PAROXETINE

WARNINGS Clinical Worsening and Suicide Risk: Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children,adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4,400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1,000 patients treated) are provided in Table 1. Table 1 Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1,000 Patients Treated Increases Compared to Placebo <18 14 additional cases 18-24 5 additional cases Decreases Compared to Placebo 25-64 1 fewer case ≥65 6 fewer cases No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms. If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms (see PRECAUTIONS and DOSAGE AND ADMINISTRATION: Discontinuation of Treatment With Paroxetine), for a description of the risks of discontinuation of paroxetine). Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for paroxetine tablets should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Screening Patients for Bipolar Disorder: A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that paroxetine tablets are not approved for use in treating bipolar depression. Serotonin Syndrome The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including paroxetine, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John's Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome. The concomitant use of paroxetine with MAOIs intended to treat psychiatric disorders is contraindicated. Paroxetine should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking paroxetine. Paroxetine should be discontinued before initiating treatment with the MAOI (see CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION). If concomitant use of paroxetine with certain other serotonergic drugs, i.e., triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John's Wort is clinically warranted, be aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases. Treatment with paroxetine and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated. Angle-Closure Glaucoma: The pupillary dilation that occurs following use of many antidepressant drugs including paroxetine may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. Potential Interaction with Thioridazine: Thioridazine administration alone produces prolongation of the QTc interval, which is associated with serious ventricular arrhythmias, such as torsade de pointes-type arrhythmias, and sudden death. This effect appears to be dose related. An in vivo study suggests that drugs which inhibit CYP2D6, such as paroxetine, will elevate plasma levels of thioridazine. Therefore, it is recommended that paroxetine not be used in combination with thioridazine (see CONTRAINDICATIONS and PRECAUTIONS). Usage in Pregnancy Teratogenic Effects: Epidemiological studies have shown that infants exposed to paroxetine in the first trimester of pregnancy have an increased risk of congenital malformations, particularly cardiovascular malformations. The findings from these studies are summarized below: A study based on Swedish national registry data demonstrated that infants exposed to paroxetine during pregnancy (n = 815) had an increased risk of cardiovascular malformations (2% risk in paroxetine-exposed infants) compared to the entire registry population (1% risk), for an odds ratio (OR) of 1.8 (95% confidence interval 1.1 to 2.8). No increase in the risk of overall congenital malformations was seen in the paroxetine-exposed infants. The cardiac malformations in the paroxetine-exposed infants were primarily ventricular septal defects (VSDs) and atrial septal defects (ASDs). Septal defects range in severity from those that resolve spontaneously to those which require surgery. A separate retrospective cohort study from the United States (United Healthcare data) evaluated 5,956 infants of mothers dispensed antidepressants during the first trimester (n = 815 for paroxetine). This study showed a trend towards an increased risk for cardiovascular malformations for paroxetine (risk of 1.5%) compared to other antidepressants (risk of 1%), for an OR of 1.5 (95% confidence interval 0.8 to 2.9). Of the 12 paroxetine-exposed infants with cardiovascular malformations, 9 had VSDs. This study also suggested an increased risk of overall major congenital malformations including cardiovascular defects for paroxetine (4% risk) compared to other (2% risk) antidepressants (OR 1.8; 95% confidence interval 1.2 to 2.8). Two large case-control studies using separate databases, each with > 9,000 birth defect cases and > 4,000 controls, found that maternal use of paroxetine during the first trimester of pregnancy was associated with a 2- to 3-fold increased risk of right ventricular outflow tract obstructions. In one study the odds ratio was 2.5 (95% confidence interval, 1 to 6, 7 exposed infants) and in the other study the odds ratio was 3.3 (95% confidence interval, 1.3 to 8.8, 6 exposed infants). Other studies have found varying results as to whether there was an increased risk of overall, cardiovascular, or specific congenital malformations. A meta-analysis of epidemiological data over a 16-year period (1992 to 2008) on first trimester paroxetine use in pregnancy and congenital malformations included the above-noted studies in addition to others (n = 17 studies that included overall malformations and n = 14 studies that included cardiovascular malformations; n = 20 distinct studies). While subject to limitations, this meta-analysis suggested an increased occurrence of cardiovascular malformations (prevalence odds ratio [POR] 1.5; 95% confidence interval 1.2 to 1.9) and overall malformations (POR 1.2; 95% confidence interval 1.1 to 1.4) with paroxetine use during the first trimester. It was not possible in this meta-analysis to determine the extent to which the observed prevalence of cardiovascular malformations might have contributed to that of overall malformations, nor was it possible to determine whether any specific types of cardiovascular malformations might have contributed to the observed prevalence of all cardiovascular malformations. If a patient becomes pregnant while taking paroxetine, she should be advised of the potential harm to the fetus. Unless the benefits of paroxetine to the mother justify continuing treatment, consideration should be given to either discontinuing paroxetine therapy or switching to another antidepressant (see PRECAUTIONS: Discontinuation of Treatment With Paroxetine Tablets). For women who intend to become pregnant or are in their first trimester of pregnancy, paroxetine should only be initiated after consideration of the other available treatment options. Animal Findings: Reproduction studies were performed at doses up to 50 mg/kg/day in rats and 6 mg/kg/day in rabbits administered during organogenesis. These doses are approximately 8 (rat) and 2 (rabbit) times the maximum recommended human dose (MRHD) on an mg/m2 basis. These studies have revealed no evidence of teratogenic effects. However, in rats, there was an increase in pup deaths during the first 4 days of lactation when dosing occurred during the last trimester of gestation and continued throughout lactation. This effect occurred at a dose of 1 mg/kg/day or approximately one-sixth of the MRHD on an mg/m2 basis. The no-effect dose for rat pup mortality was not determined. The cause of these deaths is not known. Nonteratogenic Effects: Neonates exposed to paroxetine tablets and other SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs), late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see WARNINGS— Serotonin Syndrome). Infants exposed to SSRIs in pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 – 2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. Several recent epidemiologic studies suggest a positive statistical association between SSRI use (including paroxetine) in pregnancy and PPHN. Other studies do not show a significant statistical association. Physicians should also note the results of a prospective longitudinal study of 201 pregnant women with a history of major depression, who were either on antidepressants or had received antidepressants less than 12 weeks prior to their last menstrual period, and were in remission. Women who discontinued antidepressant medication during pregnancy showed a significant increase in relapse of their major depression compared to those women who remained on antidepressant medication throughout pregnancy. When treating a pregnant woman with paroxetine, the physician should carefully consider both the potential risks of taking an SSRI, along with the established benefits of treating depression with an antidepressant. This decision can only be made on a case by case basis (see DOSAGE AND ADMINISTRATION and ADVERSE REACTIONS: Postmarketing Reports).

ADVERSE REACTIONS Associated with Discontinuation of Treatment: Twenty percent (1,199/6,145) of patients treated with paroxetine tablets in worldwide clinical trials in major depressive disorder and 16.1% (84/522), 11.8% (64/542), 9.4% (44/469), and 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, and GAD, respectively, discontinued treatment due to an adverse event. The most common events (≥1%) associated with discontinuation and considered to be drug related (i.e., those events associated with dropout at a rate approximately twice or greater for paroxetine tablets compared to placebo) included the following: Major Depressive Disorder OCD Panic Disorder Social Anxiety Disorder Generalized Anxiety Disorder Paroxetine Tablets Placebo Paroxetine Tablets Placebo Paroxetine Tablets Placebo Paroxetine Tablets Placebo Paroxetine Tablets Placebo Where numbers are not provided the incidence of the adverse events in patients treated with paroxetine tablets were not >1% or were not greater than or equal to 2 times the incidence of placebo. * Incidence corrected for gender. CNS Somnolence 2.3% 0.7% — 1.9% 0.3% 3.4% 0.3% 2.0% 0.2% Insomnia — — 1.7% 0% 1.3% 0.3% 3.1% 0% Agitation 1.1% 0.5% — Tremor 1.1% 0.3% — 1.7% 0% Anxiety — — — 1.1% 0% Dizziness — — 1.5% 0% 1.9% 0% 1.0% 0.2% Gastrointestinal Constipation — 1.1% 0% Nausea 3.2% 1.1% 1.9% 0% 3.2% 1.2% 4.0% 0.3% 2.0% 0.2% Diarrhea 1.0% 0.3% — Dry Mouth 1.0% 0.3% — Vomiting 1.0% 0.3% — 1.0% 0% Flatulence 1.0% 0.3% Other Asthenia 1.6% 0.4% 1.9% 0.4% 2.5% 0.6% 1.8% 0.2% Abnormal ejaculation* 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. Incidence in Controlled Clinical Trials: The prescriber should be aware that the figures in the tables following cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the populations studied. Major Depressive Disorder: Table 2 enumerates adverse events that occurred at an incidence of 1% or more among paroxetine-treated patients who participated in short-term (6-week) placebo-controlled trials in which patients were dosed in a range of 20 mg to 50 mg/day. Reported adverse events were classified using a standard COSTART-based Dictionary terminology. Table 2 Treatment-Emergent Adverse Experience Incidence in Placebo-Controlled Clinical Trials for Major Depressive Disorder* Body System Preferred Term Paroxetine Tablets Placebo (n = 421) (n = 421) * 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.”

ADVERSE REACTIONS II Obsessive Compulsive Disorder, Panic Disorder, and Social Anxiety Disorder: Table 3 enumerates adverse events that occurred at a frequency of 2% or more among OCD patients on paroxetine tablets who participated in placebo-controlled trials of 12-weeks duration in which patients were dosed in a range of 20 mg to 60 mg/day or among patients with panic disorder on paroxetine tablets who participated in placebo-controlled trials of 10- to 12-weeks duration in which patients were dosed in a range of 10 mg to 60 mg/day or among patients with social anxiety disorder on paroxetine tablets who participated in placebo-controlled trials of 12-weeks duration in which patients were dosed in a range of 20 mg to 50 mg/day. Table 3 Treatment-Emergent Adverse Experience Incidence in Placebo-Controlled Clinical Trials for Obsessive Compulsive Disorder, Panic Disorder, and Social Anxiety Disorder* Obsessive Compulsive Disorder Panic Disorder Social Anxiety Disorder Paroxetine Tablets Placebo Paroxetine Tablets Placebo Paroxetine Tablets Placebo Body System Preferred Term (n = 542) (n = 265) (n = 469) (n = 324) (n = 425) (n = 339) * 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. 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 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. Table 4 Treatment-Emergent Adverse Experience Incidence in Placebo Controlled Clinical Trials for Generalized Anxiety Disorder* Generalized Anxiety Disorder Body System Preferred Term Paroxetine Tablets Placebo (n = 735) (n = 529) * Events reported by at least 2% of GAD 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. † Percentage corrected for gender.

Obsessive Compulsive Disorder, Panic Disorder, and Social Anxiety Disorder: Table 3 enumerates adverse events that occurred at a frequency of 2% or more among OCD patients on paroxetine tablets who participated in placebo-controlled trials of 12-weeks duration in which patients were dosed in a range of 20 mg to 60 mg/day or among patients with panic disorder on paroxetine tablets who participated in placebo-controlled trials of 10- to 12-weeks duration in which patients were dosed in a range of 10 mg to 60 mg/day or among patients with social anxiety disorder on paroxetine tablets who participated in placebo-controlled trials of 12-weeks duration in which patients were dosed in a range of 20 mg to 50 mg/day. Table 3 Treatment-Emergent Adverse Experience Incidence in Placebo-Controlled Clinical Trials for Obsessive Compulsive Disorder, Panic Disorder, and Social Anxiety Disorder* Obsessive Compulsive Disorder Panic Disorder Social Anxiety Disorder Paroxetine Tablets Placebo Paroxetine Tablets Placebo Paroxetine Tablets Placebo Body System Preferred Term (n = 542) (n = 265) (n = 469) (n = 324) (n = 425) (n = 339) * 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. 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 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. Generalized Anxiety Disorder Body System Preferred Term Paroxetine Tablets Placebo (n = 735) (n = 529) * Events reported by at least 2% of GAD 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. † Percentage corrected for gender.

ADVERSE REACTIONS III Generalized Anxiety 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. Table 4 Treatment-Emergent Adverse Experience Incidence in Placebo Controlled Clinical Trials for Generalized Anxiety Disorder* Generalized Anxiety Disorder Body System Preferred Term Paroxetine Tablets Placebo (n = 735) (n = 529) * Events reported by at least 2% of GAD 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. † Percentage corrected for gender. Body as a Whole Asthenia 14% 6% Headache 17% 14% Infection 6% 3% Abdominal Pain Trauma Cardiovascular Vasodilation 3% 1% Dermatologic Sweating 6% 2% Gastrointestinal Nausea 20% 5% Dry Mouth 11% 5% Constipation 10% 2% Diarrhea 9% 7% Decreased Appetite 5% 1% Vomiting 3% 2% Dyspepsia — — Nervous System Insomnia 11% 8% Somnolence 15% 5% Dizziness 6% 5% Tremor 5% 1% Nervousness 4% 3% Libido Decreased 9% 2% Abnormal Dreams Respiratory System Respiratory Disorder 7% 5% Sinusitis 4% 3% Yawn 4% — Special Senses Abnormal Vision 2% 1% Urogenital System Abnormal 25% 2% Ejaculation† Female Genital 4% 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* 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 * 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 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