FDA label 3cf4bc43-63cb-157f-e054-00144ff8d46c

BOXED WARNING Suicidality and Antidepressant Drugs Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of paroxetine tablets or any other antidepressants in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves assoicated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriver. Paroxetine is not approved for usein pediatric patients. (See WARNINGS: Clinical Worsening and Suicide Risk,PRECAUTIONS: Information for Patients, andPRECAUTIONS: Pediatric Use.)

WARNINGS Clinical Worsening and Suicide Risk 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 RangeDrug-Placebo Difference in Number of Cases of Suicidality per 1,000 Patients TreatedIncreases Compared to Placebo<1814 additional cases18-245 additional casesDecreases Compared to Placebo25-641 fewer case6 fewer casesNo 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 Tablets ), 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 healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for paroxetine should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Screening Patients for Bipolar Disorder Potential for Interaction With Monoamine Oxidase Inhibitors In patients receiving another serotonin reuptake inhibitor drug in combination with a monoamine oxidase inhibitor (MAOI), there have been reports of serious, sometimes fatal, reactions including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. These reactions have also been reported in patients who have recently discontinued that drug and have been started on an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. While there are no human data showing such an interaction with paroxetine, limited animal data on the effects of combined use of paroxetine and MAOIs suggest that these drugs may act synergistically to elevate blood pressure and evoke behavioral excitation. Therefore, it is recommended that paroxetine not be used in combination with an MAOI (including linezolid, an antibiotic which is a reversible non-selective MAOI), or within 14 days of discontinuing treatment with an MAOI (see CONTRAINDICATIONS ). At least 2 weeks should be allowed after stopping paroxetine before starting an MAOI. Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions The development of a potentially life-threatening serotonin syndrome or Neuroleptic Malignant Syndrome (NMS)-like reactions have been reported with SNRIs and SSRIs alone, including treatment with paroxetine, but particularly with concomitant use of serotonergic drugs (including triptans) with drugs which impair metabolism of serotonin (including MAOIs), or with antipsychotics or other dopamine antagonists. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Serotonin syndrome, in its most severe form can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes. Patients should be monitored for the emergence of serotonin syndrome or NMS-like signs and symptoms. The concomitant use of paroxetine with MAOIs intended to treat depression is contraindicated. If concomitant treatment of paroxetine with a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases. The concomitant use of paroxetine with serotonin precursors (such as tryptophan) is not recommended. Treatment with paroxetine and any concomitant serotonergic or antidopaminergic agents, including antipsychotics, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated. Potential Interaction With Thioridazine Thioridazine administration alone produces prolongation of the QTc interval, which is associated with serious ventricular arrhythmias, such as torsade de pointestype 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 born to women who had first trimester paroxetine exposure had an increased risk of cardiovascular malformations, primarily ventricular and atrial septal defects (VSDs and ASDs). In general, septal defects range from those that are symptomatic and may require surgery to those that are asymptomatic and may resolve spontaneously. If a patient becomes pregnant while taking paroxetine, she should be advised of the potential harm to the fetus. Unless the benefits of paroxetine to the mother justify continuing treatment, consideration should be given to either discontinuing paroxetine therapy or switching to another antidepressant (see 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 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 SyndromePotential for Interaction With Monoamine Oxidase Inhibitors ). There have also been postmarketing reports of premature births in pregnant women exposed to paroxetine or other SSRIs. When treating a pregnant woman with paroxetine during the third trimester, the physician should carefully consider both the potential risks and benefits of treatment (see DOSAGE AND ADMINISTRATION ). Physicians should note that in a prospective longitudinal study of 201 women with a history of major depression who were euthymic at the beginning of pregnancy, women who discontinued antidepressant medication during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressant medication.

ADVERSE REACTIONS Associated With Discontinuation of Treatment Twenty percent (1,199/6,145) of patients treated with paroxetine in worldwide clinical trials in major depressive disorder and 11.8% (84/522), 11.8% (64/542), 9.4% (44/469), and 10.7% (79/735) of patients treated with paroxetine in worldwide trials in OCD, panic disorder, and GAD, respectively, discontinued treatment due to an adverse event. The most common events (associated with discontinuation and considered to be drug related (i.e., those events associated with dropout at a rate approximately twice or greater for paroxetine compared to placebo) included the following: Major Depressive Disorder OCD Panic Disorder Generalized Anxiety Disorder ParoxetinePlaceboParoxetinePlaceboParoxetinePlaceboParoxetinePlacebo Where numbers are not provided the incidence of the adverse events in patients treated with paroxetine was not >1% or was not greater than or equal to 2 times the incidence of placebo. 1. Incidence corrected for gender.CNSSomnolence2.3%0.7%1.9%0.3%2%0.2%Insomnia1.7%0%1.3%0.3%Agitation1.1%0.5%Tremor1.1%0.3%AnxietyDizziness1.5%0%1%0.2%GastrointestinalConstipation1.1%0%Nausea3.2%1.1%1.9%0%3.2%1.2%2%0.2%Diarrhea1%0.3%Dry mouth1%0.3%Vomiting1%0.3%FlatulenceOtherAsthenia1.6%0.4%1.9%0.4%1.8%0.2%Abnormal ejaculation11.6%0%2.1%0%2.5%0.5%Sweating1%0.3%1.1%0.2%Impotence11.5%0%Libido DecreasedCommonly Observed Adverse Events Major Depressive Disorder The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or greater and incidence for paroxetine at least twice that for placebo, derived from 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 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 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. Generalized Anxiety Disorder The most commonly observed adverse events associated with the use of paroxetine (incidence of 5% or greater and incidence for paroxetine at least twice that for placebo, derived from 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 Disorder1 Body SystemPreferred TermParoxetine (n=421)Placebo (n=421) 1. Events reported by at least 1% of patients treated with paroxetine are included, except the following events which had an incidence on placeboparoxetine: Abdominal pain, agitation, back pain, chest pain, CNS stimulation, fever, increased appetite, myoclonus, pharyngitis, postural hypotension, respiratory disorder (includes mostlycold symptomsorURI), trauma, and vomiting. 2. Includes mostlylump in throatandtightness in throat.3. Percentage corrected for gender. 4. Mostlyejaculatory delay.5. Includesanorgasmia,erectile difficulties,delayed ejaculation/orgasm,andsexual dysfunction,andimpotence.6. Includes mostlydifficulty with micturitionandurinary hesitancy.7. Includes mostlyanorgasmiaanddifficulty reaching climax/orgasm.Body as a WholeHeadache18%17%Asthenia15%6%CardiovascularPalpitation3%1%Vasodilation3%1%DermatologicSweating11%2%Rash2%1%GastrointestinalNausea26%9%Dry Mouth18%12%Constipation14%9%Diarrhea12%8%Decreased Appetite6%2%Flatulence4%2%Oropharynx Disorder22%0%Dyspepsia2%1%MusculoskeletalMyopathy2%1%Myalgia2%1%Myasthenia1%0%Nervous SystemSomnolence23%9%Dizziness13%6%Insomnia13%6%Tremor8%2%Nervousness5%3%Anxiety5%3%Paresthesia4%2%Libido Decreased3%0%Drugged Feeling2%1%Confusion1%0%RespirationYawn4%0%Special SensesBlurred Vision4%1%Taste Perversion2%0%Urogenital SystemEjaculatory Disturbance3,413%0%Other Male Genital Disorders3,510%0%Urinary Frequency3%1%Urination Disorder63%0%Female Genital Disorders3,72%0%Obsessive Compulsive Disorder and Panic Disorder Table 3 enumerates adverse events that occurred at a frequency of 2% or more among OCD patients on paroxetine who participated in placebo-controlled trials of 12-weeks duration in which patients were dosed in a range of 20 mg to 60 mg/day or among patients with panic disorder on paroxetine who participated in placebo-controlled trials of 10- to 12-weeks duration in which patients were dosed in a range of 10 mg to 60 mg/day. Table 3. Treatment-Emergent Adverse Experience Incidence in Placebo-Controlled Clinical Trials for Obsessive Compulsive Disorder and Panic Disorder1 Body SystemPreferred TermObsessive Compulsive Disorder Panic Disorder Paroxetine (n = 542)Placebo (n = 265)Paroxetine (n = 469)Placebo (n = 324) 1. Events reported by at least 2% of OCD and panic disorder in patients treated with paroxetine are included, except the following events which had an incidence on placeboparoxetine: [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. 2. Percentage corrected for gender.Body as a WholeAsthenia22%14%14%5%Abdominal Pain4%3%Chest Pain3%2%Back Pain3%2%Chills2%1%2%1%TraumaCardiovascularVasodilation4%1%Palpitation2%0%DermatologicSweating9%3%14%6%Rash3%2%GastrointestinalNausea23%10%23%17%Dry Mouth18%9%18%11%Constipation16%6%8%5%Diarrhea10%10%12%7%Decreased Appetite9%3%7%3%DyspepsiaFlatulenceIncreased Appetite4%3%2%1%VomitingMusculoskeletalMyalgiaNervous SystemInsomnia24%13%18%10%Somnolence24%7%19%11%Dizziness12%6%14%10%Tremor11%1%9%1%Nervousness9%8%Libido Decreased7%4%9%1%Agitation5%4%Anxiety5%4%Abnormal Dreams4%1%Concentration Impaired3%2%Depersonalization3%0%Myoclonus3%0%3%2%Amnesia2%1%Respiratory SystemRhinitis3%0%PharyngitisYawnSpecial SensesAbnormal Vision4%2%Taste Perversion2%0%Urogenital SystemAbnormal Ejaculation223%1%21%1%DysmenorrheaFemale Genital Disorder23%0%9%1%Impotence28%1%5%0%Urinary Frequency3%1%2%0%Urination Impaired3%0%Urinary Tract Infection2%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 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 Disorder1 Body SystemPreferred TermGeneralized Anxiety Disorder Paroxetine (n=735)Placebo (n=529) 1. Events reported by at least 2% of GAD in patients treated with paroxetine are included, except the following events which had an incidence on placeboparoxetine [GAD]: Abdominal pain, back pain, trauma, dyspepsia, myalgia, and pharyngitis. 2. Percentage corrected for gender.Body as a WholeAsthenia14%6%Headache17%14%Infection6%3%Abdominal PainTraumaCardiovascularVasodilation3%1%DermatologicSweating6%2%GastrointestinalNausea20%5%Dry Mouth11%5%Constipation10%2%Diarrhea9%7%Decreased Appetite5%1%Vomiting3%2%DyspepsiaNervous SystemInsomnia11%8%Somnolence15%5%Dizziness6%5%Tremor5%1%Nervousness4%3%Libido Decreased9%2%Abnormal DreamsRespiratory SystemRespiratory Disorder7%5%Sinusitis4%3%Yawn4%Special SensesAbnormal Vision2%1%Urogenital SystemAbnormal Ejaculation225%2%Female Genital Disorder24%1%Impotence24%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 with placebo in the treatment of major depressive disorder revealed a clear dose dependency for some of the more common adverse events associated with use of paroxetine, as shown in Table 5: Table 5. Treatment-Emergent Adverse Experience Incidence in a Dose-Comparison Trial in the Treatment of Major Depressive Disorder* Body System/Preferred TermPlaceboParoxetine n = 5110 mg n = 10220 mg n = 10430 mg n = 10140 mg n = 102 * Rule for including adverse events in table: Incidence at least 5% for 1 of paroxetine groups andtwice the placebo incidence for at least 1 paroxetine group.Body as a WholeAsthenia0%2.9%10.6%13.9%12.7%DermatologySweating2%1%6.7%8.9%11.8%GastrointestinalConstipation5.9%4.9%7.7%9.9%12.7%Decreased Appetite2%2%5.8%4%4.9%Diarrhea7.8%9.8%19.2%7.9%14.7%Dry Mouth2%10.8%18.3%15.8%20.6%Nausea13.7%14.7%26.9%34.7%36.3%Nervous SystemAnxiety0%2%5.8%5.9%5.9%Dizziness3.9%6.9%6.7%8.9%12.7%Nervousness0%5.9%5.8%4%2.9%Paresthesia0%2.9%1%5%5.9%Somnolence7.8%12.7%18.3%20.8%21.6%Tremor0%0%7.7%7.9%14.7%Special SensesBlurred Vision2%2.9%2.9%2%7.8%Urogenital SystemAbnormal Ejaculation0%5.8%6.5%10.6%13%Impotence0%1.9%4.3%6.4%1.9%Male Genital Disorders0%3.8%8.7%6.4%3.7%In a fixed-dose study comparing placebo and 20, 40, and 60 mg of paroxetine in the treatment of OCD, there was no clear relationship between adverse events and the dose of paroxetine to which patients were assigned. No new adverse events were observed in the group treated with 60 mg of paroxetine compared to any of the other treatment groups. In a fixed-dose study comparing placebo and 10, 20, and 40 mg of paroxetine in the treatment of panic disorder, there was no clear relationship between adverse events and the dose of paroxetine to which patients were assigned, except for asthenia, dry mouth, anxiety, libido decreased, tremor, and abnormal ejaculation. In flexible-dose studies, no new adverse events were observed in patients receiving 60 mg of paroxetine compared to any of the other treatment groups. In a fixed-dose study comparing placebo and 20 mg and 40 mg of paroxetine in the treatment of generalized anxiety disorder, for most of the adverse events, there was no clear relationship between adverse events and the dose of paroxetine to which patients were assigned, except for the following adverse events: Asthenia, constipation, and abnormal ejaculation. Adaptation to Certain Adverse Events Over a 4- to 6-week period, there was evidence of 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 and GAD are displayed in Table 6. Table 6. Incidence of Sexual Adverse Events in Controlled Clinical Trials ParoxetinePlacebon (males)14461042 Decreased Libido6-15%0-5%Ejaculatory Disturbance13-28%0-2%Impotence2-9%0-3%n (females)18221340Decreased Libido0-9%0-2%Orgasmic Disturbance2-9%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 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 in controlled clinical trials. ECG Changes In an analysis of ECGs obtained in 682 patients treated with paroxetine and 415 patients treated with placebo in controlled clinical trials, no clinically significant changes were seen in the ECGs of either group. Liver Function Tests In placebo-controlled clinical trials, patients treated with paroxetine exhibited abnormal values on liver function tests at no greater rate than that seen in placebo-treated patients. In particular, the paroxetine-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 During its premarketing assessment in major depressive disorder, multiple doses of paroxetine were administered to 6,145 patients in phase 2 and 3 studies. The conditions and duration of exposure to paroxetine varied greatly and included (in overlapping categories) open and double-blind studies, uncontrolled and controlled studies, inpatient and outpatient studies, and fixed-dose, and titration studies. During premarketing clinical trials in OCD, panic disorder and generalized anxiety disorder, 542, 469, and 735 patients, respectively, received multiple doses of paroxetine. Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories. In the tabulations that follow, reported adverse events were classified using a standard COSTART-based Dictionary terminology. The frequencies presented, therefore, represent the proportion of the 9,089 patients exposed to multiple doses of paroxetine who experienced an event of the type cited on at least 1 occasion while receiving paroxetine. All reported events are included except those already listed in Tables 2 to 5, those reported in terms so general as to be uninformative and those events where a drug cause was remote. It is important to emphasize that although the events reported occurred during treatment with paroxetine, they were not necessarily caused by it. PRECAUTIONS section. Body as a Whole Cardiovascular System Digestive System Endocrine System Rare: Diabetes mellitus, goiter, hyperthyroidism, hypothyroidism, thyroiditis. Hemic and Lymphatic Systems Metabolic and Nutritional Musculoskeletal System Nervous System Respiratory System Skin and Appendages Special Senses Urogenital System Postmarketing Reports Voluntary reports of adverse events in patients taking paroxetine that have been received since market introduction and not listed above that may have no causal relationship with the drug include acute pancreatitis, elevated liver function tests (the most severe cases were deaths due to liver necrosis, and grossly elevated transaminases associated with severe liver dysfunction), Guillain-Barrpurpura). There has been a case report of an elevated phenytoin level after 4 weeks of paroxetine and phenytoin coadministration. There has been a case report of severe hypotension when paroxetine was added to chronic metoprolol treatment.