell your healthcare provider if you:

are pregnant, may be pregnant, or plan to become pregnant. There is a possibility that

paroxetine tablets may harm your unborn baby, including an increased risk of birth defects,

particularly heart defects. Other risks may include a serious condition in which there is not enough

oxygen in the baby's blood. Your baby may also have certain other symptoms shortly after birth.

Premature births have also been reported in some women who used paroxetine tablets during

pregnancy.

are breastfeeding. Paroxetine passes into your milk. Talk to your healthcare provider about the

best way to feed your baby while taking paroxetine.

are taking certain drugs such as:

triptans used to treat migraine headache

other antidepressants (SSRIs, SNRIs, tricyclics, or lithium) or antipsychotics

drugs that affect serotonin, such as lithium, tramadol, tryptophan, St. John's wort

certain drugs used to treat irregular heart beats

certain drugs used to treat schizophrenia

®*

®*

®*

certain drugs used to treat HIV infection

certain drugs that affect the blood, such as warfarin, aspirin, and ibuprofen

certain drugs used to treat epilepsy

atomoxetine

cimetidine

fentanyl

metoprolol

pimozide

procyclidine

tamoxifen

have liver problems

have kidney problems

have heart problems

have or had seizures or convulsions

have bipolar disorder or mania

have low sodium levels in your blood

have a history of a stroke

have high blood pressure

have or had bleeding problems

have glaucoma (high pressure in the eye)

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

prescription medicines, vitamins, and herbal supplements. Paroxetine 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 paroxetine tablets with your

other medicines. Do not start or stop any medicine while taking paroxetine tablets without talking to

your healthcare provider first.

If you take paroxetine tablets, you should not take any other medicines that contain paroxetine hydrochloride.

How should I take paroxetine tablets?

Take paroxetine tablets exactly as prescribed. Your healthcare provider may need to change the

dose of paroxetine tablets until it is the right dose for you.

Paroxetine tablets may be taken with or without food.

If you miss a dose of paroxetine tablets, 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 paroxetine tablets at the same time.

If you take too much paroxetine tablets, call your healthcare provider or poison control center right

away, or get emergency treatment.

Do not stop taking paroxetine tablets suddenly without talking to your doctor (unless you have

symptoms of a severe allergic reaction). If you need to stop taking paroxetine tablets, your

healthcare provider can tell you how to safely stop taking it.

What should I avoid while taking paroxetine?

Paroxetine 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 paroxetine affects you. Do not drink alcohol while using paroxetine.

What are possible side effects of paroxetine?

Paroxetine may cause serious side effects, including all of those described in the section entitled "What

is the most important information I should know about paroxetine?"

Common possible side effects in people who take paroxetine include:

nausea

sleepiness

weakness

dizziness

feeling anxious or trouble sleeping

sexual problems

sweating

shaking

not feeling hungry

dry mouth

constipation

infection

yawning

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 paroxetine. 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 or 1-800-332-1088.

How should I store paroxetine tablets?

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

Keep paroxetine tablets away from light.

Keep bottle of paroxetine tablets closed tightly.

Keep paroxetine tablets and all medicines out of the reach of children.

General information about paroxetine tablets

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

use paroxetine tablets for a condition for which they were not prescribed. Do not give paroxetine

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

This Medication Guide summarizes the most important information about paroxetine. If you would like

more information, talk with your healthcare provider. You may ask your healthcare provider or

pharmacist for information about paroxetine that is written for healthcare professionals.

Address medical inquiries to, Telephone: 1-877-993-8779 or MedicalAffairs@zydususa.com.

What are the ingredients in paroxetine tablets, USP?

Active ingredient: paroxetine hydrochloride, USP

Inactive ingredients: dibasic calcium phosphate anhydrous, hypromellose 6 cP, lactose anhydrous,

magnesium stearate, polyethylene glycol 6000, povidone, sodium starch glycolate, talc, and titanium

dioxide.

are the registered trademarks of their respective owners.

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

This product's package insert may have been updated. For current package insert, please visit

www.zydususa.com

Manufactured by:

Cadila Healthcare Ltd.

India

Distributed by:

Zydus Pharmaceuticals (USA) Inc.

Pennington, NJ 08534

Rev.: 08/17

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

PAROXETINE

paroxetine tablet, film coated

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:6 8 0 71-49 9 7(NDC:6 8 38 2-0 0 1)

Route of Administration

ORAL

NuCare Pharmaceuticals,Inc.

Active Ingredient/Active Moiety

Ingredient Name

Basis of

Stre ng th

Stre ng th

PARO XETINE HYDRO CHLO RIDE HEMIHYDRATE (UNII: X2ELS0 50 D8 ) (PAROXETINE -

UNII:41VRH5220 H)

PAROXETINE

40 mg

Inactive Ingredients

Ingredient Name

Stre ng th

ANHYDRO US DIBASIC CALCIUM PHO SPHATE (UNII: L11K75P9 2J)

ANHYDRO US LACTO SE (UNII: 3SY5LH9 PMK)

HYPRO MELLO SES (UNII: 3NXW29 V3WO)

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

PO LYETHYLENE GLYCO L 6 0 0 0 (UNII: 30 IQX730 WE)

SO DIUM STARCH GLYCO LATE TYPE A PO TATO (UNII: 58 56 J3G2A2)

PO VIDO NE (UNII: FZ9 8 9 GH9 4E)

TALC (UNII: 7SEV7J4R1U)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

Product Characteristics

Color

white (WHITE TO OFF-WHITE)

S core

no sco re

S hap e

ROUND (ROUND)

S iz e

11mm

Flavor

Imprint Code

ZC18

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:6 8 0 71-49 9 7-3

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

0 7/26 /20 19

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 7758 4

0 4/13/20 0 7

Labeler -

NuCare Pharmaceuticals,Inc. (010632300)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

NuCare Pharmaceuticals,Inc.

0 10 6 3230 0

re la be l(6 8 0 71-49 9 7)

Revised: 7/2019

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