PAROXETINE

Paroxetine tablets, USP are an orally administered psychotropic drug. It is the hydrochloride salt of a phenylpiperidine compound identified chemically as (-)-trans - 4R -(4' - fluorophenyl)- 3S -[(3',4'-methylenedioxyphenoxy) methyl] piperidine hydrochloride hemihydrate and has the molecular formula of C 19 H 20 FNO 3 •HCl•1/2H 2 O. The molecular weight is 374.8 (329.4 as free base). The structural formula of paroxetine hydrochloride hemihydrate is: Paroxetine hydrochloride, USP is an odorless, white to off-white crystalline powder, having a melting point range of 120° to 138°C. It is freely soluble in methanol, soluble in ethanol, sparingly soluble in dichloromethane and slightly soluble in water. Each paroxetine tablet, USP intended for oral administration contains paroxetine hydrochloride hemihydrate equivalent to 10 mg or 20 mg or 30 mg or 40 mg of paroxetine. In addition, each tablet contains the following inactive ingredients: dibasic calcium phosphate anhydrous, hypromellose 6 cP, lactose anhydrous, magnesium stearate, polyethylene glycol 6000, povidone, sodium starch glycolate, talc, and titanium dioxide. Structured formula for Paroxetine

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 ).

Major Depressive Disorder: Usual Initial Dosage: Paroxetine tablets should be administered as a single daily dose with or without food, usually in the morning. The recommended initial dose is 20 mg/day. Patients were dosed in a range of 20 to 50 mg/day in the clinical trials demonstrating the effectiveness of paroxetine tablets in the treatment of major depressive disorder. As with all drugs effective in the treatment of major depressive disorder, the full effect may be delayed. Some patients not responding to a 20-mg dose may benefit from dose increases, in 10-mg/day increments, up to a maximum of 50 mg/day. Dose changes should occur at intervals of at least 1 week. Maintenance Therapy: There is no body of evidence available to answer the question of how long the patient treated with paroxetine tablets should remain on it. It is generally agreed that acute episodes of major depressive disorder require several months or longer of sustained pharmacologic therapy. Whether the dose needed to induce remission is identical to the dose needed to maintain and/or sustain euthymia is unknown. Systematic evaluation of the efficacy of paroxetine tablets has shown that efficacy is maintained for periods of up to 1 year with doses that averaged about 30 mg. Obsessive Compulsive Disorder: Usual Initial Dosage: Paroxetine tablets should be administered as a single daily dose with or without food, usually in the morning. The recommended dose of paroxetine tablets in the treatment of OCD is 40 mg daily. Patients should be started on 20 mg/day and the dose can be increased in 10-mg/day increments. Dose changes should occur at intervals of at least 1 week. Patients were dosed in a range of 20 to 60 mg/day in the clinical trials demonstrating the effectiveness of paroxetine tablets in the treatment of OCD. The maximum dosage should not exceed 60 mg/day. Maintenance Therapy: Long-term maintenance of efficacy was demonstrated in a 6-month relapse prevention trial. In this trial, patients with OCD assigned to paroxetine demonstrated a lower relapse rate compared to patients on placebo (see CLINICAL PHARMACOLOGY — Clinical Trials ). OCD is a chronic condition, and it is reasonable to consider continuation for a responding patient. Dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for continued treatment. Panic Disorder: Usual Initial Dosage: Paroxetine tablets should be administered as a single daily dose with or without food, usually in the morning. The target dose of paroxetine tablets in the treatment of panic disorder is 40 mg/day. Patients should be started on 10 mg/day. Dose changes should occur in 10-mg/day increments and at intervals of at least 1 week. Patients were dosed in a range of 10 to 60 mg/day in the clinical trials demonstrating the effectiveness of paroxetine tablets. The maximum dosage should not exceed 60 mg/day. Maintenance Therapy: Long-term maintenance of efficacy was demonstrated in a 3-month relapse prevention trial. In this trial, patients with panic disorder assigned to paroxetine demonstrated a lower relapse rate compared to patients on placebo (see CLINICAL PHARMACOLOGY — Clinical Trials ). Panic disorder is a chronic condition, and it is reasonable to consider continuation for a responding patient. Dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for continued treatment. Social Anxiety Disorder: Usual Initial Dosage: Paroxetine tablets should be administered as a single daily dose with or without food, usually in the morning. The recommended and initial dosage is 20 mg/day. In clinical trials the effectiveness of paroxetine tablets was demonstrated in patients dosed in a range of 20 to 60 mg/day. While the safety of paroxetine tablets has been evaluated in patients with social anxiety disorder at doses up to 60 mg/day, available information does not suggest any additional benefit for doses above 20 mg/day (see CLINICAL PHARMACOLOGY — Clinical Trials ). Maintenance Therapy: There is no body of evidence available to answer the question of how long the patient treated with paroxetine tablets should remain on it. Although the efficacy of paroxetine tablets beyond 12 weeks of dosing has not been demonstrated in controlled clinical trials, social anxiety disorder is recognized as a chronic condition, and it is reasonable to consider continuation of treatment for a responding patient. Dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for continued treatment. Generalized Anxiety Disorder: Usual Initial Dosage: Paroxetine tablets should be administered as a single daily dose with or without food, usually in the morning. In clinical trials the effectiveness of paroxetine tablets was demonstrated in patients dosed in a range of 20 to 50 mg/day. The recommended starting dosage and the established effective dosage is 20 mg/day. There is not sufficient evidence to suggest a greater benefit to doses higher than 20 mg/day. Dose changes should occur in 10 mg/day increments and at intervals of at least 1 week. Maintenance Therapy: Systematic evaluation of continuing paroxetine tablets for periods of up to 24 weeks in patients with Generalized Anxiety Disorder who had responded while taking paroxetine tablets during an 8-week acute treatment phase has demonstrated a benefit of such maintenance (see CLINICAL PHARMACOLOGY — Clinical Trials ). Nevertheless, patients should be periodically reassessed to determine the need for maintenance treatment. Posttraumatic Stress Disorder: Usual Initial Dosage: Paroxetine tablets should be administered as a single daily dose with or without food, usually in the morning. The recommended starting dosage and the established effective dosage is 20 mg/day. In 1 clinical trial, the effectiveness of paroxetine tablets was demonstrated in patients dosed in a range of 20 to 50 mg/day. However, in a fixed dose study, there was not sufficient evidence to suggest a greater benefit for a dose of 40 mg/day compared to 20 mg/day. Dose changes, if indicated, should occur in 10 mg/day increments and at intervals of at least 1 week. Maintenance Therapy: There is no body of evidence available to answer the question of how long the patient treated with paroxetine tablets should remain on it. Although the efficacy of paroxetine tablets beyond 12 weeks of dosing has not been demonstrated in controlled clinical trials, PTSD is recognized as a chronic condition, and it is reasonable to consider continuation of treatment for a responding patient. Dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for continued treatment. Special Populations: Treatment of Pregnant Women During the Third Trimester: Neonates exposed to paroxetine tablets and other SSRIs or SNRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding (see WARNINGS : Usage in Pregnancy ). When treating pregnant women with paroxetine during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. Dosage for Elderly or Debilitated Patients, and Patients with Severe Renal or Hepatic Impairment: The recommended initial dose is 10 mg/day for elderly patients, debilitated patients, and/or patients with severe renal or hepatic impairment. Increases may be made if indicated. Dosage should not exceed 40 mg/day. Switching a Patient to or from a Monoamine Oxidase Inhibitor (MAOI) Intended To Treat Psychiatric Disorders: At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with paroxetine tablets. Conversely, at least 14 days should be allowed after stopping paroxetine tablets before starting an MAOI intended to treat psychiatric disorders (see CONTRAINDICATIONS ). Use of Paroxetine Tablets With Other MAOIs Such as Linezolid or Methylene Blue: Do not start paroxetine tablets in a patient who is being treated with linezolid or intravenous methylene blue because there is increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered (see CONTRAINDICATIONS ). In some cases, a patient already receiving therapy with paroxetine tablets may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, paroxetine tablets should be stopped promptly, and linezolid or methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for 2 weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with paroxetine tablets may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue (see WARNINGS ). The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with paroxetine is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use (see WARNINGS ). Discontinuation of Treatment with Paroxetine Tablets: Symptoms associated with discontinuation of paroxetine tablets have been reported(see PRECAUTIONS : Discontinuation of Treatment With Paroxetine Tablets ). Patients should be monitored for these symptoms when discontinuing treatment, regardless of the indication for which paroxetine tablets are being prescribed. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate.

The use of MAOIs intended to treat psychiatric disorders with paroxetine tablets or within 14 days of stopping treatment with paroxetine tablets is contraindicated because of an increased risk of serotonin syndrome. The use of paroxetine tablets within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated (see WARNINGS and DOSAGE AND ADMINISTRATION ). Starting paroxetine tablets in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome (see WARNINGS and DOSAGE AND ADMINISTRATION ). Concomitant use with thioridazine is contraindicated (see WARNINGS and PRECAUTIONS ). Concomitant use in patients taking pimozide is contraindicated (see PRECAUTIONS ). Paroxetine tablets are contraindicated in patients with a hypersensitivity to paroxetine or any of the inactive ingredients in paroxetine tablets.

Associated with Discontinuation of Treatment: Twenty percent (1,199/6,145) of patients treated with paroxetine tablets in worldwide clinical trials in major depressive disorder and 16.1% (84/522), 11.8% (64/542), 9.4% (44/469), 10.7% (79/735) and 11.7% (79/676) of patients treated with paroxetine tablets in worldwide trials in social anxiety disorder, OCD, panic disorder, GAD and PTSD, respectively, discontinued treatment due to an adverse event. The most common events (≥1%) associated with discontinuation and considered to be drug related (i.e., those events associated with dropout at a rate approximately twice or greater for paroxetine tablets compared to placebo) included the following: Where numbers are not provided the incidence of the adverse events in patients treated with paroxetine tablets were not >1% or were not greater than or equal to 2 times the incidence of placebo. Major Depressive Disorder OCD Panic Disorder Social Anxiety Disorder Generalized Anxiety Disorder PTSD Paroxetine Tablets Placebo Paroxetine Tablets Placebo Paroxetine Tablets Placebo Paroxetine Tablets Placebo Paroxetine Tablets Placebo Paroxetine Tablets Placebo CNS Somnolence 2.3% 0.7% — 1.9% 0.3% 3.4% 0.3% 2.0% 0.2% 2.8% 0.6% Insomnia — — 1.7% 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% - - Gastrointestinal - - Constipation — 1.1% 0% - - Nausea 3.2% 1.1% 1.9% 0% 3.2% 1.2% 4.0% 0.3% 2.0% 0.2% 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 - - ejaculation Incidence corrected for gender. 1.6% 0% 2.1% 0% 4.9% 0.6% 2.5% 0.5% - - Sweating 1.0% 0.3% — 1.1% 0% 1.1% 0.2% - - Impotence — 1.5% 0% - - Libido Decreased 1.0% 0% - - Commonly Observed Adverse Events: Major Depressive Disorder: The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or greater and incidence for paroxetine tablets at least twice that for placebo, derived from Table 2 ) were: Asthenia, sweating, nausea, decreased appetite, somnolence, dizziness, insomnia, tremor, nervousness, ejaculatory disturbance, and other male genital disorders. Obsessive Compulsive Disorder: The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or greater and incidence for paroxetine tablets at least twice that of placebo, derived from Table 3 ) were: Nausea, dry mouth, decreased appetite, constipation, dizziness, somnolence, tremor, sweating, impotence, and abnormal ejaculation. Panic Disorder: The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or greater and incidence for paroxetine tablets at least twice that for placebo, derived from Table 3 ) were: Asthenia, sweating, decreased appetite, libido decreased, tremor, abnormal ejaculation, female genital disorders, and impotence. Social Anxiety Disorder: The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or greater and incidence for paroxetine tablets at least twice that for placebo, derived from Table 3 ) were: Sweating, nausea, dry mouth, constipation, decreased appetite, somnolence, tremor, libido decreased, yawn, abnormal ejaculation, female genital disorders, and impotence. Generalized Anxiety Disorder: The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or greater and incidence for paroxetine tablets at least twice that for placebo, derived from Table 4 ) were: Asthenia, infection, constipation, decreased appetite, dry mouth, nausea, libido decreased, somnolence, tremor, sweating, and abnormal ejaculation. Posttraumatic Stress Disorder: The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or greater and incidence for paroxetine tablets at least twice that for placebo, derived from Table 4) were: Asthenia, sweating, nausea, dry mouth, diarrhea, decreased appetite, somnolence, libido decreased, abnormal ejaculation, female genital disorders, and impotence. Incidence in Controlled Clinical Trials: The prescriber should be aware that the figures in the tables following cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the populations studied. Major Depressive Disorder: Table 2 enumerates adverse events that occurred at an incidence of 1% or more among paroxetine-treated patients who participated in short-term (6-week) placebo-controlled trials in which patients were dosed in a range of 20 mg to 50 mg/day. Reported adverse events were classified using a standard COSTART-based Dictionary terminology. Table 2 Treatment-Emergent Adverse Experience Incidence in Placebo-Controlled Clinical Trials for Major Depressive Disorder * * Events reported by at least 1% of patients treated with paroxetine tablets are included, except the following events which had an incidence on placebo ≥ paroxetine tablets: Abdominal pain, agitation, back pain, chest pain, CNS stimulation, fever, increased appetite, myoclonus, pharyngitis, postural hypotension, respiratory disorder (includes mostly "cold symptoms" or "URI"), trauma, and vomiting. † Includes mostly "lump in throat" and "tightness in throat." ‡ Percentage corrected for gender. § Mostly "ejaculatory delay." ¶ Includes "anorgasmia," "erectile difficulties," "delayed ejaculation/orgasm," and "sexual dysfunction," and "impotence." # Includes mostly "difficulty with micturition" and "urinary hesitancy." Þ Includes mostly "anorgasmia" and "difficulty reaching climax/orgasm." Body System Preferred Term Paroxetine Tablets Placebo (n = 421) (n = 421) Body as a Whole Headache 18% 17% Asthenia 15% 6% Cardiovascular Palpitation 3% 1% Vasodilation 3% 1% Dermatologic Sweating 11% 2% Rash 2% 1% Gastrointestinal Nausea 26% 9% Dry Mouth 18% 12% Constipation 14% 9% Diarrhea 12% 8% Decreased Appetite 6% 2% Flatulence 4% 2% Oropharynx Disorder † 2% 0% Dyspepsia 2% 1% Musculoskeletal Myopathy 2% 1% Myalgia 2% 1% Myasthenia 1% 0% Nervous System Somnolence 23% 9% Dizziness 13% 6% Insomnia 13% 6% Tremor 8% 2% Nervousness 5% 3% Anxiety 5% 3% Paresthesia 4% 2% Libido Decreased 3% 0% Drugged Feeling 2% 1% Confusion 1% 0% Respiration Yawn 4% 0% Special Senses Blurred Vision 4% 1% Taste Perversion 2% 0% Urogenital System Ejaculatory Disturbance ‡,§ 13% 0% Other Male Genital Disorders ‡,¶ 10% 0% Urinary Frequency 3% 1% Urination Disorder # 3% 0% Female Genital Disorders ‡,Þ 2% 0% Obsessive Compulsive Disorder, Panic Disorder, and Social Anxiety Disorder: Table 3 enumerates adverse events that occurred at a frequency of 2% or more among OCD patients on paroxetine tablets who participated in placebo-controlled trials of 12-weeks duration in which patients were dosed in a range of 20 mg to 60 mg/day or among patients with panic disorder on paroxetine tablets who participated in placebo-controlled trials of 10- to 12-weeks duration in which patients were dosed in a range of 10 mg to 60 mg/day or among patients with social anxiety disorder on paroxetine tablets who participated in placebo-controlled trials of 12-weeks duration in which patients were dosed in a range of 20 mg to 50 mg/day. Table 3 Treatment-Emergent Adverse Experience Incidence in Placebo-Controlled Clinical Trials for Obsessive Compulsive Disorder, Panic Disorder, and Social Anxiety Disorder * * Events reported by at least 2% of OCD, panic disorder, and social anxiety disorder in patients treated with paroxetine tablets are included, except the following events which had an incidence on placebo ≥ paroxetine tablets: [OCD]: Abdominal pain, agitation, anxiety, back pain, cough increased, depression, headache, hyperkinesia, infection, paresthesia, pharyngitis, respiratory disorder, rhinitis, and sinusitis. [panic disorder]: Abnormal dreams, abnormal vision, chest pain, cough increased, depersonalization, depression, dysmenorrhea, dyspepsia, flu syndrome, headache, infection, myalgia, nervousness, palpitation, paresthesia, pharyngitis, rash, respiratory disorder, sinusitis, taste perversion, trauma, urination impaired, and vasodilation. [social anxiety disorder]: Abdominal pain, depression, headache, infection, respiratory disorder, and sinusitis. † Percentage corrected for gender. Obsessive Compulsive Disorder Panic Disorder Social Anxiety Disorder Paroxetine Tablets Placebo Paroxetine Tablets Placebo Paroxetine Tablets Placebo Body System Preferred Term (n = 542) (n = 265) (n = 469) (n = 324) (n = 425) (n = 339) Body as a Whole Asthenia 22% 14% 14% 5% 22% 14% Abdominal Pain — — 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 † 23% 1% 21% 1% 28% 1% Dysmenorrhea — — — — 5% 4% Female Genital Disorder † 3% 0% 9% 1% 9% 1% Impotence † 8% 1% 5% 0% 5% 1% Urinary Frequency 3% 1% 2% 0% — — Urination Impaired 3% 0% — — — — Urinary Tract Infection 2% 1% 2% 1% — — Generalized Anxiety Disorderand and Posttraumatic Stress Disorder: Table 4 enumerates adverse events that occurred at a frequency of 2% or more among GAD patients on paroxetine tablets who participated in placebo-controlled trials of 8-weeks duration in which patients were dosed in a range of 10 mg/day to 50 mg/day or among PTSD patients on paroxetine tablets who participated in placebo-controlled trials of 12-weeks duration in which patients were dosed in a range of 20 mg/day to 50 mg/day. Table 4 Treatment-Emergent Adverse Experience Incidence in Placebo Controlled Clinical Trials for Generalized Anxiety Disorder and Posttraumatic Stress Disorder * * Events reported by at least 2% of GAD and PTSD in patients treated with paroxetine tablets are included, except the following events which had an incidence on placebo ≥ paroxetine tablets [GAD]: Abdominal pain, back pain, trauma, dyspepsia, myalgia, and pharyngitis. [PTSD]: Back pain, headache, anxiety, depression, nervousness, respiratory disorder, pharyngitis, and sinusitis. † Percentage corrected for gender. Generalized Anxiety Disorder Posttraumatic Stress Disorder Body System Preferred Term Paroxetine Tablets Placebo Paroxetine Tablets Placebo (n = 735) (n = 529) (n = 676) (n = 504) Body as a Whole Asthenia 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% Gastrointestinal 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% 2% Respiratory System Respiratory Disorder 7% 5% - - Sinusitis 4% 3% - - Yawn 4% — 2% <1% Special Senses Abnormal Vision 2% 1% 3% 1% Urogenital System Abnormal 25% 2% 13% 2% Ejaculation † 5% 1% Female Genital 4% 1% 9% 1% Disorder † Impotence † 4% 3% Dose Dependency of Adverse Events: A comparison of adverse event rates in a fixed-dose study comparing 10, 20, 30, and 40 mg/day of paroxetine tablets with placebo in the treatment of major depressive disorder revealed a clear dose dependency for some of the more common adverse events associated with use of paroxetine tablets, as shown in Table 5: Table 5 Treatment-Emergent Adverse Experience Incidence in a Dose-Comparison Trial in the Treatment of Major Depressive Disorder * * Rule for including adverse events in table: Incidence at least 5% for 1 of paroxetine groups and ≥ twice the placebo incidence for at least 1 paroxetine group. Body System/Preferred Term Placebo Paroxetine Tablets n=51 10 mg n=102 20 mg n=104 30 mg n=101 40 mg n=102 Body As A Whole Asthenia 0.0% 2.9% 10.6% 13.9% 12.7% Dermatology Sweating 2.0% 1.0% 6.7% 8.9% 11.8% Gastrointestinal Constipation 5.9% 4.9% 7.7% 9.9% 12.7% Decreased Appetite 2.0% 2.0% 5.8% 4.0% 4.9% Diarrhea 7.8% 9.8% 19.2% 7.9% 14.7% Dry Mouth 2.0% 10.8% 18.3% 15.8% 20.6% Nausea 13.7% 14.7% 26.9% 34.7% 36.3% Nervous System Anxiety 0.0% 2.0% 5.8% 5.9% 5.9% Dizziness 3.9% 6.9% 6.7% 8.9% 12.7% Nervousness 0.0% 5.9% 5.8% 4.0% 2.9% Paresthesia 0.0% 2.9% 1.0% 5.0% 5.9% Somnolence 7.8% 12.7% 18.3% 20.8% 21.6% Tremor 0.0% 0.0% 7.7% 7.9% 14.7% Special Senses Blurred Vision 2.0% 2.9% 2.9% 2.0% 7.8% Urogenital System Abnormal Ejaculation 0.0% 5.8% 6.5% 10.6% 13.0% Impotence 0.0% 1.9% 4.3% 6.4% 1.9% Male Genital Disorders 0.0% 3.8% 8.7% 6.4% 3.7% In a fixed-dose study comparing placebo and 20, 40, and 60 mg of paroxetine tablets in the treatment of OCD, there was no clear relationship between adverse events and the dose of paroxetine tablets to which patients were assigned. No new adverse events were observed in the group treated with 60 mg of paroxetine tablets compared to any of the other treatment groups. In a fixed-dose study comparing placebo and 10, 20, and 40 mg of paroxetine tablets in the treatment of panic disorder, there was no clear relationship between adverse events and the dose of paroxetine tablets to which patients were assigned, except for asthenia, dry mouth, anxiety, libido decreased, tremor, and abnormal ejaculation. In flexible-dose studies, no new adverse events were observed in patients receiving 60 mg of paroxetine tablets compared to any of the other treatment groups. In a fixed-dose study comparing placebo and 20, 40, and 60 mg of paroxetine tablets in the treatment of social anxiety disorder, for most of the adverse events, there was no clear relationship between adverse events and the dose of paroxetine tablets to which patients were assigned. In a fixed-dose study comparing placebo and 20 and 40 mg of paroxetine tablets in the treatment of generalized anxiety disorder, for most of the adverse events, there was no clear relationship between adverse events and the dose of paroxetine tablets to which patients were assigned, except for the following adverse events: Asthenia, constipation, and abnormal ejaculation. In a fixed-dose study comparing placebo and 20 and 40 mg of paroxetine tablets in the treatment of posttraumatic stress disorder, for most of the adverse events, there was no clear relationship between adverse events and the dose of paroxetine tablets to which patients were assigned, except for impotence and abnormal ejaculation. Adaptation to Certain Adverse Events: Over a 4- to 6-week period, there was evidence of adaptation to some adverse events with continued therapy (e.g., nausea and dizziness), but less to other effects (e.g., dry mouth, somnolence, and asthenia). Male and Female Sexual Dysfunction with SSRIs: Although changes in sexual desire, sexual performance, and sexual satisfaction often occur as manifestations of a psychiatric disorder, they may also be a consequence of pharmacologic treatment. In particular, some evidence suggests that selective serotonin reuptake inhibitors (SSRIs) can cause such untoward sexual experiences. Reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance, and satisfaction are difficult to obtain, however, in part because patients and physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance cited in product labeling are likely to underestimate their actual incidence. In placebo-controlled clinical trials involving more than 3,200 patients, the ranges for the reported incidence of sexual side effects in males and females with major depressive disorder, OCD, panic disorder, social anxiety disorder, GAD and PTSD are displayed in Table 6. Table 6 Incidence of Sexual Adverse Events in Controlled Clinical Trials Paroxetine Tablets Placebo n (males) 1446 1042 Decreased Libido 6-15% 0-5% Ejaculatory Disturbance 13-28% 0-2% Impotence 2-9% 0-3% n (females) 1822 1340 Decreased Libido 0-9% 0-2% Orgasmic Disturbance 2-9% 0-1% There are no adequate and well-controlled studies examining sexual dysfunction with paroxetine treatment. Paroxetine treatment has been associated with several cases of priapism. In those cases with a known outcome, patients recovered without sequelae. While it is difficult to know the precise risk of sexual dysfunction associated with the use of SSRIs, physicians should routinely inquire about such possible side effects. Weight and Vital Sign Changes: Significant weight loss may be an undesirable result of treatment with paroxetine tablets for some patients but, on average, patients in controlled trials had minimal (about 1 pound) weight loss versus smaller changes on placebo and active control. No significant changes in vital signs (systolic and diastolic blood pressure, pulse and temperature) were observed in patients treated with paroxetine tablets in controlled clinical trials. ECG Changes: In an analysis of ECGs obtained in 682 patients treated with paroxetine tablets and 415 patients treated with placebo in controlled clinical trials, no clinically significant changes were seen in the ECGs of either group. Liver Function Tests: In placebo-controlled clinical trials, patients treated with paroxetine tablets exhibited abnormal values on liver function tests at no greater rate than that seen in placebo-treated patients. In particular, the paroxetine tablets-versus-placebo comparisons for alkaline phosphatase, SGOT, SGPT, and bilirubin revealed no differences in the percentage of patients with marked abnormalities. Hallucinations: In pooled clinical trials of immediate-release paroxetine hydrochloride, hallucinations were observed in 22 of 9089 patients receiving drug and 4 of 3187 patients receiving placebo. Other Events Observed During the Premarketing Evaluation of Paroxetine Tablets: During its premarketing assessment in major depressive disorder, multiple doses of paroxetine tablets were administered to 6,145 patients in phase 2 and 3 studies. The conditions and duration of exposure to paroxetine tablets varied greatly and included (in overlapping categories) open and double-blind studies, uncontrolled and controlled studies, inpatient and outpatient studies, and fixed-dose, and titration studies. During premarketing clinical trials in OCD, panic disorder, social anxiety disorder, generalized anxiety disorder, and posttraumatic stress disorder 542, 469, 522, 735 and 676 patients, respectively, received multiple doses of paroxetine tablets. Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories. In the tabulations that follow, reported adverse events were classified using a standard COSTART-based Dictionary terminology. The frequencies presented, therefore, represent the proportion of the 9,089 patients exposed to multiple doses of paroxetine tablets who experienced an event of the type cited on at least 1 occasion while receiving paroxetine tablets. All reported events are included except those already listed in Tables 2 to 5, those reported in terms so general as to be uninformative and those events where a drug cause was remote. It is important to emphasize that although the events reported occurred during treatment with paroxetine, they were not necessarily caused by it. Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: Frequent adverse events are those occurring on 1 or more occasions in at least 1/100 patients (only those not already listed in the tabulated results from placebo-controlled trials appear in this listing); infrequent adverse events are those occurring in 1/100 to 1/1,000 patients; rare events are those occurring in fewer than 1/1,000 patients. Events of major clinical importance are also described in the PRECAUTIONS section. Body as a Whole: Infrequent: Allergic reaction, chills, face edema, malaise, neck pain; rare: Adrenergic syndrome, cellulitis, moniliasis, neck rigidity, pelvic pain, peritonitis, sepsis, ulcer. Cardiovascular System: Frequent: Hypertension, tachycardia; infrequent: Bradycardia, hematoma, hypotension, migraine, postural hypotension, syncope; rare: Angina pectoris, arrhythmia nodal, atrial fibrillation, bundle branch block, cerebral ischemia, cerebrovascular accident, congestive heart failure, heart block, low cardiac output, myocardial infarct, myocardial ischemia, pallor, phlebitis, pulmonary embolus, supraventricular extrasystoles, thrombophlebitis, thrombosis, varicose vein, vascular headache, ventricular extrasystoles. Digestive System: Infrequent: Bruxism, colitis, dysphagia, eructation, gastritis, gastroenteritis, gingivitis, glossitis, increased salivation, liver function tests abnormal, rectal hemorrhage, ulcerative stomatitis; rare: Aphthous stomatitis, bloody diarrhea, bulimia, cardiospasm, cholelithiasis, duodenitis, enteritis, esophagitis, fecal impactions, fecal incontinence, gum hemorrhage, hematemesis, hepatitis, ileitis, ileus, intestinal obstruction, jaundice, melena, mouth ulceration, peptic ulcer, salivary gland enlargement, sialadenitis, stomach ulcer, stomatitis, tongue discoloration, tongue edema, tooth caries. Endocrine System: Rare: Diabetes mellitus, goiter, hyperthyroidism, hypothyroidism, thyroiditis. Hemic and Lymphatic Systems: Infrequent: Anemia, leukopenia, lymphadenopathy, purpura; rare: Abnormal erythrocytes, basophilia, bleeding time increased, eosinophilia, hypochromic anemia, iron deficiency anemia, leukocytosis, lymphedema, abnormal lymphocytes, lymphocytosis, microcytic anemia, monocytosis, normocytic anemia, thrombocythemia, thrombocytopenia. Metabolic and Nutritional: Frequent: Weight gain; infrequent: Edema, peripheral edema, SGOT increased, SGPT increased, thirst, weight loss; rare: Alkaline phosphatase increased, bilirubinemia, BUN increased, creatinine phosphokinase increased, dehydration, gamma globulins increased, gout, hypercalcemia, hypercholesteremia, hyperglycemia, hyperkalemia, hyperphosphatemia, hypocalcemia, hypoglycemia, hypokalemia, hyponatremia, ketosis, lactic dehydrogenase increased, non-protein nitrogen (NPN) increased. Musculoskeletal System: Frequent: Arthralgia; infrequent: Arthritis, arthrosis; rare: Bursitis, myositis, osteoporosis, generalized spasm, tenosynovitis, tetany. Nervous System: Frequent: Emotional lability, vertigo; infrequent: Abnormal thinking, alcohol abuse, ataxia, dystonia, dyskinesia, euphoria, hallucinations, hostility, hypertonia, hypesthesia, hypokinesia, incoordination, lack of emotion, libido increased, manic reaction, neurosis, paralysis, paranoid reaction; rare: Abnormal gait, akinesia, antisocial reaction, aphasia, choreoathetosis, circumoral paresthesias, convulsion, delirium, delusions, diplopia, drug dependence, dysarthria, extrapyramidal syndrome, fasciculations, grand mal convulsion, hyperalgesia, hysteria, manic-depressive reaction, meningitis, myelitis, neuralgia, neuropathy, nystagmus, peripheral neuritis, psychotic depression, psychosis, reflexes decreased, reflexes increased, stupor, torticollis, trismus, withdrawal syndrome. Respiratory System: Infrequent: Asthma, bronchitis, dyspnea, epistaxis, hyperventilation, pneumonia, respiratory flu; rare: Emphysema, hemoptysis, hiccups, lung fibrosis, pulmonary edema, sputum increased, stridor, voice alteration. Skin and Appendages: Frequent: Pruritus; infrequent: Acne, alopecia, contact dermatitis, dry skin, ecchymosis, eczema, herpes simplex, photosensitivity, urticaria; rare: Angioedema, erythema nodosum, erythema multiforme, exfoliative dermatitis, fungal dermatitis, furunculosis; herpes zoster, hirsutism, maculopapular rash, seborrhea, skin discoloration, skin hypertrophy, skin ulcer, sweating decreased, vesiculobullous rash. Special Senses: Frequent: Tinnitus; infrequent: Abnormality of accommodation, conjunctivitis, ear pain, eye pain, keratoconjunctivitis, mydriasis, otitis media; rare: Amblyopia, anisocoria, blepharitis, cataract, conjunctival edema, corneal ulcer, deafness, exophthalmos, eye hemorrhage, glaucoma, hyperacusis, night blindness, otitis externa, parosmia, photophobia, ptosis, retinal hemorrhage, taste loss, visual field defect. Urogenital System: Infrequent: Amenorrhea, breast pain, cystitis, dysuria, hematuria, menorrhagia, nocturia, polyuria, pyuria, urinary incontinence, urinary retention, urinary urgency, vaginitis; rare: Abortion, breast atrophy, breast enlargement, endometrial disorder, epididymitis, female lactation, fibrocystic breast, kidney calculus, kidney pain, leukorrhea, mastitis, metrorrhagia, nephritis, oliguria, salpingitis, urethritis, urinary casts, uterine spasm, urolith, vaginal hemorrhage, vaginal moniliasis. Postmarketing Reports: Voluntary reports of adverse events in patients taking paroxetine tablets that have been received since market introduction and not listed above that may have no causal relationship with the drug include acute pancreatitis, elevated liver function tests (the most severe cases were deaths due to liver necrosis, and grossly elevated transaminases associated with severe liver dysfunction), Guillain-Barre syndrome, Stevens-Johnson syndrome, toxic epidermal necrolysis, priapism, syndrome of inappropriate ADH secretion, symptoms suggestive of prolactinemia and galactorrhea, extrapyramidal symptoms which have included akathisia, bradykinesia, cogwheel rigidity, dystonia, hypertonia, oculogyric crisis which has been associated with concomitant use of pimozide; tremor and trismus; status epilepticus, acute renal failure, pulmonary hypertension, allergic alveolitis, anaphylaxis, eclampsia, laryngismus, optic neuritis, porphyria, restless legs syndrome (RLS), ventricular fibrillation, ventricular tachycardia (including torsade de pointes), thrombocytopenia, hemolytic anemia, events related to impaired hematopoiesis (including aplastic anemia, pancytopenia, bone marrow aplasia, and agranulocytosis), vasculitic syndromes (such as Henoch-Schonlein purpura), and premature births in pregnant women. There has been a case report of an elevated phenytoin level after 4 weeks of paroxetine tablets and phenytoin coadministration. There has been a case report of severe hypotension when paroxetine tablets were added to chronic metoprolol treatment.