PAROXETINE- paroxetine hydrochloride_tablet, film coated

CLINICAL PHARMACOLOGY
The efficacy of paroxetine in the treatment of major depressive disorder, social anxiety disorder, obsessive compulsive disorder (OCD), panic disorder (PD), and 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. In vitro In vitro 1 2 2 1 2 1 1 Because the relative potencies of paroxetine’s major metabolites are at most 1/50 of the parent compound, they are essentially inactive. Paroxetine hydrochloride is completely absorbed after oral dosing of a solution of the hydrochloride salt. The mean elimination half-life is approximately 21 hours (CV 32%) after oral dosing of paroxetine tablets, 30 mg daily for 30 days. Paroxetine is extensively metabolized and the metabolites are considered to be inactive. Nonlinearity in pharmacokinetics is observed with increasing doses. Paroxetine metabolism is mediated in part by CYP2D6, and the metabolites are primarily excreted in the urine and to some extent in the feces. Pharmacokinetic behavior of paroxetine has not been evaluated in subjects who are deficient in CYP2D6 (poor metabolizers). Paroxetine hydrochloride hemihydrate is completely absorbed after oral dosing of a solution of the hydrochloride salt. In a study in which normal male subjects (n = 15) received 30 mg tablets daily for 30 days, steady-state paroxetine concentrations were achieved by approximately 10 days for most subjects, although it may take substantially longer in an occasional patient. At steady state, mean values of C max max min ½ 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 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 100 ng/mL and 400 ng/mL, respectively. Under clinical conditions, paroxetine concentrations would normally be less than 400 ng/mL. Paroxetine does not alter the in vitro The mean elimination half-life is approximately 21 hours (CV 32%) after oral dosing of paroxetine tablets, 30 mg tablets daily for 30 days. In steady-state dose proportionality studies involving elderly and nonelderly patients, at doses of 20 mg to 40 mg daily for the elderly and 20 mg to 50 mg daily for the nonelderly, some nonlinearity was observed in both populations, again reflecting a saturable metabolic pathway. In comparison to C 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. Increased plasma concentrations of paroxetine occur in subjects with renal and hepatic impairment. The mean plasma concentrations in patients with creatinine clearance below 30 mL/min. were approximately 4 times greater than seen in normal volunteers. Patients with creatinine clearance of 30 to 60 mL/min. and patients with hepatic functional impairment had about a 2-fold increase in plasma concentrations (AUC, C 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 In a multiple-dose study in the elderly at daily paroxetine doses of 20, 30, and 40 mg, C min min DOSAGE AND ADMINISTRATION In vitro PRECAUTIONS ─ Drug Interactions The efficacy of paroxetine tablets as a treatment for major depressive disorder has been established in 6 placebo-controlled studies of patients with major depressive disorder (aged 18 to 73). In these studies, paroxetine tablets were shown to be significantly more effective than placebo in treating major depressive disorder by at least 2 of the following measures: Hamilton Depression Rating Scale (HDRS), the Hamilton depressed mood item, and the Clinical Global Impression (CGI)-Severity of Illness. Paroxetine tablets were significantly better than placebo in improvement of the HDRS sub-factor scores, including the depressed mood item, sleep disturbance factor, and anxiety factor. A study of outpatients with major depressive disorder who had responded to paroxetine tablets (HDRS total score <8) during an initial 8-week open-treatment phase and were then randomized to continuation on paroxetine tablets or placebo for 1 year demonstrated a significantly lower relapse rate for patients taking paroxetine tablets (15%) compared to those on placebo (39%). Effectiveness was similar for male and female patients. The effectiveness of paroxetine tablets in the treatment of obsessive compulsive disorder (OCD) was demonstrated in two 12-week multicenter placebo-controlled studies of adult outpatients (Studies 1 and 2). Patients in all studies had moderate to severe OCD (DSM-IIIR) with mean baseline ratings on the Yale Brown Obsessive Compulsive Scale (YBOCS) total score ranging from 23 to 26. Study 1, a dose-range finding study where patients were treated with fixed doses of 20, 40, or 60 mg of paroxetine/day demonstrated that daily doses of paroxetine 40 and 60 mg are effective in the treatment of OCD. Patients receiving doses of 40 and 60 mg paroxetine experienced a mean reduction of approximately 6 and 7 points, respectively, on the YBOCS total score which was significantly greater than the approximate 4-point reduction at 20 mg and a 3-point reduction in the placebo-treated patients. Study 2 was a flexible-dose study comparing paroxetine (20 to 60 mg daily) with clomipramine (25 to 250 mg daily). In this study, patients receiving paroxetine experienced a mean reduction of approximately 7 points on the YBOCS total score, which was significantly greater than the mean reduction of approximately 4 points in placebo-treated patients. The following table provides the outcome classification by treatment group on Global Improvement items of the Clinical Global Impression (CGI) scale for Study 1. Outcome Classification (%) on CGI - Global Improvement Item for Completers in Study 1 Outcome Classification Placebo ( n = 74 ) Paroxetine Tablets USP , 20 mg ( n = 75 ) Paroxetine Tablets USP , 40 mg ( n = 66 ) Paroxetine Tablets USP , 60 mg ( n = 66 ) Worse 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 tablets in OCD were demonstrated in a long-term extension to Study 1. Patients who were responders on paroxetine during the 3-month double-blind phase and a 6-month extension on open-label paroxetine (20 to 60 mg/day) were randomized to either paroxetine or placebo in a 6-month double-blind relapse prevention phase. Patients randomized to paroxetine were significantly less likely to relapse than comparably treated patients who were randomized to placebo. The effectiveness of paroxetine tablets in the treatment of panic disorder was demonstrated in three 10- to 12-week multicenter, placebo-controlled studies of adult outpatients (Studies 1-3). Patients in all studies had panic disorder (DSM-IIIR), with or without agoraphobia. In these studies, paroxetine tablets were shown to be significantly more effective than placebo in treating panic disorder by at least 2 out of 3 measures of panic attack frequency and on the Clinical Global Impression Severity of Illness score. Study 1 was a 10-week dose-range finding study; patients were treated with fixed paroxetine doses of 10, 20, or 40 mg/day or placebo. A significant difference from placebo was observed only for the 40 mg/day group. At endpoint, 76% of patients receiving paroxetine 40 mg/day were free of panic attacks, compared to 44% of placebo-treated patients. Study 2 was a 12-week flexible-dose study comparing paroxetine (10 to 60 mg daily) and placebo. At endpoint, 51% of paroxetine patients were free of panic attacks compared to 32% of placebo-treated patients. Study 3 was a 12-week flexible-dose study comparing paroxetine (10 to 60 mg daily) to placebo in patients concurrently receiving standardized cognitive behavioral therapy. At endpoint, 33% of the paroxetine-treated patients showed a reduction to 0 or 1 panic attacks compared to 14% of placebo patients. In both Studies 2 and 3, the mean paroxetine dose for completers at endpoint was approximately 40 mg/day of paroxetine. Long-term maintenance effects of paroxetine tablets in panic disorder were demonstrated in an extension to Study 1. Patients who were responders during the 10-week double-blind phase and during a 3-month double-blind extension phase were randomized to either paroxetine (10, 20, or 40 mg/day) or placebo in a 3-month double-blind relapse prevention phase. Subgroup analyses did not indicate that there were any differences in treatment outcomes as a function of age or gender. The effectiveness of paroxetine tablets in the treatment of social anxiety disorder was demonstrated in three 12-week, multicenter, placebo-controlled studies (Studies 1, 2, and 3) of adult outpatients with social anxiety disorder (DSM-IV). In these studies, the effectiveness of paroxetine tablets compared to placebo was evaluated on the basis of (1) the proportion of responders, as defined by a Clinical Global Impression (CGI) Improvement score of 1 (very much improved) or 2 (much improved), and (2) change from baseline in the Liebowitz Social Anxiety Scale (LSAS). Studies 1 and 2 were flexible-dose studies comparing paroxetine (20 to 50 mg daily) and placebo. Paroxetine demonstrated statistically significant superiority over placebo on both the CGI Improvement responder criterion and the Liebowitz Social Anxiety Scale (LSAS). In Study 1, for patients who completed to week 12, 69% of paroxetine-treated patients compared to 29% of placebo-treated patients were CGI Improvement responders. In Study 2, CGI Improvement responders were 77% and 42% for the paroxetine- and placebo-treated patients, respectively. Study 3 was a 12-week study comparing fixed paroxetine doses of 20, 40, or 60 mg/day with placebo. Paroxetine 20 mg was demonstrated to be significantly superior to placebo on both the LSAS Total Score and the CGI Improvement responder criterion; there were trends for superiority over placebo for the 40 mg and 60 mg/day dose groups. There was no indication in this study of any additional benefit for doses higher than 20 mg/day. Subgroup analyses generally did not indicate differences in treatment outcomes as a function of age, race, or gender. The effectiveness of paroxetine tablets in the treatment of Generalized Anxiety Disorder (GAD) was demonstrated in two 8-week, multicenter, placebo-controlled studies (Studies 1 and 2) of adult outpatients with Generalized Anxiety Disorder (DSM-IV). Study 1 was an 8-week study comparing fixed paroxetine doses of 20 mg or 40 mg/day with placebo. Doses of 20 mg or 40 mg of paroxetine tablets were both demonstrated to be significantly superior to placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score. There was not sufficient evidence in this study to suggest a greater benefit for the 40 mg/day dose compared to the 20 mg/day dose. Study 2 was a flexible-dose study comparing paroxetine (20 mg to 50 mg daily) and placebo. Paroxetine tablets demonstrated statistically significant superiority over placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score. A third study, also flexible-dose comparing paroxetine (20 mg to 50 mg daily), did not demonstrate statistically significant superiority of paroxetine tablets over placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score, the primary outcome. Subgroup analyses did not indicate differences in treatment outcomes as a function of race or gender. There were insufficient elderly patients to conduct subgroup analyses on the basis of age. In a longer-term trial, 566 patients meeting DSM-IV criteria for Generalized Anxiety Disorder, who had responded during a single-blind, 8-week acute treatment phase with 20 to 50 mg/day of paroxetine tablets, were randomized to continuation of paroxetine tablets at their same dose, or to placebo, for up to 24 weeks of observation for relapse. Response during the single-blind phase was defined by having a decrease of >= 2 points compared to baseline on the CGI-Severity of Illness scale, to a score of <= 3. Relapse during the double-blind phase was defined as an increase of >= 2 points compared to baseline on the CGI-Severity of Illness scale to a score of >= 4, or withdrawal due to lack of efficacy. Patients receiving continued paroxetine tablets experienced a significantly lower relapse rate over the subsequent 24 weeks compared to those receiving placebo.
Pharmacodynamics:
The efficacy of paroxetine in the treatment of major depressive disorder, social anxiety disorder, obsessive compulsive disorder (OCD), panic disorder (PD), and 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. In vitro In vitro 1 2 2 1 2 1 1 Because the relative potencies of paroxetine’s major metabolites are at most 1/50 of the parent compound, they are essentially inactive.
Pharmacokinetics:
Paroxetine hydrochloride is completely absorbed after oral dosing of a solution of the hydrochloride salt. The mean elimination half-life is approximately 21 hours (CV 32%) after oral dosing of paroxetine tablets, 30 mg daily for 30 days. Paroxetine is extensively metabolized and the metabolites are considered to be inactive. Nonlinearity in pharmacokinetics is observed with increasing doses. Paroxetine metabolism is mediated in part by CYP2D6, and the metabolites are primarily excreted in the urine and to some extent in the feces. Pharmacokinetic behavior of paroxetine has not been evaluated in subjects who are deficient in CYP2D6 (poor metabolizers).
Absorption and Distribution:
Paroxetine hydrochloride hemihydrate is completely absorbed after oral dosing of a solution of the hydrochloride salt. In a study in which normal male subjects (n = 15) received 30 mg tablets daily for 30 days, steady-state paroxetine concentrations were achieved by approximately 10 days for most subjects, although it may take substantially longer in an occasional patient. At steady state, mean values of C max max min ½ 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 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 100 ng/mL and 400 ng/mL, respectively. Under clinical conditions, paroxetine concentrations would normally be less than 400 ng/mL. Paroxetine does not alter the in vitro
Metabolism and Excretion:
The mean elimination half-life is approximately 21 hours (CV 32%) after oral dosing of paroxetine tablets, 30 mg tablets daily for 30 days. In steady-state dose proportionality studies involving elderly and nonelderly patients, at doses of 20 mg to 40 mg daily for the elderly and 20 mg to 50 mg daily for the nonelderly, some nonlinearity was observed in both populations, again reflecting a saturable metabolic pathway. In comparison to C 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.
Cimetidine:
Cimetidine inhibits many cytochrome P 450
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 450 max ½ Concomitant use of paroxetine tablets with other drugs metabolized by cytochrome CYP2D6 has not been formally studied but may require lower doses than usually prescribed for either paroxetine tablets or the other drug. Therefore, coadministration of paroxetine tablets with other drugs that are metabolized by this isozyme, including certain drugs effective in the treatment of major depressive disorder (e.g., nortriptyline, amitriptyline, imipramine, desipramine, and fluoxetine), phenothiazines, risperidone, tamoxifen, and Type 1C antiarrhythmics (e.g., propafenone, flecainide, and encainide), or that inhibit this enzyme (e.g., quinidine), should be approached with caution. However, due to the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, paroxetine and thioridazine should not be coadministered (see CONTRAINDICATIONS 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 and hence reduced efficacy of tamoxifen. At steady state, when the CYP2D6 pathway is essentially saturated, paroxetine clearance is governed by alternative P450 is ozymes that, unlike CYP2D6, show no evidence of saturation (see PRECAUTIONS
Mutagenesis:
Paroxetine produced no genotoxic effects in a battery of 5 in vitro in vivo in vivo in vitro

Paroxetine tablets are indicated for the treatment of major depressive disorder, obsessive compulsive disorder, panic disorder (with or without agoraphobia), social anxiety disorder, and generalized anxiety disorder in adults, with efficacy demonstrated in multiple placebo-controlled clinical studies showing significant improvement on standard rating scales and a lower relapse rate compared to placebo, and generally similar treatment response across age and gender subgroups.

Usual Initial Dosage: Paroxetine tablets should be administered as a single daily dose with or without food, usually in the morning. The recommended initial dose is 20 mg/day. Patients were dosed in a range of 20 to 50 mg/day in the clinical trials demonstrating the effectiveness of paroxetine tablets in the treatment of major depressive disorder. As with all drugs effective in the treatment of major depressive disorder, the full effect may be delayed. Some patients not responding to a 20-mg dose may benefit from dose increases, in 10-mg/day increments, up to a maximum of 50 mg/day. Dose changes should occur at intervals of at least 1 week. There is no body of evidence available to answer the question of how long the patient treated with paroxetine tablets should remain on it. It is generally agreed that acute episodes of major depressive disorder require several months or longer of sustained pharmacologic therapy. Whether the dose needed to induce remission is identical to the dose needed to maintain and/or sustain euthymia is unknown. Systematic evaluation of the efficacy of paroxetine tablets has shown that efficacy is maintained for periods of up to 1 year with doses that averaged about 30 mg. The recommended dose of paroxetine tablets in the treatment of OCD is 40 mg daily. Patients should be started on 20 mg/day and the dose can be increased in 10-mg/day increments. Patients were dosed in a range of 20 to 60 mg/day in the clinical trials demonstrating the effectiveness of paroxetine tablets in the treatment of OCD. The maximum dosage should not exceed 60 mg/day. Long-term maintenance of efficacy was demonstrated in a 6-month relapse prevention trial. In this trial, patients with OCD assigned to paroxetine demonstrated a lower relapse rate compared to patients on placebo (see CLINICAL PHARMACOLOGY em dash Clinical Trials Usual Initial Dosage: Paroxetine tablets should be administered as a single daily dose with or without food, usually in the morning. The target dose of paroxetine tablets in the treatment of panic disorder is 40 mg/day. Patients should be started on 10 mg/day. Dose changes should occur in 10-mg/day increments and at intervals of at least 1 week. Patients were dosed in a range of 10 to 60 mg/day in the clinical trials demonstrating the effectiveness of paroxetine tablets. Long-term maintenance of efficacy was demonstrated in a 3-month relapse prevention trial. In this trial, patients with panic disorder assigned to paroxetine demonstrated a lower relapse rate compared to patients on placebo (see CLINICAL PHARMACOLOGY em dash Clinical Trials Usual Initial Dosage: Paroxetine tablets should be administered as a single daily dose with or without food, usually in the morning. The recommended and initial dosage is 20 mg/day. In clinical trials the effectiveness of paroxetine tablets was demonstrated in patients dosed in a range of 20 to 60 mg/day. While the safety of paroxetine tablets has been evaluated in patients with social anxiety disorder at doses up to 60 mg/day, available information does not suggest any additional benefit for doses above 20 mg/day (see CLINICAL PHARMACOLOGY em dash Clinical Trials There is no body of evidence available to answer the question of how long the patient treated with paroxetine tablets should remain on it. Although the efficacy of paroxetine tablets beyond 12 weeks of dosing has not been demonstrated in controlled clinical trials, social anxiety disorder is recognized as a chronic condition, and it is reasonable to consider continuation of treatment for a responding patient. Dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for continued treatment. In clinical trials the effectiveness of paroxetine tablets was demonstrated in patients dosed in a range of 20 to 50 mg/day. The recommended starting dosage and the established effective dosage is 20 mg/day. There is not sufficient evidence to suggest a greater benefit to doses higher than 20 mg/day. Dose changes should occur in 10 mg/day increments and at intervals of at least 1 week. Systematic evaluation of continuing paroxetine tablets for periods of up to 24 weeks in patients with Generalized Anxiety Disorder who had responded while taking paroxetine tablets during an 8-week acute treatment phase has demonstrated a benefit of such maintenance (see CLINICAL PHARMACOLOGY em dash Clinical Trials Treatment of Pregnant Women During the Third Trimester: Neonates exposed to paroxetine tablets and other SSRIs or SNRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding (see WARNINGS Usage in Pregnancy The recommended initial dose is 10 mg/day for elderly patients, debilitated patients, and/or patients with severe renal or hepatic impairment. Increases may be made if indicated. Dosage should not exceed 40 mg/day. At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with paroxetine tablets. Similarly, at least 14 days should be allowed after stopping paroxetine tablets before starting an MAOI. Symptoms associated with discontinuation of paroxetine tablets have been reported(see PRECAUTIONS.

Serotonin Syndrome:
Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions: The development of a potentially life-threatening serotonin syndrome or Neuroleptic Malignant Syndrome (NMS)-like reactions have been reported with SNRIs and SSRIs alone, including treatment with paroxetine, but particularly with concomitant use of serotonergic drugs (including triptans) with drugs which impair metabolism of serotonin (including MAOIs), or with antipsychotics or other dopamine antagonists. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Serotonin syndrome, in its most severe form can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes. Patients should be monitored for the emergence of serotonin syndrome or NMS-like signs and symptoms. The concomitant use of paroxetine with MAOIs intended to treat depression is contraindicated. If concomitant treatment of paroxetine with a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. The concomitant use of paroxetine with serotonin precursors (such as tryptophan) is not recommended. Treatment with paroxetine and any concomitant serotonergic or antidopaminergic agents, including antipsychotics, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.
Akathisia:
The use of paroxetine or other SSRIs has been associated with the development of akathisia, which is characterized by an inner sense of restlessness and psychomotor agitation such as an inability to sit or stand still usually associated with subjective distress. This is most likely to occur within the first few weeks of treatment.
Hyponatremia:
Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including paroxetine. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk (see PRECAUTIONS Geriatric Use 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.
ADVERSE REACTIONS
Twenty percent (1,199/6,145) of patients treated with paroxetine tablets in worldwide clinical trials in major depressive disorder and 16. 1% (84/522), 11. 8% (64/542), 9. 4% (44/469), and 10. 7% (79/735) of patients treated with paroxetine tablets 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. , those events associated with dropout at a rate approximately twice or greater for paroxetine tablets compared to placebo) included the following: Major Depressive Disorder OCD Panic Disorder Social Anxiety Disorder Generalized Anxiety Disorder Paroxetine Tablets Placebo Paroxetine Tablets Placebo Paroxetine Tablets Placebo Paroxetine Tablets Placebo Paroxetine Tablets Placebo Where numbers are not provided the incidence of the adverse events in patients treated with paroxetine tablets were not >1% or were not greater than or equal to 2 times the incidence of placebo. CNS Somnolence 2. 7% em dash 1. 2% Insomnia em dash em dash 1. 1% 0% Agitation 1. 5% em dash Tremor 1. 3% em dash 1. 7% 0% Anxiety em dash em dash em dash 1. 1% 0% Dizziness em dash em dash 1. 2% Gastrointestinal Constipation em dash 1. 1% 0% Nausea 3. 2% Diarrhea 1. 3% em dash Dry Mouth 1. 3% em dash Vomiting 1. 0% 0% Flatulence 1. 3% Other Asthenia 1. 2% Abnormal ejaculation Incidence corrected for gender. 5% Sweating 1. 2% Impotence em dash 1. 5% 0% Libido Decreased 1. 0% 0% Major Depressive Disorder: The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or greater and incidence for paroxetine tablets at least twice that for placebo, derived from Table 2 The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or greater and incidence for paroxetine tablets at least twice that of placebo, derived from Table 3 The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or greater and incidence for paroxetine tablets at least twice that for placebo, derived from Table 3 The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or greater and incidence for paroxetine tablets at least twice that for placebo, derived from Table 3 The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or greater and incidence for paroxetine tablets at least twice that for placebo, derived from Table 4 The prescriber should be aware that the figures in the tables following cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the populations studied. Table 2 enumerates adverse events that occurred at an incidence of 1% or more among paroxetine-treated patients who participated in short-term (6-week) placebo-controlled trials in which patients were dosed in a range of 20 mg to 50 mg/day. Reported adverse events were classified using a standard COSTART-based Dictionary terminology. Table 2 Treatment-Emergent Adverse Experience Incidence in Placebo-Controlled Clinical Trials for Major Depressive Disorder Body System Preferred Term Paroxetine Tablets Placebo ( n = 421 ) ( n = 421 ) Body as a Whole Headache 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 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 Percentage corrected for gender. , 13% 0% Other Male Genital Disorders , 10% 0% Urinary Frequency 3% 1% Urination Disorder 3% 0% Female Genital Disorders , 2% 0% Table 3 enumerates adverse events that occurred at a frequency of 2% or more among OCD patients on paroxetine tablets who participated in placebo-controlled trials of 12-weeks duration in which patients were dosed in a range of 20 mg to 60 mg/day or among patients with panic disorder on paroxetine tablets who participated in placebo-controlled trials of 10- to 12-weeks duration in which patients were dosed in a range of 10 mg to 60 mg/day or among patients with social anxiety disorder on paroxetine tablets who participated in placebo-controlled trials of 12-weeks duration in which patients were dosed in a range of 20 mg to 50 mg/day. Table 3 Treatment-Emergent Adverse Experience Incidence in Placebo-Controlled Clinical Trials for Obsessive Compulsive Disorder, Panic Disorder, and Social Anxiety Disorder Obsessive Compulsive Disorder Panic Disorder Social Anxiety Disorder Paroxetine Tablets Placebo Paroxetine Tablets Placebo Paroxetine Tablets Placebo Body System Preferred Term ( n = 542 ) ( n = 265 ) ( n = 469 ) ( n = 324 ) ( n = 425 ) ( n = 339 ) Body as a Whole Asthenia 22% 14% 14% 5% 22% 14% Abdominal Pain em dash em dash 4% 3% em dash em dash Chest Pain 3% 2% em dash em dash em dash em dash Back Pain em dash em dash 3% 2% em dash em dash Chills 2% 1% 2% 1% em dash em dash Trauma em dash em dash em dash em dash 3% 1% Cardiovascular Vasodilation 4% 1% em dash em dash em dash em dash Palpitation 2% 0% em dash em dash em dash em dash Dermatologic Sweating 9% 3% 14% 6% 9% 2% Rash 3% 2% em dash em dash em dash em dash 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 em dash em dash em dash em dash 4% 2% Flatulence em dash em dash em dash em dash 4% 2% Increased Appetite 4% 3% 2% 1% em dash em dash Vomiting em dash em dash em dash em dash 2% 1% Musculoskeletal Myalgia em dash em dash em dash em dash 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% em dash em dash 8% 7% Libido Decreased 7% 4% 9% 1% 12% 1% Agitation em dash em dash 5% 4% 3% 1% Anxiety em dash em dash 5% 4% 5% 4% Abnormal Dreams 4% 1% em dash em dash em dash em dash Concentration Impaired 3% 2% em dash em dash 4% 1% Depersonalization 3% 0% em dash em dash em dash em dash Myoclonus 3% 0% 3% 2% 2% 1% Amnesia 2% 1% em dash em dash em dash em dash Respiratory System Rhinitis em dash em dash 3% 0% em dash em dash Pharyngitis em dash em dash em dash em dash 4% 2% Yawn em dash em dash em dash em dash 5% 1% Special Senses Abnormal Vision 4% 2% em dash em dash 4% 1% Taste Perversion 2% 0% em dash em dash em dash em dash Urogenital System Abnormal Ejaculation Percentage corrected for gender. 23% 1% 21% 1% 28% 1% Dysmenorrhea em dash em dash em dash em dash 5% 4% Female Genital Disorder 3% 0% 9% 1% 9% 1% Impotence 8% 1% 5% 0% 5% 1% Urinary Frequency 3% 1% 2% 0% em dash em dash Urination Impaired 3% 0% em dash em dash em dash em dash Urinary Tract Infection 2% 1% 2% 1% em dash em dash Table 4 enumerates adverse events that occurred at a frequency of 2% or more among GAD patients on paroxetine tablets who participated in placebo-controlled trials of 8-weeks duration in which patients were dosed in a range of 10 mg/day to 50 mg/day. Table 4 Treatment-Emergent Adverse Experience Incidence in Placebo Controlled Clinical Trials for Generalized Anxiety Disorder Generalized Anxiety Disorder Body System Preferred Term Paroxetine Tablets Placebo ( n = 735 ) ( 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 em dash em dash 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% em dash Special Senses Abnormal Vision 2% 1% Urogenital System Abnormal 25% 2% Ejaculation Percentage corrected for gender. Female Genital 4% 1% Disorder Impotence 4% 3% A comparison of adverse event rates in a fixed-dose study comparing 10, 20, 30, and 40 mg/day of paroxetine tablets with placebo in the treatment of major depressive disorder revealed a clear dose dependency for some of the more common adverse events associated with use of paroxetine tablets, as shown in Table 5: Table 5 Treatment-Emergent Adverse Experience Incidence in a Dose-Comparison Trial in the Treatment of Major Depressive Disorder Body System / Preferred Term Placebo Paroxetine Tablets n = 51 10 mg n = 102 20 mg n = 104 30 mg n = 101 40 mg n = 102 Body As A Whole Asthenia 0. 7% Dermatology Sweating 2. 8% Gastrointestinal Constipation 5. 7% Decreased Appetite 2. 9% Diarrhea 7. 7% Dry Mouth 2. 6% Nausea 13. 3% Nervous System Anxiety 0. 9% Dizziness 3. 7% Nervousness 0. 9% Paresthesia 0. 9% Somnolence 7. 6% Tremor 0. 7% Special Senses Blurred Vision 2. 8% Urogenital System Abnormal Ejaculation 0. 0% Impotence 0. 9% Male Genital Disorders 0. 7% In a fixed-dose study comparing placebo and 20, 40, and 60 mg of paroxetine tablets in the treatment of OCD, there was no clear relationship between adverse events and the dose of paroxetine tablets to which patients were assigned. No new adverse events were observed in the group treated with 60 mg of paroxetine tablets compared to any of the other treatment groups. In a fixed-dose study comparing placebo and 10, 20, and 40 mg of paroxetine tablets in the treatment of panic disorder, there was no clear relationship between adverse events and the dose of paroxetine tablets to which patients were assigned, except for asthenia, dry mouth, anxiety, libido decreased, tremor, and abnormal ejaculation. In flexible-dose studies, no new adverse events were observed in patients receiving 60 mg of paroxetine tablets compared to any of the other treatment groups. In a fixed-dose study comparing placebo and 20, 40, and 60 mg of paroxetine tablets in the treatment of social anxiety disorder, for most of the adverse events, there was no clear relationship between adverse events and the dose of paroxetine tablets to which patients were assigned. In a fixed-dose study comparing placebo and 20 and 40 mg of paroxetine tablets in the treatment of generalized anxiety disorder, for most of the adverse events, there was no clear relationship between adverse events and the dose of paroxetine tablets to which patients were assigned, except for the following adverse events: Asthenia, constipation, and abnormal ejaculation. Over a 4- to 6-week period, there was evidence of adaptation to some adverse events with continued therapy (e. , nausea and dizziness), but less to other effects (e. , dry mouth, somnolence, and asthenia). 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 Table 6. Table 6 Incidence of Sexual Adverse Events in Controlled Clinical Trials Paroxetine Tablets Placebo n ( males ) 1446 1042 Decreased Libido 6-15% 0-5% Ejaculatory Disturbance 13-28% 0-2% Impotence 2-9% 0-3% n ( females ) 1822 1340 Decreased Libido 0-9% 0-2% Orgasmic Disturbance 2-9% 0-1% There are no adequate and well-controlled studies examining sexual dysfunction with paroxetine treatment. Paroxetine treatment has been associated with several cases of priapism. In those cases with a known outcome, patients recovered without sequelae. While it is difficult to know the precise risk of sexual dysfunction associated with the use of SSRIs, physicians should routinely inquire about such possible side effects. Significant weight loss may be an undesirable result of treatment with paroxetine tablets for some patients but, on average, patients in controlled trials had minimal (about 1 pound) weight loss versus smaller changes on placebo and active control. No significant changes in vital signs (systolic and diastolic blood pressure, pulse and temperature) were observed in patients treated with paroxetine tablets in controlled clinical trials. In an analysis of ECGs obtained in 682 patients treated with paroxetine tablets and 415 patients treated with placebo in controlled clinical trials, no clinically significant changes were seen in the ECGs of either group. In placebo-controlled clinical trials, patients treated with paroxetine tablets exhibited abnormal values on liver function tests at no greater rate than that seen in placebo-treated patients. In particular, the paroxetine tablets-versus-placebo comparisons for alkaline phosphatase, SGOT, SGPT, and bilirubin revealed no differences in the percentage of patients with marked abnormalities. In pooled clinical trials of immediate-release paroxetine hydrochloride, hallucinations were observed in 22 of 9089 patients receiving drug and 4 of 3187 patients receiving placebo. During its premarketing assessment in major depressive disorder, multiple doses of paroxetine tablets were administered to 6,145 patients in phase 2 and 3 studies. The conditions and duration of exposure to paroxetine tablets varied greatly and included (in overlapping categories) open and double-blind studies, uncontrolled and controlled studies, inpatient and outpatient studies, and fixed-dose, and titration studies. During premarketing clinical trials in OCD, panic disorder, social anxiety disorder, and generalized anxiety disorder, 542, 469, 522, and 735 patients, respectively, received multiple doses of paroxetine tablets. Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories. In the tabulations that follow, reported adverse events were classified using a standard COSTART-based Dictionary terminology. The frequencies presented, therefore, represent the proportion of the 9,089 patients exposed to multiple doses of paroxetine tablets who experienced an event of the type cited on at least 1 occasion while receiving paroxetine tablets. All reported events are included except those already listed in Tables 2 to 5, those reported in terms so general as to be uninformative and those events where a drug cause was remote. It is important to emphasize that although the events reported occurred during treatment with paroxetine, they were not necessarily caused by it. Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: Frequent adverse events are those occurring on 1 or more occasions in at least 1/100 patients (only those not already listed in the tabulated results from placebo-controlled trials appear in this listing); infrequent adverse events are those occurring in 1/100 to 1/1,000 patients; rare events are those occurring in fewer than 1/1,000 patients. Events of major clinical importance are also described in the PRECAUTIONS Infrequent: rare: Frequent: infrequent: rare: Infrequent: rare: Rare: Infrequent: rare: Frequent: infrequent: rare: Frequent: infrequent: rare: Frequent: infrequent: rare: Infrequent: rare: Frequent: infrequent: rare: Frequent: infrequent: rare: Infrequent: rare: Voluntary reports of adverse events in patients taking paroxetine tablets that have been received since market introduction and not listed above that may have no causal relationship with the drug include acute pancreatitis, elevated liver function tests (the most severe cases were deaths due to liver necrosis, and grossly elevated transaminases associated with severe liver dysfunction), Guillain-Barre syndrome, 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), and vasculitic syndromes (such as Henoch-Schonlein purpura). There has been a case report of an elevated phenytoin level after 4 weeks of paroxetine tablets and phenytoin coadministration. There has been a case report of severe hypotension when paroxetine tablets were added to chronic metoprolol treatment.
Associated with Discontinuation of Treatment:
Twenty percent (1,199/6,145) of patients treated with paroxetine tablets in worldwide clinical trials in major depressive disorder and 16.1% (84/522), 11.8% (64/542), 9.4% (44/469), and 10.7% (79/735) of patients treated with paroxetine tablets 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 tablets compared to placebo) included the following: Major Depressive Disorder OCD Panic Disorder Social Anxiety Disorder Generalized Anxiety Disorder Paroxetine Tablets Placebo Paroxetine Tablets Placebo Paroxetine Tablets Placebo Paroxetine Tablets Placebo Paroxetine Tablets Placebo Where numbers are not provided the incidence of the adverse events in patients treated with paroxetine tablets were not >1% or were not greater than or equal to 2 times the incidence of placebo. CNS Somnolence 2.3% 0.7% em dash 1.9% 0.3% 3.4% 0.3% 2.0% 0.2% Insomnia em dash em dash 1.7% 0% 1.3% 0.3% 3.1% 0% Agitation 1.1% 0.5% em dash Tremor 1.1% 0.3% em dash 1.7% 0% Anxiety em dash em dash em dash 1.1% 0% Dizziness em dash em dash 1.5% 0% 1.9% 0% 1.0% 0.2% Gastrointestinal Constipation em dash 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% em dash Dry Mouth 1.0% 0.3% em dash Vomiting 1.0% 0.3% em dash 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 Incidence corrected for gender. 1.6% 0% 2.1% 0% 4.9% 0.6% 2.5% 0.5% Sweating 1.0% 0.3% em dash 1.1% 0% 1.1% 0.2% Impotence em dash 1.5% 0% Libido Decreased 1.0% 0%
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 tablets at least twice that for placebo, derived from Table 2
Obsessive Compulsive Disorder,Panic Disorder, and Social Anxiety Disorder:
Table 3 enumerates adverse events that occurred at a frequency of 2% or more among OCD patients on paroxetine tablets who participated in placebo-controlled trials of 12-weeks duration in which patients were dosed in a range of 20 mg to 60 mg/day or among patients with panic disorder on paroxetine tablets who participated in placebo-controlled trials of 10- to 12-weeks duration in which patients were dosed in a range of 10 mg to 60 mg/day or among patients with social anxiety disorder on paroxetine tablets who participated in placebo-controlled trials of 12-weeks duration in which patients were dosed in a range of 20 mg to 50 mg/day. Table 3 Treatment-Emergent Adverse Experience Incidence in Placebo-Controlled Clinical Trials for Obsessive Compulsive Disorder, Panic Disorder, and Social Anxiety Disorder Obsessive Compulsive Disorder Panic Disorder Social Anxiety Disorder Paroxetine Tablets Placebo Paroxetine Tablets Placebo Paroxetine Tablets Placebo Body System Preferred Term ( n = 542 ) ( n = 265 ) ( n = 469 ) ( n = 324 ) ( n = 425 ) ( n = 339 ) Body as a Whole Asthenia 22% 14% 14% 5% 22% 14% Abdominal Pain em dash em dash 4% 3% em dash em dash Chest Pain 3% 2% em dash em dash em dash em dash Back Pain em dash em dash 3% 2% em dash em dash Chills 2% 1% 2% 1% em dash em dash Trauma em dash em dash em dash em dash 3% 1% Cardiovascular Vasodilation 4% 1% em dash em dash em dash em dash Palpitation 2% 0% em dash em dash em dash em dash Dermatologic Sweating 9% 3% 14% 6% 9% 2% Rash 3% 2% em dash em dash em dash em dash 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 em dash em dash em dash em dash 4% 2% Flatulence em dash em dash em dash em dash 4% 2% Increased Appetite 4% 3% 2% 1% em dash em dash Vomiting em dash em dash em dash em dash 2% 1% Musculoskeletal Myalgia em dash em dash em dash em dash 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% em dash em dash 8% 7% Libido Decreased 7% 4% 9% 1% 12% 1% Agitation em dash em dash 5% 4% 3% 1% Anxiety em dash em dash 5% 4% 5% 4% Abnormal Dreams 4% 1% em dash em dash em dash em dash Concentration Impaired 3% 2% em dash em dash 4% 1% Depersonalization 3% 0% em dash em dash em dash em dash Myoclonus 3% 0% 3% 2% 2% 1% Amnesia 2% 1% em dash em dash em dash em dash Respiratory System Rhinitis em dash em dash 3% 0% em dash em dash Pharyngitis em dash em dash em dash em dash 4% 2% Yawn em dash em dash em dash em dash 5% 1% Special Senses Abnormal Vision 4% 2% em dash em dash 4% 1% Taste Perversion 2% 0% em dash em dash em dash em dash Urogenital System Abnormal Ejaculation Percentage corrected for gender. 23% 1% 21% 1% 28% 1% Dysmenorrhea em dash em dash em dash em dash 5% 4% Female Genital Disorder 3% 0% 9% 1% 9% 1% Impotence 8% 1% 5% 0% 5% 1% Urinary Frequency 3% 1% 2% 0% em dash em dash Urination Impaired 3% 0% em dash em dash em dash em dash Urinary Tract Infection 2% 1% 2% 1% em dash em dash
Dose Dependency of Adverse Events:
A comparison of adverse event rates in a fixed-dose study comparing 10, 20, 30, and 40 mg/day of paroxetine tablets with placebo in the treatment of major depressive disorder revealed a clear dose dependency for some of the more common adverse events associated with use of paroxetine tablets, as shown in Table 5: Table 5 Treatment-Emergent Adverse Experience Incidence in a Dose-Comparison Trial in the Treatment of Major Depressive Disorder Body System / Preferred Term Placebo Paroxetine Tablets n = 51 10 mg n = 102 20 mg n = 104 30 mg n = 101 40 mg n = 102 Body As A Whole Asthenia 0.0% 2.9% 10.6% 13.9% 12.7% Dermatology Sweating 2.0% 1.0% 6.7% 8.9% 11.8% Gastrointestinal Constipation 5.9% 4.9% 7.7% 9.9% 12.7% Decreased Appetite 2.0% 2.0% 5.8% 4.0% 4.9% Diarrhea 7.8% 9.8% 19.2% 7.9% 14.7% Dry Mouth 2.0% 10.8% 18.3% 15.8% 20.6% Nausea 13.7% 14.7% 26.9% 34.7% 36.3% Nervous System Anxiety 0.0% 2.0% 5.8% 5.9% 5.9% Dizziness 3.9% 6.9% 6.7% 8.9% 12.7% Nervousness 0.0% 5.9% 5.8% 4.0% 2.9% Paresthesia 0.0% 2.9% 1.0% 5.0% 5.9% Somnolence 7.8% 12.7% 18.3% 20.8% 21.6% Tremor 0.0% 0.0% 7.7% 7.9% 14.7% Special Senses Blurred Vision 2.0% 2.9% 2.9% 2.0% 7.8% Urogenital System Abnormal Ejaculation 0.0% 5.8% 6.5% 10.6% 13.0% Impotence 0.0% 1.9% 4.3% 6.4% 1.9% Male Genital Disorders 0.0% 3.8% 8.7% 6.4% 3.7% In a fixed-dose study comparing placebo and 20, 40, and 60 mg of paroxetine tablets in the treatment of OCD, there was no clear relationship between adverse events and the dose of paroxetine tablets to which patients were assigned. No new adverse events were observed in the group treated with 60 mg of paroxetine tablets compared to any of the other treatment groups. In a fixed-dose study comparing placebo and 10, 20, and 40 mg of paroxetine tablets in the treatment of panic disorder, there was no clear relationship between adverse events and the dose of paroxetine tablets to which patients were assigned, except for asthenia, dry mouth, anxiety, libido decreased, tremor, and abnormal ejaculation. In flexible-dose studies, no new adverse events were observed in patients receiving 60 mg of paroxetine tablets compared to any of the other treatment groups. In a fixed-dose study comparing placebo and 20, 40, and 60 mg of paroxetine tablets in the treatment of social anxiety disorder, for most of the adverse events, there was no clear relationship between adverse events and the dose of paroxetine tablets to which patients were assigned. In a fixed-dose study comparing placebo and 20 and 40 mg of paroxetine tablets in the treatment of generalized anxiety disorder, for most of the adverse events, there was no clear relationship between adverse events and the dose of paroxetine tablets to which patients were assigned, except for the following adverse events: Asthenia, constipation, and abnormal ejaculation.
Hallucinations:
In pooled clinical trials of immediate-release paroxetine hydrochloride, hallucinations were observed in 22 of 9089 patients receiving drug and 4 of 3187 patients receiving placebo.
Body as a Whole:
Infrequent: rare:
Cardiovascular System:
Frequent: infrequent: rare:
Digestive System:
Infrequent: rare:
Hemic and Lymphatic Systems:
Infrequent: rare:
Musculoskeletal System:
Frequent: infrequent: rare:
Respiratory System:
Infrequent: rare:
Skin and Appendages:
Frequent: infrequent: rare:
Urogenital System:
Infrequent: rare:
Postmarketing Reports:
Voluntary reports of adverse events in patients taking paroxetine tablets that have been received since market introduction and not listed above that may have no causal relationship with the drug include acute pancreatitis, elevated liver function tests (the most severe cases were deaths due to liver necrosis, and grossly elevated transaminases associated with severe liver dysfunction), Guillain-Barre syndrome, 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), and vasculitic syndromes (such as Henoch-Schonlein purpura). There has been a case report of an elevated phenytoin level after 4 weeks of paroxetine tablets and phenytoin coadministration. There has been a case report of severe hypotension when paroxetine tablets were added to chronic metoprolol treatment.

CONTRAINDICATIONS
Concomitant use in patients taking either monoamine oxidase inhibitors (MAOIs), including linezolid, an antibiotic which is a reversible non-selective MAOI, or thioridazine is contraindicated (see WARNINGS PRECAUTIONS Concomitant use in patients taking pimozide is contraindicated (see PRECAUTIONS Paroxetine tablets are contraindicated in patients with a hypersensitivity to paroxetine or any of the inactive ingredients in paroxetine tablets.
Thioridazine:
See CONTRAINDICATIONS WARNINGS

Renal and Liver Disease:
Increased plasma concentrations of paroxetine occur in subjects with renal and hepatic impairment. The mean plasma concentrations in patients with creatinine clearance below 30 mL/min. were approximately 4 times greater than seen in normal volunteers. Patients with creatinine clearance of 30 to 60 mL/min. and patients with hepatic functional impairment had about a 2-fold increase in plasma concentrations (AUC, C 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 40 mg, C min min DOSAGE AND ADMINISTRATION
Nonteratogenic Effects:
Neonates exposed to paroxetine tablets and other SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs), late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see WARNINGS Serotonin Syndrome Potential for Interaction with Monoamine Oxidase Inhibitors Infants exposed to SSRIs in late pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 en dash 2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. In a retrospective case-control study of 377 women whose infants were born with PPHN and 836 women whose infants were born healthy, the risk for developing PPHN was approximately sixfold higher for infants exposed to SSRIs after the 20 th When treating a pregnant woman with paroxetine during the third trimester, the physician should carefully consider both the potential risks and benefits of treatment (see DOSAGE AND ADMINISTRATION
Use in Patients with Concomitant Illness:
Clinical experience with paroxetine tablets in patients with certain concomitant systemic illness is limited. Caution is advisable in using paroxetine tablets in patients with diseases or conditions that could affect metabolism or hemodynamic responses. As with other SSRIs, mydriasis has been infrequently reported in premarketing studies with paroxetine tablets. A few cases of acute angle closure glaucoma associated with paroxetine therapy have been reported in the literature. As mydriasis can cause acute angle closure in patients with narrow angle glaucoma, caution should be used when paroxetine tablets are prescribed for patients with narrow angle glaucoma. Paroxetine tablets have not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from clinical studies during the product’s premarket testing. Evaluation of electrocardiograms of 682 patients who received paroxetine tablets in double-blind, placebo-controlled trials, however, did not indicate that paroxetine tablets are associated with the development of significant ECG abnormalities. Similarly, paroxetine tablets do not cause any clinically important changes in heart rate or blood pressure. Increased plasma concentrations of paroxetine occur in patients with severe renal impairment (creatinine clearance < 30 mL/min.) or severe hepatic impairment. A lower starting dose should be used in such patients (see DOSAGE AND ADMINISTRATION
Pregnancy:
Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy (see WARNINGS em dash Usage in Pregnancy Teratogenic Effects Nonteratogenic Effects
Nursing:
Patients should be advised to notify their physician if they are breastfeeding an infant (see PRECAUTIONS em dash Nursing Mothers
Pregnancy:
Pregnancy Category D. WARNINGS Usage in Pregnancy Teratogenic effects Nonteratogenic Effects
Nursing Mothers:
Like many other drugs, paroxetine is secreted in human milk, and caution should be exercised when paroxetine tablets are administered to a nursing woman.
Pediatric Use:
Safety and effectiveness in the pediatric population have not been established (see BOX WARNING WARNINGS In placebo-controlled clinical trials conducted with pediatric patients, the following adverse events were reported in at least 2% of pediatric patients treated with paroxetine tablets and occurred at a rate at least twice that for pediatric patients receiving placebo: emotional lability (including self-harm, suicidal thoughts, attempted suicide, crying, and mood fluctuations), hostility, decreased appetite, tremor, sweating, hyperkinesia, and agitation. Events reported upon discontinuation of treatment with paroxetine tablets in the pediatric clinical trials that included a taper phase regimen, which occurred in at least 2% of patients who received paroxetine tablets and which occurred at a rate at least twice that of placebo, were: emotional lability (including suicidal ideation, suicide attempt, mood changes, and tearfulness), nervousness, dizziness, nausea, and abdominal pain (see DOSAGE AND ADMINISTRATION Discontinuation of Treatment with Paroxetine Tablets
Geriatric Use:
SSRIs and SNRIs, including paroxetine, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event (see PRECAUTIONS, Hyponatremia In worldwide premarketing clinical trials with paroxetine tablets, 17% of patients treated with paroxetine tablets (approximately 700) were 65 years of age or older. Pharmacokinetic studies revealed a decreased clearance in the elderly, and a lower starting dose is recommended; there were, however, no overall differences in the adverse event profile between elderly and younger patients, and effectiveness was similar in younger and older patients (see CLINICAL PHARMACOLOGY DOSAGE AND ADMINISTRATION
Special Senses:
Frequent: infrequent: rare:
Special Populations:
Treatment of Pregnant Women During the Third Trimester: Neonates exposed to paroxetine tablets and other SSRIs or SNRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding (see WARNINGS Usage in Pregnancy
Dosage for Elderly or Debilitated Patients,and Patients with Severe Renal or Hepatic Impairment:
The recommended initial dose is 10 mg/day for elderly patients, debilitated patients, and/or patients with severe renal or hepatic impairment. Increases may be made if indicated. Dosage should not exceed 40 mg/day.

Drug-Drug Interactions:
In vitro PRECAUTIONS ─ Drug Interactions
Potential for Interaction with Monoamine Oxidase Inhibitors:
In patients receiving another serotonin reuptake inhibitor drug in combination with a monoamine oxidase inhibitor (MAOI), there have been reports of serious, sometimes fatal, reactions including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. These reactions have also been reported in patients who have recently discontinued that drug and have been started on an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. While there are no human data showing such an interaction with paroxetine tablets, limited animal data on the effects of combined use of paroxetine and MAOIs suggest that these drugs may act synergistically to elevate blood pressure and evoke behavioral excitation. Therefore, it is recommended that paroxetine tablets not be used in combination with an MAOI, (including linezolid, an antibiotic which is a reversible non-selective MAOI), or within 14 days of discontinuing treatment with an MAOI. (see CONTRAINDICATIONS
Potential Interaction with Thioridazine:
Thioridazine administration alone produces prolongation of the QTc interval, which is associated with serious ventricular arrhythmias, such as torsade de pointes-type arrhythmias, and sudden death. This effect appears to be dose related. An in vivo study suggests that drugs which inhibit CYP2D6, such as paroxetine, will elevate plasma levels of thioridazine. Therefore, it is recommended that paroxetine not be used in combination with thioridazine (see CONTRAINDICATIONS PRECAUTIONS
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.
Concomitant Medication:
Patients should be advised to inform their physician if they are taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for interactions.
Tryptophan:
As with other serotonin reuptake inhibitors, and interaction between paroxetine and tryptophan may occur when they are coadministered. Adverse experiences, consisting primarily of headache, nausea, sweating, and dizziness, have been reported when tryptophan was administered to patients taking paroxetine tablets. Consequently, concomitant use of paroxetine tablets with tryptophan is not recommended (see WARNINGS Serotonin Syndrome
Monoamine Oxidase Inhibitors:
See CONTRAINDICATIONS WARNINGS
Pimozide:
In a controlled study of healthy volunteers, after paroxetine tablets were titrated to 60 mg daily, co-administration of a single dose of 2 mg pimozide was associated with mean increases in pimozide AUC of 151% and C 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, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, fentanyl, tramadol, or St. John’s Wort (see WARNINGS Serotonin Syndrome CONTRAINDICATIONS PRECAUTIONS Drug Interactions Tryptophan
Warfarin:
Preliminary data suggest that there may be a pharmacodynamic interaction (that causes an increased bleeding diathesis in the face of unaltered prothrombin time) between paroxetine and warfarin. Since there is little clinical experience, the concomitant administration of paroxetine tablets and warfarin should be undertaken with caution (see PRECAUTIONS Drugs That Interfere with Hemostasis
Triptans:
There have been rare postmarketing reports of serotonin syndrome with the use of an SSRI and a triptan. If concomitant use of paroxetine with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS Serotonin Syndrome
Drugs Affecting Hepatic Metabolism:
The metabolism and pharmacokinetics of paroxetine may be affected by the induction or inhibition of drug-metabolizing enzymes.
Phenobarbital:
Phenobarbital induces many cytochrome P 450 ½
Phenytoin:
When a single oral 30-mg dose of paroxetine tablets was administered at phenytoin steady state (300 mg once daily for 14 days), paroxetine AUC and T ½ ADVERSE REACTIONS Postmarketing Reports
Drugs Metabolized by Cytochrome CYP3A4:
An in vivo in vitro in vitro i in vivo
Tricyclic Antidepressants (TCAs):
Caution is indicated in the coadministration of tricyclic antidepressants (TCAs) with paroxetine tablets, because paroxetine may inhibit TCA metabolism. Plasma TCA concentrations may need to be monitored, and the dose of TCA may need to be reduced, if a TCA is coadministered with paroxetine tablets (see PRECAUTIONSem dash Drugs Metabolized by Cytochrome CYP2D6
Drugs Highly Bound to Plasma Protein:
Because paroxetine is highly bound to plasma protein, administration of paroxetine tablets to a patient taking another drug that is highly protein bound may cause increased free concentrations of the other drug, potentially resulting in adverse events. Conversely, adverse effects could result from displacement of paroxetine by other highly bound drugs.
Drugs That Interfere with Hemostasis (e.g.,NSAIDs, Aspirin and Warfarin):
Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs or SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when paroxetine is initiated or discontinued.
Lithium:
A multiple-dose study has shown that there is no pharmacokinetic interaction between paroxetine tablets and lithium carbonate. However, due to the potential for serotonin syndrome, caution is advised when paroxetine tablets are coadministered with lithium.
Digoxin:
The steady-state pharmacokinetics of paroxetine was not altered when administered with digoxin at steady state. Mean digoxin AUC at steady state decreased by 15% in the presence of paroxetine. Since there is little clinical experience, the concurrent administration of paroxetine and digoxin should be undertaken with caution.
Beta-Blockers:
In a study where propranolol (80 mg twice daily) was dosed orally for 18 days, the established steady-state plasma concentrations of propranolol were unaltered during coadministration with paroxetine tablets (30 mg once daily) for the final 10 days. The effects of propranolol on paroxetine have not been evaluated (see ADVERSE REACTIONS Postmarketing Reports
Theophylline:
Reports of elevated theophylline levels associated with treatment with paroxetine tablets have been reported. While this interaction has not been formally studied, it is recommended that theophylline levels be monitored when these drugs are concurrently administered.
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).
Switching Patients to or from a Monoamine Oxidase Inhibitor:
At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with paroxetine tablets. Similarly, at least 14 days should be allowed after stopping paroxetine tablets before starting an MAOI.

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

WARNINGS
Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children,adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4,400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1,000 patients treated) are provided in Table 1. Table 1 Age Range Drug - Placebo Difference in Number of Cases of Suicidality per 1 , 000 Patients Treated Increases Compared to Placebo <18 14 additional cases 18-24 5 additional cases Decreases Compared to Placebo 25-64 1 fewer case >=65 6 fewer cases No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. It is unknown whether the suicidality risk extends to longer-term use, i. , beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient''s presenting symptoms. If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms (see PRECAUTIONS DOSAGE AND ADMINISTRATION Discontinuation of Treatment With Paroxetine Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that paroxetine tablets are not approved for use in treating bipolar depression. In patients receiving another serotonin reuptake inhibitor drug in combination with a monoamine oxidase inhibitor (MAOI), there have been reports of serious, sometimes fatal, reactions including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. These reactions have also been reported in patients who have recently discontinued that drug and have been started on an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. While there are no human data showing such an interaction with paroxetine tablets, limited animal data on the effects of combined use of paroxetine and MAOIs suggest that these drugs may act synergistically to elevate blood pressure and evoke behavioral excitation. Therefore, it is recommended that paroxetine tablets not be used in combination with an MAOI, (including linezolid, an antibiotic which is a reversible non-selective MAOI), or within 14 days of discontinuing treatment with an MAOI. (see CONTRAINDICATIONS Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions: The development of a potentially life-threatening serotonin syndrome or Neuroleptic Malignant Syndrome (NMS)-like reactions have been reported with SNRIs and SSRIs alone, including treatment with paroxetine, but particularly with concomitant use of serotonergic drugs (including triptans) with drugs which impair metabolism of serotonin (including MAOIs), or with antipsychotics or other dopamine antagonists. Serotonin syndrome symptoms may include mental status changes (e. , agitation, hallucinations, coma), autonomic instability (e. , tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e. , hyperreflexia, incoordination) and/or gastrointestinal symptoms (e. , nausea, vomiting, diarrhea). Serotonin syndrome, in its most severe form can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes. Patients should be monitored for the emergence of serotonin syndrome or NMS-like signs and symptoms. The concomitant use of paroxetine with MAOIs intended to treat depression is contraindicated. If concomitant treatment of paroxetine with a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. The concomitant use of paroxetine with serotonin precursors (such as tryptophan) is not recommended. Treatment with paroxetine and any concomitant serotonergic or antidopaminergic agents, including antipsychotics, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated. Thioridazine administration alone produces prolongation of the QTc interval, which is associated with serious ventricular arrhythmias, such as torsade de pointes-type arrhythmias, and sudden death. This effect appears to be dose related. An in vivo study suggests that drugs which inhibit CYP2D6, such as paroxetine, will elevate plasma levels of thioridazine. Therefore, it is recommended that paroxetine not be used in combination with thioridazine (see CONTRAINDICATIONS PRECAUTIONS Epidemiological studies have shown that infants born to women who had first trimester paroxetine exposure had an increased risk of cardiovascular malformations, primarily ventricular and atrial septal defects (VSDs and ASDs). In general, septal defects range from those that are symptomatic and may require surgery to those that are asymptomatic and may resolve spontaneously. 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 PRECAUTIONSem dashDiscontinuation of Treatment With paroxetine A study based on Swedish national registry data evaluated infants of 6,896 women exposed to antidepressants in early pregnancy (5,123 women exposed to SSRIs; including 815 for paroxetine). Infants exposed to paroxetine in early pregnancy had an increased risk of cardiovascular malformations (primarily VSDs and ASDs) compared to the entire registry population (OR 1. 8; 95% confidence interval 1. The rate of cardiovascular malformations following early pregnancy paroxetine exposure was 2% vs. 1% in the entire registry population. Among the same paroxetine exposed infants, an examination of the data showed no increase in the overall risk for congenital malformations. A separate retrospective cohort study using US United Healthcare data evaluated 5,956 infants of mothers dispensed paroxetine or other antidepressants during the first trimester (n = 815 for paroxetine). This study showed a trend towards an increased risk for cardiovascular malformations for paroxetine compared to other antidepressants (OR 1. 5; 95% confidence interval 0. The prevalence of cardiovascular malformations following first trimester dispensing was 1. 5% for paroxetine vs. 1% for other antidepressants. Nine out of 12 infants with cardiovascular malformations whose mothers were dispensed paroxetine in the first trimester had VSDs. This study also suggested an increased risk of overall major congenital malformations (inclusive of the cardiovascular defects) for paroxetine compared to other antidepressants (OR 1. The prevalence of all congenital malformations following first trimester exposure was 4% for paroxetine vs. 2% for other antidepressants. Reproduction studies were performed at doses up to 50 mg/kg/day in rats and 6 mg/kg/day in rabbits administered during organogenesis. These doses are approximately 8 (rat) and 2 (rabbit) times the maximum recommended human dose (MRHD) on an mg/m 2 2 Neonates exposed to paroxetine tablets and other SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs), late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see WARNINGS Serotonin Syndrome Potential for Interaction with Monoamine Oxidase Inhibitors Infants exposed to SSRIs in late pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 en dash 2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. In a retrospective case-control study of 377 women whose infants were born with PPHN and 836 women whose infants were born healthy, the risk for developing PPHN was approximately sixfold higher for infants exposed to SSRIs after the 20 th When treating a pregnant woman with paroxetine during the third trimester, the physician should carefully consider both the potential risks and benefits of treatment (see DOSAGE AND ADMINISTRATION.
Teratogenic Effects:
Epidemiological studies have shown that infants born to women who had first trimester paroxetine exposure had an increased risk of cardiovascular malformations, primarily ventricular and atrial septal defects (VSDs and ASDs). In general, septal defects range from those that are symptomatic and may require surgery to those that are asymptomatic and may resolve spontaneously.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 PRECAUTIONSem dashDiscontinuation of Treatment With paroxetine A study based on Swedish national registry data evaluated infants of 6,896 women exposed to antidepressants in early pregnancy (5,123 women exposed to SSRIs; including 815 for paroxetine). Infants exposed to paroxetine in early pregnancy had an increased risk of cardiovascular malformations (primarily VSDs and ASDs) compared to the entire registry population (OR 1.8; 95% confidence interval 1.1 to 2.8). The rate of cardiovascular malformations following early pregnancy paroxetine exposure was 2% vs. 1% in the entire registry population. Among the same paroxetine exposed infants, an examination of the data showed no increase in the overall risk for congenital malformations. A separate retrospective cohort study using US United Healthcare data evaluated 5,956 infants of mothers dispensed paroxetine or other antidepressants during the first trimester (n = 815 for paroxetine). This study showed a trend towards an increased risk for cardiovascular malformations for paroxetine compared to other antidepressants (OR 1.5; 95% confidence interval 0.8 to 2.9). The prevalence of cardiovascular malformations following first trimester dispensing was 1.5% for paroxetine vs. 1% for other antidepressants. Nine out of 12 infants with cardiovascular malformations whose mothers were dispensed paroxetine in the first trimester had VSDs. This study also suggested an increased risk of overall major congenital malformations (inclusive of the cardiovascular defects) for paroxetine compared to other antidepressants (OR 1.8; 95% confidence interval 1.2 to 2.8). The prevalence of all congenital malformations following first trimester exposure was 4% for paroxetine vs. 2% for other antidepressants.
Animal Findings:
Reproduction studies were performed at doses up to 50 mg/kg/day in rats and 6 mg/kg/day in rabbits administered during organogenesis. These doses are approximately 8 (rat) and 2 (rabbit) times the maximum recommended human dose (MRHD) on an mg/m 2 2
Procyclidine:
Daily oral dosing of paroxetine tablets (30 mg once daily) increased steady-state AUC 0-24 max min
Electroconvulsive Therapy (ECT):
There are no clinical studies of the combined use of ECT and paroxetine tablets.
Carcinogenesis,Mutagenesis, Impairment of Fertility:
Carcinogenesis: Two-year carcinogenicity studies were conducted in rodents given paroxetine in the diet at 1, 5, and 25 mg/kg/day (mice) and 1, 5, and 20 mg/kg/day (rats). These doses are up to 2.4 (mouse) and 3.9 (rat) times the MRHD for major depressive disorder, social anxiety disorder, and GAD on a mg/m 2
Labor and Delivery:
The effect of paroxetine on labor and delivery in humans is unknown.
Incidence in Controlled Clinical Trials:
The prescriber should be aware that the figures in the tables following cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the populations studied.
Adaptation to Certain Adverse Events:
Over a 4- to 6-week period, there was evidence of adaptation to some adverse events with continued therapy (e.g., nausea and dizziness), but less to other effects (e.g., dry mouth, somnolence, and asthenia).
Male and Female Sexual Dysfunction with SSRIs:
Although changes in sexual desire, sexual performance, and sexual satisfaction often occur as manifestations of a psychiatric disorder, they may also be a consequence of pharmacologic treatment. In particular, some evidence suggests that selective serotonin reuptake inhibitors (SSRIs) can cause such untoward sexual experiences. Reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance, and satisfaction are difficult to obtain, however, in part because patients and physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance cited in product labeling are likely to underestimate their actual incidence. In placebo-controlled clinical trials involving more than 3,200 patients, the ranges for the reported incidence of sexual side effects in males and females with major depressive disorder, OCD, panic disorder, social anxiety disorder, and GAD are displayed in Table 6. Table 6 Incidence of Sexual Adverse Events in Controlled Clinical Trials Paroxetine Tablets Placebo n ( males ) 1446 1042 Decreased Libido 6-15% 0-5% Ejaculatory Disturbance 13-28% 0-2% Impotence 2-9% 0-3% n ( females ) 1822 1340 Decreased Libido 0-9% 0-2% Orgasmic Disturbance 2-9% 0-1% There are no adequate and well-controlled studies examining sexual dysfunction with paroxetine treatment. Paroxetine treatment has been associated with several cases of priapism. In those cases with a known outcome, patients recovered without sequelae. While it is difficult to know the precise risk of sexual dysfunction associated with the use of SSRIs, physicians should routinely inquire about such possible side effects.
ECG Changes:
In an analysis of ECGs obtained in 682 patients treated with paroxetine tablets and 415 patients treated with placebo in controlled clinical trials, no clinically significant changes were seen in the ECGs of either group.
Other Events Observed During the Premarketing Evaluation of Paroxetine Tablets:
During its premarketing assessment in major depressive disorder, multiple doses of paroxetine tablets were administered to 6,145 patients in phase 2 and 3 studies. The conditions and duration of exposure to paroxetine tablets varied greatly and included (in overlapping categories) open and double-blind studies, uncontrolled and controlled studies, inpatient and outpatient studies, and fixed-dose, and titration studies. During premarketing clinical trials in OCD, panic disorder, social anxiety disorder, and generalized anxiety disorder, 542, 469, 522, and 735 patients, respectively, received multiple doses of paroxetine tablets. Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories. In the tabulations that follow, reported adverse events were classified using a standard COSTART-based Dictionary terminology. The frequencies presented, therefore, represent the proportion of the 9,089 patients exposed to multiple doses of paroxetine tablets who experienced an event of the type cited on at least 1 occasion while receiving paroxetine tablets. All reported events are included except those already listed in Tables 2 to 5, those reported in terms so general as to be uninformative and those events where a drug cause was remote. It is important to emphasize that although the events reported occurred during treatment with paroxetine, they were not necessarily caused by it. Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: Frequent adverse events are those occurring on 1 or more occasions in at least 1/100 patients (only those not already listed in the tabulated results from placebo-controlled trials appear in this listing); infrequent adverse events are those occurring in 1/100 to 1/1,000 patients; rare events are those occurring in fewer than 1/1,000 patients. Events of major clinical importance are also described in the PRECAUTIONS
Endocrine System:
Rare:
Metabolic and Nutritional:
Frequent: infrequent: rare:
OVERDOSAGE
Since the introduction of paroxetine tablets in the United States, 342 spontaneous cases of deliberate or accidental overdosage during paroxetine treatment have been reported worldwide (circa 1999). These include overdoses with paroxetine alone and in combination with other substances. Of these, 48 cases were fatal and of the fatalities, 17 appeared to involve paroxetine alone. Eight fatal cases that documented the amount of paroxetine ingested were generally confounded by the ingestion of other drugs or alcohol or the presence of significant comorbid conditions. Of 145 non-fatal cases with known outcome, most recovered without sequelae. The largest known ingestion involved 2,000 mg of paroxetine (33 times the maximum recommended daily dose) in a patient who recovered. Commonly reported adverse events associated with paroxetine overdosage include somnolence, coma, nausea, tremor, tachycardia, confusion, vomiting, and dizziness. Other notable signs and symptoms observed with overdoses involving paroxetine (alone or with other substances) include mydriasis, convulsions (including status epilepticus), ventricular dysrhythmias (including torsade de pointes), hypertension, aggressive reactions, syncope, hypotension, stupor, bradycardia, dystonia, rhabdomyolysis, symptoms of hepatic dysfunction (including hepatic failure, hepatic necrosis, jaundice, hepatitis, and hepatic steatosis), serotonin syndrome, manic reactions, myoclonus, acute renal failure, and urinary retention. 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 perfusion 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 Physicians’ Desk Reference.
Human Experience:
Since the introduction of paroxetine tablets in the United States, 342 spontaneous cases of deliberate or accidental overdosage during paroxetine treatment have been reported worldwide (circa 1999). These include overdoses with paroxetine alone and in combination with other substances. Of these, 48 cases were fatal and of the fatalities, 17 appeared to involve paroxetine alone. Eight fatal cases that documented the amount of paroxetine ingested were generally confounded by the ingestion of other drugs or alcohol or the presence of significant comorbid conditions. Of 145 non-fatal cases with known outcome, most recovered without sequelae. The largest known ingestion involved 2,000 mg of paroxetine (33 times the maximum recommended daily dose) in a patient who recovered. Commonly reported adverse events associated with paroxetine overdosage include somnolence, coma, nausea, tremor, tachycardia, confusion, vomiting, and dizziness. Other notable signs and symptoms observed with overdoses involving paroxetine (alone or with other substances) include mydriasis, convulsions (including status epilepticus), ventricular dysrhythmias (including torsade de pointes), hypertension, aggressive reactions, syncope, hypotension, stupor, bradycardia, dystonia, rhabdomyolysis, symptoms of hepatic dysfunction (including hepatic failure, hepatic necrosis, jaundice, hepatitis, and hepatic steatosis), serotonin syndrome, manic reactions, myoclonus, acute renal failure, and urinary retention.
Overdosage Management:
No specific antidotes for paroxetine are known.Treatment should consist of those general measures employed in the management of overdosage with any drugs effective in the treatment of major depressive disorder. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion, or exchange perfusion 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 Physicians’ Desk Reference
Maintenance Therapy:
There is no body of evidence available to answer the question of how long the patient treated with paroxetine tablets should remain on it. It is generally agreed that acute episodes of major depressive disorder require several months or longer of sustained pharmacologic therapy. Whether the dose needed to induce remission is identical to the dose needed to maintain and/or sustain euthymia is unknown. Systematic evaluation of the efficacy of paroxetine tablets has shown that efficacy is maintained for periods of up to 1 year with doses that averaged about 30 mg.
Maintenance Therapy:
Long-term maintenance of efficacy was demonstrated in a 6-month relapse prevention trial. In this trial, patients with OCD assigned to paroxetine demonstrated a lower relapse rate compared to patients on placebo (see CLINICAL PHARMACOLOGY em dash Clinical Trials
Maintenance Therapy:
There is no body of evidence available to answer the question of how long the patient treated with paroxetine tablets should remain on it. Although the efficacy of paroxetine tablets beyond 12 weeks of dosing has not been demonstrated in controlled clinical trials, social anxiety disorder is recognized as a chronic condition, and it is reasonable to consider continuation of treatment for a responding patient. Dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for continued treatment.
Maintenance Therapy:
Systematic evaluation of continuing paroxetine tablets for periods of up to 24 weeks in patients with Generalized Anxiety Disorder who had responded while taking paroxetine tablets during an 8-week acute treatment phase has demonstrated a benefit of such maintenance (see CLINICAL PHARMACOLOGY em dash Clinical Trials
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PAROXETINE- paroxetine hydrochloride_tablet, film coated Product manual source documgent