FDA label FC07FDD4-EEDE-7835-B2AD-23B14C1E152B

WARNING Suicidality in Children and Adolescents- Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children and adolescents with major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of fluoxetine or any other antidepressant in a child or adolescent must balance this risk with the clinical need. Patients who are started on therapy should be 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 prescriber. Eli Lilly’s fluoxetine is approved for use in pediatric patients with MDD and obsessive compulsive disorder (OCD) ( see WARNINGS and PRECAUTIONS, Pediatric Use). Pooled analyses of short-term (4 to 16 weeks) placebo-controlled trials of 9 antidepressant drugs (SSRIs and others) in children and adolescents with major depressive disorder (MDD), obsessive compulsive disorder (OCD), or other psychiatric disorders (a total of 24 trials involving over 4400 patients) have revealed a greater risk of adverse events representing suicidal thinking or behavior (suicidality) during the first few months of treatment in those receiving antidepressants. The average risk of such events in patients receiving antidepressants was 4%, twice the placebo risk of 2%. No suicides occurred in these trials.

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. There has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients. Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children and adolescents with major depressive disorder (MDD) and other psychiatric disorders. Pooled analyses of short-term placebo-controlled trials of 9 antidepressant drugs (SSRIs and others) in children and adolescents with MDD, OCD, or other psychiatric disorders (a total of 24 trials involving over 4400 patients) have revealed a greater risk of adverse events representing suicidal behavior or thinking (suicidality) during the first few months of treatment in those receiving antidepressants. The average risk of such events in patients receiving antidepressants was 4%, twice the placebo risk of 2%. There was considerable variation in risk among drugs, but a tendency toward an increase for almost all drugs studied .The risk of suicidality was most consistently observed in the MDD trials, but there were signals of risk arising from some trials in other psychiatric indications (obsessive compulsive disorder and social anxiety disorder) as well. No suicides occurred in any of these trials. It is unknown whether the suicidality risk in pediatric patients extends to longer-term use, i.e., beyond several months. It is also unknown whether the suicidality risk extends to adults. Information related to the efficacy of fluoxetine in the treatment of children and adolescents is approved for Eli Lilly and Company’s fluoxetine hydrochloride drug products. However, due to Eli Lilly’s marketing exclusivity rights, this drug product is not labeled for pediatric use. However, all pediatric patients being treated with antidepressants for any indication should be 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. Such observation would generally include at least weekly face-to-face contact with patients or their family members or caregivers during the first 4 weeks of treatment, then every other week visits for the next 4 weeks, then at 12 weeks, and as clinically indicated beyond 12 weeks. Additional contact by telephone may be appropriate between face-to-face visits. Adults with MDD or co-morbid depression in the setting of other psychiatric illness being treated with antidepressants should be observed similarly for clinical worsening and suicidality, 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 Fluoxetine , for a description of the risks of discontinuation of fluoxetine). Families and caregivers of pediatric 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 fluoxetine hydrochloride should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Families and caregivers of adults being treated for depression should be similarly advised. It should be noted that Eli Lilly and Company’s fluoxetine is approved in the pediatric population only for major depressive disorder and obsessive compulsive disorder. Screening Patients for Bipolar Disorder A major depressive episode may be the initial presehydrochloride ntation of bipolar disorder. It is generally be lieved (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 despressive 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 fluoxetine is not approved for use in treating bipolar depression. Rash and Possibly Allergic Events In U.S. fluoxetine clinical trials as of May 8, 1995, 7% of 10,782 patients developed various types of rashes and/or urticaria. Among the cases of rash and/or urticaria reported in premarketing clinical trials, almost a third were withdrawn from treatment because of the rash and/or systemic signs or symptoms associated with the rash. Clinical findings reported in association with rash include fever, leukocytosis, arthralgias, edema, carpal tunnel syndrome, respiratory distress, lymphadenopathy, proteinuria, and mild transaminase elevation. Most patients improved promptly with discontinuation of fluoxetine and/or adjunctive treatment with antihistamines or steroids, and all patients experiencing these events were reported to recover completely. In premarketing clinical trials, two patients are known to have developed a serious cutaneous systemic illness. In neither patient was there an unequivocal diagnosis, but one was considered to have a leukocytoclastic vasculitis, and the other, a severe desquamating syndrome that was considered variously to be a vasculitis or erythema multiforme. Other patients have had systemic syndromes suggestive of serum sickness. Since the introduction of fluoxetine, systemic events, possibly related to vasculitis and including lupus-like syndrome, have developed in patients with rash. Although these events are rare, they may be serious, involving the lung, kidney, or liver. Death has been reported to occur in association with these systemic events. Anaphylactoid events, including bronchospasm, angioedema, laryngospasm, and urticaria alone and in combination, have been reported. Pulmonary events, including inflammatory processes of varying histopathology and/or fibrosis, have been reported rarely. These events have occurred with dyspnea as the only preceding symptom. Whether these systemic events and rash have a common underlying cause or are due to different etiologies or pathogenic processes is not known. Furthermore, a specific underlying immunologic basis for these events has not been identified. Upon the appearance of rash or of other possibly allergic phenomena for which an alternative etiology cannot be identified, fluoxetine should be discontinued. Potential Interaction with Thioridazine In a study of 19 healthy male subjects, which included 6 slow and 13 rapid hydroxylators of debrisoquin, a single 25 mg oral dose of thioridazine produced a 2.4-fold higher C max and a 4.5-fold higher AUC for thioridazine in the slow hydroxylators compared to the rapid hydroxylators. The rate of debrisoquin hydroxylation is felt to depend on the level of CYP2D6 isozyme activity. Thus, this study suggests that drugs which inhibit CYP2D6, such as certain SSRIs, including fluoxetine, will produce elevated plasma levels of thioridazine ( see PRECAUTIONS ). Thioridazine administration produces a dose-related prolongation of the QT c interval, which is associated with serious ventricular arrhythmias, such as torsades de pointes-type arrhythmias, and sudden death. This risk is expected to increase with fluoxetine-induced inhibition of thioridazine metabolism ( see CONTRAINDICATIONS ).

ADVERSE REACTIONS Multiple doses of fluoxetine had been administered to 10,782 patients with various diagnoses in U.S. clinical trials as of May 8, 1995. Adverse events were recorded by clinical investigators using descriptive 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 events into a limited (i.e., reduced) number of standardized event categories. In the tables and tabulations that follow, COSTART Dictionary terminology has been used to classify reported adverse events. The stated frequencies represent the proportion of individuals who experienced, at least once, a treatment emergent adverse event of the type listed. An event was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. It is important to emphasize that events reported during therapy were not necessarily caused by it. The prescriber should be aware that the figures in the tables and tabulations 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 population studied. Incidence in major depressive disorder, OCD, and bulimia placebo-controlled clinical trials (excluding data from extensions of trials). Table 1 enumerates the most common treatment-emergent adverse events associated with the use of fluoxetine (incidence of at least 5% for fluoxetine and at least twice that for placebo within at least one of the indications) for the treatment of major depressive disorder, OCD, and bulimia in U.S. controlled clinical trials. Table 1 Most Common Treatment-Emergent Adverse Events: Incidence in Major Depressive Disorder, OCD, and Bulimia Placebo-Controlled Clinical Trials 1 Percentage of Patients Reporting Event Major Despressive Disorder OCD Bulimia Body System/ Adverse Event) Fluoxetine (N=1728) Placebo (N=975) Fluoxetine (N=266) Placebo (N=89) Fluoxetine (N=450) Placebo (N=267) Body as a Whole Asthenia 9 5 15 11 21 9 Flu syndrome 3 4 10 7 8 3 Cardiovascular System Vasodilatation 3 2 5 — 2 1 Digestive System Nausea 21 9 26 13 29 11 Diarrhea 12 8 18 13 8 6 Anorexia 11 2 17 10 8 4 Dry mouth 10 7 12 3 9 6 Dyspepsia 7 5 10 4 10 6 Nervous System Insomnia 16 9 28 22 33 13 Anxiety 12 7 14 7 15 9 Nervousness 14 9 14 15 11 5 Somnolence 13 6 17 7 13 5 Tremor 10 3 9 1 13 1 Libido decreased 3 — 11 2 5 1 Abnormal dreams 1 1 5 2 5 3 Respiratory System Pharyngitis 3 3 11 9 10 5 Sinusitis 1 4 5 2 6 4 Yawn — — 7 — 11 — Skin and Appendages Sweating 8 3 7 — 8 3 Rash 4 3 6 3 4 4 Urogenital System Impotence 2 2 — — — 7 — Abnormal ejaculation 2 — — 7 — 7 — 1 Includes U.S. data for major depressive disorder, OCD and bulimia clinical trials. 2 Denominator used was for males only (N=690 fluoxetine major depressive disorder; N=410 placebo major depressive disorder; N=116 fluoxetine OCD; N=43 placebo OCD; N=14 fluoxetine bulimia; N=1 placebo bulimia). — Incidence less than 1%. Associated with discontinuation in major depressive disorder, OCD, and bulimia placebo-controlled clinical trials (excluding data from extensions of trials) Table 2 lists the adverse events associated with discontinuation of fluoxetine treatment (incidence at least twice that for placebo and at least 1% for fluoxetine in clinical trials collecting only a primary event associated with discontinuation) in major depressive disorder, OCD, and bulimia clinical trials. Table 2 Most Common Adverse Events Associated with Discontinuation in Major Depressive Disorder, OCD, and Bulimia Placebo-Controlled Clinical Trials 1 Major Depressive Disorder (N=392) OCD (N=266) Bulimia (N=450) — Anxiety (2%) — — — Insomnia (2%) Nervousness (1%) — — — Rash (1%) — 1 Includes U.S. major depressive disorder, OCD and bulimia trials. Other adverse events in pediatric patients (children and adolescents) Treatment-emergent adverse events were collected in 322 pediatric patients (180 fluoxetine-treated, 142 placebo-treated). The overall profile of adverse events was generally similar to that seen in adult studies, as shown in Tables 1 and 2. However, the following adverse events (excluding those which appear in the body or footnotes of Tables 1 and 2 and those for which the COSTART terms were uninformative or misleading) were reported at an incidence of at least 2% for fluoxetine and greater than placebo: thirst, hyperkinesia, agitation, personality disorder, epistaxis, urinary frequency, and menorrhagia. The most common adverse event (incidence at least 1% for fluoxetine and greater than placebo) associated with discontinuation in three pediatric placebo-controlled trials (N=418 randomized; 228 fluoxetine-treated; 190 placebo-treated) was mania/hypomania (1.8% for fluoxetine-treated, 0% for placebo-treated). In these clinical trials, only a primary event associated with discontinuation was collected. 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 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 patients enrolled in U.S. major depressive disorder, OCD and bulimia placebo-controlled clinical trials, decreased libido was the only sexual side effect reported by at least 2% of patients taking fluoxetine (4% fluoxetine, <1% placebo). There have been spontaneous reports in women taking fluoxetine of orgasmic dysfunction, including anorgasmia. There are no adequate and well-controlled studies examining sexual dysfunction with fluoxetine treatment. Priapism has been reported with all SSRIs. 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. Other Events Observed in Clinical Trials Following is a list of all treatment-emergent adverse events reported at anytime by individuals taking fluoxetine in U.S. clinical trials as of May 8, 1995 (10,782 patients) except (1) those listed in the body or footnotes of Tables 1 and 2 above or elsewhere in labeling; (2) those for which the COSTART terms were uninformative or misleading; (3) those events for which a causal relationship to fluoxetine use was considered remote; and (4) events occurring in only one patient treated with fluoxetine and which did not have a substantial probability of being acutely life-threatening. Events are classified within body system categories using the following definitions: frequent adverse events are defined as those occurring on one or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1,000 patients; rare events are those occurring in less than 1/1,000 patients. Body as Whole Frequent : chest pain, chills; Infrequent : chills and fever, face edema, intentional overdose, malaise, pelvic pain, suicide attempt; Rare : acute abdominal syndrome, hypothermia, intentional injury, neuroleptic malignant syndrome 1 , photosensitivity reaction. Cardiovascular System Frequent : hemorrhage, hypertension, palpitation; Infrequent : angina pectoris, arrhythmia, congestive heart failure, hypotension, migraine, myocardial infarct, postural hypotension, syncope, tachycardia, vascular headache; Rare : atrial fibrillation, bradycardia, cerebral embolism, cerebral ischemia, cerebrovascular accident, extrasystoles, heart arrest, heart block, pallor, peripheral vascular disorder, phlebitis, shock, thrombophlebitis, thrombosis, vasospasm, ventricular arrhythmia, ventricular extrasystoles, ventricular fibrillation. Digestive System Frequent : increased appetite, nausea and vomiting; Infrequent : aphthous stomatitis, cholelithiasis, colitis, dysphagia, eructation, esophagitis, gastritis, gastroenteritis, glossitis, gum hemorrhage, hyperchlorhydria, increased salivation, liver function tests abnormal, melena, mouth ulceration, nausea/vomiting/diarrhea, stomach ulcer, stomatitis, thirst; Rare : biliary pain, bloody diarrhea, cholecystitis, duodenal ulcer, enteritis, esophageal ulcer, fecal incontinence, gastrointestinal hemorrhage, hematemesis, hemorrhage of colon, hepatitis, intestinal obstruction, liver fatty deposit, pancreatitis, peptic ulcer, rectal hemorrhage, salivary gland enlargement, stomach ulcer hemorrhage, tongue edema. Endocrine System Infrequent : hypothyroidism; Rare : diabetic acidosis, diabetes mellitus. Hemic and Lymphatic System Infrequent : anemia, ecchymosis; Rare : blood dyscrasia, hypochromic anemia, leukopenia, lymphedema, lymphocytosis, petechia, purpura, thrombocythemia, thrombocytopenia. Metabolic and Nutritional Frequent : weight gain; Infrequent : dehydration, generalized edema, gout, hypercholesteremia, hyperlipemia, hypokalemia, peripheral edema; Rare : alcohol intolerance, alkaline phosphatase increased, BUN increased, creatine phosphokinase increased, hyperkalemia, hyperuricemia, hypocalcemia, iron deficiency anemia, SGPT increased. Musculoskeletal System Infrequent : arthritis, bone pain, bursitis, leg cramps, tenosynovitis; Rare : arthrosis, chondrodystrophy, myasthenia, myopathy, myositis, osteomyelitis, osteoporosis, rheumatoid arthritis. Nervous System Frequent : agitation, amnesia, confusion, emotional lability, sleep disorder; Infrequent : abnormal gait, acute brain syndrome, akathisia, apathy, ataxia, buccoglossal syndrome, CNS depression, CNS stimulation, depersonalization, euphoria, hallucinations, hostility, hyperkinesia, hypertonia, hypesthesia, incoordination, libido increased, myoclonus, neuralgia, neuropathy, neurosis, paranoid reaction, personality disorder 2 , psychosis, vertigo; Rare : abnormal electroencephalogram, antisocial reaction, circumoral paresthesia, coma, delusions, dysarthria, dystonia, extrapyramidal syndrome, foot drop, hyperesthesia, neuritis, paralysis, reflexes decreased, reflexes increased, stupor. Respiratory System Infrequent : asthma, epistaxis, hiccup, hyperventilation; Rare : apnea, atelectasis, cough decreased, emphysema, hemoptysis, hypoventilation, hypoxia, larynx edema, lung edema, pneumothorax, stridor. Skin and Appendages Infrequent : acne, alopecia, contact dermatitis, eczema, maculopapular rash, skin discoloration, skin ulcer, vesiculobullous rash; Rare : furunculosis, herpes zoster, hirsutism, petechial rash, psoriasis, purpuric rash, pustular rash, seborrhea. Special Senses Frequent : ear pain, taste perversion, tinnitus; Infrequent : conjunctivitis, dry eyes, mydriasis, photophobia; Rare : blepharitis, deafness, diplopia, exophthalmos, eye hemorrhage, glaucoma, hyperacusis, iritis, parosmia, scleritis, strabismus, taste loss, visual field defect. Urogenital System Frequent : urinary frequency; Infrequent : abortion 3 , albuminuria, amenorrhea 3 , anorgasmia, breast enlargement, breast pain, cystitis, dysuria, female lactation 3 , fibrocystic breast 3 , hematuria, leukorrhea 3 , menorrhagia 3 , metrorrhagia 3 , nocturia, polyuria, urinary incontinence, urinary retention, urinary urgency, vaginal hemorrhage 3 ; Rare : breast engorgement, glycosuria, hypomenorrhea 3 , kidney pain, oliguria, priapism 3 , uterine hemorrhage 3 , uterine fibroids enlarged 3 . 1 Neuroleptic malignant syndrome is the COSTART term which best captures serotonin syndrome. 2 Personality disorder is the COSTART term for designating nonaggressive objectionable behavior. 3 Adjusted for gender. Postintroduction Reports Voluntary reports of adverse events temporally associated with fluoxetine that have been received since market introduction and that may have no causal relationship with the drug include the following: aplastic anemia, atrial fibrillation, cataract, cerebral vascular accident, cholestatic jaundice, confusion, dyskinesia (including, for example, a case of buccal-lingual-masticatory syndrome with involuntary tongue protrusion reported to develop in a 77-year-old female after 5 weeks of fluoxetine therapy and which completely resolved over the next few months following drug discontinuation), eosinophilic pneumonia, epidermal necrolysis, erythema nodosum, exfoliative dermatitis, gynecomastia, heart arrest, hepatic failure/necrosis, hyperprolactinemia, hypoglycemia, immune-related hemolytic anemia, kidney failure, misuse/abuse, movement disorders developing in patients with risk factors including drugs associated with such events and worsening of preexisting movement disorders, neuroleptic malignant syndrome-like events, optic neuritis, pancreatitis, pancytopenia, priapism, pulmonary embolism, pulmonary hypertension, QT prolongation, serotonin syndrome (a range of signs and symptoms that can rarely, in its most severe form, resemble neuroleptic malignant syndrome), Stevens-Johnson syndrome, sudden unexpected death, suicidal ideation, thrombocytopenia, thrombocytopenic purpura, vaginal bleeding after drug withdrawal, ventricular tachycardia (including torsades de pointes-type arrhythmias), and violent behaviors.

<table ID="ID_1AF8C821-6F33-4349-B6E4-F1539453206B" border="single" frame="box" width="454"> <col width="26.432%"/> <col width="13.436%"/> <col width="11.013%"/> <col width="13.216%"/> <col width="11.233%"/> <col width="13.436%"/> <col width="11.233%"/> <tbody> <tr ID="ID_FE43F212-460A-40AC-85FA-E79891630C89"> <td align="left" valign="top"/> <td align="center" colspan="6" valign="top">Percentage of Patients Reporting Event</td> </tr> <tr ID="ID_6380D5D0-9D46-41C2-9BAA-6C4EA43CC768"> <td align="left" valign="top"/> <td align="center" colspan="2" valign="top"> <paragraph>Major</paragraph>Despressive Disorder</td> <td align="center" colspan="2" valign="top">OCD</td> <td align="center" colspan="2" valign="top"> <paragraph>Bulimia</paragraph> </td> </tr> <tr ID="ID_9253151D-713B-450E-BDAB-6216C5FDDA5F"> <td align="left" valign="top"> <paragraph>Body System/</paragraph> <paragraph>Adverse Event) </paragraph> </td> <td align="center" valign="top"> <paragraph>Fluoxetine</paragraph>(N=1728)</td> <td align="center" valign="top"> <paragraph>Placebo</paragraph>(N=975)</td> <td align="center" valign="top"> <paragraph>Fluoxetine</paragraph>(N=266)</td> <td align="center" valign="top"> <paragraph>Placebo</paragraph>(N=89)</td> <td align="center" valign="top"> <paragraph>Fluoxetine</paragraph>(N=450)</td> <td align="center" valign="top"> <paragraph>Placebo</paragraph>(N=267)</td> </tr> <tr ID="ID_C3697D6F-3F54-4EAF-9372-E84B388EF58B"> <td align="left" valign="top"> <content styleCode="bold"> <content styleCode="emphasis">Body as a Whole</content> </content> </td> <td align="left" valign="top"/> <td align="left" valign="top"/> <td align="left" valign="top"/> <td align="left" valign="top"/> <td align="left" valign="top"/> <td align="left" valign="top"/> </tr> <tr ID="ID_530C2996-6A08-4C99-B1C2-F15851F90C14"> <td align="left" valign="top">Asthenia</td> <td align="center" valign="middle">9</td> <td align="center" valign="middle">5</td> <td align="center" valign="middle">15</td> <td align="center" valign="middle">11</td> <td align="center" valign="middle">21</td> <td align="center" valign="middle">9</td> </tr> <tr ID="ID_B3A88CFA-BBBD-4A12-AC95-5BBB28F68AB9"> <td align="left" valign="top">Flu syndrome </td> <td align="center" valign="middle">3</td> <td align="center" valign="middle">4</td> <td align="center" valign="middle">10</td> <td align="center" valign="middle">7</td> <td align="center" valign="middle">8</td> <td align="center" valign="middle">3</td> </tr> <tr ID="ID_5F66D35F-66ED-4226-B827-F6BA92BE7B4F"> <td align="left" valign="top"> <content styleCode="bold"> <content styleCode="emphasis">Cardiovascular System</content> </content> </td> <td align="center" valign="middle"/> <td align="center" valign="middle"/> <td align="center" valign="middle"/> <td align="center" valign="middle"/> <td align="center" valign="middle"/> <td align="center" valign="middle"/> </tr> <tr ID="ID_E435AD1C-63F5-43E4-81F0-9F8A0D571401"> <td align="left" valign="top">Vasodilatation </td> <td align="center" valign="middle">3</td> <td align="center" valign="middle">2</td> <td align="center" valign="middle">5</td> <td align="center" valign="middle">&#x2014;</td> <td align="center" valign="middle">2</td> <td align="center" valign="middle">1</td> </tr> <tr ID="ID_2F8EC2F8-74A4-49DA-9CA8-4EEFABB94498"> <td align="left" valign="top"> <content styleCode="bold"> <content styleCode="emphasis">Digestive System</content> </content> </td> <td align="center" valign="middle"/> <td align="center" valign="middle"/> <td align="center" valign="middle"/> <td align="center" valign="middle"/> <td align="center" valign="middle"/> <td align="center" valign="middle"/> </tr> <tr ID="ID_2251CB59-DB66-451E-935C-AC9594D1547C"> <td align="left" valign="top">Nausea</td> <td align="center" valign="middle">21</td> <td align="center" valign="middle">9</td> <td align="center" valign="middle">26</td> <td align="center" valign="middle">13</td> <td align="center" valign="middle">29</td> <td align="center" valign="middle">11</td> </tr> <tr ID="ID_0E037746-80F7-411F-95E1-71B177C8816B"> <td align="left" valign="top">Diarrhea </td> <td align="center" valign="middle">12</td> <td align="center" valign="middle">8</td> <td align="center" valign="middle">18</td> <td align="center" valign="middle">13</td> <td align="center" valign="middle">8</td> <td align="center" valign="middle">6</td> </tr> <tr ID="ID_C2C352FE-BDF4-467A-815A-5411CCEAC513"> <td align="left" valign="top">Anorexia</td> <td align="center" valign="middle">11</td> <td align="center" valign="middle">2</td> <td align="center" valign="middle">17</td> <td align="center" valign="middle">10</td> <td align="center" valign="middle">8</td> <td align="center" valign="middle">4</td> </tr> <tr ID="ID_75E59CF5-78B3-48EB-9B58-0BD710957A9F"> <td align="left" valign="top">Dry mouth</td> <td align="center" valign="middle">10</td> <td align="center" valign="middle">7</td> <td align="center" valign="middle">12</td> <td align="center" valign="middle">3</td> <td align="center" valign="middle">9</td> <td align="center" valign="middle">6</td> </tr> <tr ID="ID_F5F02387-D8FC-46D6-84D2-4E7FA44C3B13"> <td align="left" valign="top">Dyspepsia </td> <td align="center" valign="middle">7</td> <td align="center" valign="middle">5</td> <td align="center" valign="middle">10</td> <td align="center" valign="middle">4</td> <td align="center" valign="middle">10</td> <td align="center" valign="middle">6</td> </tr> <tr ID="ID_21F9CC04-8632-40D9-AC69-C3882F4644C9"> <td align="left" valign="top"> <content styleCode="bold"> <content styleCode="emphasis">Nervous System</content> </content> </td> <td align="center" valign="middle"/> <td align="center" valign="middle"/> <td align="center" valign="middle"/> <td align="center" valign="middle"/> <td align="center" valign="middle"/> <td align="center" valign="middle"/> </tr> <tr ID="ID_8B56EF34-3052-4C98-9681-ABAA99B47306"> <td align="left" valign="top">Insomnia</td> <td align="center" valign="middle">16</td> <td align="center" valign="middle">9</td> <td align="center" valign="middle">28</td> <td align="center" valign="middle">22</td> <td align="center" valign="middle">33</td> <td align="center" valign="middle">13</td> </tr> <tr ID="ID_6D7152BA-E208-4A3E-A535-0E0B9754AFF4"> <td align="left" valign="top">Anxiety</td> <td align="center" valign="middle">12</td> <td align="center" valign="middle">7</td> <td align="center" valign="middle">14</td> <td align="center" valign="middle">7</td> <td align="center" valign="middle">15</td> <td align="center" valign="middle">9</td> </tr> <tr ID="ID_5CB5E2A9-DD1A-48E2-9E1E-D2B12019BB18"> <td align="left" valign="top">Nervousness </td> <td align="center" valign="middle">14</td> <td align="center" valign="middle">9</td> <td align="center" valign="middle">14</td> <td align="center" valign="middle">15</td> <td align="center" valign="middle">11</td> <td align="center" valign="middle">5</td> </tr> <tr ID="ID_9F5D2743-CD2C-4315-AF8A-6BE5F61B8C02"> <td align="left" valign="top">Somnolence</td> <td align="center" valign="middle">13</td> <td align="center" valign="middle">6</td> <td align="center" valign="middle">17</td> <td align="center" valign="middle">7</td> <td align="center" valign="middle">13</td> <td align="center" valign="middle">5</td> </tr> <tr ID="ID_B20C8F6F-A298-4807-86EF-ED896F2E9386"> <td align="left" valign="top">Tremor </td> <td align="center" valign="middle">10</td> <td align="center" valign="middle">3</td> <td align="center" valign="middle">9</td> <td align="center" valign="middle">1</td> <td align="center" valign="middle">13</td> <td align="center" valign="middle">1</td> </tr> <tr ID="ID_2BD04731-80C9-4223-AAB9-F05DAD8540E8"> <td align="left" valign="top">Libido decreased</td> <td align="center" valign="middle">3</td> <td align="center" valign="middle">&#x2014;</td> <td align="center" valign="middle">11</td> <td align="center" valign="middle">2</td> <td align="center" valign="middle">5</td> <td align="center" valign="middle">1</td> </tr> <tr ID="ID_6B493747-75B6-46AF-927E-54B57C87F0F1"> <td align="left" valign="top">Abnormal dreams</td> <td align="center" valign="middle">1</td> <td align="center" valign="middle">1</td> <td align="center" valign="middle">5</td> <td align="center" valign="middle">2</td> <td align="center" valign="middle">5</td> <td align="center" valign="middle">3</td> </tr> <tr ID="ID_41DA65A1-AD1A-49C6-AAB2-06E3B27EA6E7"> <td align="left" valign="top"> <content styleCode="bold"> <content styleCode="emphasis">Respiratory System</content> </content> </td> <td align="center" valign="middle"/> <td align="center" valign="middle"/> <td align="center" valign="middle"/> <td align="center" valign="middle"/> <td align="center" valign="middle"/> <td align="center" valign="middle"/> </tr> <tr ID="ID_18E23F3C-6FBE-42DB-AF19-96B692688904"> <td align="left" valign="top">Pharyngitis </td> <td align="center" valign="middle">3</td> <td align="center" valign="middle">3</td> <td align="center" valign="middle">11</td> <td align="center" valign="middle">9</td> <td align="center" valign="middle">10</td> <td align="center" valign="middle">5</td> </tr> <tr ID="ID_B5DEFF9A-4DD4-4573-997D-DFB71C900A7A"> <td align="left" valign="top">Sinusitis</td> <td align="center" valign="middle">1</td> <td align="center" valign="middle">4</td> <td align="center" valign="middle">5</td> <td align="center" valign="middle">2</td> <td align="center" valign="middle">6</td> <td align="center" valign="middle">4</td> </tr> <tr ID="ID_86AA9C17-391B-4679-A952-5AFB8EDE94F7"> <td align="left" valign="top">Yawn </td> <td align="center" valign="middle">&#x2014;</td> <td align="center" valign="middle">&#x2014;</td> <td align="center" valign="middle">7</td> <td align="center" valign="middle">&#x2014;</td> <td align="center" valign="middle">11</td> <td align="center" valign="middle">&#x2014;</td> </tr> <tr ID="ID_58140967-4BE4-4DD2-95F3-105214AD7CAF"> <td align="left" valign="top"> <content styleCode="bold"> <content styleCode="emphasis">Skin and Appendages</content> </content> </td> <td align="center" valign="middle"/> <td align="center" valign="middle"/> <td align="center" valign="middle"/> <td align="center" valign="middle"/> <td align="center" valign="middle"/> <td align="center" valign="middle"/> </tr> <tr ID="ID_73B84685-E4A7-41E0-AE75-06FAE7A9A068"> <td align="left" valign="top">Sweating</td> <td align="center" valign="middle">8</td> <td align="center" valign="middle">3</td> <td align="center" valign="middle">7</td> <td align="center" valign="middle">&#x2014;</td> <td align="center" valign="middle">8</td> <td align="center" valign="middle">3</td> </tr> <tr ID="ID_85798A6B-64AA-4DE2-9083-4556AA1C3D41"> <td align="left" valign="top">Rash</td> <td align="center" valign="middle">4</td> <td align="center" valign="middle">3</td> <td align="center" valign="middle">6</td> <td align="center" valign="middle">3</td> <td align="center" valign="middle">4</td> <td align="center" valign="middle">4</td> </tr> <tr ID="ID_3F6E15FC-7883-445A-A532-BD819907D1FD"> <td align="left" valign="top"> <content styleCode="bold"> <content styleCode="emphasis">Urogenital System</content> </content> </td> <td align="center" valign="middle"/> <td align="center" valign="middle"/> <td align="center" valign="middle"/> <td align="center" valign="middle"/> <td align="center" valign="middle"/> <td align="center" valign="middle"/> </tr> <tr ID="ID_05EBFB29-C273-4AC9-9139-0C64CCEAFB3C"> <td align="left" valign="top">Impotence² </td> <td align="center" valign="middle">2</td> <td align="center" valign="middle">&#x2014;</td> <td align="center" valign="middle">&#x2014;</td> <td align="center" valign="middle">&#x2014;</td> <td align="center" valign="middle">7</td> <td align="center" valign="middle">&#x2014;</td> </tr> <tr ID="ID_5954940E-5685-444F-AA61-1AED8840851F"> <td align="left" valign="top">Abnormal ejaculation² </td> <td align="center" valign="middle">&#x2014;</td> <td align="center" valign="middle">&#x2014;</td> <td align="center" valign="middle">7</td> <td align="center" valign="middle">&#x2014;</td> <td align="center" valign="middle">7</td> <td align="center" valign="middle">&#x2014;</td> </tr> </tbody> </table>

<table ID="ID_2010162C-62F6-4848-9E85-6B697F996CAF" border="single" frame="box" width="431.09999999999996"> <col width="33.333%"/> <col width="33.333%"/> <col width="33.333%"/> <tbody> <tr ID="ID_10358975-4275-421A-88BE-096176BD4B59"> <td align="center" valign="top"> <paragraph>Major Depressive</paragraph> <paragraph>Disorder</paragraph>(N=392)</td> <td align="center" valign="top"> <paragraph>OCD</paragraph>(N=266)</td> <td align="center" valign="top"> <paragraph>Bulimia</paragraph> <paragraph>(N=450)</paragraph> </td> </tr> <tr ID="ID_88C5A5A9-6B19-4DA0-A63C-A6ADE4D89558"> <td align="center" valign="top">&#x2014;</td> <td align="center" valign="top">Anxiety (2%)</td> <td align="center" valign="top">&#x2014;</td> </tr> <tr ID="ID_D82F687F-8CC8-40DD-AAB2-AA107CBD749B"> <td align="center" valign="top">&#x2014;</td> <td align="center" valign="top">&#x2014;</td> <td align="center" valign="top">Insomnia (2%)</td> </tr> <tr ID="ID_E51EC06A-9DE7-4DEC-BC05-D710E4880456"> <td align="center" valign="top">Nervousness (1%)</td> <td align="center" valign="top">&#x2014;</td> <td align="center" valign="top">&#x2014;</td> </tr> <tr ID="ID_59E4FD25-EF4E-4B5F-86E1-85C12D15EE86"> <td align="center" valign="top">&#x2014;</td> <td align="center" valign="top">Rash (1%)</td> <td align="center" valign="top">&#x2014;</td> </tr> </tbody> </table>