PAROXETINE: 21,439 Adverse Event Reports & Safety Profile

PHARMACOLOGY

12.1 Mechanism of Action Nonclinical studies have shown that paroxetine is an SSRI; paroxetine is not an estrogen. The mechanism of action of paroxetine for the treatment of moderate to severe VMS associated with menopause is unknown. Studies at clinically relevant paroxetine doses in humans have demonstrated that paroxetine blocks the uptake of serotonin into human platelets. Paroxetine is a neuronal serotonin reuptake inhibitor with weak effects on norepinephrine and dopamine neuronal reuptake in vitro. Paroxetine also has low affinity for muscarinic alpha 1 -, alpha 2 -, beta-adrenergic, dopamine (D 2 )-, 5-HT 1 -, 5-HT 2 -, and histamine (H 1 )-receptors.

12.2 Pharmacodynamics The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of paroxetine for the treatment of moderate to severe VMS associated with menopause have not been fully characterized.

12.3 Pharmacokinetics Absorption Paroxetine is completely absorbed after oral dosing. In a study in which healthy postmenopausal females (n=24) received paroxetine capsules 7.5 mg once daily for 14 days, steady-state paroxetine concentrations were achieved by approximately 12 days of dosing for most subjects, although it may take substantially longer in an occasional patient. Peak concentrations were reached at a median of 6 hours (3 to 8 hours range). Steady-state mean values of C max , C min , and AUC 0-last were 13.10 ng/mL (CV 91%), 7.17 ng/mL (CV 99%), and 237 hr * ng/mL (CV 94%), respectively. Steady-state AUC 0-24 values were about 3 times those of AUC 0-inf following a single paroxetine dose, indicating non-linear pharmacokinetics. Steady-state C max values were approximately 5 times greater than those attained after a single paroxetine dose and steady-state exposure based on AUC 0-24 was about 10 times greater than AUC 0-24 after a single dose. The nonlinear kinetics and excess accumulation are due to the fact that CYP2D6, an enzyme that is in part responsible for paroxetine metabolism, is readily saturable. Effect of Food: The effects of food on the bioavailability of paroxetine were studied after administration of another paroxetine product with a dosage higher than paroxetine. AUC was slightly increased (6%) when paroxetine was administered with food and the C max was 29% greater, while the time to reach peak plasma concentration decreased from 6.4 hours post-dosing to 4.9 hours. These changes are not clinically significant <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.1 )]</span> .

Distribution

Paroxetine distributes throughout the body, including the central nervous system, 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. Paroxetine does not alter the in vitro protein binding of phenytoin or warfarin.

Elimination

Metabolism: 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 cytochrome CYP2D6. The role of this enzyme in paroxetine metabolism also suggests potential drug interactions [see Drug Interactions ( 7 )] . At steady state, when the CYP2D6 pathway is essentially saturated, paroxetine clearance is governed by alternative P450 isozymes, which, unlike CYP2D6, show no evidence of saturation. Excretion: Approximately 64% of a 30 mg oral solution of another paroxetine product (four times the recommended paroxetine capsules dosage) was excreted in the urine with 2% as the parent compound and 62% as metabolites over a 10-day post-dosing period.

About

36% of the dose 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.

Specific Populations

Patients with Renal and Hepatic Impairment: Increased plasma concentrations of paroxetine occur in subjects with renal and hepatic impairment. The mean plasma concentration in patients with creatinine clearance below 30 mL/min was approximately 4 times greater than seen in normal volunteers. Patients with creatinine clearance of 30 to 60 mL/min and patients with hepatic impairment had about a 2-fold increase in plasma concentrations (AUC, C max ) [see Use in Specific Populations ( 8.6 , 8.7 )].

Geriatric

Patients: In a multiple-dose study in geriatric patients with another paroxetine product at doses of 20, 30, and 40 mg (1.7, 4, and 5.3, times the maximum recommended paroxetine capsules dosage, respectively), C min concentrations were about 70% to 80% greater than the respective C min concentrations in younger adult subjects [see Use in Specific Populations ( 8.5 )].

Drug Interaction Studies Potential

Effect of Paroxetine Capsules on Other Drugs

• Drugs Metabolized by CYP3A4: An in vivo drug interaction study involving the concomitant use of paroxetine and terfenadine, a substrate for cytochrome CYP3A4, under steady-state conditions revealed no effect of paroxetine on terfenadine pharmacokinetics. In vitro studies have shown ketoconazole, a potent CYP3A4 inhibitor, to be at least 100 times more potent than paroxetine as an inhibitor of the metabolism of several substrates for CYP3A4, including astemizole, triazolam, and cyclosporine. Based on the assumption that the relationship between paroxetine’s in vitro Ki and its lack of effect on terfenadine’s in vivo clearance predicts its effect on other CYP3A4 substrates, paroxetine’s extent of CYP3A4 inhibition is not likely to be of clinical significance.
• Drugs Metabolized by CYP2D6: Many drugs are metabolized by the cytochrome P450 isozyme CYP2D6. Like other agents that are metabolized by CYP2D6, paroxetine may significantly inhibit the activity of this isozyme. In most patients (> 90%), this CYP2D6 isozyme is saturated early during paroxetine dosing. Specific studies investigating the effect of paroxetine on drugs metabolized by CYP2D6 are listed below: o Pimozide: In a controlled study of healthy volunteers, after another paroxetine product was titrated to 60 mg daily (8 times the maximum recommended paroxetine capsules dosage), concomitant use of paroxetine with a single 2 mg dose of pimozide was associated with mean increases in pimozide AUC of 151% and C max of 62%, compared to pimozide administered alone [see Drug Interactions ( 7.1 )] . o Desipramine: In one study, daily dosing of another paroxetine product (20 mg once daily) (2.7 times the recommended paroxetine capsules dosage) under steady-state conditions with a concomitant single dose of desipramine (100 mg) increased desipramine C max , AUC, and T ½ by an average of approximately 2-, 5-, and 3-fold, respectively [see Drug Interactions ( 7.1 )] . o Risperidone: Daily dosing of another paroxetine product at 20 mg in patients stabilized on risperidone (4 to 8 mg/day), a CYP2D6 substrate, increased mean plasma risperidone concentrations approximately 4-fold, decreased 9hydroxyrisperidone concentrations approximately 10%, and increased concentrations of the active moiety (the sum of risperidone plus 9-hydroxyrisperidone) approximately 1.4-fold [see Drug Interactions ( 7.1 )] . o Atomoxetine: The effect of paroxetine on the pharmacokinetics of atomoxetine has been evaluated when both drugs were at steady state. In healthy volunteers who were extensive metabolizers of CYP2D6, 20 mg daily of another paroxetine product was given in combination with 20 mg atomoxetine every 12 hours resulting in increases in steady-state atomoxetine AUC values that were 6-to 8-fold greater and in atomoxetine C max values that were 3-to 4-fold greater than when atomoxetine was given alone [see Drug Interactions ( 7.1 )] . o Digoxin: Mean digoxin AUC at steady state decreased by 15% in the presence of paroxetine [see Drug Interactions ( 7.1 )] . o Beta Blockers: In a study in which propranolol (80 mg twice daily) was dosed orally for 18 days, the steady-state plasma concentrations of propranolol were unaltered during concomitant use with another paroxetine product (30 mg once daily) (4 times the recommended paroxetine capsules dosage) for the final 10 days. The effects of propranolol on paroxetine have not been evaluated.

Potential

Effect of Other Drugs on Paroxetine Capsules Concomitant use of paroxetine with other drugs that alter CYP enzymes activities including CYP2D6 may affect the plasma concentrations of paroxetine. Specific studies investigating the effect of other drugs on paroxetine are listed below: o Cimetidine: Cimetidine inhibits many cytochrome P450 enzymes. In a study in which another paroxetine product was dosed orally at 30 mg once daily (4 times the recommended paroxetine capsules dosage) for 4 weeks, steady-state plasma concentrations of paroxetine were increased by approximately 50% during concomitant use with oral cimetidine (300 mg three times daily) for the final week [see Drug Interactions ( 7.2 )] . o Phenobarbital: Phenobarbital induces many cytochrome P450 enzymes. When a single oral 30 mg dose of another paroxetine product (4 times the recommended paroxetine capsules dosage) was administered at phenobarbital steady state (100 mg once daily for 14 days), paroxetine AUC and T ½ were reduced (by an average of 25% and 38%, respectively) compared to paroxetine administered alone. The effect of paroxetine on phenobarbital pharmacokinetics was not studied. Because paroxetine exhibits nonlinear pharmacokinetics, the results of this study may not address the case where the two drugs are both being chronically dosed [see Drug Interactions ( 7.2 )] . o Phenytoin: When a single oral 30 mg dose of another paroxetine product (4 times the recommended paroxetine capsules dosage) was administered at phenytoin steady state (300 mg once daily for 14 days), paroxetine AUC and T ½ were reduced (by an average of 50% and 35%, respectively) compared to paroxetine administered alone. In a separate study, when a single oral 300 mg dose of phenytoin was administered with another paroxetine product (30 mg once daily for 14 days) at paroxetine steady state, phenytoin AUC was slightly reduced (12% on average) compared to phenytoin administered alone. Because both drugs exhibit nonlinear pharmacokinetics, the above studies may not address the case where the two drugs are both being chronically dosed [see Drug Interactions ( 7.2 )] . o Digoxin: A clinical drug interaction study showed that concurrent use of digoxin did not affect paroxetine exposure. Diazepam: A clinical drug interaction study showed that concurrent use of diazepam did not affect paroxetine exposure.

INDICATIONS AND USAGE Major Depressive Disorder: Paroxetine tablets, USP are indicated for the treatment of major depressive disorder. The efficacy of paroxetine tablets, USP in the treatment of a major depressive episode was established in 6-week controlled trials of outpatients whose diagnoses corresponded most closely to the DSM-III category of major depressive disorder (see CLINICAL PHARMACOLOGY —Clinical Trials ). A major depressive episode implies a prominent and relatively persistent depressed or dysphoric mood that usually interferes with daily functioning (nearly every day for at least 2 weeks); it should include at least 4 of the following 8 symptoms: Change in appetite, change in sleep, psychomotor agitation or retardation, loss of interest in usual activities or decrease in sexual drive, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, and a suicide attempt or suicidal ideation. The effects of paroxetine tablets, USP in hospitalized depressed patients have not been adequately studied. The efficacy of paroxetine tablets, USP in maintaining a response in major depressive disorder for up to 1 year was demonstrated in a placebo-controlled trial (see CLINICAL PHARMACOLOGY —Clinical Trials ). Nevertheless, the physician who elects to use paroxetine tablets, USP for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

Obsessive Compulsive

Disorder: Paroxetine tablets, USP are indicated for the treatment of obsessions and compulsions in patients with obsessive compulsive disorder (OCD) as defined in the DSM-IV. The obsessions or compulsions cause marked distress, are time-consuming, or significantly interfere with social or occupational functioning. The efficacy of paroxetine tablets, USP were established in two 12-week trials with obsessive compulsive outpatients whose diagnoses corresponded most closely to the DSM-IIIR category of obsessive compulsive disorder (see CLINICAL PHARMACOLOGY —Clinical Trials ). Obsessive compulsive disorder is characterized by recurrent and persistent ideas, thoughts, impulses, or images (obsessions) that are ego-dystonic and/or repetitive, purposeful, and intentional behaviors (compulsions) that are recognized by the person as excessive or unreasonable. Long-term maintenance of efficacy was demonstrated in a 6-month relapse prevention trial. In this trial, patients assigned to paroxetine showed a lower relapse rate compared to patients on placebo (see CLINICAL PHARMACOLOGY — Clinical Trials ). Nevertheless, the physician who elects to use paroxetine tablets, USP for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION ).

Panic

Disorder: Paroxetine tablets, USP are indicated for the treatment of panic disorder, with or without agoraphobia, as defined in DSM-IV. Panic disorder is characterized by the occurrence of unexpected panic attacks and associated concern about having additional attacks, worry about the implications or consequences of the attacks, and/or a significant change in behavior related to the attacks. The efficacy of paroxetine tablets, USP were established in three 10- to 12-week trials in panic disorder patients whose diagnoses corresponded to the DSM-IIIR category of panic disorder (see CLINICAL PHARMACOLOGY —Clinical Trials ). Panic disorder (DSM-IV) is characterized by recurrent unexpected panic attacks, i.e., a discrete period of intense fear or discomfort in which 4 (or more) of the following symptoms develop abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart, or accelerated heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of breath or smothering; (5) feeling of choking; (6) chest pain or discomfort; (7) nausea or abdominal distress; (8) feeling dizzy, unsteady, lightheaded, or faint; (9) derealization (feelings of unreality) or depersonalization (being detached from oneself); (10) fear of losing control; (11) fear of dying; (12) paresthesias (numbness or tingling sensations); (13) chills or hot flushes. Long-term maintenance of efficacy was demonstrated in a 3-month relapse prevention trial. In this trial, patients with panic disorder assigned to paroxetine demonstrated a lower relapse rate compared to patients on placebo (see CLINICAL PHARMACOLOGY —Clinical Trials ). Nevertheless, the physician who prescribes paroxetine tablets, USP for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION ).

Social Anxiety

Disorder: Paroxetine tablets, USP are indicated for the treatment of social anxiety disorder, also known as social phobia, as defined in DSM-IV (300.23). Social anxiety disorder is characterized by a marked and persistent fear of 1 or more social or performance situations in which the person is exposed to unfamiliar people or to possible scrutiny by others. Exposure to the feared situation almost invariably provokes anxiety, which may approach the intensity of a panic attack. The feared situations are avoided or endured with intense anxiety or distress. The avoidance, anxious anticipation, or distress in the feared situation(s) interferes significantly with the person's normal routine, occupational or academic functioning, or social activities or relationships, or there is marked distress about having the phobias. Lesser degrees of performance anxiety or shyness generally do not require psychopharmacological treatment. The efficacy of paroxetine tablets, USP were established in three 12-week trials in adult patients with social anxiety disorder (DSM-IV). Paroxetine tablets, USP have not been studied in children or adolescents with social phobia (see CLINICAL PHARMACOLOGY — Clinical Trials ). The effectiveness of paroxetine tablets, USP in long-term treatment of social anxiety disorder, i.e., for more than 12 weeks, has not been systematically evaluated in adequate and well-controlled trials. Therefore, the physician who elects to prescribe paroxetine tablets, USP for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION ).

Generalized Anxiety

Disorder: Paroxetine tablets, USP are indicated for the treatment of Generalized Anxiety Disorder (GAD), as defined in DSM-IV. Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic. The efficacy of paroxetine tablets, USP in the treatment of GAD was established in two 8-week placebo-controlled trials in adults with GAD. Paroxetine tablets, USP have not been studied in children or adolescents with Generalized Anxiety Disorder (see CLINICAL PHARMACOLOGY— Clinical Trials ).

Generalized Anxiety

Disorder (DSM-IV) is characterized by excessive anxiety and worry (apprehensive expectation) that is persistent for at least 6 months and which the person finds difficult to control. It must be associated with at least 3 of the following 6 symptoms: Restlessness or feeling keyed up or on edge, being easily fatigued, difficulty concentrating or mind going blank, irritability, muscle tension, sleep disturbance. The efficacy of paroxetine tablets, USP in maintaining a response in patients with Generalized Anxiety Disorder, who responded during an 8-week acute treatment phase while taking paroxetine tablets, USP and were then observed for relapse during a period of up to 24 weeks, was demonstrated in a placebo-controlled trial (see CLINICAL PHARMACOLOGY —Clinical Trials ). Nevertheless, the physician who elects to use paroxetine tablets, USP for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION ).

Posttraumatic Stress

Disorder: Paroxetine tablets, USP are indicated for the treatment of Posttraumatic Stress Disorder (PTSD). The efficacy of paroxetine tablets, USP in the treatment of PTSD was established in two 12-week placebo-controlled trials in adults with PTSD (DSM-IV) (see CLINICAL PHARMACOLOGY: Clinical Trials ). PTSD, as defined by DSM-IV, requires exposure to a traumatic event that involved actual or threatened death or serious injury, or threat to the physical integrity of self or others, and a response that involves intense fear, helplessness, or horror. Symptoms that occur as a result of exposure to the traumatic event include re-experiencing of the event in the form of intrusive thoughts, flashbacks, or dreams, and intense psychological distress and physiological reactivity on exposure to cues to the event; avoidance of situations reminiscent of the traumatic event, inability to recall details of the event, and/or numbing of general responsiveness manifested as diminished interest in significant activities, estrangement from others, restricted range of affect, or sense of foreshortened future; and symptoms of autonomic arousal including hypervigilance, exaggerated startle response, sleep disturbance, impaired concentration, and irritability or outbursts of anger. A PTSD diagnosis requires that the symptoms are present for at least a month and that they cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. The efficacy of paroxetine tablets, USP in longer-term treatment of PTSD, i.e., for more than 12 weeks, has not been systematically evaluated in placebo-controlled trials. Therefore, the physician who elects to prescribe paroxetine tablets, USP for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION ).

DOSAGE AND ADMINISTRATION Major Depressive Disorder Usual Initial Dosage Paroxetine tablets, USP 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, USP in the treatment of major depressive disorder. As with all drugs effective in the treatment of major depressive disorder, the full effect may be delayed. Some patients not responding to a 20 mg dose may benefit from dose increases, in 10 mg/day increments, up to a maximum of 50 mg/day. Dose changes should occur at intervals of at least 1 week.

Maintenance Therapy

There is no body of evidence available to answer the question of how long the patient treated with paroxetine tablets, USP 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, USP has shown that efficacy is maintained for periods of up to 1 year with doses that averaged about 30 mg.

Obsessive Compulsive Disorder Usual Initial

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

Maintenance Therapy

Long-term maintenance of efficacy was demonstrated in a 6-month relapse prevention trial. In this trial, patients with OCD assigned to paroxetine demonstrated a lower relapse rate compared to patients on placebo (see CLINICAL PHARMACOLOGY: Clinical Trials ). OCD is a chronic condition, and it is reasonable to consider continuation for a responding patient. Dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for continued treatment.

Panic Disorder Usual Initial Dosage

Paroxetine tablets, USP should be administered as a single daily dose with or without food, usually in the morning. The target dose of paroxetine tablets, USP 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, USP. The maximum dosage should not exceed 60 mg/day.

Maintenance Therapy

Long-term maintenance of efficacy was demonstrated in a 3-month relapse prevention trial. In this trial, patients with panic disorder assigned to paroxetine demonstrated a lower relapse rate compared to patients on placebo (see CLINICAL PHARMACOLOGY: Clinical Trials ). Panic disorder is a chronic condition, and it is reasonable to consider continuation for a responding patient. Dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for continued treatment.

Social Anxiety Disorder Usual Initial

Dosage Paroxetine tablets, USP 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, USP was demonstrated in patients dosed in a range of 20 to 60 mg/day. While the safety of paroxetine tablets, USP has been evaluated in patients with social anxiety disorder at doses up to 60 mg/day, available information does not suggest any additional benefit for doses above 20 mg/day (see CLINICAL PHARMACOLOGY: Clinical Trials ).

Maintenance Therapy

There is no body of evidence available to answer the question of how long the patient treated with paroxetine tablets, USP should remain on it. Although the efficacy of paroxetine tablets, USP beyond 12 weeks of dosing has not been demonstrated in controlled clinical trials, social anxiety disorder is recognized as a chronic condition, and it is reasonable to consider continuation of treatment for a responding patient. Dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for continued treatment.

Generalized Anxiety Disorder Usual Initial

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

Maintenance Therapy

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

Posttraumatic Stress Disorder Usual Initial

Dosage Paroxetine tablets, USP should be administered as a single daily dose with or without food, usually in the morning. The recommended starting dosage and the established effective dosage is 20 mg/day.

In

1 clinical trial, the effectiveness of paroxetine tablets, USP was demonstrated in patients dosed in a range of 20 to 50 mg/day. However, in a fixed dose study, there was not sufficient evidence to suggest a greater benefit for a dose of 40 mg/day compared to 20 mg/day. Dose changes, if indicated, should occur in 10 mg/day increments and at intervals of at least 1 week.

Maintenance Therapy

There is no body of evidence available to answer the question of how long the patient treated with paroxetine tablets, USP should remain on it. Although the efficacy of paroxetine tablets, USP beyond 12 weeks of dosing has not been demonstrated in controlled clinical trials, PTSD is recognized as a chronic condition, and it is reasonable to consider continuation of treatment for a responding patient. Dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for continued treatment.

Special Populations

Treatment of Pregnant Women During the Third Trimester Neonates exposed to paroxetine tablets, USP and other SSRIs or SNRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding (see WARNINGS: Usage in Pregnancy ). When treating pregnant women with paroxetine during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. Dosage for Elderly or Debilitated Patients, and Patients With Severe Renal or Hepatic Impairment The recommended initial dose is 10 mg/day for elderly patients, debilitated patients, and/or patients with severe renal or hepatic impairment. Increases may be made if indicated. Dosage should not exceed 40 mg/day. Switching a Patient to or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with paroxetine tablets, USP. Conversely, at least 14 days should be allowed after stopping paroxetine tablets, USP before starting an MAOI intended to treat psychiatric disorders (see CONTRAINDICATIONS). Use of Paroxetine Tablets, USP With Other MAOIs, Such as Linezolid or Methylene Blue Do not start paroxetine tablets, USP in a patient who is being treated with linezolid or intravenous methylene blue because there is increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered (see CONTRAINDICATIONS ). In some cases, a patient already receiving therapy with paroxetine tablets, USP may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, paroxetine tablets, USP should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for 2 weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with paroxetine tablets, USP may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue (see WARNINGS ). The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with paroxetine tablets is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use (see WARNINGS ). Discontinuation of Treatment With Paroxetine Tablets, USP Symptoms associated with discontinuation of paroxetine tablets, USP have been reported (see PRECAUTIONS: Discontinuation of Treatment With Paroxetine Tablets ). Patients should be monitored for these symptoms when discontinuing treatment, regardless of the indication for which paroxetine tablets, USP is being prescribed. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate.

4 CONTRAINDICATIONS

• Concurrent use with monoamine oxidase inhibitors (MAOI) or use within 14 days of MAOI use ( 2.2 , 4.1 , 5.2 , 7.3 )
• Use with thioridazine ( 4.2 , 7.1 )
• Use with pimozide ( 4.3 , 7.1 )
• Hypersensitivity to any ingredient in paroxetine capsules ( 4.4 )
• Pregnancy ( 4.5 , 8.1 )

4.1 Monoamine Oxidase Inhibitors Concomitant use of an MAOI with paroxetine capsules or within 14 days of stopping treatment with paroxetine capsules is contraindicated because of an increased risk of serotonin syndrome. The use of paroxetine capsules within 14 days of stopping an MAOI is also contraindicated <span class="opacity-50 text-xs">[see Dosage and Administration (2.2), Warnings and Precautions (5.2) and Drug Interactions (7.3)]</span> . Starting paroxetine capsules in a patient who is being treated with linezolid or intravenous methylene blue, both of which inhibit monoamine oxidase, is also contraindicated because of an increased risk of serotonin syndrome <span class="opacity-50 text-xs">[see Dosage and Administration (2.2), Warnings and Precautions (5.2) and Drug Interactions (7.3)]</span> .

4.2 Thioridazine Concomitant use of paroxetine capsules with thioridazine is contraindicated, because thioridazine prolongs the QT interval, and paroxetine can increase thioridazine levels <span class="opacity-50 text-xs">[see Drug Interactions (7.1)]</span> .

4.3 Pimozide Concomitant use of paroxetine capsules with pimozide is contraindicated because pimozide prolongs the QT interval, and paroxetine increases pimozide levels <span class="opacity-50 text-xs">[see Drug Interactions (7.1)]</span> .

4.4 Hypersensitivity to any Ingredient in Paroxetine Capsules Paroxetine capsules are contraindicated in patients with a history of hypersensitivity to paroxetine or any of the other ingredients in paroxetine capsules.

4.5 Pregnancy Menopausal VMS does not occur during pregnancy and paroxetine capsules may cause fetal harm <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1)]</span>.

6 ​ADVERSE REACTIONS The following adverse reactions are included in more detail in other sections of the prescribing information: Hypersensitivity reactions to paroxetine [see Contraindications (4)]

Suicidal

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

Serotonin

Syndrome [see Warnings and Precautions (5.2)] Embryofetal and Neonatal Toxicity [see Warnings and Precautions (5.4)]

Increased

Risk of Bleeding [see Warnings and Precautions ( 5.5 )] Activation of Mania/Hypomania [see Warnings and Precautions (5.6)]

Discontinuation

Syndrome [see Warnings and Precautions (5.7)] Seizures [see Warnings and Precautions (5.8)] Angle-closure Glaucoma [see Warnings and Precautions (5.9)] Hyponatremia [see Warnings and Precautions (5.10)]

Bone

Fracture [see Warnings and Precautions (5.12)]

Sexual

Dysfunction [see Warnings and Precautions (5.13)] Most common adverse reactions (≥5% and at least twice placebo) are abnormal ejaculation, asthenia, constipation, decreased appetite, diarrhea, dizziness, dry mouth, female genital disorder, impotence, infection, insomnia, libido decreased, male genital disorder, nausea, nervousness, somnolence, sweating, tremor, yawn. (6) To report SUSPECTED ADVERSE REACTIONS, contact Yiling Pharmaceutical, Inc. at 1-877-736-5697 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety data for paroxetine are from: 6-week clinical trials in MDD patients who received paroxetine 20 mg to 50 mg once daily 12-week clinical trials in OCD patients who received paroxetine 20 mg to 60 mg once daily 10- to 12-week clinical trials in PD patients who received paroxetine 10 mg to 60 mg once daily 12-week clinical trials in SAD patients who received paroxetine 20 mg to 50 mg once daily 8-week clinical trials in GAD patients who received paroxetine 10 mg to 50 mg once daily 12-week clinical trials in PTSD patients who received paroxetine 20 mg to 50 mg once daily Adverse Reactions Leading to Discontinuation Twenty percent (1,199/6,145) of patients treated with paroxetine in clinical trials in MDD and 16.1% (84/522), 11.8% (64/542), 9.4% (44/469), 10.7% (79/735), and 11.7% (79/676) of patients treated with paroxetine in clinical trials in SAD, OCD, PD, GAD, and PTSD, respectively, discontinued treatment due to an adverse reaction. The most common adverse reactions (≥1%) associated with discontinuation (i.e., those adverse reactions associated with dropout at a rate approximately twice or greater for paroxetine compared to placebo) are presented in Table 3: Table 3: Adverse Reactions Reported as Leading to Discontinuation ( ≥ 1% of Paroxetine- Treated Patients and Greater than Placebo) in MDD, OCD, PD, SAD, GAD, and PTSD Trials MDD OCD PD SAD GAD PTSD Paroxetine % Placebo % Paroxetine % Placebo % Paroxetine % Placebo % Paroxetine % Placebo % Paroxetine % Placebo % Paroxetine % Placebo % CNS Somnolence 2.3 0.7 — 1.9 0.3 3.4 0.3 2.0 0.2 2.8

0.6 Insomnia — — 1.7 0 1.3 0.3 3.1 0 — — Agitation 1.1 0.5 — — — Tremor 1.1 0.3 — 1.7 0 1.0

0.2 Anxiety — — — 1.1 0 — — Dizziness — — 1.5 0 1.9 0 1.0 0.2 — — Gastroin- testinal Constipation — 1.1 0 — — Nausea 3.2 1.1 1.9 0 3.2 1.2 4.0 0.3 2.0 0.2 2.2

0.6 Diarrhea 1.0 0.3 — Dry mouth 1.0 0.3 — — — Vomiting 1.0 0.3 — 1.0 0 — — Flatulence 1.0 0.3 — — Other Asthenia 1.6 0.4 1.9 0.4 2.5 0.6 1.8 0.2 1.6

0.2 Abnormal Ejaculationa a 1.6 0 2.1 0 4.9 0.6 2.5 0.5 — — Sweating 1.0 0.3 — 1.1 0 1.1 0.2 — — Impotencea a — 1.5 0 — — Libido Decreased 1.0 0 — — Where numbers are not provided the incidence of the adverse reactions in patients treated with paroxetine was not &gt;1% or was not greater than or equal to 2 times the incidence of placebo. a. Incidence corrected for gender.

Most Common Adverse Reactions

The most commonly observed adverse reactions associated with the use of paroxetine (incidence of 5% or greater and at least twice that for placebo) were: MDD: Asthenia, sweating, nausea, decreased appetite, somnolence, dizziness, insomnia, tremor, nervousness, ejaculatory disturbance, and other male genital disorders. OCD : Nausea, dry mouth, decreased appetite, constipation, dizziness, somnolence, tremor, sweating, impotence, and abnormal ejaculation. PD: Asthenia, sweating, decreased appetite, libido decreased, tremor, abnormal ejaculation, female genital disorders, and impotence. SAD: Sweating, nausea, dry mouth, constipation, decreased appetite, somnolence, tremor, libido decreased, yawn, abnormal ejaculation, female genital disorders, and impotence. GAD: Asthenia, infection, constipation, decreased appetite, dry mouth, nausea, libido decreased, somnolence, tremor, sweating, and abnormal ejaculation. PTSD: Asthenia, sweating, nausea, dry mouth, diarrhea, decreased appetite, somnolence, libido decreased, abnormal ejaculation, female genital disorders, and impotence.

Adverse

Reactions in Patients with MDD Table 4 presents the adverse reactions that occurred at an incidence of 1% or more and greater than placebo in clinical trials of paroxetine-treated patients with MDD.

Table

4: Adverse Reactions ( ≥ 1% of Paroxetine-Treated Patients and Greater than Placebo) in 6-Week Clinical Trials for MDD Body System/ Adverse Reaction Paroxetine (n = 421) % Placebo (n = 421) % Body as a Whole Headache 18 17 Asthenia 15 6 Cardiovascular Palpitation 3 1 Vasodilation 3 1 Dermatologic Sweating 11 2 Rash 2 1 Gastrointestinal Nausea 26 9 Dry Mouth 18 12 Constipation 14 9 Diarrhea 12 8 Decreased Appetite 6 2 Flatulence 4 2 Oropharynx Disorder a 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 b,c 13 0 Other Male Genital Disorders b,d 10 0 Urinary Frequency 3 1 Urination Disorder e 3 0 Female Genital Disorders b,f 2 0 a. Includes mostly “lump in throat” and “tightness in throat.” b. Percentage corrected for gender. c. Mostly “ejaculatory delay.” d. Includes “anorgasmia,” “erectile difficulties,” “delayed ejaculation/orgasm,” and “sexual dysfunction,” and “impotence.” e. Includes mostly “difficulty with micturition” and “urinary hesitancy.” f. Includes mostly “anorgasmia” and “difficulty reaching climax/orgasm.” Adverse Reactions in Patients with OCD, PD, and SAD Table 5 presents adverse reactions that occurred at a frequency of 2% or more in clinical trials in patients with OCD, PD, and SAD.

Table

5.

Adverse

Reactions (≥2% of Paroxetine-Treated Patients and Greater than Placebo) in 10 to 12-Week Clinical Trials for OCD, PD, and SA D Body System/Preferred Term Obsessive Compulsive Disorder Panic Disorder Social Anxiety Disorder Paroxetine (n = 542 ) % Placebo (n = 265) % Paroxetine (n = 469) % Placebo (n = 324) % Paroxetine (n = 425) % Placebo (n = 339) % Body as a Whole Asthenia 22 14 14 5 22 14 Abdominal Pain - - 4 3 — — Chest Pain 3 2 - - - - Back Pain - - 3 2 - - Chills 2 1 2 1 — — Trauma — — — — 3 1 Cardiovascular Vasodilation 4 1 — — — — Palpitation 2 0 — — — — Dermatologic Sweating 9 3 14 6 9 2 Rash 3 2 — — — — Gastrointestinal Nausea 23 10 23 17 25 7 Dry Mouth 18 9 18 11 9 3 Constipation 16 6 8 5 5 2 Diarrhea 10 10 12 7 9 6 Decreased Appetite 9 3 7 3 8 2 Dyspepsia - - - - 4 2 Flatulence - - - - 4 2 Increased Appetite 4 3 2 1 - - Vomiting - - - - 2 1 Musculoskeletal Myalgia — — — — 4 3 Nervous System Insomnia 24 13 18 10 21 16 Somnolence 24 7 19 11 22 5 Dizziness 12 6 14 10 11 7 Tremor 11 1 9 1 9 1 Nervousness 9 8 — — 8 7 Libido Decreased 7 4 9 1 12 1 Agitation — — 5 4 3 1 Anxiety — — 5 4 5 4 Abnormal Dreams 4 1 — — — — Concentration Impaired 3 2 — — 4 1 Depersonalization 3 0 — — — — Myoclonus 3 0 3 2 2 1 Amnesia 2 1 - - - - Respiratory System Rhinitis - - 3 0 - - Pharyngitis — — — — 4 2 Yawn - - - - 5 1 Special Senses Abnormal Vision 4 2 — — 4 1 Taste Perversion 2 0 - - - - Urogenital System Abnormal Ejaculation a 23 1 21 1 28 1 Dysmenorrhea — — — — 5 4 Female Genital Disorder a 3 0 9 1 9 1 Impotence a 8 1 5 0 5 1 Urinary Frequency 3 1 2 0 — — Urination Impaired 3 0 — — — — Urinary Tract Infection 2 1 2 1 — — a. Percentage corrected for gender.

Adverse

Reactions in Patients with GAD and PTSD Table 6 presents adverse reactions that occurred at a frequency of 2% or more in clinical trials in patients with GAD and PTSD.

Table

6.

Adverse

Reactions ( ≥ 2% of Paroxetine-Treated Patients and Greater than Placebo) in 8- to 12-Week Clinical Trials for GAD and PTSD a Body System/Preferred Term Generalized Anxiety Disorder Posttraumatic Stress Disorder Paroxetine (n = 735) % Placebo (n = 529) % Paroxetine (n = 676) % Placebo (n = 504) % Body as a Whole Asthenia 14 6 12 4 Headache 17 14 — — Infection 6 3 5 4 Abdominal Pain 4 3 Trauma 6 5 Cardiovascular Vasodilation 3 1 2 1 Dermatologic Sweating 6 2 5 1 Gastrointestin al Nausea 20 5 19 8 Dry Mouth 11 5 10 5 Constipation 10 2 5 3 Diarrhea 9 7 11 5 Decreased Appetite 5 1 6 3 Vomiting 3 2 3 2 Dyspepsia — — 5 3 Nervous System Insomnia 11 8 12 11 Somnolence 15 5 16 5 Dizziness 6 5 6 5 Tremor 5 1 4 1 Nervousness 4 3 — — Libido Decreased 9 2 5 2 Abnormal Dreams 3 Respiratory System Respiratory Disorder 7 5 — — Sinusitis 4 3 — — Yawn 4 — 2 <1 Special Senses Abnormal Vision 2 1 3 1 Urogenital System Abnormal Ejaculation a 25 2 13 2 Female Genital Disorder a 4 1 5 1 Impotence a 4 3 9 1 a. Percentage corrected for gender.

Dose Dependent Adverse

Reactions MDD A comparison of adverse reaction rates in a fixed-dose study comparing PAROXETINE10 mg, 20 mg, 30 mg, and 40 mg once daily with placebo in the treatment of MDD revealed dose dependent adverse reactions, as shown in Table 7: Table 7.

Adverse

Reactions ( ≥ 5% of Paroxetine-Treated Patients and ≥ Twice the Rate of Placebo) (in a Dose-Comparison Trial in the Treatment of MDD Body System/Preferred Term Placebo n = 51 % Paroxetine 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 OCD In a fixed-dose study comparing placebo and paroxetine 20 mg, 40 mg, and 60 mg in the treatment of OCD, there was no clear relationship between adverse reactions and the dose of paroxetine to which patients were assigned. PD In a fixed-dose study comparing placebo and paroxetine 10 mg, 20 mg, and 40 mg in the treatment of PD, the following adverse reactions were shown to be dose-dependent: asthenia, dry mouth, anxiety, libido decreased, tremor, and abnormal ejaculation.

Sad

In a fixed-dose study comparing placebo and paroxetine 20 mg, 40 mg and 60 mg in the treatment of SAD, for most of the adverse reactions, there was no clear relationship between adverse reactions and the dose of paroxetine to which patients were assigned.

Gad

In a fixed-dose study comparing placebo and paroxetine 20 mg and 40 mg in the treatment of GAD, the following adverse reactions were shown to be dose-dependent: asthenia, constipation, and abnormal ejaculation.

Ptsd

In a fixed-dose study comparing placebo and paroxetine 20 mg and 40 mg in the treatment of PTSD, the following adverse reactions were shown to be dose-dependent: impotence and abnormal ejaculation. Male and Female Sexual Dysfunction Although changes in sexual desire, sexual performance, and sexual satisfaction often occur as manifestations of a psychiatric disorder, they may also be a consequence of SSRI treatment. However, reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance, and satisfaction are difficult to obtain, however, in part because patients and healthcare providers may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance cited in labeling may underestimate their actual incidence. The percentage of patients reporting symptoms of sexual dysfunction in males and females with MDD, OCD, PD, SAD, GAD, and PTSD are displayed in Table 8.

Table

8.

Adverse Reactions

Related to Sexual Dysfunction in Patients Treated with Paroxetine in Clinical Trials of MDD, OCD, PD, SAD, GAD, and PTSD Paroxetine Placebo n (males) 1446 % 1042% Decreased Libido 6 to15 0 to 5 Ejaculatory Disturbance 13 to 28 0 to 2 Impotence 2 to 9 0 to 3 n (females) 1822% 1340% Decreased Libido 0 to 9 0 to 2 Orgasmic Disturbance 2 to 9 0 to 1 Paroxetine treatment has been associated with several cases of priapism. In those cases with a known outcome, patients recovered without sequelae. Hallucinations In pooled clinical trials of paroxetine, hallucinations were observed in 0.2% of paroxetine-treated patients compared to 0.1% of patients receiving placebo.

Less Common Adverse Reactions

The following adverse reactions occurred during the clinical studies of paroxetine and are not included elsewhere in the labeling. Adverse reactions are categorized by body system and listed in order of decreasing frequency according to the following definitions: Frequent adverse reactions are those occurring on 1 or more occasions in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1,000 patients; rare adverse reactions are those occurring in fewer than 1/1,000 patients. Body as a Whole Infrequent : Allergic reaction, chills, face edema, malaise, neck pain; rare: Adrenergic syndrome, cellulitis, moniliasis, neck rigidity, pelvic pain, peritonitis, sepsis, ulcer.

Cardiovascular System

Frequent: Hypertension, tachycardia; infrequent: Bradycardia, hematoma, hypotension, migraine, postural hypotension, syncope; rare: Angina pectoris, arrhythmia nodal, atrial fibrillation, bundle branch block, cerebral ischemia, cerebrovascular accident, congestive heart failure, heart block, low cardiac output, myocardial infarct, myocardial ischemia, pallor, phlebitis, pulmonary embolus, supraventricular extrasystoles, thrombophlebitis, thrombosis, varicose vein, vascular headache, ventricular extrasystoles.

Digestive System

Infrequent: Bruxism, colitis, dysphagia, eructation, gastritis, gastroenteritis, gingivitis, glossitis, increased salivation, abnormal liver function tests, rectal hemorrhage, ulcerative stomatitis; rare: Aphthous stomatitis, bloody diarrhea, bulimia, cardiospasm, cholelithiasis, duodenitis, enteritis, esophagitis, fecal impactions, fecal incontinence, gum hemorrhage, hematemesis, hepatitis, ileitis, ileus, intestinal obstruction, jaundice, melena, mouth ulceration, peptic ulcer, salivary gland enlargement, sialadenitis, stomach ulcer, stomatitis, tongue discoloration, tongue edema, tooth caries.

Endocrine System

Rare: Diabetes mellitus, goiter, hyperthyroidism, hypothyroidism, thyroiditis. Hemic and Lymphatic Systems Infrequent: Anemia, leukopenia, lymphadenopathy, purpura; rare: Abnormal erythrocytes, basophilia, bleeding time increased, eosinophilia, hypochromic anemia, iron deficiency anemia, leukocytosis, lymphedema, abnormal lymphocytes, lymphocytosis, microcytic anemia, monocytosis, normocytic anemia, thrombocythemia, thrombocytopenia. Metabolic and Nutritional Frequent: Weight gain; infrequent: Edema, peripheral edema, SGOT increased, SGPT increased, thirst, weight loss; rare: Alkaline phosphatase increased, bilirubinemia, BUN increased, creatinine phosphokinase increased, dehydration, gamma globulins increased, gout, hypercalcemia, hypercholesteremia, hyperglycemia, hyperkalemia, hyperphosphatemia, hypocalcemia, hypoglycemia, hypokalemia, hyponatremia, ketosis, lactic dehydrogenase increased, non-protein nitrogen (NPN) increased.

Musculoskeletal System

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

Nervous System

Frequent: Emotional lability, vertigo; infrequent: Abnormal thinking, alcohol abuse, ataxia, dystonia, dyskinesia, euphoria, hostility, hypertonia, hypesthesia, hypokinesia, incoordination, lack of emotion, libido increased, manic reaction, neurosis, paralysis, paranoid reaction; rare: Abnormal gait, akinesia, antisocial reaction, aphasia, choreoathetosis, circumoral paresthesias, convulsion, delirium, delusions, diplopia, drug dependence, dysarthria, extrapyramidal syndrome, fasciculations, grand mal convulsion, hyperalgesia, hysteria, manic-depressive reaction, meningitis, myelitis, neuralgia, neuropathy, nystagmus, peripheral neuritis, psychotic depression, psychosis, reflexes decreased, reflexes increased, stupor, torticollis, trismus, withdrawal syndrome.

Respiratory System

Infrequent: Asthma, bronchitis, dyspnea, epistaxis, hyperventilation, pneumonia, respiratory flu; rare: Emphysema, hemoptysis, hiccups, lung fibrosis, pulmonary edema, sputum increased, stridor, voice alteration. Skin and Appendages Frequent: Pruritus; infrequent: Acne, alopecia, contact dermatitis, dry skin, ecchymosis, eczema, herpes simplex, photosensitivity, urticaria; rare: Angioedema, erythema nodosum, erythema multiforme, exfoliative dermatitis, fungal dermatitis, furunculosis; herpes zoster, hirsutism, maculopapular rash, seborrhea, skin discoloration, skin hypertrophy, skin ulcer, sweating decreased, vesiculobullous rash.

Special Senses

Frequent : Tinnitus; infrequent: Abnormality of accommodation, conjunctivitis, ear pain, eye pain, keratoconjunctivitis, mydriasis, otitis media; rare: Amblyopia, anisocoria, blepharitis, cataract, conjunctival edema, corneal ulcer, deafness, exophthalmos, eye hemorrhage, glaucoma, hyperacusis, night blindness, otitis externa, parosmia, photophobia, ptosis, retinal hemorrhage, taste loss, visual field defect.

Urogenital System

Infrequent: Amenorrhea, breast pain, cystitis, dysuria, hematuria, menorrhagia, nocturia, polyuria, pyuria, urinary incontinence, urinary retention, urinary urgency, vaginitis; rare: Abortion, breast atrophy, breast enlargement, endometrial disorder, epididymitis, female lactation, fibrocystic breast, kidney calculus, kidney pain, leukorrhea, mastitis, metrorrhagia, nephritis, oliguria, salpingitis, urethritis, urinary casts, uterine spasm, urolith, vaginal hemorrhage, vaginal moniliasis. 6.2 ​Postmarketing Experience The following reactions have been identified during post approval use of paroxetine. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. 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-Barré syndrome, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), syndrome of inappropriate ADH secretion, prolactinemia and galactorrhea; extrapyramidal symptoms which have included akathisia, bradykinesia, cogwheel rigidity, oculogyric crisis which has been associated with concomitant use of pimozide; status epilepticus, acute renal failure, pulmonary hypertension, allergic alveolitis, anosmia, hyposmia, anaphylaxis, eclampsia, laryngismus, optic neuritis, porphyria, restless legs syndrome (RLS), ventricular fibrillation, ventricular tachycardia (including torsade de pointes), hemolytic anemia, events related to impaired hematopoiesis (including aplastic anemia, pancytopenia, bone marrow aplasia, and agranulocytosis), vasculitic syndromes (such as Henoch-Schönlein purpura), and premature births in pregnant women. There has been a case report of severe hypotension when paroxetine was added to chronic metoprolol treatment.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety data for paroxetine are from: 6-week clinical trials in MDD patients who received paroxetine 20 mg to 50 mg once daily 12-week clinical trials in OCD patients who received paroxetine 20 mg to 60 mg once daily 10- to 12-week clinical trials in PD patients who received paroxetine 10 mg to 60 mg once daily 12-week clinical trials in SAD patients who received paroxetine 20 mg to 50 mg once daily 8-week clinical trials in GAD patients who received paroxetine 10 mg to 50 mg once daily 12-week clinical trials in PTSD patients who received paroxetine 20 mg to 50 mg once daily Adverse Reactions Leading to Discontinuation Twenty percent (1,199/6,145) of patients treated with paroxetine in clinical trials in MDD and 16.1% (84/522), 11.8% (64/542), 9.4% (44/469), 10.7% (79/735), and 11.7% (79/676) of patients treated with paroxetine in clinical trials in SAD, OCD, PD, GAD, and PTSD, respectively, discontinued treatment due to an adverse reaction. The most common adverse reactions (≥1%) associated with discontinuation (i.e., those adverse reactions associated with dropout at a rate approximately twice or greater for paroxetine compared to placebo) are presented in Table 3: Table 3: Adverse Reactions Reported as Leading to Discontinuation ( ≥ 1% of Paroxetine- Treated Patients and Greater than Placebo) in MDD, OCD, PD, SAD, GAD, and PTSD Trials MDD OCD PD SAD GAD PTSD Paroxetine % Placebo % Paroxetine % Placebo % Paroxetine % Placebo % Paroxetine % Placebo % Paroxetine % Placebo % Paroxetine % Placebo % CNS Somnolence 2.3 0.7 — 1.9 0.3 3.4 0.3 2.0 0.2 2.8

0.6 Insomnia — — 1.7 0 1.3 0.3 3.1 0 — — Agitation 1.1 0.5 — — — Tremor 1.1 0.3 — 1.7 0 1.0

0.2 Anxiety — — — 1.1 0 — — Dizziness — — 1.5 0 1.9 0 1.0 0.2 — — Gastroin- testinal Constipation — 1.1 0 — — Nausea 3.2 1.1 1.9 0 3.2 1.2 4.0 0.3 2.0 0.2 2.2

0.6 Diarrhea 1.0 0.3 — Dry mouth 1.0 0.3 — — — Vomiting 1.0 0.3 — 1.0 0 — — Flatulence 1.0 0.3 — — Other Asthenia 1.6 0.4 1.9 0.4 2.5 0.6 1.8 0.2 1.6

0.2 Abnormal Ejaculationa a 1.6 0 2.1 0 4.9 0.6 2.5 0.5 — — Sweating 1.0 0.3 — 1.1 0 1.1 0.2 — — Impotencea a — 1.5 0 — — Libido Decreased 1.0 0 — — Where numbers are not provided the incidence of the adverse reactions in patients treated with paroxetine was not &gt;1% or was not greater than or equal to 2 times the incidence of placebo. a. Incidence corrected for gender.

Most Common Adverse Reactions

The most commonly observed adverse reactions associated with the use of paroxetine (incidence of 5% or greater and at least twice that for placebo) were: MDD: Asthenia, sweating, nausea, decreased appetite, somnolence, dizziness, insomnia, tremor, nervousness, ejaculatory disturbance, and other male genital disorders. OCD : Nausea, dry mouth, decreased appetite, constipation, dizziness, somnolence, tremor, sweating, impotence, and abnormal ejaculation. PD: Asthenia, sweating, decreased appetite, libido decreased, tremor, abnormal ejaculation, female genital disorders, and impotence. SAD: Sweating, nausea, dry mouth, constipation, decreased appetite, somnolence, tremor, libido decreased, yawn, abnormal ejaculation, female genital disorders, and impotence. GAD: Asthenia, infection, constipation, decreased appetite, dry mouth, nausea, libido decreased, somnolence, tremor, sweating, and abnormal ejaculation. PTSD: Asthenia, sweating, nausea, dry mouth, diarrhea, decreased appetite, somnolence, libido decreased, abnormal ejaculation, female genital disorders, and impotence.

Adverse

Reactions in Patients with MDD Table 4 presents the adverse reactions that occurred at an incidence of 1% or more and greater than placebo in clinical trials of paroxetine-treated patients with MDD.

Table

4: Adverse Reactions ( ≥ 1% of Paroxetine-Treated Patients and Greater than Placebo) in 6-Week Clinical Trials for MDD Body System/ Adverse Reaction Paroxetine (n = 421) % Placebo (n = 421) % Body as a Whole Headache 18 17 Asthenia 15 6 Cardiovascular Palpitation 3 1 Vasodilation 3 1 Dermatologic Sweating 11 2 Rash 2 1 Gastrointestinal Nausea 26 9 Dry Mouth 18 12 Constipation 14 9 Diarrhea 12 8 Decreased Appetite 6 2 Flatulence 4 2 Oropharynx Disorder a 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 b,c 13 0 Other Male Genital Disorders b,d 10 0 Urinary Frequency 3 1 Urination Disorder e 3 0 Female Genital Disorders b,f 2 0 a. Includes mostly “lump in throat” and “tightness in throat.” b. Percentage corrected for gender. c. Mostly “ejaculatory delay.” d. Includes “anorgasmia,” “erectile difficulties,” “delayed ejaculation/orgasm,” and “sexual dysfunction,” and “impotence.” e. Includes mostly “difficulty with micturition” and “urinary hesitancy.” f. Includes mostly “anorgasmia” and “difficulty reaching climax/orgasm.” Adverse Reactions in Patients with OCD, PD, and SAD Table 5 presents adverse reactions that occurred at a frequency of 2% or more in clinical trials in patients with OCD, PD, and SAD.

Table

5.

Adverse

Reactions (≥2% of Paroxetine-Treated Patients and Greater than Placebo) in 10 to 12-Week Clinical Trials for OCD, PD, and SA D Body System/Preferred Term Obsessive Compulsive Disorder Panic Disorder Social Anxiety Disorder Paroxetine (n = 542 ) % Placebo (n = 265) % Paroxetine (n = 469) % Placebo (n = 324) % Paroxetine (n = 425) % Placebo (n = 339) % Body as a Whole Asthenia 22 14 14 5 22 14 Abdominal Pain - - 4 3 — — Chest Pain 3 2 - - - - Back Pain - - 3 2 - - Chills 2 1 2 1 — — Trauma — — — — 3 1 Cardiovascular Vasodilation 4 1 — — — — Palpitation 2 0 — — — — Dermatologic Sweating 9 3 14 6 9 2 Rash 3 2 — — — — Gastrointestinal Nausea 23 10 23 17 25 7 Dry Mouth 18 9 18 11 9 3 Constipation 16 6 8 5 5 2 Diarrhea 10 10 12 7 9 6 Decreased Appetite 9 3 7 3 8 2 Dyspepsia - - - - 4 2 Flatulence - - - - 4 2 Increased Appetite 4 3 2 1 - - Vomiting - - - - 2 1 Musculoskeletal Myalgia — — — — 4 3 Nervous System Insomnia 24 13 18 10 21 16 Somnolence 24 7 19 11 22 5 Dizziness 12 6 14 10 11 7 Tremor 11 1 9 1 9 1 Nervousness 9 8 — — 8 7 Libido Decreased 7 4 9 1 12 1 Agitation — — 5 4 3 1 Anxiety — — 5 4 5 4 Abnormal Dreams 4 1 — — — — Concentration Impaired 3 2 — — 4 1 Depersonalization 3 0 — — — — Myoclonus 3 0 3 2 2 1 Amnesia 2 1 - - - - Respiratory System Rhinitis - - 3 0 - - Pharyngitis — — — — 4 2 Yawn - - - - 5 1 Special Senses Abnormal Vision 4 2 — — 4 1 Taste Perversion 2 0 - - - - Urogenital System Abnormal Ejaculation a 23 1 21 1 28 1 Dysmenorrhea — — — — 5 4 Female Genital Disorder a 3 0 9 1 9 1 Impotence a 8 1 5 0 5 1 Urinary Frequency 3 1 2 0 — — Urination Impaired 3 0 — — — — Urinary Tract Infection 2 1 2 1 — — a. Percentage corrected for gender.

Adverse

Reactions in Patients with GAD and PTSD Table 6 presents adverse reactions that occurred at a frequency of 2% or more in clinical trials in patients with GAD and PTSD.

Table

6.

Adverse

Reactions ( ≥ 2% of Paroxetine-Treated Patients and Greater than Placebo) in 8- to 12-Week Clinical Trials for GAD and PTSD a Body System/Preferred Term Generalized Anxiety Disorder Posttraumatic Stress Disorder Paroxetine (n = 735) % Placebo (n = 529) % Paroxetine (n = 676) % Placebo (n = 504) % Body as a Whole Asthenia 14 6 12 4 Headache 17 14 — — Infection 6 3 5 4 Abdominal Pain 4 3 Trauma 6 5 Cardiovascular Vasodilation 3 1 2 1 Dermatologic Sweating 6 2 5 1 Gastrointestin al Nausea 20 5 19 8 Dry Mouth 11 5 10 5 Constipation 10 2 5 3 Diarrhea 9 7 11 5 Decreased Appetite 5 1 6 3 Vomiting 3 2 3 2 Dyspepsia — — 5 3 Nervous System Insomnia 11 8 12 11 Somnolence 15 5 16 5 Dizziness 6 5 6 5 Tremor 5 1 4 1 Nervousness 4 3 — — Libido Decreased 9 2 5 2 Abnormal Dreams 3 Respiratory System Respiratory Disorder 7 5 — — Sinusitis 4 3 — — Yawn 4 — 2 <1 Special Senses Abnormal Vision 2 1 3 1 Urogenital System Abnormal Ejaculation a 25 2 13 2 Female Genital Disorder a 4 1 5 1 Impotence a 4 3 9 1 a. Percentage corrected for gender.

Dose Dependent Adverse

Reactions MDD A comparison of adverse reaction rates in a fixed-dose study comparing PAROXETINE10 mg, 20 mg, 30 mg, and 40 mg once daily with placebo in the treatment of MDD revealed dose dependent adverse reactions, as shown in Table 7: Table 7.

Adverse

Reactions ( ≥ 5% of Paroxetine-Treated Patients and ≥ Twice the Rate of Placebo) (in a Dose-Comparison Trial in the Treatment of MDD Body System/Preferred Term Placebo n = 51 % Paroxetine 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 OCD In a fixed-dose study comparing placebo and paroxetine 20 mg, 40 mg, and 60 mg in the treatment of OCD, there was no clear relationship between adverse reactions and the dose of paroxetine to which patients were assigned. PD In a fixed-dose study comparing placebo and paroxetine 10 mg, 20 mg, and 40 mg in the treatment of PD, the following adverse reactions were shown to be dose-dependent: asthenia, dry mouth, anxiety, libido decreased, tremor, and abnormal ejaculation.

Sad

In a fixed-dose study comparing placebo and paroxetine 20 mg, 40 mg and 60 mg in the treatment of SAD, for most of the adverse reactions, there was no clear relationship between adverse reactions and the dose of paroxetine to which patients were assigned.

Gad

In a fixed-dose study comparing placebo and paroxetine 20 mg and 40 mg in the treatment of GAD, the following adverse reactions were shown to be dose-dependent: asthenia, constipation, and abnormal ejaculation.

Ptsd

In a fixed-dose study comparing placebo and paroxetine 20 mg and 40 mg in the treatment of PTSD, the following adverse reactions were shown to be dose-dependent: impotence and abnormal ejaculation. Male and Female Sexual Dysfunction Although changes in sexual desire, sexual performance, and sexual satisfaction often occur as manifestations of a psychiatric disorder, they may also be a consequence of SSRI treatment. However, reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance, and satisfaction are difficult to obtain, however, in part because patients and healthcare providers may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance cited in labeling may underestimate their actual incidence. The percentage of patients reporting symptoms of sexual dysfunction in males and females with MDD, OCD, PD, SAD, GAD, and PTSD are displayed in Table 8.

Table

8.

Adverse Reactions

Related to Sexual Dysfunction in Patients Treated with Paroxetine in Clinical Trials of MDD, OCD, PD, SAD, GAD, and PTSD Paroxetine Placebo n (males) 1446 % 1042% Decreased Libido 6 to15 0 to 5 Ejaculatory Disturbance 13 to 28 0 to 2 Impotence 2 to 9 0 to 3 n (females) 1822% 1340% Decreased Libido 0 to 9 0 to 2 Orgasmic Disturbance 2 to 9 0 to 1 Paroxetine treatment has been associated with several cases of priapism. In those cases with a known outcome, patients recovered without sequelae. Hallucinations In pooled clinical trials of paroxetine, hallucinations were observed in 0.2% of paroxetine-treated patients compared to 0.1% of patients receiving placebo.

Less Common Adverse Reactions

The following adverse reactions occurred during the clinical studies of paroxetine and are not included elsewhere in the labeling. Adverse reactions are categorized by body system and listed in order of decreasing frequency according to the following definitions: Frequent adverse reactions are those occurring on 1 or more occasions in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1,000 patients; rare adverse reactions are those occurring in fewer than 1/1,000 patients. Body as a Whole Infrequent : Allergic reaction, chills, face edema, malaise, neck pain; rare: Adrenergic syndrome, cellulitis, moniliasis, neck rigidity, pelvic pain, peritonitis, sepsis, ulcer.

Cardiovascular System

Frequent: Hypertension, tachycardia; infrequent: Bradycardia, hematoma, hypotension, migraine, postural hypotension, syncope; rare: Angina pectoris, arrhythmia nodal, atrial fibrillation, bundle branch block, cerebral ischemia, cerebrovascular accident, congestive heart failure, heart block, low cardiac output, myocardial infarct, myocardial ischemia, pallor, phlebitis, pulmonary embolus, supraventricular extrasystoles, thrombophlebitis, thrombosis, varicose vein, vascular headache, ventricular extrasystoles.

Digestive System

Infrequent: Bruxism, colitis, dysphagia, eructation, gastritis, gastroenteritis, gingivitis, glossitis, increased salivation, abnormal liver function tests, rectal hemorrhage, ulcerative stomatitis; rare: Aphthous stomatitis, bloody diarrhea, bulimia, cardiospasm, cholelithiasis, duodenitis, enteritis, esophagitis, fecal impactions, fecal incontinence, gum hemorrhage, hematemesis, hepatitis, ileitis, ileus, intestinal obstruction, jaundice, melena, mouth ulceration, peptic ulcer, salivary gland enlargement, sialadenitis, stomach ulcer, stomatitis, tongue discoloration, tongue edema, tooth caries.

Endocrine System

Rare: Diabetes mellitus, goiter, hyperthyroidism, hypothyroidism, thyroiditis. Hemic and Lymphatic Systems Infrequent: Anemia, leukopenia, lymphadenopathy, purpura; rare: Abnormal erythrocytes, basophilia, bleeding time increased, eosinophilia, hypochromic anemia, iron deficiency anemia, leukocytosis, lymphedema, abnormal lymphocytes, lymphocytosis, microcytic anemia, monocytosis, normocytic anemia, thrombocythemia, thrombocytopenia. Metabolic and Nutritional Frequent: Weight gain; infrequent: Edema, peripheral edema, SGOT increased, SGPT increased, thirst, weight loss; rare: Alkaline phosphatase increased, bilirubinemia, BUN increased, creatinine phosphokinase increased, dehydration, gamma globulins increased, gout, hypercalcemia, hypercholesteremia, hyperglycemia, hyperkalemia, hyperphosphatemia, hypocalcemia, hypoglycemia, hypokalemia, hyponatremia, ketosis, lactic dehydrogenase increased, non-protein nitrogen (NPN) increased.

Musculoskeletal System

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

Nervous System

Frequent: Emotional lability, vertigo; infrequent: Abnormal thinking, alcohol abuse, ataxia, dystonia, dyskinesia, euphoria, hostility, hypertonia, hypesthesia, hypokinesia, incoordination, lack of emotion, libido increased, manic reaction, neurosis, paralysis, paranoid reaction; rare: Abnormal gait, akinesia, antisocial reaction, aphasia, choreoathetosis, circumoral paresthesias, convulsion, delirium, delusions, diplopia, drug dependence, dysarthria, extrapyramidal syndrome, fasciculations, grand mal convulsion, hyperalgesia, hysteria, manic-depressive reaction, meningitis, myelitis, neuralgia, neuropathy, nystagmus, peripheral neuritis, psychotic depression, psychosis, reflexes decreased, reflexes increased, stupor, torticollis, trismus, withdrawal syndrome.

Respiratory System

Infrequent: Asthma, bronchitis, dyspnea, epistaxis, hyperventilation, pneumonia, respiratory flu; rare: Emphysema, hemoptysis, hiccups, lung fibrosis, pulmonary edema, sputum increased, stridor, voice alteration. Skin and Appendages Frequent: Pruritus; infrequent: Acne, alopecia, contact dermatitis, dry skin, ecchymosis, eczema, herpes simplex, photosensitivity, urticaria; rare: Angioedema, erythema nodosum, erythema multiforme, exfoliative dermatitis, fungal dermatitis, furunculosis; herpes zoster, hirsutism, maculopapular rash, seborrhea, skin discoloration, skin hypertrophy, skin ulcer, sweating decreased, vesiculobullous rash.

Special Senses

Frequent : Tinnitus; infrequent: Abnormality of accommodation, conjunctivitis, ear pain, eye pain, keratoconjunctivitis, mydriasis, otitis media; rare: Amblyopia, anisocoria, blepharitis, cataract, conjunctival edema, corneal ulcer, deafness, exophthalmos, eye hemorrhage, glaucoma, hyperacusis, night blindness, otitis externa, parosmia, photophobia, ptosis, retinal hemorrhage, taste loss, visual field defect.

Urogenital System

Infrequent: Amenorrhea, breast pain, cystitis, dysuria, hematuria, menorrhagia, nocturia, polyuria, pyuria, urinary incontinence, urinary retention, urinary urgency, vaginitis; rare: Abortion, breast atrophy, breast enlargement, endometrial disorder, epididymitis, female lactation, fibrocystic breast, kidney calculus, kidney pain, leukorrhea, mastitis, metrorrhagia, nephritis, oliguria, salpingitis, urethritis, urinary casts, uterine spasm, urolith, vaginal hemorrhage, vaginal moniliasis.

6.2 ​Postmarketing Experience The following reactions have been identified during post approval use of paroxetine. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. 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-Barré syndrome, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), syndrome of inappropriate ADH secretion, prolactinemia and galactorrhea; extrapyramidal symptoms which have included akathisia, bradykinesia, cogwheel rigidity, oculogyric crisis which has been associated with concomitant use of pimozide; status epilepticus, acute renal failure, pulmonary hypertension, allergic alveolitis, anosmia, hyposmia, anaphylaxis, eclampsia, laryngismus, optic neuritis, porphyria, restless legs syndrome (RLS), ventricular fibrillation, ventricular tachycardia (including torsade de pointes), hemolytic anemia, events related to impaired hematopoiesis (including aplastic anemia, pancytopenia, bone marrow aplasia, and agranulocytosis), vasculitic syndromes (such as Henoch-Schönlein purpura), and premature births in pregnant women. There has been a case report of severe hypotension when paroxetine was added to chronic metoprolol treatment.

5 ​WARNINGS AND PRECAUTIONS Serotonin Syndrome : Increased risk when co-administered with other serotonergic agents (e.g., SSRI, SNRI, triptans), but also when taken alone. If occurs, discontinue paroxetine and initiate supportive measures. (5.2) Embryofetal and Neonatal Toxicity : Can cause fetal and neonatal harm. Increased risk of cardiovascular malformations with exposure during the first trimester. Exposure in late pregnancy may lead to an increased risk for persistent pulmonary hypertension of the newborn. (5.4, 8.1)

Increased

Risk of Bleeding : Concomitant use of aspirin, nonsteroidal anti- inflammatory drugs, other antiplatelet drugs, warfarin, and other anticoagulant drugs may increase risk. (5.5) Activation of Mania/Hypomania : Screen patients for bipolar disorder. (5.6) Seizures : Use with caution in patients with seizure disorders. (5.8) Angle-Closure Glaucoma : Angle-closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants. (5.9)

Sexual

Dysfunction : Paroxetine may cause symptoms of sexual dysfunction. (5.13) 5.1 ​Suicidal Thoughts and Behaviors in Adolescents and Young Adults In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and 4,500 pediatric patients, the incidence of suicidal thoughts and behaviors in antidepressant-treated patients age 24 years and younger was greater than in placebo-treated patients. There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied. There were differences in absolute risk of suicidal thoughts and behaviors across the different indications, with the highest incidence in patients with MDD. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1000 patients treated are provided in Table 2.

Table

2: Risk Differences of the Number of Patients with Suicidal Thoughts and Behaviors in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Patients Age Range Drug-Placebo Difference in Number of Patients with Suicidal Thoughts and Behaviors per 1,000 Patients Treated Increases Compared to Placebo <18 years old 14 additional cases 18-24 years old 5 additional cases Decreases Compared to Placebo 25-64 years old 1 fewer case ≥65 years old 6 fewer cases Paroxetine is not approved for use in pediatric patients. It is unknown whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with MDD that antidepressants delay the recurrence of depression and that depression itself is a risk factor for suicidal thoughts and behaviors. Monitor all antidepressant-treated patients for any indication for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy, and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing paroxetine, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.

5.2 Serotonin Syndrome SSRIs, including paroxetine, can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, meperidine, methadone, tryptophan, buspirone, amphetamines and St. John’s Wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs <span class="opacity-50 text-xs">[see Contraindications (4), Drug Interactions (7.1)]</span> . Serotonin syndrome can also occur when these drugs are used alone. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The concomitant use of paroxetine with MAOIs is contraindicated. In addition, do not initiate paroxetine in a patient being treated with MAOIs such as linezolid or intravenous methylene blue. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. If it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking paroxetine discontinue paroxetine before initiating treatment with the MAOI <span class="opacity-50 text-xs">[see Contraindications (4), Drug Interactions (7)]</span> . Monitor all patients taking paroxetine for the emergence of serotonin syndrome. Discontinue treatment with paroxetine and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of paroxetine with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms. 5.3 ​Drug Interactions Leading to QT Prolongation The CYP2D6 inhibitory properties of paroxetine can elevate plasma levels of thioridazine and pimozide. Since thioridazine and pimozide given alone produce prolongation of the QTc interval and increase the risk of serious ventricular arrhythmias, the use of paroxetine is contraindicated in combination with thioridazine and pimozide <span class="opacity-50 text-xs">[see Contraindications (4), Drug Interactions (7), Clinical Pharmacology (12.3)]</span>. 5.4 ​Embryofetal and Neonatal Toxicity Paroxetine can cause fetal harm when administered to a pregnant woman. Epidemiological studies have shown that infants exposed to paroxetine in the first trimester of pregnancy have an increased risk of cardiovascular malformations. Exposure to paroxetine in late pregnancy may lead to an increased risk for persistent pulmonary hypertension of the newborn (PPNH) and/or neonatal complications requiring prolonged hospitalization, respiratory support, and tube feeding. If paroxetine are used during pregnancy, or if the patient becomes pregnant while taking paroxetine, the patient should be apprised of the potential hazard to the fetus <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1)]</span>. 5.5 ​ Increased Risk of Bleeding Drugs that interfere with serotonin reuptake inhibition, including paroxetine, increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDS), other antiplatelet drugs, warfarin, and other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Based on data from the published observational studies, exposure to SSRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1)]</span>. Bleeding events related to drugs that interfere with serotonin reuptake have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages. Inform patients about the increased risk of bleeding associated with the concomitant use of paroxetine and antiplatelet agents or anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio. 5.6 ​Activation of Mania or Hypomania In patients with bipolar disorder, treating a depressive episode with paroxetine or another antidepressant may precipitate a mixed/manic episode. During controlled clinical trials of paroxetine, hypomania or mania occurred in approximately 1% of paroxetine-treated unipolar patients compared to 1.1% of active-control and 0.3% of placebo-treated unipolar patients. Prior to initiating treatment with paroxetine, screen patients for any personal or family history of bipolar disorder, mania, or hypomania. 5.7 ​Discontinuation Syndrome Adverse reactions after discontinuation of serotonergic antidepressants, particularly after abrupt discontinuation, include: nausea, sweating, dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia, such as electric shock sensations), tremor, anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. A gradual reduction in dosage rather than abrupt cessation is recommended whenever possible <span class="opacity-50 text-xs">[see Dosage and Administration (2.7)]</span>. During clinical trials of GAD and PTSD, gradual decreases in the daily dose by 10 mg/day at weekly intervals followed by 1 week at 20 mg/day was used before treatment was discontinued. The following adverse reactions were reported at an incidence of 2% or greater for paroxetine and were at least twice that reported for placebo: Abnormal dreams, paresthesia, and dizziness Adverse reactions have been reported upon discontinuation of treatment with paroxetine in pediatric patients. The safety and effectiveness of paroxetine in pediatric patients have not been established <span class="opacity-50 text-xs">[see Boxed Warning, Warnings and Precautions (5.1), Use in Specific Populations (8.4)]</span>. 5.8 ​Seizures Paroxetine tablets have not been systematically evaluated in patients with seizure disorders. Patients with history of seizures were excluded from clinical studies. During clinical studies, seizures occurred in 0.1% of patients treated with paroxetine. Paroxetine should be prescribed with caution in patients with a seizure disorder. Discontinue paroxetine in any patient who develops seizures. 5.9 ​Angle-Closure Glaucoma The pupillary dilation that occurs following use of many antidepressant drugs including paroxetine may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. Cases of angle-closure glaucoma associated with use of paroxetine have been reported. Avoid use of antidepressants, including paroxetine in patients with untreated anatomically narrow angles. 5.10 ​Hyponatremia Hyponatremia may occur as a result of treatment with SSRIs, including paroxetine. Cases with serum sodium lower than 110mmol/L have been reported. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). In patients with symptomatic hyponatremia, discontinue paroxetine and institute appropriate medical intervention. Elderly patients, patients taking diuretics, and those who are volume-depleted may be at greater risk of developing hyponatremia with SSRIs <span class="opacity-50 text-xs">[see Use in Specific Populations (8.5)]</span>. 5.11 ​Reduction of Efficacy of Tamoxifen Some studies have shown that the efficacy of tamoxifen, as measured by the risk of breast cancer relapse/mortality, may be reduced with concomitant use of paroxetine as a result of paroxetine’s irreversible inhibition of CYP2D6 and lower blood levels of tamoxifen <span class="opacity-50 text-xs">[see Drug Interactions (7)]</span> . One study suggests that the risk may increase with longer duration of coadministration. However, other studies have failed to demonstrate such a risk. When tamoxifen is used for the treatment or prevention of breast cancer, prescribers should consider using an alternative antidepressant with little or no CYP2D6 inhibition. 5.12 ​Bone Fracture Epidemiological studies on bone fracture risk during exposure to some antidepressants, including SSRIs, have reported an association between antidepressant treatment and fractures. There are multiple possible causes for this observation, and it is unknown to what extent fracture risk is directly attributable to SSRI treatment. 5.13 ​Sexual Dysfunction Use of SSRIs, including paroxetine, may cause symptoms of sexual dysfunction <span class="opacity-50 text-xs">[see Adverse Reactions (6.1)]</span> . In male patients, SSRI use may result in ejaculatory delay or failure, decreased libido, and erectile dysfunction. In female patients, SSRI use may result in decreased libido and delayed or absent orgasm. It is important for prescribers to inquire about sexual function prior to initiation of paroxetine and to inquire specifically about changes in sexual function during treatment, because sexual function may not be spontaneously reported. When evaluating changes in sexual function, obtaining a detailed history (including timing of symptom onset) is important because sexual symptoms may have other causes, including the underlying psychiatric disorder. Discuss potential management strategies to support patients in making informed decisions about treatment.

5.1 ​Suicidal Thoughts and Behaviors in Adolescents and Young Adults In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and 4,500 pediatric patients, the incidence of suicidal thoughts and behaviors in antidepressant-treated patients age 24 years and younger was greater than in placebo-treated patients. There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied. There were differences in absolute risk of suicidal thoughts and behaviors across the different indications, with the highest incidence in patients with MDD. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1000 patients treated are provided in Table 2.

Table

2: Risk Differences of the Number of Patients with Suicidal Thoughts and Behaviors in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Patients Age Range Drug-Placebo Difference in Number of Patients with Suicidal Thoughts and Behaviors per 1,000 Patients Treated Increases Compared to Placebo <18 years old 14 additional cases 18-24 years old 5 additional cases Decreases Compared to Placebo 25-64 years old 1 fewer case ≥65 years old 6 fewer cases Paroxetine is not approved for use in pediatric patients. It is unknown whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with MDD that antidepressants delay the recurrence of depression and that depression itself is a risk factor for suicidal thoughts and behaviors. Monitor all antidepressant-treated patients for any indication for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy, and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing paroxetine, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.

5.2 Serotonin Syndrome SSRIs, including paroxetine, can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, meperidine, methadone, tryptophan, buspirone, amphetamines and St. John’s Wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs <span class="opacity-50 text-xs">[see Contraindications (4), Drug Interactions (7.1)]</span> . Serotonin syndrome can also occur when these drugs are used alone. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The concomitant use of paroxetine with MAOIs is contraindicated. In addition, do not initiate paroxetine in a patient being treated with MAOIs such as linezolid or intravenous methylene blue. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. If it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking paroxetine discontinue paroxetine before initiating treatment with the MAOI <span class="opacity-50 text-xs">[see Contraindications (4), Drug Interactions (7)]</span> . Monitor all patients taking paroxetine for the emergence of serotonin syndrome. Discontinue treatment with paroxetine and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of paroxetine with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms.

5.3 ​Drug Interactions Leading to QT Prolongation The CYP2D6 inhibitory properties of paroxetine can elevate plasma levels of thioridazine and pimozide. Since thioridazine and pimozide given alone produce prolongation of the QTc interval and increase the risk of serious ventricular arrhythmias, the use of paroxetine is contraindicated in combination with thioridazine and pimozide [see Contraindications (4), Drug Interactions (7), Clinical Pharmacology (12.3)].

5.4 ​Embryofetal and Neonatal Toxicity Paroxetine can cause fetal harm when administered to a pregnant woman. Epidemiological studies have shown that infants exposed to paroxetine in the first trimester of pregnancy have an increased risk of cardiovascular malformations. Exposure to paroxetine in late pregnancy may lead to an increased risk for persistent pulmonary hypertension of the newborn (PPNH) and/or neonatal complications requiring prolonged hospitalization, respiratory support, and tube feeding. If paroxetine are used during pregnancy, or if the patient becomes pregnant while taking paroxetine, the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations (8.1)].

5.5 ​ Increased Risk of Bleeding Drugs that interfere with serotonin reuptake inhibition, including paroxetine, increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDS), other antiplatelet drugs, warfarin, and other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Based on data from the published observational studies, exposure to SSRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [see Use in Specific Populations (8.1)]. Bleeding events related to drugs that interfere with serotonin reuptake have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages. Inform patients about the increased risk of bleeding associated with the concomitant use of paroxetine and antiplatelet agents or anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio.

5.6 ​Activation of Mania or Hypomania In patients with bipolar disorder, treating a depressive episode with paroxetine or another antidepressant may precipitate a mixed/manic episode. During controlled clinical trials of paroxetine, hypomania or mania occurred in approximately 1% of paroxetine-treated unipolar patients compared to 1.1% of active-control and 0.3% of placebo-treated unipolar patients. Prior to initiating treatment with paroxetine, screen patients for any personal or family history of bipolar disorder, mania, or hypomania.

5.7 ​Discontinuation Syndrome Adverse reactions after discontinuation of serotonergic antidepressants, particularly after abrupt discontinuation, include: nausea, sweating, dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia, such as electric shock sensations), tremor, anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. A gradual reduction in dosage rather than abrupt cessation is recommended whenever possible [see Dosage and Administration (2.7)]. During clinical trials of GAD and PTSD, gradual decreases in the daily dose by 10 mg/day at weekly intervals followed by 1 week at 20 mg/day was used before treatment was discontinued. The following adverse reactions were reported at an incidence of 2% or greater for paroxetine and were at least twice that reported for placebo: Abnormal dreams, paresthesia, and dizziness Adverse reactions have been reported upon discontinuation of treatment with paroxetine in pediatric patients. The safety and effectiveness of paroxetine in pediatric patients have not been established [see Boxed Warning, Warnings and Precautions (5.1), Use in Specific Populations (8.4)].

5.8 ​Seizures Paroxetine tablets have not been systematically evaluated in patients with seizure disorders. Patients with history of seizures were excluded from clinical studies. During clinical studies, seizures occurred in 0.1% of patients treated with paroxetine. Paroxetine should be prescribed with caution in patients with a seizure disorder. Discontinue paroxetine in any patient who develops seizures.

5.9 ​Angle-Closure Glaucoma The pupillary dilation that occurs following use of many antidepressant drugs including paroxetine may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. Cases of angle-closure glaucoma associated with use of paroxetine have been reported. Avoid use of antidepressants, including paroxetine in patients with untreated anatomically narrow angles.

5.10 ​Hyponatremia Hyponatremia may occur as a result of treatment with SSRIs, including paroxetine. Cases with serum sodium lower than 110mmol/L have been reported. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). In patients with symptomatic hyponatremia, discontinue paroxetine and institute appropriate medical intervention. Elderly patients, patients taking diuretics, and those who are volume-depleted may be at greater risk of developing hyponatremia with SSRIs [see Use in Specific Populations (8.5)].

5.11 ​Reduction of Efficacy of Tamoxifen Some studies have shown that the efficacy of tamoxifen, as measured by the risk of breast cancer relapse/mortality, may be reduced with concomitant use of paroxetine as a result of paroxetine’s irreversible inhibition of CYP2D6 and lower blood levels of tamoxifen [see Drug Interactions (7)] . One study suggests that the risk may increase with longer duration of coadministration. However, other studies have failed to demonstrate such a risk. When tamoxifen is used for the treatment or prevention of breast cancer, prescribers should consider using an alternative antidepressant with little or no CYP2D6 inhibition.

5.12 ​Bone Fracture Epidemiological studies on bone fracture risk during exposure to some antidepressants, including SSRIs, have reported an association between antidepressant treatment and fractures. There are multiple possible causes for this observation, and it is unknown to what extent fracture risk is directly attributable to SSRI treatment.

5.13 ​Sexual Dysfunction Use of SSRIs, including paroxetine, may cause symptoms of sexual dysfunction [see Adverse Reactions (6.1)] . In male patients, SSRI use may result in ejaculatory delay or failure, decreased libido, and erectile dysfunction. In female patients, SSRI use may result in decreased libido and delayed or absent orgasm. It is important for prescribers to inquire about sexual function prior to initiation of paroxetine and to inquire specifically about changes in sexual function during treatment, because sexual function may not be spontaneously reported. When evaluating changes in sexual function, obtaining a detailed history (including timing of symptom onset) is important because sexual symptoms may have other causes, including the underlying psychiatric disorder. Discuss potential management strategies to support patients in making informed decisions about treatment.

PRECAUTIONS General Activation of Mania/Hypomania During premarketing testing, hypomania or mania occurred in approximately 1.0% of unipolar patients treated with paroxetine tablets compared to 1.1% of active-control and 0.3% of placebo-treated unipolar patients. In a subset of patients classified as bipolar, the rate of manic episodes was 2.2% for paroxetine tablets and 11.6% for the combined active-control groups. As with all drugs effective in the treatment of major depressive disorder, paroxetine tablets should be used cautiously in patients with a history of mania.

Seizures

During premarketing testing, seizures occurred in 0.1% of patients treated with paroxetine tablets, a rate similar to that associated with other drugs effective in the treatment of major depressive disorder. Paroxetine tablets should be used cautiously in patients with a history of seizures. It should be discontinued in any patient who develops seizures. Discontinuation of Treatment with Paroxetine Tablets Recent clinical trials supporting the various approved indications for paroxetine tablets employed a taper-phase regimen, rather than an abrupt discontinuation of treatment. The taper-phase regimen used in GAD and PTSD clinical trials involved an incremental decrease in the daily dose by 10 mg/day at weekly intervals. When a daily dose of 20 mg/day was reached, patients were continued on this dose for 1 week before treatment was stopped. With this regimen in those studies, the following adverse events were reported at an incidence of 2% or greater for paroxetine tablets and were at least twice that reported for placebo: Abnormal dreams, paresthesia, and dizziness. In the majority of patients, these events were mild to moderate and were self-limiting and did not require medical intervention. During marketing of paroxetine tablets and other SSRIs and SNRIs, there have been spontaneous reports of adverse events occurring upon the discontinuation of these drugs (particularly when abrupt), including the following: Dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations and tinnitus), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms. Patients should be monitored for these symptoms when discontinuing treatment with paroxetine tablets. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate (see DOSAGE AND ADMINISTRATION ). See also PRECAUTIONS: Pediatric Use , for adverse events reported upon discontinuation of treatment with paroxetine tablets in pediatric patients.

Tamoxifen

Some studies have shown that the efficacy of tamoxifen, as measured by the risk of breast cancer relapse/mortality, may be reduced when co-prescribed with paroxetine as a result of paroxetine’s irreversible inhibition of CYP2D6 (see Drug Interactions ). However, other studies have failed to demonstrate such a risk. It is uncertain whether the coadministration of paroxetine and tamoxifen has a significant adverse effect on the efficacy of tamoxifen. One study suggests that the risk may increase with longer duration of coadministration. When tamoxifen is used for the treatment or prevention of breast cancer, prescribers should consider using an alternative antidepressant with little or no CYP2D6 inhibition.

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 tablets. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk (see PRECAUTIONS: Geriatric Use ). Discontinuation of paroxetine tablets, should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.

Abnormal

Bleeding SSRIs and SNRIs, including paroxetine, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages. Patients should be cautioned about the risk of bleeding associated with the concomitant use of paroxetine and NSAIDs, aspirin, or other drugs that affect coagulation.

Bone Fracture

Epidemiological studies on bone fracture risk following exposure to some antidepressants, including SSRIs, have reported an association between antidepressant treatment and fractures. There are multiple possible causes for this observation and it is unknown to what extent fracture risk is directly attributable to SSRI treatment. The possibility of a pathological fracture, that is, a fracture produced by minimal trauma in a patient with decreased bone mineral density, should be considered in patients treated with paroxetine who present with unexplained bone pain, point tenderness, swelling, or bruising. Use in Patients with Concomitant Illness Clinical experience with paroxetine tablets in patients with certain concomitant systemic illness is limited. Caution is advisable in using paroxetine tablets in patients with diseases or conditions that could affect metabolism or hemodynamic responses. As with other SSRIs, mydriasis has been infrequently reported in premarketing studies with paroxetine tablets. A few cases of acute angle-closure glaucoma associated with paroxetine therapy have been reported in the literature. As mydriasis can cause acute angle-closure in patients with narrow angle glaucoma, caution should be used when paroxetine tablets are prescribed for patients with narrow angle glaucoma. Paroxetine tablets have not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from clinical studies during the product’s premarket testing. Evaluation of electrocardiograms of 682 patients who received paroxetine tablets in double-blind, placebo-controlled trials, however, did not indicate that paroxetine tablets are associated with the development of significant ECG abnormalities. Similarly, paroxetine tablets do not cause any clinically important changes in heart rate or blood pressure. Increased plasma concentrations of paroxetine occur in patients with severe renal impairment (creatinine clearance < 30 mL/min) or severe hepatic impairment. A lower starting dose should be used in such patients (see DOSAGE AND ADMINISTRATION ). Information for Patients Paroxetine tablets should not be chewed or crushed, and should be swallowed whole. Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of paroxetine tablets and triptans, tramadol, or other serotonergic agents. Patients should be advised that taking paroxetine tablets can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle-closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle-closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle-closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle-closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible. Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with paroxetine tablets and should counsel them in its appropriate use. A patient Medication Guide is available for paroxetine tablets. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking paroxetine tablets.

Clinical

Worsening and Suicide Risk Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.

Drugs That

Interfere with Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin) Patients should be cautioned about the concomitant use of paroxetine and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding. Interference with Cognitive and Motor Performance Any psychoactive drug may impair judgment, thinking, or motor skills. Although in controlled studies paroxetine tablets have not been shown to impair psychomotor performance, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that therapy with paroxetine tablets do not affect their ability to engage in such activities.

Completing

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

Concomitant Medication

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

Alcohol

Although paroxetine tablets have not been shown to increase the impairment of mental and motor skills caused by alcohol, patients should be advised to avoid alcohol while taking paroxetine tablets.

Pregnancy

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

Nursing

Patients should be advised to notify their physician if they are breastfeeding an infant (see PRECAUTIONS: Nursing Mothers ).

Laboratory Tests

There are no specific laboratory tests recommended.

Drug Interactions

Tryptophan As with other serotonin reuptake inhibitors, an interaction between paroxetine and tryptophan may occur when they are coadministered. Adverse experiences, consisting primarily of headache, nausea, sweating, and dizziness, have been reported when tryptophan was administered to patients taking paroxetine tablets. Consequently, concomitant use of paroxetine tablets with tryptophan is not recommended (see WARNINGS: Serotonin Syndrome ).

Monoamine Oxidase Inhibitors

See CONTRAINDICATIONS and WARNINGS . Pimozide In a controlled study of healthy volunteers, after paroxetine tablets were titrated to 60 mg daily, co-administration of a single dose of 2 mg pimozide was associated with mean increases in pimozide AUC of 151% and C max of 62%, compared to pimozide administered alone. The increase in pimozide AUC and C max is due to the CYP2D6 inhibitory properties of paroxetine. Due to the narrow therapeutic index of pimozide and its known ability to prolong the QT interval, concomitant use of pimozide and paroxetine tablets are contraindicated (see CONTRAINDICATIONS ).

Serotonergic Drugs

Based on the mechanism of action of SNRIs and SSRIs, including paroxetine hydrochloride, and the potential for serotonin syndrome, caution is advised when paroxetine tablets are coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, lithium, fentanyl, tramadol, amphetamines, or St. John's Wort (see WARNINGS: Serotonin Syndrome ). The concomitant use of paroxetine tablets with MAOIs (including linezolid and intravenous methylene blue) is contraindicated (see CONTRAINDICATIONS ). The concomitant use of paroxetine tablets with other SSRIs, SNRIs or tryptophan is not recommended (see PRECAUTIONS: Drug Interactions: Tryptophan ).

Thioridazine

See CONTRAINDICATIONS and WARNINGS .

Warfarin

Preliminary data suggest that there may be a pharmacodynamic interaction (that causes an increased bleeding diathesis in the face of unaltered prothrombin time) between paroxetine and warfarin. Since there is little clinical experience, the concomitant administration of paroxetine tablets and warfarin should be undertaken with caution (see PRECAUTIONS: Information for Patients: 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 tablets 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.

Cimetidine

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

Phenobarbital

Phenobarbital induces many cytochrome P 450 (oxidative) enzymes. When a single oral 30 mg dose of paroxetine tablets were administered at phenobarbital steady state (100 mg once daily for 14 days), paroxetine AUC and T 1/2 were reduced (by an average of 25% and 38%, respectively) compared to paroxetine administered alone. The effect of paroxetine on phenobarbital pharmacokinetics was not studied. Since paroxetine tablets exhibit nonlinear pharmacokinetics, the results of this study may not address the case where the 2 drugs are both being chronically dosed. No initial dosage adjustment of paroxetine tablets are considered necessary when coadministered with phenobarbital; any subsequent adjustment should be guided by clinical effect.

Phenytoin

When a single oral 30 mg dose of paroxetine tablets were administered at phenytoin steady state (300 mg once daily for 14 days), paroxetine AUC and T 1/2 were reduced (by an average of 50% and 35%, respectively) compared to paroxetine tablets administered alone. In a separate study, when a single oral 300 mg dose of phenytoin was administered at paroxetine steady state (30 mg once daily for 14 days), phenytoin AUC was slightly reduced (12% on average) compared to phenytoin administered alone. Since both drugs exhibit nonlinear pharmacokinetics, the above studies may not address the case where the 2 drugs are both being chronically dosed. No initial dosage adjustments are considered necessary when these drugs are coadministered; any subsequent adjustments should be guided by clinical effect (see ADVERSE REACTIONS: Postmarketing Reports ).

Drugs

Metabolized by CYP2D6 Many drugs, including most drugs effective in the treatment of major depressive disorder (paroxetine, other SSRIs and many tricyclics), are metabolized by the cytochrome P 450 isozyme CYP2D6. Like other agents that are metabolized by CYP2D6, paroxetine may significantly inhibit the activity of this isozyme. In most patients (> 90%), this CYP2D6 isozyme is saturated early during dosing with paroxetine tablets.

In

1 study, daily dosing of paroxetine tablets (20 mg once daily) under steady-state conditions increased single dose desipramine (100 mg) C max , AUC, and T 1/2 by an average of approximately 2-, 5-, and 3-fold, respectively. Concomitant use of paroxetine with risperidone, a CYP2D6 substrate has also been evaluated.

In

1 study, daily dosing of paroxetine 20 mg in patients stabilized on risperidone (4 to 8 mg/day) increased mean plasma concentrations of risperidone approximately 4-fold, decreased 9-hydroxyrisperidone concentrations approximately 10%, and increased concentrations of the active moiety (the sum of risperidone plus 9-hydroxyrisperidone) approximately 1.4-fold. The effect of paroxetine on the pharmacokinetics of atomoxetine has been evaluated when both drugs were at steady state. In healthy volunteers who were extensive metabolizers of CYP2D6, paroxetine 20 mg daily was given in combination with 20 mg atomoxetine every 12 hours. This resulted in increases in steady state atomoxetine AUC values that were 6- to 8-fold greater and in atomoxetine C max values that were 3- to 4-fold greater than when atomoxetine was given alone. Dosage adjustment of atomoxetine may be necessary and it is recommended that atomoxetine be initiated at a reduced dose when it is given with paroxetine. Concomitant use of paroxetine tablets with other drugs metabolized by cytochrome CYP2D6 has not been formally studied but may require lower doses than usually prescribed for either paroxetine tablets or the other drug. Therefore, coadministration of paroxetine tablets with other drugs that are metabolized by this isozyme, including certain drugs effective in the treatment of major depressive disorder (e.g., nortriptyline, amitriptyline, imipramine, desipramine, and fluoxetine), phenothiazines, risperidone, and Type 1C antiarrhythmics (e.g., propafenone, flecainide, and encainide), or that inhibit this enzyme (e.g., quinidine), should be approached with caution. However, due to the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, paroxetine and thioridazine should not be coadministered (see CONTRAINDICATIONS and WARNINGS ). Tamoxifen is a pro-drug requiring metabolic activation by CYP2D6. Inhibition of CYP2D6 by paroxetine may lead to reduced plasma concentrations of an active metabolite (endoxifen) and hence reduced efficacy of tamoxifen (see PRECAUTIONS ). At steady state, when the CYP2D6 pathway is essentially saturated, paroxetine clearance is governed by alternative P 450 isozymes that, unlike CYP2D6, show no evidence of saturation (see PRECAUTIONS: Drug Interactions: Tricyclic Antidepressants (TCAs) ).

Drugs

Metabolized by Cytochrome CYP3A4 An in vivo interaction study involving the co-administration under steady-state conditions of paroxetine and terfenadine, a substrate for cytochrome CYP3A4, revealed no effect of paroxetine on terfenadine pharmacokinetics. In addition, in vitro studies have shown ketoconazole, a potent inhibitor of CYP3A4 activity, to be at least 100 times more potent than paroxetine as an inhibitor of the metabolism of several substrates for this enzyme, including terfenadine, astemizole, cisapride, triazolam, and cyclosporine. Based on the assumption that the relationship between paroxetine’s in vitro K i and its lack of effect on terfenadine’s in vivo clearance predicts its effect on other CYP3A4 substrates, paroxetine’s extent of inhibition of CYP3A4 activity is not likely to be of clinical significance.

Tricyclic

Antidepressants (TCAs) Caution is indicated in the coadministration of tricyclic antidepressants (TCAs) with paroxetine tablets, because paroxetine may inhibit TCA metabolism. Plasma TCA concentrations may need to be monitored, and the dose of TCA may need to be reduced, if a TCA is coadministered with paroxetine tablets (see PRECAUTIONS: Drugs Metabolized by Cytochrome CYP2D6 ).

Drugs Highly

Bound to Plasma Protein Because paroxetine is highly bound to plasma protein, administration of paroxetine tablets to a patient taking another drug that is highly protein bound may cause increased free concentrations of the other drug, potentially resulting in adverse events. Conversely, adverse effects could result from displacement of paroxetine by other highly bound drugs.

Drugs That

Interfere with Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin) Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs or SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when paroxetine is initiated or discontinued.

Alcohol

Although paroxetine tablets do not increase the impairment of mental and motor skills caused by alcohol, patients should be advised to avoid alcohol while taking paroxetine tablets. Lithium A multiple-dose study has shown that there is no pharmacokinetic interaction between paroxetine tablets and lithium carbonate. However, due to the potential for serotonin syndrome, caution is advised when paroxetine tablets are coadministered with lithium.

Digoxin

The steady-state pharmacokinetics of paroxetine was not altered when administered with digoxin at steady state. Mean digoxin AUC at steady state decreased by 15% in the presence of paroxetine. Since there is little clinical experience, the concurrent administration of paroxetine and digoxin should be undertaken with caution.

Diazepam

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

Procyclidine

Daily oral dosing of paroxetine tablets (30 mg once daily) increased steady-state AUC 0-24 , C max , and C min values of procyclidine (5 mg oral once daily) by 35%, 37%, and 67%, respectively, compared to procyclidine alone at steady state. If anticholinergic effects are seen, the dose of procyclidine should be reduced. Beta-Blockers In a study where propranolol (80 mg twice daily) was dosed orally for 18 days, the established steady-state plasma concentrations of propranolol were unaltered during co-administration 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).

Electroconvulsive

Therapy (ECT) There are no clinical studies of the combined use of ECT and paroxetine tablets. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Two year carcinogenicity studies were conducted in rodents given paroxetine in the diet at 1, 5, and 25 mg/kg/day (mice) and 1, 5, and 20 mg/kg/day (rats). These doses are up to 2.4 (mouse) and 3.9 (rat) times the MRHD for major depressive disorder, social anxiety disorder, GAD, and PTSD on a mg/m 2 basis. Because the MRHD for major depressive disorder is slightly less than that for OCD (50 mg versus 60 mg), the doses used in these carcinogenicity studies were only 2.0 (mouse) and 3.2 (rat) times the MRHD for OCD. There was a significantly greater number of male rats in the high-dose group with reticulum cell sarcomas (1/100, 0/50, 0/50, and 4/50 for control, low-, middle-, and high-dose groups, respectively) and a significantly increased linear trend across dose groups for the occurrence of lymphoreticular tumors in male rats. Female rats were not affected. Although there was a dose-related increase in the number of tumors in mice, there was no drug-related increase in the number of mice with tumors. The relevance of these findings to humans is unknown.

Mutagenesis

Paroxetine produced no genotoxic effects in a battery of 5 in vitro and 2 in vivo assays that included the following: Bacterial mutation assay, mouse lymphoma mutation assay, unscheduled DNA synthesis assay, and tests for cytogenetic aberrations in vivo in mouse bone marrow and in vitro in human lymphocytes and in a dominant lethal test in rats. Impairment of Fertility Some clinical studies have shown that SSRIs (including paroxetine) may affect sperm quality during SSRI treatment, which may affect fertility in some men. A reduced pregnancy rate was found in reproduction studies in rats at a dose of paroxetine of 15 mg/kg/day, which is 2.9 times the MRHD for major depressive disorder, social anxiety disorder, GAD, and PTSD or 2.4 times the MRHD for OCD on a mg/m 2 basis. Irreversible lesions occurred in the reproductive tract of male rats after dosing in toxicity studies for 2 to 52 weeks. These lesions consisted of vacuolation of epididymal tubular epithelium at 50 mg/kg/day and atrophic changes in the seminiferous tubules of the testes with arrested spermatogenesis at 25 mg/kg/day (9.8 and 4.9 times the MRHD for major depressive disorder, social anxiety disorder, and GAD; 8.2 and 4.1 times the MRHD for OCD and PD on a mg/m 2 basis).

Pregnancy Pregnancy

Category D See WARNINGS: Usage In Pregnancy: Teratogenic Effects and Nonteratogenic Effects . Labor and Delivery The effect of paroxetine on labor and delivery in humans is unknown.

Nursing Mothers

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

Pediatric Use

Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS: Clinical Worsening and Suicide Risk ). Three placebo-controlled trials in 752 pediatric patients with MDD have been conducted with immediate-release paroxetine tablets, and the data were not sufficient to support a claim for use in pediatric patients. Anyone considering the use of paroxetine tablets in a child or adolescent must balance the potential risks with the clinical need. Decreased appetite and weight loss have been observed in association with the use of SSRIs. Consequently, regular monitoring of weight and growth should be performed in children and adolescents treated with an SSRI such as paroxetine tablets. 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 tablets, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event (see PRECAUTIONS: Hyponatremia ). In worldwide premarketing clinical trials with paroxetine tablets, 17% of patients treated with paroxetine tablets (approximately 700) were 65 years of age or older. Pharmacokinetic studies revealed a decreased clearance in the elderly, and a lower starting dose is recommended; there were, however, no overall differences in the adverse event profile between elderly and younger patients, and effectiveness was similar in younger and older patients (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION ).

Drug Interactions Tryptophan As with other serotonin reuptake inhibitors, an interaction between paroxetine and tryptophan may occur when they are coadministered. Adverse experiences, consisting primarily of headache, nausea, sweating, and dizziness, have been reported when tryptophan was administered to patients taking paroxetine hydrochloride. Consequently, concomitant use of paroxetine hydrochloride with tryptophan is not recommended (see WARNINGS: Serotonin Syndrome ).

Monoamine Oxidase Inhibitors

See CONTRAINDICATIONS and WARNINGS . Pimozide In a controlled study of healthy volunteers, after paroxetine hydrochloride was titrated to 60 mg daily, coadministration of a single dose of 2 mg pimozide was associated with mean increases in pimozide AUC of 151% and C max of 62%, compared to pimozide administered alone. The increase in pimozide AUC and C max is due to the CYP2D6 inhibitory properties of paroxetine. Due to the narrow therapeutic index of pimozide and its known ability to prolong the QT interval, concomitant use of pimozide and paroxetine hydrochloride is contraindicated (see CONTRAINDICATIONS ).

Serotonergic Drugs

Based on the mechanism of action of SNRIs and SSRIs, including paroxetine hydrochloride and the potential for serotonin syndrome, caution is advised when paroxetine hydrochloride is coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, lithium, fentanyl, tramadol or St. John's Wort (see WARNINGS: Serotonin Syndrome ). The concomitant use of paroxetine hydrochloride with MAOIs (including linezolid and intravenous methylene blue) is contradicated (see CONTRADICATIONS ). The concomitant use of paroxetine hydrochloride with other SSRIs, SNRIs or tryptophan is not recommended (see PRECAUTIONS: Drug Interactions: Tryptophan ).

Thioridazine

See CONTRAINDICATIONS and WARNINGS .

Warfarin

Preliminary data suggest that there may be a pharmacodynamic interaction (that causes an increased bleeding diathesis in the face of unaltered prothrombin time) between paroxetine and warfarin. Since there is little clinical experience, the concomitant administration of paroxetine hydrochloride and warfarin should be undertaken with caution (see PRECAUTIONS: Information for Patients: Drugs That Interfere with Hemostasis ).

Triptans

There have been rare post-marketing reports of serotonin syndrome with the use of an SSRI and a triptan. If concomitant use of paroxetine hydrochloride 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.

Cimetidine

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

Phenobarbital

Phenobarbital induces many cytochrome P 450 (oxidative) enzymes. When a single oral 30 mg dose of paroxetine hydrochloride was administered at phenobarbital steady-state (100 mg once daily for 14 days), paroxetine AUC and T 1/2 were reduced (by an average of 25% and 38%, respectively) compared to paroxetine administered alone. The effect of paroxetine on phenobarbital pharmacokinetics was not studied. Since paroxetine hydrochloride exhibits nonlinear pharmacokinetics, the results of this study may not address the case where the two drugs are both being chronically dosed. No initial dosage adjustment of paroxetine hydrochloride is considered necessary when coadministered with phenobarbital; any subsequent adjustment should be guided by clinical effect.

Phenytoin

When a single oral 30 mg dose of paroxetine hydrochloride was administered at phenytoin steady-state (300 mg once daily for 14 days), paroxetine AUC and T 1/2 were reduced (by an average of 50% and 35%, respectively) compared to paroxetine hydrochloride administered alone. In a separate study, when a single oral 300 mg dose of phenytoin was administered at paroxetine steady-state (30 mg once daily for 14 days), phenytoin AUC was slightly reduced (12% on average) compared to phenytoin administered alone. Since both drugs exhibit nonlinear pharmacokinetics, the above studies may not address the case where the two drugs are both being chronically dosed. No initial dosage adjustments are considered necessary when these drugs are coadministered; any subsequent adjustments should be guided by clinical effect (see ADVERSE REACTIONS: Post-Marketing Reports ).

Drugs

Metabolized by CYP2D6 Many drugs, including most drugs effective in the treatment of major depressive disorder (paroxetine, other SSRIs and many tricyclics), are metabolized by the cytochrome P 450 isozyme CYP2D6. Like other agents that are metabolized by CYP2D6, paroxetine may significantly inhibit the activity of this isozyme. In most patients (> 90%), this CYP2D6 isozyme is saturated early during dosing with paroxetine hydrochloride. In one study, daily dosing of paroxetine hydrochloride (20 mg once daily) under steady-state conditions increased single dose desipramine (100 mg) C max , AUC, and T 1/2 by an average of approximately 2-, 5-, and 3-fold, respectively. Concomitant use of paroxetine with risperidone, a CYP2D6 substrate has also been evaluated. In one study, daily dosing of paroxetine 20 mg in patients stabilized on risperidone (4 to 8 mg/day) increased mean plasma concentrations of risperidone approximately 4-fold, decreased 9-hydroxyrisperidone concentrations approximately 10%, and increased concentrations of the active moiety (the sum of risperidone plus 9-hydroxyrisperidone) approximately 1.4-fold. The effect of paroxetine on the pharmacokinetics of atomoxetine has been evaluated when both drugs were at steady-state. In healthy volunteers who were extensive metabolizers of CYP2D6, paroxetine 20 mg daily was given in combination with 20 mg atomoxetine every 12 hours. This resulted in increases in steady-state atomoxetine AUC values that were 6- to 8-fold greater and in atomoxetine C max values that were 3- to 4-fold greater than when atomoxetine was given alone. Dosage adjustment of atomoxetine may be necessary and it is recommended that atomoxetine be initiated at a reduced dose when it is given with paroxetine. Concomitant use of paroxetine hydrochloride with other drugs metabolized by cytochrome CYP2D6 has not been formally studied but may require lower doses than usually prescribed for either paroxetine hydrochloride or the other drug. Therefore, coadministration of paroxetine hydrochloride with other drugs that are metabolized by this isozyme, including certain drugs effective in the treatment of major depressive disorder (e.g., nortriptyline, amitriptyline, imipramine, desipramine, and fluoxetine), phenothiazines, risperidone and Type 1C antiarrhythmics (e.g., propafenone, flecainide, and encainide), or that inhibit this enzyme (e.g., quinidine), should be approached with caution. However, due to the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, paroxetine and thioridazine should not be coadministered (see CONTRAINDICATIONS and WARNINGS ). Tamoxifen is a pro-drug requiring metabolic activation by CYP2D6. Inhibition of CYP2D6 by paroxetine may lead to reduced plasma concentrations of an active metabolite (endoxifen) and hence reduced efficacy of tamoxifen (see PRECAUTIONS ). At steady-state, when the CYP2D6 pathway is essentially saturated, paroxetine clearance is governed by alternative P 450 isozymes that, unlike CYP2D6, show no evidence of saturation (see PRECAUTIONS: Drug Interactions: Tricyclic Antidepressants (TCAs) ).

Drugs

Metabolized by Cytochrome CYP3A4 An in vivo interaction study involving the coadministration under steady-state conditions of paroxetine and terfenadine, a substrate for cytochrome CYP3A4, revealed no effect of paroxetine on terfenadine pharmacokinetics. In addition, in vitro studies have shown ketoconazole, a potent inhibitor of CYP3A4 activity, to be at least 100 times more potent than paroxetine as an inhibitor of the metabolism of several substrates for this enzyme, including terfenadine, astemizole, cisapride, triazolam, and cyclosporine. Based on the assumption that the relationship between paroxetine’s in vitro K i and its lack of effect on terfenadine’s in vivo clearance predicts its effect on other CYP3A4 substrates, paroxetine’s extent of inhibition of CYP3A4 activity is not likely to be of clinical significance.

Tricyclic

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

Drugs Highly

Bound to Plasma Protein Because paroxetine is highly bound to plasma protein, administration of paroxetine hydrochloride to a patient taking another drug that is highly protein bound may cause increased free concentrations of the other drug, potentially resulting in adverse events. Conversely, adverse effects could result from displacement of paroxetine by other highly bound drugs.

Drugs That

Interfere with Hemostasis (e.g., NSAIDs, Aspirin and Warfarin) Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs or SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when paroxetine is initiated or discontinued.

Alcohol

Although paroxetine hydrochloride does not increase the impairment of mental and motor skills caused by alcohol, patients should be advised to avoid alcohol while taking paroxetine hydrochloride. Lithium A multiple-dose study has shown that there is no pharmacokinetic interaction between paroxetine hydrochloride and lithium carbonate. However, due to the potential for serotonin syndrome, caution is advised when paroxetine hydrochloride is coadministered with lithium.

Digoxin

The steady-state pharmacokinetics of paroxetine was not altered when administered with digoxin at steady-state. Mean digoxin AUC at steady-state decreased by 15% in the presence of paroxetine. Since there is little clinical experience, the concurrent administration of paroxetine and digoxin should be undertaken with caution.

Diazepam

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

Procyclidine

Daily oral dosing of paroxetine tablets (30 mg once daily) increased steady-state AUC 0-24 , C max , and C min values of procyclidine (5 mg oral once daily) by 35%, 37%, and 67%, respectively, compared to procyclidine alone at steady-state. If anticholinergic effects are seen, the dose of procyclidine should be reduced. Beta-Blockers In a study where propranolol (80 mg twice daily) was dosed orally for 18 days, the established steady-state plasma concentrations of propranolol were unaltered during coadministration with paroxetine hydrochloride (30 mg once daily) for the final 10 days. The effects of propranolol on paroxetine have not been evaluated (see ADVERSE REACTIONS: Post-Marketing Reports ).

Theophylline

Reports of elevated theophylline levels associated with treatment with paroxetine hydrochloride 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

Coadministration of fosamprenavir/ritonavir with paroxetine significantly decreased plasma levels of paroxetine. Any dose adjustment should be guided by clinical effect (tolerability and efficacy).

Electroconvulsive

Therapy (ECT) There are no clinical studies of the combined use of ECT and paroxetine hydrochloride.