Paroxetine tablet, film coated

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, USP 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, USP are not approved for use in pediatric patients. (See : , : and : .) WARNINGS Clinical Worsening and Suicide Risk PRECAUTIONS Information for Patients, PRECAUTIONS Pediatric Use

Description

Paroxetine hydrochloride is an orally administered psychotropic drug. It is the hydrochloride salt of a phenylpiperidine compound identified chemically as (-)- -4 -(4'-fluorophenyl)-3 -[(3',4'-methylenedioxyphenoxy) methyl] piperidine hydrochlorideanhydrous and has the empirical formula of C H FNO HCl . The molecular weight is 365.8 (anhydrous)(329.4 as free base). The structural formula of paroxetine hydrochloride is: trans R S 19 20 3

structure

Paroxetine hydrochloride is an odorless, off-white powder, having a melting point range of 116 to 120C and a solubility of 5.4mg/mL in water.

Each film-coated tablet, for oral administration, contains paroxetine hydrochloride equivalent to paroxetine as follows: 10 mg; 20 mg; 30 mg; 40 mg. Inactive ingredients consist of anhydrous lactose, hydroxypropyl cellulose, hypromellose, magnesium stearate, polyethylene glycol, sodium starch glycolate and titanium dioxide. Paroxetine tablets comply with USP Related Impurities Test 1.

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) 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. 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. radioligand binding studies indicate that paroxetine has little affinity for muscarinic, alpha -, alpha -, beta-adrenergic-, dopamine (D )-, 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. In vitro In vitro 1 2 2 1 2 1 1

Because the relative potencies of paroxetines 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 21hours (CV32%) after oral dosing of 30mg tablets of paroxetine daily for 30days. 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. max

Absorption and distribution

Paroxetine is equally bioavailable from the oral suspension and tablet.

Paroxetine hydrochloride is completely absorbed after oral dosing of a solution of the hydrochloride salt. In a study in which normal male subjects (n=15) received 30mg tablets daily for 30days, steady-state paroxetine concentrations were achieved by approximately 10days for most subjects, although it may take substantially longer in an occasional patient. At steady state, mean values of C , T , C , and T were 61.7ng/mL (CV45%), 5.2hr. (CV10%), 30.7ng/mL (CV67%), and 21.0 hours (CV32%), 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. max max min max min 0-24

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 6.4hours post-dosing to 4.9hours. max

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 100ng/mL and 400ng/mL, respectively. Under clinical conditions, paroxetine concentrations would normally be less than 400ng/mL. Paroxetine does not alter the protein binding of phenytoin or warfarin. in vitro

Metabolism and excretion

The mean elimination half-life is approximately 21hours (CV32%) after oral dosing of 30mg tablets daily for 30days of Paroxetinehydrochloride. In steady-state dose proportionality studies involving elderly and nonelderly patients, at doses of 20mg to 40mg daily for the elderly and 20mg to 50mg daily for the nonelderly, some nonlinearity was observed in both populations, again reflecting a saturable metabolic pathway. In comparison to C values after 20mg daily, values after 40mg daily were only about 2 to 3 times greater than doubled. min

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 30mL/min. were approximately 4times greater than seen in normal volunteers. Patients with creatinine clearance of 30 to 60mL/min. and patients with hepatic functional impairment had about a 2-fold increase in plasma concentrations (AUC, C ). max

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 40mg, C concentrations were about70% to 80% greater than the respective C concentrations in nonelderly subjects. Therefore the initial dosage in the elderly should be reduced (see ). min min DOSAGE AND ADMINISTRATION

Drug-drug interactions

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 ). In vitro PRECAUTIONS: Drug Interactions

Clinical trials

Major depressive disorder

The efficacy of paroxetine 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 was 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 was 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(HDRS total score <8) during an initial 8-week open-treatment phase and were then randomized to continuation on paroxetine or placebo for 1 year demonstrated a significantly lower relapse rate for patients taking paroxetine (15%) compared to those on placebo (39%). Effectiveness was similar for male and female patients.

Obsessive compulsive disorder

The effectiveness of paroxetine 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 60mg of paroxetine/day demonstrated that daily doses of paroxetine 40 and 60mg are effective in the treatment of OCD. Patients receiving doses of 40 and 60mg paroxetine experienced a mean reduction of approximately 6 and 7points, respectively, on the YBOCS total score which was significantly greater than the approximate 4-point reduction at 20mg and a 3-point reduction in the placebo-treated patients. Study 2 was a flexible-dose study comparing paroxetine (20 to 60mg daily) with clomipramine (25 to 250mg daily). In this study, patients receiving paroxetine experienced a mean reduction of approximately 7points on the YBOCS total score, which was significantly greater than the mean reduction of approximately 4points 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 20 mg Paroxetine 40 mg Paroxetine 60 mg
(n=75) (n=66) (n=66)
Worse 14% 7% 7% 3%
No Change 44% 35% 22% 19%
Minimally Improved 24% 33% 29% 34%
Much Improved 11% 18% 22% 24%
Very Much Improved 7% 7% 20% 20%

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 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 60mg/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 in the treatment of panic disorder was demonstrated in three 10- to 12-week multicenter, placebo-controlled studies of adult outpatients (Studies 1 to 3). Patients in all studies had panic disorder (DSM-IIIR), with or without agoraphobia. In these studies, paroxetine was 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 40mg/day or placebo. A significant difference from placebo was observed only for the 40mg/day group. At endpoint, 76% of patients receiving paroxetine 40mg/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 60mg 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 60mg 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 40mg/day of paroxetine.

Long-term maintenance effects of paroxetine 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 40mg/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 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 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 50mg 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 Study1, for patients who completed to week12, 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 60mg/day with placebo. Paroxetine 20mg 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 40mg and 60mg/day dose groups. There was no indication in this study of any additional benefit for doses higher than 20mg/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 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 20mg or 40mg/day with placebo. Doses of 20mg or 40mg of paroxetine 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 40mg/day dose compared to the 20mg/day dose.

Study2 was a flexible-dose study comparing paroxetine (20mg to 50mg daily) and placebo. Paroxetine 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 (20mg to 50mg daily), did not demonstrate statistically significant superiority of paroxetine 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 50mg/day of paroxetine, were randomized to continuation of paroxetine at their same dose, or to placebo, for up to 24weeks 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 experienced a significantly lower relapse rate over the subsequent 24weeks compared to those receiving placebo.

Indications and usage

Major depressive disorder

Paroxetine is indicated for the treatment of major depressive disorder.

The efficacy of paroxetine 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 ). 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 2weeks); it should include at least 4 of the following 8symptoms: 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. CLINICAL PHARMACOLOGY: Clinical Trials

The effects of paroxetine in hospitalized depressed patients have not been adequately studied.

The efficacy of paroxetine in maintaining a response in major depressive disorder for up to 1year was demonstrated in a placebo-controlled trial (see ). Nevertheless, the physician who elects to use paroxetine for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient. CLINICAL PHARMACOLOGY: Clinical Trials

Obsessive compulsive disorder

Paroxetine is 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 was 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 ). Nevertheless, the physician who elects to use paroxetine for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see ). CLINICAL PHARMACOLOGY: Clinical Trials DOSAGE AND ADMINISTRATION

Panic disorder

Paroxetine is 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 was 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 ). Nevertheless, the physician who prescribes paroxetine for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see ). CLINICAL PHARMACOLOGY: Clinical Trials DOSAGE AND ADMINISTRATION

Social anxiety disorder

Paroxetine is 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 was established in three 12-week trials in adult patients with social anxiety disorder (DSM-IV). Paroxetine has not been studied in children or adolescents with social phobia (see ). CLINICAL PHARMACOLOGY: Clinical Trials

The effectiveness of paroxetine in long-term treatment of social anxiety disorder, i.e., for more than 12weeks, has not been systematically evaluated in adequate and well-controlled trials. Therefore, the physician who elects to prescribe paroxetine 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 is 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 in the treatment of GAD was established in two 8-week placebo-controlled trials in adults with GAD. Paroxetine has not been studied in children or adolescents with Generalized Anxiety Disorder (see ). CLINICAL PHARMACOLOGY: Clinical Trials

Generalized Anxiety Disorder (DSM-IV) is characterized by excessive anxiety and worry (apprehensive expectation) that is persistent for at least 6months 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 in maintaining a response in patients with Generalized Anxiety Disorder, who responded during an 8-week acute treatment phase while taking paroxetine and were then observed for relapse during a period of up to 24 weeks, was demonstrated in a placebo-controlled trial (see ). Nevertheless, the physician who elects to use paroxetine for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see ). CLINICAL PHARMACOLOGY: Clinical Trials 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 within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated (see and ). WARNINGS 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 and WARNINGS DOSAGE AND ADMINISTRATION ).

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

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

Paroxetine tablets, USP are contraindicated in patients with a hypersensitivity to paroxetine or any of the inactive ingredients in paroxetine tablets, USP.

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 to 24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.

The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 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 to 24 5 additional cases
Decreases Compared to Placebo
25 to 64 1 fewer case
65 6 fewer cases

No suicides occurred in any of the pediatric 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 and , for a description of the risks of discontinuation of paroxetine). PRECAUTIONS DOSAGE AND ADMINISTRATION: Discontinuation of Treatment with Paroxetine

Prescriptions for paroxetine should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers.

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 is 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 tablets, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. Johns 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 and ). CONTRAINDICATIONS DOSAGE AND ADMINISTRATION

If concomitant use of paroxetine tablets with certain other serotonergic drugs, i.e., triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. Johns Wort is clinically warranted, be aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.

Treatment with paroxetine tablets and any concomitant serotonergic agents, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.

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 and CONTRAINDICATIONS 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 to2.8).
  • 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, 1.0 to 6.0, 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 . 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. PRECAUTIONS: Discontinuation of Treatment With Paroxetine )

Animal findings

Reproduction studies were performed at doses up to 50mg/kg/day in rats and 6mg/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 teratogeniceffects. However, in rats, there was an increase in pup deaths during thefirst 4days of lactation when dosing occurred during the last trimesterof gestation and continued throughout lactation. This effect occurred at adose of 1mg/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. 2 2

Nonteratogenic effects

Neonates exposed to paroxetine hydrochloride 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 to 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 tablets, USP) 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 tablets, 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 and ). DOSAGE AND ADMINISTRATION : 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 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 and 11.6% for the combined active-control groups. As with all drugs effective in the treatment of major depressive disorder, paroxetine 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, a rate similar to that associated with other drugs effective in the treatment of major depressive disorder. Paroxetine 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

Recent clinical trials supporting the various approved indications for paroxetine employed a taper-phase regimen, rather than an abrupt discontinuation of treatment. The taper-phase regimen used in GADclinical trials involved an incremental decrease in the daily dose by 10mg/day at weekly intervals. When a daily dose of 20mg/day was reached, patients were continued on this dose for 1week 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 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 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 self-limiting, there have been reports of serious discontinuation symptoms.

Patients should be monitored for these symptoms when discontinuing treatment with paroxetine. 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 , for adverse events reported upon discontinuation of treatment with paroxetine in pediatric patients. PRECAUTIONS: Pediatric Use

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 paroxetines irreversible inhibition of CYP2D6 (see ). 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. Drug Interactions

Akathisia

The use of paroxetine or other SSRIs has been associatedwith the development of akathisia, which is characterized by an inner senseof restlessness and psychomotor agitation such as an inability to sit or standstill usually associated with subjective distress. This is most likely tooccur 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 ). Discontinuation of paroxetine should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted. PRECAUTIONS: Geriatric Use

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 in patients with certain concomitant systemic illness is limited. Caution is advisable in using paroxetinein 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. 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 is prescribed for patients with narrow angle glaucoma.

Paroxetine has 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 products premarket testing. Evaluation of electrocardiograms of 682 patients who received paroxetine in double-blind, placebo-controlled trials, however, did not indicate that paroxetineis associated with the development of significant ECG abnormalities. Similarly, paroxetine does 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 tablets, USPshould 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.

Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with paroxetine and should counsel them in its appropriate use. A patient Medication Guide is available for paroxetine tablets, USP. 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 tablets, USP.

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 has 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 does not affect their ability to engage in such activities.

Completing course of therapy

While patients may notice improvement with treatment with paroxetine in 1 to 4weeks, they should be advised to continue therapy as directed.

Concomitant medication

Patients should be advised to inform their physician ifthey are taking, or plan to take, any prescription or over-the-counter drugs,since there is a potential for interactions.

Alcohol

Althoughparoxetine has 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.

Pregnancy

Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy (see and . WARNINGS: Usage in Pregnancy: Teratogenic Effects Nonteratogenic Effects )

Nursing

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. Consequently, concomitant use of paroxetine with tryptophan is not recommended (see ). WARNINGS: Serotonin Syndrome

Monoamine oxidase inhibitors

Pimozide

In a controlled study of healthy volunteers, after paroxetine was 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 is contraindicated (see ). max max 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, or St. John's Wort (see ). WARNINGS: Serotonin Syndrome

The concomitant use of paroxetine with MAOIs (including linezolid and intravenous methylene blue) is contraindicated (see ). The concomitant use of paroxetine with other SSRIs, SNRIs or tryptophan is not recommended (see ). CONTRAINDICATIONS PRECAUTIONS: Drug Interactions: Tryptophan

Thioridazine

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 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 ). WARNINGS: Serotonin Syndrome

Drugs affecting hepatic metabolism

The metabolism and pharmacokinetics of paroxetine may beaffected by the induction or inhibition of drug-metabolizing enzymes.

Cimetidine

Cimetidine inhibits many cytochrome P (oxidative) enzymes. In a study where paroxetine (30 mg once daily) was dosed orally for 4weeks, steady-state plasma concentrations of paroxetine were increased by approximately 50% during coadministration with oral cimetidine (300mg three times daily) for the final week. Therefore, when these drugs are administered concurrently, dosage adjustment of paroxetine after the 20-mg starting dose should be guided by clinical effect. The effect of paroxetine on cimetidine's pharmacokinetics was not studied. 450

Phenobarbital

Phenobarbital induces many cytochrome P (oxidative)enzymes. When a single oral 30-mg dose of paroxetine was administered at phenobarbitalsteady state (100mg once daily for 14days), paroxetine AUC andT were reduced (by an average of 25% and 38%, respectively) comparedto paroxetine administered alone. The effect of paroxetine on phenobarbitalpharmacokinetics was not studied. Since paroxetine exhibits nonlinear pharmacokinetics,the results of this study may not address the case where the 2 drugs are bothbeing chronically dosed. No initial dosage adjustment of paroxetine is considerednecessary when coadministered with phenobarbital; any subsequent adjustmentshould be guided by clinical effect. 450

Phenytoin

When a single oral 30-mg dose of paroxetine was administered at phenytoin steady state (300mg once daily for 14days), paroxetine AUC and T were reduced (by an average of 50% and 35%, respectively) compared to paroxetine administered alone. In a separate study, when a single oral 300-mg dose of phenytoin was administered at paroxetine steady state (30mg once daily for 14days), 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. In 1 study, daily dosing of paroxetine (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 C 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. 450 max max

Concomitant use of paroxetine with other drugs metabolized by cytochrome CYP2D6 has not been formally studied but may require lower doses than usually prescribed for either paroxetine or the other drug.

Therefore, coadministration of paroxetine 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 and ). CONTRAINDICATIONS 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 P isozymes that, unlike CYP2D6, show no evidence of saturation (see ). 450 PRECAUTIONS: Tricyclic Antidepressants [TCAs]

Drugs metabolized by cytochrome cyp3a4

An 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, 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 paroxetines K and its lack of effect on terfenadines clearance predicts its effect on other CYP3A4 substrates, paroxetines extent of inhibition of CYP3A4 activity is not likely to be of clinical significance. in vivo in vitro in vitro i in vivo

Tricyclic antidepressants (tcas)

Caution is indicated in the coadministration of tricyclic antidepressants (TCAs) with paroxetine, 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 (see . : PRECAUTIONS Drugs Metabolized by Cytochrome CYP2D6 )

Drugs highly bound to plasma protein

Because paroxetine is highly bound to plasma protein, administrationof paroxetine to a patient taking another drug that is highly protein bound maycause increased free concentrations of the other drug, potentially resultingin adverse events. Conversely, adverse effects could result from displacementof 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 does not increase the impairment of mentaland motor skills caused by alcohol, patients should be advised to avoid alcoholwhile taking paroxetine.

Lithium

A multiple-dose study has shown that there is no pharmacokineticinteraction between paroxetine and lithium carbonate. However, due to the potentialfor serotonin syndrome, caution is advised when paroxetine is coadministered withlithium.

Digoxin

The steady-state pharmacokinetics of paroxetine was notaltered when administered with digoxin at steady state. Mean digoxin AUC atsteady state decreased by 15% in the presence of paroxetine. Since there islittle clinical experience, the concurrent administration of paroxetine anddigoxin should be undertaken with caution.

Diazepam

Under steady-state conditions, diazepam does not appearto affect paroxetine kinetics. The effects of paroxetine on diazepam werenot evaluated.

Procyclidine

Daily oral dosing of paroxetine (30mg once daily) increased steady-state AUC , C , and C values of procyclidine (5mg 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. 0-24 max min

Beta-blockers

In a study where propranolol (80mg twice daily) was dosed orally for 18days, the established steady-state plasma concentrations of propranolol were unaltered during coadministration with paroxetine (30mg once daily) for the final 10days. The effects of propranolol on paroxetine have not been evaluated (see ). ADVERSE REACTIONS: Postmarketing Reports

Theophylline

Reports of elevated theophylline levels associated withtreatment with paroxetine have been reported. While this interaction has not beenformally studied, it is recommended that theophylline levels be monitoredwhen these drugs are concurrently administered.

Fosamprenavir/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 ECTand paroxetine.

Carcinogenesis, mutagenesis, impairment of fertility

Carcinogenesis

Two-year carcinogenicity studies were conducted in rodents given paroxetine in the diet at 1, 5, and 25mg/kg/day (mice) and 1, 5, and 20mg/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, and GAD on a mg/m basis. Because the MRHD for major depressive disorder is slightly less than that for OCD (50mg versus 60mg), 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. 2

Mutagenesis

Paroxetine produced no genotoxic effects in a battery of 5 and 2 assays that included the following: Bacterial mutation assay, mouse lymphoma mutation assay, unscheduled DNA synthesis assay, and tests for cytogenetic aberrations in mouse bone marrow and in human lymphocytes and in a dominant lethal test in rats. in vitro in vivo in vivo in vitro

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 15mg/kg/day, which is 2.9times the MRHD for major depressive disorder, social anxiety disorder, and GAD or 2.4times 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 52weeks. These lesions consisted of vacuolation of epididymal tubular epithelium at 50mg/kg/day and atrophic changes in the seminiferous tubules of the testes with arrested spermatogenesis at 25mg/kg/day (9.8 and 4.9times the MRHD for major depressive disorder, social anxiety disorder, and GAD; 8.2 and 4.1times the MRHD for OCD and PD on a mg/m basis). 2 2

Pregnancy

Labor and delivery

The effect of paroxetine on labor and delivery in humansis unknown.

Nursing mothers

Like many other drugs, paroxetine is secreted in human milk,and caution should be exercised when paroxetine is administered to a nursing woman.

Pediatric use

Safety and effectiveness in the pediatric population have not been established (see and ). Three placebo-controlled trials in 752 pediatric patients with MDD have been conducted with paroxetine, and the data were not sufficient to support a claim for use in pediatric patients. Anyone considering the use of paroxetine 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. BOX WARNING WARNINGS: Clinical Worsening and Suicide Risk

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

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, 17% of patients treated with paroxetine (approximately 700) were 65years 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 and ). CLINICAL PHARMACOLOGY DOSAGE AND ADMINISTRATION

Adverse reactions

Associated with discontinuation of treatment

Twenty percent (1,199/6,145) of patients treated with paroxetine in worldwide clinical trials in major depressive disorder and 16.1% (84/522), 11.8% (64/542), 9.4% (44/469), and10.7% (79/735) of patients treated with paroxetine in worldwide trials in social anxiety disorder, OCD, panic disorder, and GAD 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 compared to placebo) included the following:

Major Depressive Disorder

OCD

Panic Disorder

Social Anxiety Disorder

Generalized Anziety Disorder
Paroxetine Placebo Paroxetine Placebo Paroxetine Placebo Paroxetine Placebo Paroxetine Placebo
CNS
Somnolence 2.3% 0.7% 1.9% 0.3% 3.4% 0.3% 2.0% 0.2%
Insomnia 1.7% 0% 1.3% 0.3% 3.1% 0%
Agitation 1.1% 0.5%
Tremor 1.1% 0.3% 1.7% 0%
Anxiety 1.1% 0%
Dizziness 1.5% 0% 1.9% 0% 1.0% 0.2%
Gastrointestinal
Constipation 1.1% 0%
Nausea 3.2% 1.1% 1.9% 0% 3.2% 1.2% 4.0% 0.3% 2.0% 0.2%
Diarrhea 1.0% 0.3%
Dry mouth 1.0% 0.3%
Vomiting 1.0% 0.3% 1.0% 0%
Flatulence 1.0% 0.3%
Other
Asthenia 1.6% 0.4% 1.9% 0.4% 2.5% 0.6% 1.8% 0.2%
Abnormal ejaculation a 1.6% 0% 2.1% 0% 4.9% 0.6% 2.5% 0.5%
Sweating 1.0% 0.3% 1.1% 0% 1.1% 0.2%
Impotence a 1.5% 0%
Libido Decreased 1.0% 0%

Where numbers are not provided the incidence of the adverse events in patients treated with paroxetine was not >1% or was not greater than or equal to 2 times the incidence of placebo.

a. Incidence corrected for gender.

Commonly observed adverse events

Major depressive disorder

The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or greater and incidence for paroxetine at least twice that for placebo, derived from Table2) 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 at least twice that of placebo, derived from Table3) 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 at least twice that for placebo, derived from Table3) 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 at least twice that for placebo, derived from Table3) 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 at least twice that for placebo, derived from Table4) were: Asthenia, infection, constipation, decreased appetite, dry mouth, nausea, libido decreased, somnolence, tremor, sweating, and abnormal ejaculation.

Incidence in controlled clinical trials

The prescriber should be aware that the figures in the tablesfollowing cannot be used to predict the incidence of side effects in the courseof usual medical practice where patient characteristics and other factorsdiffer from those that prevailed in the clinical trials. Similarly, the citedfrequencies cannot be compared with figures obtained from other clinical investigationsinvolving different treatments, uses, and investigators. The cited figures,however, do provide the prescribing physician with some basis for estimatingthe relative contribution of drug and nondrug factors to the side effect incidencerate in the populations studied.

Major depressive disorder

Table2 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 50mg/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 a

Body System

Preferred Term

Paroxetine (n = 421)

Placebo (n = 421)

Body as a Whole

Headache

18%

17%

Asthenia

15%

6%

Cardiovascular

Palpitation

3%

1%

Vasodilation

3%

1%

Dermatologic

Sweating

11%

2%

Rash

2%

1%

Gastrointestinal

Nausea

26%

9%

Dry Mouth

18%

12%

Constipation

14%

9%

Diarrhea

12%

8%

Decreased Appetite

6%

2%

Flatulence

4%

2%

Oropharynx Disorder b

2%

0%

Dyspepsia

2%

1%

Musculoskeletal

Myopathy

2%

1%

Myalgia

2%

1%

Myasthenia

1%

0%

Nervous System

Somnolence

23%

9%

Dizziness

13%

6%

Insomnia

13%

6%

Tremor

8%

2%

Nervousness

5%

3%

Anxiety

5%

3%

Paresthesia

4%

2%

Libido Decreased

3%

0%

Drugged Feeling

2%

1%

Confusion

1%

0%

Respiration

Yawn

4%

0%

Special Senses

Blurred Vision

4%

1%

Taste Perversion

2%

0%

Urogenital System

Ejaculatory Disturbance c,d

13%

0%

Other Male Genital Disorders c,e

10%

0%

Urinary Frequency

3%

1%

Urination Disorder f

3%

0%

Female Genital Disorders c,g

2%

0%

a. Events reported by at least 1% of patients treated with paroxetine are included, except the following events which had an incidence on placebo paroxetine: 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.

b. Includes mostly lump in throat and tightness in throat.

c. Percentage corrected for gender.

d. Mostly ejaculatory delay.

e. Includes anorgasmia, erectile difficulties, delayed ejaculation/orgasm, and sexual dysfunction, and impotence.

f. Includes mostly difficulty with micturition and urinary hesitancy.

g. Includes mostly anorgasmia and difficulty reaching climax/orgasm.

Obsessive compulsive disorder, panic disorder, and social anxiety disorder

Table3 enumerates adverse events that occurred at a frequency of 2% or more among OCD patients on paroxetine who participated in placebo-controlled trials of 12-weeks duration in which patients were dosed in a range of 20mg to 60mg/day or among patients with panic disorder on paroxetine who participated in placebo-controlled trials of 10- to 12-weeks duration in which patients were dosed in a range of 10mg to 60mg/day or among patients with social anxiety disorder on paroxetine who participated in placebo-controlled trials of 12-weeks duration in which patients were dosed in a range of 20 mg to 50mg/day.

Table 3. Treatment-Emergent Adverse Experience Incidence in Placebo-Controlled Clinical Trials for Obsessive Compulsive Disorder, Panic Disorder, and Social Anxiety Disorder a

Body System

Preferred Term

Obsessive Compulsive Disorder

Panic Disorder

Social Anxiety Disorder

Paroxetine

Placebo

Paroxetine

Placebo

Paroxetine

Placezbo

(n = 542)

(n = 265) (n = 469) (n = 324) (n = 425) (n=339)

Body as a Whole

Asthenia

22%

14%

14%

5%

22%

14%

Abdominal Pain

4%

3%

Chest Pain

3%

2%

Back Pain

3%

2%

Chills

2%

1%

2%

1%

Trauma

3%

1%

Cardiovascular

Vasodilation

4%

1%

Palpitation

2%

0%

Dermatologic

Sweating

9%

3%

14%

6%

9%

2%

Rash

3%

2%

Gastrointestinal

Nausea

23%

10%

23%

17%

25%

7%

Dry Mouth

18%

9%

18%

11%

9%

3%

Constipation

16%

6%

8%

5%

5%

2%

Diarrhea

10%

10%

12%

7%

9%

6%

Decreased Appetite

9%

3%

7%

3%

8%

2%

Dyspepsia

4%

2%

Flatulence

4%

2%

Increased Appetite

4%

3%

2%

1%

Vomiting

2%

1%

Musculoskeletal

Myalgia

4%

3%

Nervous System

Insomnia

24%

13%

18%

10%

21%

16%

Somnolence

24%

7%

19%

11%

22%

5%

Dizziness

12%

6%

14%

10%

11%

7%

Tremor

11%

1%

9%

1%

9%

1%

Nervousness

9%

8%

8%

7%

Libido Decreased

7%

4%

9%

1%

12%

1%

Agitation

5%

4%

3%

1%

Anxiety

5%

4%

5%

4%

Abnormal Dreams

4%

1%

Concentration Impaired

3%

2%

4%

1%

Depersonalization

3%

0%

Myoclonus

3%

0%

3%

2%

2%

1%

Amnesia

2%

1%

Respiratory System

Rhinitis

3%

0%

Pharyngitis

4%

2%

Yawn

5%

1%

Special Senses

Abnormal Vision

4%

2%

4%

1%

Taste Perversion

2%

0%

Urogenital System

Abnormal Ejaculation b

23%

1%

21%

1%

28%

1%

Dysmenorrhea

5%

4%

Female Genital Disorder b

3%

0%

9%

1%

9%

1%

Impotence b

8%

1%

5%

0%

5%

1%

Urinary Frequency

3%

1%

2%

0%

Urination Impaired

3%

0%

Urinary Tract Infection

2%

1%

2%

1%

a. Events reported by at least 2% of OCD, panic disorder, and social anxiety disorder in patients treated with paroxetine are included, except the following events which had an incidence on placebo paroxetine: [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.

b. Percentage corrected for gender.

Generalized anxiety disorder

Table 4 enumerates adverse events that occurred at a frequency of 2% or more among GAD patients on paroxetine 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

Table 4. Treatment-Emergent Adverse Experience Incidence in Placebo-Controlled Clinical Trials for Generalized Anxiety Disorder a

Body System

Preferred Term

Generalized Anxiety Disorder

Paroxetine (n = 735)

Placebo (n = 529)

Body as a Whole

Asthenia

14%

6%

Headache

17%

14%

Infection

6%

3%

Abdominal Pain

Trauma

Cardiovascular

Vasodilation

3%

1%

Dermatologic

Sweating

6%

2%

Gastrointestinal

Nausea

20%

5%

Dry Mouth

11%

5%

Constipation

10%

2%

Diarrhea

9%

7%

Decreased Appetite

5%

1%

Vomiting

3%

2%

Dyspepsia

Nervous System

Insomnia

11%

8%

Somnolence

15%

5%

Dizziness

6%

5%

Tremor

5%

1%

Nervousness

4%

3%

Libido Decreased

9%

2%

Abnormal Dreams

Respiratory System

Respiratory Disorder

7%

5%

Sinusitis

4%

3%

Yawn

4%

Special Senses

Abnormal Vision

2%

1%

Urogenital System

Abnormal Ejaculation b

25%

2%

Female Genital Disorder b

4%

1%

Impotence b

4%

3%

a. Events reported by at least 2% of GAD in patients treated with paroxetine are included, except the following events which had an incidence on placebo paroxetine [GAD]: Abdominal pain, back pain, trauma, dyspepsia, myalgia, and pharyngitis.

b. Percentage corrected for gender.

Dose dependency of adverse events

A comparison of adverse event rates in a fixed-dose study comparing 10, 20, 30, and 40mg/day of paroxetine 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, as shown in Table 5:

Table 5. Treatment-Emergent Adverse Experience Incidence in a Dose-Comparison Trial in the Treatment of Major Depressive Disorder a

Body System/Preferred Term

Placebo

Paroxetine

n = 51

10mg n = 102

20 mg n = 104

30mg n = 101

40mg 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%

NervousSystem

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%

SpecialSenses

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%

Rule for including adverseevents in table: Incidence at least 5% for 1 of paroxetine groups and twice the placebo incidence for at least 1 paroxetine group. a

In a fixed-dose study comparing placebo and 20, 40, and 60mg of paroxetine in the treatment of OCD, there was no clear relationship between adverse events and the dose of paroxetine to which patients were assigned. No new adverse events were observed in the group treated with 60 mg of paroxetine compared to any of the other treatment groups.

In a fixed-dose study comparing placebo and 10, 20, and 40mg of paroxetine in the treatment of panic disorder, there was no clear relationship between adverse events and the dose of paroxetine 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 60mg of paroxetine compared to any of the other treatment groups.

In a fixed-dose study comparing placebo and 20, 40, and 60mg of paroxetine 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 to which patients were assigned.

In a fixed-dose study comparing placebo and 20 and 40mg of paroxetine 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 to which patients were assigned, except for the following adverse events: Asthenia, constipation, and abnormal ejaculation.

Adaptation to certain adverse events

Over a 4- to 6-week period, there was evidence of adaptationto 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, and GAD are displayed in Table6.

Table 6. Incidence of Sexual Adverse Events in Controlled Clinical Trials

Paroxetine

Placebo

n (males)

1446

1042

Decreased Libido

6 to15%

0 to 5%

Ejaculatory Disturbance

13 to 28%

0 to -2%

Impotence

2 to 9%

0 to 3%

n (females)

1822

1340

Decreased Libido

0 to 9%

0 to 2%

Orgasmic Disturbance

2 to 9%

0 to 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.

Whileit is difficult to know the precise risk of sexual dysfunction associatedwith the use of SSRIs, physicians should routinely inquire about such possibleside effects.

Weight and vital sign changes

Significant weight loss may be an undesirable result oftreatment with paroxetine for some patients but, on average, patients in controlledtrials had minimal (about 1 pound) weight loss versus smaller changes on placeboand active control. No significant changes in vital signs (systolic and diastolicblood pressure, pulse and temperature) were observed in patients treated withparoxetine in controlled clinical trials.

Ecg changes

In an analysis of ECGs obtained in 682 patients treatedwith paroxetine 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 treatedwith paroxetine exhibited abnormal values on liver function tests at no greaterrate than that seen in placebo-treated patients. In particular, the paroxetine-versus-placebocomparisons for alkaline phosphatase, SGOT, SGPT, and bilirubin revealed nodifferences in the percentage of patients with marked abnormalities.

Hallucinations

In pooled clinical trials of immediate-release paroxetinehydrochloride, hallucinations were observed in 22 of 9089 patients receivingdrug and 4 of 3187 patients receiving placebo.

Other events observed during the premarketing evaluation of paroxetine

During its premarketing assessment in major depressive disorder, multiple doses of paroxetine were administered to 6,145 patients in phase 2 and 3 studies. The conditions and duration of exposure to paroxetine 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, and generalized anxiety disorder, 542, 469, 522, and 735 patients, respectively, received multiple doses of paroxetine. 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 who experienced an event of the type cited on at least 1 occasion while receiving paroxetine. 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 section. PRECAUTIONS

Body as a whole

Allergic reaction, chills, face edema, malaise, neck pain; Adrenergic syndrome, cellulitis, moniliasis,neck rigidity, pelvic pain, peritonitis, sepsis, ulcer. Infrequent: rare:

Cardiovascular system

Hypertension, tachycardia; Bradycardia, hematoma, hypotension, migraine, postural hypotension,syncope; 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. Frequent: infrequent: rare:

Digestive system

Bruxism, colitis, dysphagia, eructation, gastritis, gastroenteritis, gingivitis, glossitis, increased salivation, liver function tests abnormal, rectal hemorrhage, ulcerative stomatitis; 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. Infrequent: rare:

Endocrine system

Diabetes mellitus,goiter, hyperthyroidism, hypothyroidism, thyroiditis. Rare:

Hemic and lymphatic systems

Anemia,leukopenia, lymphadenopathy, purpura; Abnormalerythrocytes, basophilia, bleeding time increased, eosinophilia, hypochromicanemia, iron deficiency anemia, leukocytosis, lymphedema, abnormal lymphocytes,lymphocytosis, microcytic anemia, monocytosis, normocytic anemia, thrombocythemia,thrombocytopenia. Infrequent: rare:

Metabolic and nutritional

Weightgain; Edema, peripheraledema, SGOT increased, SGPT increased, thirst, weight loss; 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 dehydrogenaseincreased, non-protein nitrogen (NPN) increased. Frequent: infrequent: rare:

Musculoskeletal system

Arthralgia; Arthritis, arthrosis; Bursitis, myositis, osteoporosis, generalized spasm, tenosynovitis,tetany. Frequent: infrequent: rare:

Nervous system

Emotionallability, vertigo; Abnormalthinking, alcohol abuse, ataxia, dystonia, dyskinesia, euphoria, hallucinations,hostility, hypertonia, hypesthesia, hypokinesia, incoordination, lack of emotion,libido increased, manic reaction, neurosis, paralysis, paranoid reaction; 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, psychoticdepression, psychosis, reflexes decreased, reflexes increased, stupor, torticollis,trismus, withdrawal syndrome. Frequent: infrequent: rare:

Respiratory system

Asthma, bronchitis, dyspnea, epistaxis, hyperventilation, pneumonia, respiratory flu; Emphysema, hemoptysis, hiccups, lung fibrosis, pulmonary edema, sputum increased, stridor, voice alteration. Infrequent: rare:

Skin and appendages

Pruritus; Acne,alopecia, contact dermatitis, dry skin, ecchymosis, eczema, herpes simplex,photosensitivity, urticaria; Angioedema,erythema nodosum, erythema multiforme, exfoliative dermatitis, fungal dermatitis,furunculosis; herpes zoster, hirsutism, maculopapular rash, seborrhea, skindiscoloration, skin hypertrophy, skin ulcer, sweating decreased, vesiculobullousrash. Frequent: infrequent: rare:

Special senses

: Tinnitus; Abnormality of accommodation, conjunctivitis,ear pain, eye pain, keratoconjunctivitis, mydriasis, otitis media; 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. Frequent infrequent: rare:

Urogenital system

Amenorrhea,breast pain, cystitis, dysuria, hematuria, menorrhagia, nocturia, polyuria,pyuria, urinary incontinence, urinary retention, urinary urgency, vaginitis; 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. Infrequent: rare:

Postmarketing reports

Voluntary reports of adverse events in patients taking paroxetine 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-Barr 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-Schnlein purpura), and premature births in pregnant women. There has been a case report of an elevated phenytoin level after 4 weeks of paroxetine and phenytoin coadministration. There has been a case report of severe hypotension when paroxetine was added to chronic metoprolol treatment.

Drug abuse and dependence

Controlled substance class

Paroxetine is not a controlled substance.

Physical and psychologic dependence

Paroxetine has 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 (e.g., development of tolerance, incrementations of dose, drug-seeking behavior).

Overdosage

Human experience

Since the introduction of paroxetine in the United States, 342spontaneous cases of deliberate or accidental overdosage during paroxetinetreatment have been reported worldwide (circa1999). These include overdoseswith paroxetine alone and in combination with other substances. Of these,48 cases were fatal and of the fatalities, 17 appeared to involve paroxetinealone. Eight fatal cases that documented the amount of paroxetine ingestedwere generally confounded by the ingestion of other drugs or alcohol or thepresence of significant comorbid conditions. Of 145 non-fatal cases with knownoutcome, most recovered without sequelae. The largest known ingestion involved2,000 mg of paroxetine (33 times the maximum recommended daily dose) in apatient who recovered.

Commonly reported adverse eventsassociated with paroxetine overdosage include somnolence, coma, nausea, tremor,tachycardia, confusion, vomiting, and dizziness. Other notable signs and symptomsobserved with overdoses involving paroxetine (alone or with other substances)include mydriasis, convulsions (including status epilepticus), ventriculardysrhythmias (including torsade de pointes), hypertension, aggressive reactions,syncope, hypotension, stupor, bradycardia, dystonia, rhabdomyolysis, symptomsof 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 ). : PRECAUTIONS Drugs 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 (PDR). Physicians' Desk Reference

Dosage and administration

Major depressive disorder

Usual initial dosage

Paroxetine should be administered as a single daily dose with or without food, usually in the morning. The recommended initial dose is 20mg/day. Patients were dosed in a range of 20 to 50mg/day in the clinical trials demonstrating the effectiveness of paroxetine 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 50mg/day. Dose changes should occur at intervals of at least 1week.

Maintenance therapy

There is no body of evidence available to answer the questionof how long the patient treated with paroxetine should remain on it. It is generallyagreed that acute episodes of major depressive disorder require several monthsor longer of sustained pharmacologic therapy. Whether the dose needed to induceremission is identical to the dose needed to maintain and/or sustain euthymiais unknown.

Systematic evaluation of the efficacy ofparoxetine has shown that efficacy is maintained for periods of up to 1yearwith doses that averaged about 30mg.

Obsessive compulsive disorder

Usual initial dosage

Paroxetine should be administered as a single daily dose with or without food, usually in the morning. The recommended dose of paroxetine in the treatment of OCD is 40mg daily. Patients should be started on 20mg/day and the dose can be increased in 10-mg/day increments. Dose changes should occur at intervals of at least 1week. Patients were dosed in a range of 20 to 60mg/day in the clinical trials demonstrating the effectiveness of paroxetine in the treatment of OCD. The maximum dosage should not exceed 60mg/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 ). 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. CLINICAL PHARMACOLOGY: Clinical Trials

Panic disorder

Usual initial dosage

P aroxetine should be administered as a single daily dose with or without food, usually in the morning. The target dose of paroxetine in the treatment of panic disorder is 40mg/day. Patients should be started on 10mg/day. Dose changes should occur in 10-mg/day increments and at intervals of at least 1week. Patients were dosed in a range of 10 to 60mg/day in the clinical trials demonstrating the effectiveness of paroxetine. The maximum dosage should not exceed 60mg/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 ). 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. CLINICAL PHARMACOLOGY: Clinical Trials

Social anxiety disorder

Usual initial dosage

Paroxetine should be administered as a single daily dose with or without food, usually in the morning. The recommended and initial dosage is 20mg/day. In clinical trials the effectiveness of paroxetine was demonstrated in patients dosed in a range of 20 to 60mg/day. While the safety of paroxetine has been evaluated in patients with social anxiety disorder at doses up to 60mg/day, available information does not suggest any additional benefit for doses above 20mg/day (see ). CLINICAL PHARMACOLOGY: Clinical Trials

Maintenance therapy

There is no bodyof evidence available to answer the question of how long the patient treatedwith paroxetine should remain on it. Although the efficacy of paroxetine beyond 12weeksof dosing has not been demonstrated in controlled clinical trials, socialanxiety disorder is recognized as a chronic condition, and it is reasonableto consider continuation of treatment for a responding patient. Dosage adjustmentsshould be made to maintain the patient on the lowest effective dosage, andpatients should be periodically reassessed to determine the need for continuedtreatment.

Generalized anxiety disorder

Usual initial dosage

Paroxetine should be administered as a single daily dose with or without food, usually in the morning. In clinical trials the effectiveness of paroxetine was demonstrated in patients dosed in a range of 20 to 50mg/day. The recommended starting dosage and the established effective dosage is 20mg/day. There is not sufficient evidence to suggest a greater benefit to doses higher than 20mg/day. Dose changes should occur in 10mg/day increments and at intervals of at least 1week.

Maintenance therapy

Systematic evaluation of continuing paroxetine for periods of up to 24weeks in patients with Generalized Anxiety Disorder who had responded while taking paroxetine during an 8-week acute treatment phase has demonstrated a benefit of such maintenance (see ). Nevertheless, patients should be periodically reassessed to determine the need for maintenance treatment. CLINICAL PHARMACOLOGY: Clinical Trials

Special populations

Treatment of pregnant women during the third trimester

Neonates exposed to paroxetine and other SSRIs or SNRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding (see ). When treating pregnant women with paroxetine during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. WARNINGS: Usage in Pregnancy

Dosage for elderly or debilitated patients, and patients with severe renal or hepatic impairment

The recommended initial dose is 10mg/day for elderlypatients, debilitated patients, and/or patients with severe renal or hepaticimpairment. Increases may be made if indicated. Dosage should not exceed 40mg/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 Conversely, at least 14 days should be allowed after stopping paroxetine before starting an MAOI intended to treat psychiatric disorders (see ). CONTRAINDICATIONS

Use of paroxetine 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 intravenous 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

Symptoms associated with discontinuation of paroxetine have been reported (see ). Patients should be monitored for these symptoms when discontinuing treatment, regardless of the indication for which paroxetine is 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. PRECAUTIONS: Discontinuation of Treatment With Paroxetine

How supplied

NDC:64725-0083-1 in a BOTTLE of 60 TABLET, FILM COATEDS

Medication guide

Paroxetine tablets, usp (pa rox e teen)

Read the Medication Guide that comes with paroxetine 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:

  • in some children, teenagers, or young adults within the . Paroxetine and other antidepressant medicines may increase suicidal thoughts or actions 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. 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

4. 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 anti-inflammatory drug (NSAIDs, like ibuprofen or naproxen), or aspirin. Abnormal bleeding: ® ®

5. Seizures or convulsions

6. : 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

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

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

  • headache
  • weakness or feeling unsteady
  • confusion, problems concentrating or thinking, or memory problems

Stopping paroxetine too quickly may cause serious symptoms including: Do not stop paroxetine without first talking to your healthcare provider.

  • 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 used to treat: . also

  • Major Depressive Disorder (MDD)
  • Obsessive Compulsive Disorder (OCD)
  • Panic Disorder
  • Social Anxiety Disorder
  • Generalized Anxiety Disorder (GAD)

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?

Do not take paroxetine if you:

  • are allergic to paroxetine 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 unless directed to do so by your physician.
    • Do not start paroxetine if you stopped taking an MAOI in the last 2 weeks unless directed to do so by your physician.
    • People who take paroxetine 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 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? Ask if you are not sure.

Before starting paroxetine, tell your healthcare provider if you:

  • There is a possibility that paroxetine 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 babys blood. Your baby may also have certain other symptoms shortly after birth. Premature births have also been reported in some women who used paroxetine during pregnancy. are pregnant, may be pregnant, or plan to become pregnant.
  • Paroxetine passes into your milk. Talk to your healthcare provider about the best way to feed your baby while taking paroxetine. are breastfeeding.
  • 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. Johns 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)

, 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. Tell your healthcare provider about all the medicines you take

Your healthcare provider or pharmacist can tell you if it is safe to take paroxetine with your other medicines. Do not start or stop any medicine while taking paroxetine without talking to your healthcare provider first.

If you take paroxetine, you should not take any other medicines that contain paroxetine hydrochloride, including PAXIL CR and PEXEVA (paroxetine mesylate). ®

How should I take paroxetine?

  • Take paroxetine exactly as prescribed. Your healthcare provider may need to change the dose of paroxetine until it is the right dose for you.
  • Paroxetine may be taken with or without food.
  • If you are taking paroxetine oral suspension, shake the suspension well before use.
  • If you miss a dose of paroxetine, 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 at the same time.
  • If you take too much paroxetine, call your healthcare provider or poison control center right away, or get emergency treatment.
  • Do not stop taking paroxetine suddenly without talking to your doctor (unless you have symptoms of a severe allergic reaction). If you need to stop taking paroxetine, 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?

  • Store at 20 to 25C (68 to 77F).
  • Keep paroxetine away from light.
  • Keep bottle of paroxetine closed tightly.

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

General information about paroxetine

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use paroxetine for a condition for which it was not prescribed. Do not give paroxetine 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.

For more information about paroxetine call Apotex Drug Information at 1-800-667-4708.

What are the ingredients in paroxetine tablets?

paroxetine hydrochloride Active ingredient:

anhydrous lactose, hydroxypropyl cellulose, hypromellose, magnesium stearate, polyethylene glycol, sodium starch glycolate and titanium dioxide. Inactive ingredients:

PAXIL and PAXIL CR are registered trademarks of GlaxoSmithKline. The other brands listed are trademarks of their respective owners. This Medication Guide has been approved by the U.S. Food and Drug Administration.

Manufactured by: Manufactured for:

Apotex Inc. Apotex Corp.

Toronto, Ontario Weston, FL

Canada M9L 1T9 33326

Revised: January 2014

Ingredients and appearance - Product information

Paroxetine tablet, film coated- Paroxetine hydrochloride

Product information

Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC: 64725-0083
Route of Administration Oral

Active Ingredient/Active Moiety

Ingredient Name Strength
Paroxetine hydrochloride anhydrous ( UNII: 3I3T11UD2S)( Paroxetine - UNII: 41VRH5220H ) 20 mgin 1

Inactive Ingredients

Ingredient Name Code
Anhydrous lactose ( UNII: 3SY5LH9PMK)
Hydroxypropyl cellulose (type h) ( UNII: RFW2ET671P)
Hypromelloses ( UNII: 3NXW29V3WO)
Magnesium stearate ( UNII: 70097M6I30)
Polyethylene glycols ( UNII: 3WJQ0SDW1A)
Sodium starch glycolate type a potato ( UNII: 5856J3G2A2)
Titanium dioxide ( UNII: 15FIX9V2JP)

Product Characteristics

Shape OVAL Score 2
Color WHITE Size 11 mm
Imprint Code APO;083

Marketing Information

Marketing Category Application Number or Monograph Citation Territorial Authority Marketing Start Date
ANDA ANDA075356 USA

Paroxetine tablet, film coated- Paroxetine hydrochloride

Product information

Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC: 64725-0097
Route of Administration Oral

Active Ingredient/Active Moiety

Ingredient Name Strength
Paroxetine hydrochloride anhydrous ( UNII: 3I3T11UD2S)( Paroxetine - UNII: 41VRH5220H ) 10 mgin 1

Inactive Ingredients

Ingredient Name Code
Anhydrous lactose ( UNII: 3SY5LH9PMK)
Hydroxypropyl cellulose (type h) ( UNII: RFW2ET671P)
Hypromelloses ( UNII: 3NXW29V3WO)
Magnesium stearate ( UNII: 70097M6I30)
Polyethylene glycols ( UNII: 3WJQ0SDW1A)
Sodium starch glycolate type a potato ( UNII: 5856J3G2A2)
Titanium dioxide ( UNII: 15FIX9V2JP)

Product Characteristics

Shape OVAL Score 2
Color WHITE Size 9 mm
Imprint Code APO;097

Marketing Information

Marketing Category Application Number or Monograph Citation Territorial Authority Marketing Start Date
ANDA ANDA075356 USA

Labeler - TYA Pharmaceuticals( 938389038)

Establishment

Name ID/FEI Business Operations
TYA Pharmaceuticals 938389038 RELABEL( 64725-0083, 64725-0097), REPACK( 64725-0083)

Package label.principal display panel

Package label.principal display panel