Fluoxetine

WARNING: SUICIDALITY AND ANTIDEPRESSANT DRUGS See full prescribing information for complete boxed warning. Increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants for Major Depressive Disorder (MDD) and other psychiatric disorders. Fluoxetine tablet is not approved for use in pediatric patients ( 5.1 ). 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 fluoxetine tablet or any other antidepressant 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 beyond 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 associated 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 prescriber. Fluoxetine tablet is not approved for use in pediatric patients [ s ee Warnings and Precautions ( 5.1 ) and Use in Specific Populations ( 8.4 )].

5 WARNINGS AND PRECAUTIONS Clinical Worsening and Suicide Risk: Monitor for clinical worsening and suicidal thinking and behavior ( 5.1 ) Serotonin Syndrome: Serotonin syndrome has been reported with SSRIs and SNRIs, including fluoxetine hydrochloride, both when taken alone, but especially when co-administered with other serotonergic agents. If such symptoms occur, discontinue fluoxetine tablet and serotonergic agents and initiate supportive treatment. If concomitant use of fluoxetine hydrochloride with other serotonergic drugs is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases ( 5.2 ) Allergic Reactions and Rash: Discontinue upon appearance of rash or allergic phenomena ( 5.3 ) Activation of Mania/Hypomania: Screen for Bipolar Disorder and monitor for mania/hypomania ( 5.4 ) Seizures: Use cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold ( 5.5 ) Altered Appetite and Weight: Significant weight loss has occurred ( 5.6 ) Abnormal Bleeding : May increase the risk of bleeding. Use with NSAIDs, aspirin, warfarin, or drugs that affect coagulation may potentiate the risk of gastrointestinal or other bleeding ( 5.7 ) Angle-Closure Glaucoma: Angle-closure glaucoma has occurred in patients who have untreated anatomically narrow angles and who are treated with antidepressants ( 5.8 ) Hyponatremia: Has been reported with fluoxetine in association with syndrome of inappropriate antidiuretic hormone (SIADH) ( 5.9 ) Anxiety and Insomnia: May occur ( 5.10 ) Potential for Cognitive and Motor Impairment: Has potential to impair judgment, thinking, and motor skills. Use caution when operating machinery ( 5.12 ) Long Half-Life: Changes in dose will not be fully reflected in plasma for several weeks ( 5.13 ) Sexual dysfunction: Fluoxetine tablets use may cause symptoms of sexual dysfunction ( 5.15 ) 5.1 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 to 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 versus 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: Suicidality per 1,000 Patients Treated 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 to 24 5 additional cases Decreases Compared to Placebo 25 to 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, that is, 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 Warnings and Precautions ( 5.14 )] . 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 fluoxetine tablet should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. It should be noted that fluoxetine tablet is not approved for treating any indication in the pediatric population. 5.2 Serotonin Syndrome The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including fluoxetine hydrochloride, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, meperidine, methadone, tryptophan, buspirone, amphetamines, and St. John's Wort) and with drugs that impair metabolism of serotonin (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 (for example, agitation, hallucinations, delirium, and coma), autonomic instability (for example, tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (for example, tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (for example, nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome. The concomitant use of fluoxetine tablet with MAOIs intended to treat psychiatric disorders is contraindicated. Fluoxetine tablet 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 1mg/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 fluoxetine tablet. Fluoxetine tablet should be discontinued before initiating treatment with the MAOI [see Contraindications ( 4.1 ) and Dosage and Administration ( 2.5 )]. If concomitant use of fluoxetine hydrochloride with other serotonergic drugs, that is, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, amphetamines, tryptophan and St. John's Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases. Treatment with fluoxetine hydrochloride and any concomitant serotonergic agents, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated. 5.3 Allergic Reactions and Rash In 4 clinical trials for PMDD, 4% of 415 patients treated with fluoxetine tablet reported rash and/or urticaria. None of these cases were classified as serious and 2 of 415 patients (both receiving 60 mg) were withdrawn from treatment because of rash and/or urticaria. In US fluoxetine clinical trials for conditions other than PMDD, 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 reactions were reported to recover completely. In premarketing clinical trials for conditions other than PMDD, 2 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 reactions, possibly related to vasculitis and including lupus-like syndrome, have developed in patients with rash. Although these reactions are rare, they may be serious, involving the lung, kidney, or liver. Death has been reported to occur in association with these systemic reactions. Anaphylactoid reactions, including bronchospasm, angioedema, laryngospasm, and urticaria alone and in combination, have been reported. Pulmonary reactions, including inflammatory processes of varying histopathology and/or fibrosis, have been reported rarely. These reactions have occurred with dyspnea as the only preceding symptom. Whether these systemic reactions 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 reactions has not been identified. Upon the appearance of rash or of other possibly allergic phenomena for which an alternative etiology cannot be identified, fluoxetine tablets should be discontinued. 5.4 Screening Patients for Bipolar Disorder and Monitoring for Mania/Hypomania 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 for clinical worsening and suicide risk 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 fluoxetine tablet is not indicated for the treatment of depressive episodes associated with Bipolar I Disorder. No patients treated with fluoxetine tablet in 4 PMDD clinical trials (N = 415) reported mania/hypomania. In all US fluoxetine clinical trials for conditions other than PMDD, 0.7% of 10,782 patients reported mania/hypomania. Activation of mania/hypomania may occur with medications used to treat depression, especially in patients predisposed to Bipolar I Disorder. 5.5 Seizures No patients treated with fluoxetine tablet in 4 PMDD clinical trials (N = 415) reported seizures. In all US fluoxetine clinical trials for conditions other than PMDD, 0.2% of 10,782 patients reported convulsions. Fluoxetine hydrochloride should be introduced with care in patients with a history of seizures. 5.6 Altered Appetite and Weight In 2 placebo-controlled clinical trials for PMDD, patients treated with fluoxetine tablets reported changes in appetite and weight [ see Table 2]. For individual rates for fluoxetine tablets 20 mg given as continuous and intermittent dosing, see Table 4 and accompanying footnote [see Adverse Reactions ( 6.1 )]. Table 2: Altered Appetite and Weight Treatment Emergent Adverse Reactions: Incidence in PMDD Placebo-Controlled Clinical Trials Percentage of Patients Reporting Adverse Reaction Treatment Emergent Adverse Reaction 20 mg (continuous and intermittent pooled) 60 mg (continuous) Placebo (pooled) Anorexia (decreased appetite) 4% 13% 2% Weight Loss (≥7%) 7% 12% 3% Weight Gain (≥7%) 8% 6% 1% In US placebo-controlled clinical trials of fluoxetine for other approved indications, changes in appetite and weight have also been reported [see Adverse Reactions ( 6.1 ) Table 5]. 5.7 Abnormal Bleeding SNRIs and SSRIs, including fluoxetine, may increase the risk of bleeding reactions. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anti-coagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Based on data from the published observational studies, exposure to SSRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [see Use in Specific Populations ( 8.1 )] . Bleeding reactions related to SNRIs and SSRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages. Patients should be cautioned about the increased risk of bleeding associated with the concomitant use of fluoxetine and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation [see Drug Interactions ( 7.6 )] . 5.8 Angle-Closure Glaucoma The pupillary dilation that occurs following use of many antidepressants and fluoxetine may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. 5.9 Hyponatremia Hyponatremia has been reported during treatment with SNRIs and SSRIs, including fluoxetine. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported and appeared to be reversible when fluoxetine was discontinued. Elderly patients may be at greater risk of developing hyponatremia with SNRIs and SSRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk [see Use in Specific Populations ( 8.5 )] . Discontinuation of fluoxetine tablet should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. More severe and/or acute cases have been associated with hallucination, syncope, seizure, coma, respiratory arrest, and death. 5.10 Anxiety and Insomnia In 2 placebo-controlled clinical trials for PMDD, patients treated with fluoxetine tablet reported anxiety, nervousness, and insomnia [see Table 3]. For individual rates of anxiety, nervousness, and insomnia with fluoxetine tablet 20 mg given as continuous or intermittent dosing, see Table 5 and accompanying footnote [see Adverse Reactions ( 6.1 )]. Table 3: Anxiety and Insomnia Treatment Emergent Adverse Reactions: Incidence in PMDD Placebo-Controlled Clinical Trials Percentage of Patients Reporting Adverse Reaction Treatment Emergent Adverse Reaction 20 mg (continuous and intermittent pooled) 60 mg (continuous) Placebo (pooled) Anxiety 3% 9% 4% Nervousness 5% 9% 3% Insomnia 9% 26% 7% Anxiety, nervousness, and insomnia were associated with discontinuation for fluoxetine tablet [see Table 4 and Warnings and Precautions ( 5.14 )]. Table 4: Anxiety, Nervousness, and Insomnia: Treatment Discontinuation Rates in PMDD Placebo-Controlled Clinical Trials Percentage of Patient Discontinuation due to Adverse Reaction Treatment Emergent Adverse Reaction 20 mg (continuous and intermittent pooled) 60 mg (continuous) Placebo (pooled) Anxiety 0% 6% 1% Nervousness 1% 0% 0.5% Insomnia 1% 4% 0.5% In US placebo-controlled clinical trials of fluoxetine for other approved indications, anxiety, nervousness, and insomnia have been among the most commonly reported adverse reactions [see Table 6 and Adverse Reactions ( 6.1 )]. 5.11 Use in Patients with Concomitant Illness Clinical experience with fluoxetine in patients with concomitant systemic illness is limited. Caution is advisable in using fluoxetine in patients with diseases or conditions that could affect metabolism or hemodynamic responses. Cardiovascular — Fluoxetine has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were systematically excluded from clinical studies during the product's premarket testing. However, the electrocardiograms of 312 patients who received fluoxetine in double-blind trials, for a condition other than PMDD, were retrospectively evaluated; no conduction abnormalities that resulted in heart block were observed. The mean heart rate was reduced by approximately 3 beats/min. Glycemic Control — In patients with diabetes, fluoxetine may alter glycemic control. Hypoglycemia has occurred during therapy with fluoxetine, and hyperglycemia has developed following discontinuation of the drug. As is true with many other types of medication when taken concurrently by patients with diabetes, insulin and/or oral hypoglycemic, dosage may need to be adjusted when therapy with fluoxetine is instituted or discontinued. 5.12 Potential for Cognitive and Motor Impairment Fluoxetine hydrochloride has the potential to impair judgment, thinking, or motor skills. Patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that the drug treatment does not affect them adversely. 5.13 Long Elimination Half-Life Because of the long elimination half-lives of the parent drug and its major active metabolite, changes in dose will not be fully reflected in plasma for several weeks, affecting both strategies for titration to final dose and withdrawal from treatment. This is of potential consequence when drug discontinuation is required or when drugs are prescribed that might interact with fluoxetine and norfluoxetine following the discontinuation of fluoxetine [see Clinical Pharmacology ( 12.3 ) and Drug Interactions ( 7 )] . 5.14 Discontinuation of Treatment During marketing of fluoxetine tablet, SNRIs, and SSRIs, there have been spontaneous reports of adverse reactions occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (for example, paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these reactions are generally self-limiting, there have been reports of serious discontinuation symptoms. Patients should be monitored for these symptoms when discontinuing treatment with fluoxetine tablet. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the dose may continue to be decreased but at a more gradual rate. Plasma fluoxetine and norfluoxetine concentration decrease gradually at the conclusion of therapy which may minimize the risk of discontinuation symptoms with this drug. 5.15 Sexual Dysfunction Use of SSRIs, including fluoxetine tablets, may cause symptoms of sexual dysfunction [see Adverse Reactions ( 6.1 , 6.2 )] . In female patients, SSRI/SNRI use may result in decreased libido and delayed or absent orgasm. It is important for prescribers to inquire about sexual function prior to initiation of fluoxetine tablets and to inquire specifically about changes in sexual function during treatment, because sexual function may not be spontaneously reported. When evaluating changes in sexual function, obtaining a detailed history (including timing of symptom onset) is important because sexual symptoms may have other causes, including the underlying psychiatric disorder. Discuss potential management strategies to support patients in making informed decisions about treatment.

<table ID="ID253" width="624px"><colgroup><col width="288"/><col width="336"/></colgroup><tbody><tr><td colspan="2" align="center" valign="top"/></tr><tr><td align="center" valign="top"><content styleCode="bold">Age Range</content></td><td align="center" valign="top"><content styleCode="bold">Drug-Placebo Difference in Number of </content> <content styleCode="bold"> Cases of Suicidality per 1,000 Patients Treated</content></td></tr><tr><td valign="top"/><td align="center" valign="top">Increases Compared to Placebo</td></tr><tr><td align="center" valign="top">&lt;18</td><td align="center" valign="top">14 additional cases</td></tr><tr><td align="center" valign="top">18 to 24</td><td align="center" valign="top">5 additional cases</td></tr><tr><td valign="top"/><td align="center" valign="top">Decreases Compared to Placebo</td></tr><tr><td align="center" valign="top">25 to 64</td><td align="center" valign="top">1 fewer case</td></tr><tr><td align="center" valign="top">&#x2265;65</td><td align="center" valign="top">6 fewer cases</td></tr></tbody></table>

<table ID="ID255" width="639px"><caption> Table 2: Altered Appetite and Weight Treatment Emergent Adverse Reactions: Incidence in PMDD Placebo-Controlled Clinical Trials </caption><colgroup><col width="160"/><col width="184"/><col width="156"/><col width="139"/></colgroup><tbody><tr><td styleCode="Botrule Lrule Rrule Toprule" align="left" valign="top"/><td styleCode="Botrule Rrule Toprule" colspan="3" align="center" valign="top"><content styleCode="bold"> Percentage of Patients Reporting Adverse Reaction</content></td></tr><tr><td styleCode="Botrule Lrule Rrule" align="center" valign="top"><content styleCode="bold"> Treatment Emergent Adverse Reaction </content></td><td styleCode="Botrule Rrule" align="center" valign="top"><content styleCode="bold"> 20 mg (continuous and intermittent pooled)</content></td><td styleCode="Botrule Rrule" align="center" valign="top"><content styleCode="bold"> 60 mg (continuous)</content></td><td styleCode="Botrule Rrule" align="center" valign="top"><content styleCode="bold"> Placebo (pooled)</content></td></tr><tr><td styleCode="Botrule Lrule Rrule" align="center" valign="top">Anorexia (decreased appetite)</td><td styleCode="Botrule Rrule" align="center" valign="top">4%</td><td styleCode="Botrule Rrule" align="center" valign="top">13%</td><td styleCode="Botrule Rrule" align="center" valign="top">2%</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="center" valign="top">Weight Loss (&#x2265;7%)</td><td styleCode="Botrule Rrule" align="center" valign="top">7%</td><td styleCode="Botrule Rrule" align="center" valign="top">12%</td><td styleCode="Botrule Rrule" align="center" valign="top">3%</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="center" valign="top">Weight Gain (&#x2265;7%)</td><td styleCode="Botrule Rrule" align="center" valign="top">8%</td><td styleCode="Botrule Rrule" align="center" valign="top">6%</td><td styleCode="Botrule Rrule" align="center" valign="top">1%</td></tr></tbody></table>

<table ID="ID257" width="640px"><caption> Table 3: Anxiety and Insomnia Treatment Emergent Adverse Reactions: Incidence in PMDD Placebo-Controlled Clinical Trials </caption><colgroup><col width="160"/><col width="160"/><col width="160"/><col width="160"/></colgroup><tbody><tr><td styleCode="Botrule Lrule Rrule Toprule" align="left" valign="top"/><td styleCode="Botrule Rrule Toprule" colspan="3" align="center" valign="top"><content styleCode="bold"> Percentage of Patients Reporting Adverse Reaction</content></td></tr><tr><td styleCode="Botrule Lrule Rrule" align="center" valign="top"><content styleCode="bold"> Treatment Emergent Adverse Reaction </content></td><td styleCode="Botrule Rrule" align="center" valign="top"><content styleCode="bold"> 20 mg (continuous and intermittent pooled)</content></td><td styleCode="Botrule Rrule" align="center" valign="top"><content styleCode="bold"> 60 mg (continuous)</content></td><td styleCode="Botrule Rrule" align="center" valign="top"><content styleCode="bold"> Placebo (pooled)</content></td></tr><tr><td styleCode="Botrule Lrule Rrule" align="center" valign="top">Anxiety</td><td styleCode="Botrule Rrule" align="center" valign="top">3%</td><td styleCode="Botrule Rrule" align="center" valign="top">9%</td><td styleCode="Botrule Rrule" align="center" valign="top">4%</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="center" valign="top">Nervousness</td><td styleCode="Botrule Rrule" align="center" valign="top">5%</td><td styleCode="Botrule Rrule" align="center" valign="top">9%</td><td styleCode="Botrule Rrule" align="center" valign="top">3%</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="center" valign="top">Insomnia</td><td styleCode="Botrule Rrule" align="center" valign="top">9%</td><td styleCode="Botrule Rrule" align="center" valign="top">26%</td><td styleCode="Botrule Rrule" align="center" valign="top">7%</td></tr></tbody></table>

6 ADVERSE REACTIONS Most common adverse reactions (incidence rate greater than or equal to 5% and greater than placebo) associated with fluoxetine tablet 20 mg (either continuous or intermittent) for PMDD: Headache, asthenia, pain, accidental injury, infection, flu syndrome, nausea, diarrhea, insomnia, dizziness, nervousness, thinking abnormal, libido decreased, rhinitis, and pharyngitis ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Torrent Pharma Inc. at 1-800-912-9561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect or predict the rates observed in practice. Multiple doses of fluoxetine have been administered to 10,782 patients with various diagnoses in US clinical trials. Adverse reactions 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 reactions without first grouping similar types of reactions into a limited (that is, reduced) number of standardized reaction categories. In the tables and tabulations that follow, COSTART Dictionary terminology has been used to classify reported adverse reactions. The stated frequencies represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse reaction of the type listed. A reaction 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 reactions 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 placebo-controlled PMDD clinical trials — In 1 of 3 placebo-controlled, continuous-dosing trials and 1 placebo-controlled, intermittent-dosing trial of fluoxetine in PMDD, treatment-emergent adverse reactions reporting rates were assessed. The information contained in Table 5 enumerates the most common treatment-emergent adverse reactions associated with the use of fluoxetine tablet 20 mg (incidence of at least 5% for fluoxetine tablet 20 mg and greater than placebo) for the treatment of PMDD and is based on data from the continuous-dosing trial at the recommended dose of fluoxetine tablet (fluoxetine tablets 20 mg, N = 104; placebo, N = 108) and data from the intermittent-dosing trial of fluoxetine in PMDD (fluoxetine tablets 20 mg, N = 86; placebo, N = 88). Table 5: Most Common Treatment-Emergent Adverse Reactions: Incidence in PMDD Placebo-Controlled Clinical Trials Percentage of Patients Reporting Adverse Reaction Body System/Adverse Reaction 1 Fluoxetine tablet 20 mg/day Continuously (N = 104) Fluoxetine tablet 20 mg/day Intermittently (N = 86) Placebo (Pooled) (N = 196) Body as a Whole Headache 13 15 11 Asthenia 12 8 4 Pain 9 3 7 Accidental injury 8 1 5 Infection 7 0 3 Flu syndrome 12 3 7 Digestive System Nausea 13 9 6 Diarrhea 6 2 6 Nervous System Insomnia 9 10 7 Dizziness 7 2 3 Nervousness 7 3 3 Thinking abnormal 2 6 5 0 Libido decreased 3 9 1 Respiratory System Rhinitis 23 16 15 Pharyngitis 10 6 5 1 Included in the table are adverse reactions reported by at least 5% of patients taking fluoxetine tablet 20 mg either continuously or intermittently. For additional adverse reaction terms referenced in Warnings and Precautions, reporting rates for fluoxetine tablet 20 mg continuous and intermittent were, respectively: anxiety 4.8%, 1.2% and anorexia 3.8%, 3.5%. 2 Thinking abnormal is the COSTART term that captures concentration difficulties. Incidence in US depression, OCD, and bulimia placebo-controlled clinical trials (excluding data from extensions of trials) — Table 6 enumerates the most common treatment-emergent adverse reactions associated with the use of fluoxetine up to 80 mg (incidence of at least 2% for fluoxetine and greater than placebo) in female patients ages 18 to 45 years from US placebo-controlled clinical trials in the treatment of depression, OCD, and bulimia. Table 6: Treatment-Emergent Adverse Reactions: Incidence in Female Patients Ages 18 to 45 Years in Depression, OCD, and Bulimia Placebo-Controlled US Clinical Trials Percentage of Patients Reporting Adverse Reaction Body System/Adverse Reaction 1 Fluo x etine (N = 1,145) Pl a ceb o (N = 553) B o d y as a Whole Headache 24 21 Asthenia 14 6 Flu syndrome 7 3 Abdominal pain 6 5 Accidental injury 4 3 Fever 3 2 Cardiovascular System Palpitation 3 2 Vasodilatation 3 1 Digestive System Nausea 27 11 Anorexia 11 4 Dry mouth 11 8 Diarrhea 10 7 Dyspepsia 7 5 Constipation 5 3 Vomiting 3 2 Metabolic and Nutritional Disorders Weight loss 3 1 Nervous System Insomnia 24 11 Nervousness 14 10 Anxiety 13 9 Somnolence 13 6 Tremor 12 1 Dizziness 11 5 Libido decreased 4 1 Abnormal dreams 3 2 Thinking abnormal 2 3 2 Respiratory System Pharyngitis 6 5 Yawn 5 - Skin and Appendages Skin and Subcutaneous Tissue Disorders Sweating 8 3 Rash 5 3 Special Senses Abnormal vision 3 1 Urogenital System Urinary frequency 2 1 1 Included are reactions reported by at least 2% of patients taking fluoxetine, except the following adverse reactions, which had an incidence on placebo greater than fluoxetine (depression, OCD, and bulimia combined): back pain, cough increased, depression (includes suicidal thoughts), dysmenorrhea, flatulence, infection, myalgia, pain, pruritus, rhinitis, sinusitis. 2 Thinking abnormal is the COSTART term that captures concentration difficulties. Incidence less than 0.5%. Adverse reactions associated with discontinuation in two placebo-controlled PMDD clinical trials — In a continuous-dosing PMDD placebo-controlled trial, the most common adverse reaction (incidence at least 2% for fluoxetine tablet 20 mg and greater than placebo) associated with discontinuation was nausea (3% for fluoxetine tablet 20 mg, N = 104 and 1% for placebo, N = 108). In an intermittent-dosing placebo-controlled trial, no reactions associated with discontinuation reached an incidence of 2% for fluoxetine tablet 20 mg. In these clinical trials, more than one reaction may have been recorded as the cause of discontinuation. Adverse reactions associated with discontinuation in depression, OCD, and bulimia placebo-controlled US clinical trials (excluding data from extensions of trials) — In female patients age 18 to 45 years in US depression, OCD, and bulimia placebo-controlled clinical trials combined, which collected a single primary reaction associated with discontinuation (incidence at least 1% for fluoxetine and at least twice that for placebo), insomnia (1%, N = 561) was the only reaction reported. Female sexual dysfunction with SSRIs — Although changes in sexual desire, sexual performance, and sexual satisfaction often occur as manifestations of a mood-related 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. For example, in women (age 18 to 45) receiving fluoxetine for indications other than PMDD, decreased libido was seen at an incidence of 4% for fluoxetine compared with 1% for placebo. There have been spontaneous reports in women (age 18 to 45) taking fluoxetine for indications other than PMDD of orgasmic dysfunction, including anorgasmia. There are no adequate and well-controlled studies examining sexual dysfunction with fluoxetine treatment. 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. 6.2 Other Reactions Following is a list of all treatment-emergent adverse reactions reported at anytime by females and males taking fluoxetine in all US clinical trials for conditions other than PMDD as of May 8, 1995 (10,782 patients) except (1) those listed in the body or footnotes of Tables 1 or 5 above or elsewhere in labeling; (2) those for which the COSTART terms were uninformative or misleading; (3) those adverse reactions for which a causal relationship to fluoxetine use was considered remote; (4) adverse reactions occurring in only 1 patient treated with fluoxetine and which did not have a substantial probability of being acutely life-threatening; and (5) adverse reactions that could only occur in males. Adverse reactions are classified within body system categories using the following definitions: frequent adverse reactions are defined as those occurring on one or more occasions in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1,000 patients; rare adverse reactions are those occurring in less than 1/1,000 patients. Body as a Whole — Frequent: chest pain and chills; Infrequent: face edema, intentional overdose, malaise, pelvic pain, suicide attempt; Rare: acute abdominal syndrome, hypothermia, intentional injury, photosensitivity reaction. Cardiovascular System — Frequent: hypertension; Infrequent: angina pectoris, arrhythmia, congestive heart failure, hypotension, migraine, myocardial infarct, postural hypotension, syncope, vascular headache; Rare: bradycardia, cerebral embolism, cerebral ischemia, extrasystoles, heart block, pallor, peripheral vascular disorder, phlebitis, shock, thrombophlebitis, thrombosis, vasospasm, ventricular arrhythmia, ventricular extrasystoles, ventricular fibrillation. Digestive System — Frequent: increased appetite; Infrequent: aphthous stomatitis, cholelithiasis, colitis, dysphagia, eructation, esophagitis, gastritis, gastroenteritis, glossitis, gum hemorrhage, hyperchlorhydria, increased salivation, liver function tests abnormal, melena, mouth ulceration, stomach ulcer, stomatitis, thirst; Rare: biliary pain, bloody diarrhea, cholecystitis, duodenal ulcer, enteritis, esophageal ulcer, fecal incontinence, hepatitis, intestinal obstruction, liver fatty deposit, pancreatitis, peptic ulcer, salivary gland enlargement, 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. Metabolic and Nutritional — 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: amnesia, emotional lability, paresthesia, and sleep disorder; Infrequent: abnormal gait, acute brain syndrome, akathisia, apathy, ataxia, buccoglossal syndrome, CNS depression, CNS stimulation, depersonalization, euphoria, hostility, hyperkinesia, hypertonia, hypesthesia, incoordination, libido increased, myoclonus, neuralgia, neuropathy, neurosis, paranoid reaction, personality disorder 1 , psychosis, vertigo; Rare: abnormal electroencephalogram, antisocial reaction, circumoral paresthesia, delusions, dysarthria, dystonia, extrapyramidal syndrome, foot drop, hyperesthesia, neuritis, paralysis, reflexes decreased, 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; Rare: furunculosis, herpes zoster, hirsutism, psoriasis, purpuric rash, seborrhea. Special Senses — Frequent: ear pain, taste perversion, tinnitus; Infrequent: conjunctivitis, dry eyes, mydriasis, photophobia; Rare: blepharitis, deafness, diplopia, exophthalmos, glaucoma, hyperacusis, iritis, parosmia, scleritis, strabismus, taste loss, visual field defect. Urogenital System — Infrequent: abortion 2 , albuminuria, amenorrhea 2 , anorgasmia, breast enlargement, breast pain, cystitis, dysuria, female lactation 2 , fibrocystic breast 2 , hematuria, leukorrhea 2 , menorrhagia 2 , metrorrhagia 2 , nocturia, polyuria, urinary incontinence, urinary retention, urinary urgency, vaginal hemorrhage 2 ; Rare: breast engorgement, glycosuria, hypomenorrhea 2 , kidney pain, oliguria, uterine hemorrhage 2 , uterine fibroids enlarged 2 . 1 Personality disorder is the COSTART term for designating non-aggressive objectionable behavior. 2 Adjusted for gender. 6.3 Postmarketing Experience The following adverse reactions have been identified during post approval use of fluoxetine. Because these reactions are reported voluntarily from a population of uncertain size, it is difficult to reliably estimate their frequency or evaluate a causal relationship to drug exposure. Voluntary reports of adverse reactions 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 1 , cataract, cerebrovascular accident 1 , cholestatic jaundice, 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 1 , epidermal necrolysis, erythema multiforme, erythema nodosum, exfoliative dermatitis, gynecomastia, heart arrest 1 , hepatic failure/necrosis, hyperprolactinemia, hypoglycemia, immune-related hemolytic anemia, kidney failure, movement disorders developing in patients with risk factors including drugs associated with such reactions and worsening of pre-existing movement disorders, optic neuritis, pancreatitis 1 , pancytopenia, pulmonary embolism, pulmonary hypertension, QT prolongation, Stevens-Johnson syndrome, thrombocytopenia 1 , thrombocytopenic purpura, ventricular tachycardia (including torsades de pointes–type arrhythmias), vaginal bleeding, and violent behaviors 1 , drug reaction with eosinophilia and systemic symptoms (DRESS), and anosmia, hyposmia. 1 These terms represent serious adverse reactions, but do not meet the definition for adverse drug reactions. They are included here because of their seriousness.

<table ID="ID261" width="640px"><caption> Table 5: Most Common Treatment-Emergent Adverse Reactions: Incidence in PMDD Placebo-Controlled Clinical Trials </caption><colgroup><col width="160"/><col width="160"/><col width="160"/><col width="160"/></colgroup><tbody><tr><td styleCode="Botrule Lrule Rrule Toprule" align="left" valign="top"/><td styleCode="Botrule Rrule Toprule" colspan="3" align="center" valign="top"><content styleCode="bold"> Percentage of Patients Reporting Adverse Reaction </content></td></tr><tr><td styleCode="Botrule Lrule Rrule" align="center" valign="top"><content styleCode="bold"> Body System/Adverse Reaction¹</content></td><td styleCode="Botrule Rrule" align="center" valign="top"><content styleCode="bold"> Fluoxetine tablet</content> <content styleCode="bold"> 20 mg/day Continuously </content> <content styleCode="bold"> (N = 104) </content></td><td styleCode="Botrule Rrule" align="center" valign="top"><content styleCode="bold"> Fluoxetine tablet</content> <content styleCode="bold"> 20 mg/day Intermittently </content> <content styleCode="bold"> (N = 86) </content></td><td styleCode="Botrule Rrule" align="center" valign="top"><content styleCode="bold"> Placebo </content> <content styleCode="bold"> (Pooled) </content> <content styleCode="bold"> (N = 196) </content></td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top"><content styleCode="bold"> Body as a Whole </content></td><td styleCode="Botrule Rrule" valign="top"/><td styleCode="Botrule Rrule" valign="top"/><td styleCode="Botrule Rrule" valign="top"/></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">Headache</td><td styleCode="Botrule Rrule" align="center" valign="top">13</td><td styleCode="Botrule Rrule" align="center" valign="top">15</td><td styleCode="Botrule Rrule" align="center" valign="top">11</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">Asthenia</td><td styleCode="Botrule Rrule" align="center" valign="top">12</td><td styleCode="Botrule Rrule" align="center" valign="top">8</td><td styleCode="Botrule Rrule" align="center" valign="top">4</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top"> Pain</td><td styleCode="Botrule Rrule" align="center" valign="top">9</td><td styleCode="Botrule Rrule" align="center" valign="top">3</td><td styleCode="Botrule Rrule" align="center" valign="top">7</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">Accidental injury</td><td styleCode="Botrule Rrule" align="center" valign="top">8</td><td styleCode="Botrule Rrule" align="center" valign="top">1</td><td styleCode="Botrule Rrule" align="center" valign="top">5</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">Infection</td><td styleCode="Botrule Rrule" align="center" valign="top">7</td><td styleCode="Botrule Rrule" align="center" valign="top">0</td><td styleCode="Botrule Rrule" align="center" valign="top">3</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">Flu syndrome</td><td styleCode="Botrule Rrule" align="center" valign="top">12</td><td styleCode="Botrule Rrule" align="center" valign="top">3</td><td styleCode="Botrule Rrule" align="center" valign="top">7</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top"><content styleCode="bold"> Digestive System </content></td><td styleCode="Botrule Rrule" valign="top"/><td styleCode="Botrule Rrule" valign="top"/><td styleCode="Botrule Rrule" valign="top"/></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">Nausea</td><td styleCode="Botrule Rrule" align="center" valign="top">13</td><td styleCode="Botrule Rrule" align="center" valign="top">9</td><td styleCode="Botrule Rrule" align="center" valign="top">6</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">Diarrhea</td><td styleCode="Botrule Rrule" align="center" valign="top">6</td><td styleCode="Botrule Rrule" align="center" valign="top">2</td><td styleCode="Botrule Rrule" align="center" valign="top">6</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top"><content styleCode="bold"> Nervous System </content></td><td styleCode="Botrule Rrule" valign="top"/><td styleCode="Botrule Rrule" valign="top"/><td styleCode="Botrule Rrule" valign="top"/></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">Insomnia</td><td styleCode="Botrule Rrule" align="center" valign="top">9</td><td styleCode="Botrule Rrule" align="center" valign="top">10</td><td styleCode="Botrule Rrule" align="center" valign="top">7</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">Dizziness</td><td styleCode="Botrule Rrule" align="center" valign="top">7</td><td styleCode="Botrule Rrule" align="center" valign="top">2</td><td styleCode="Botrule Rrule" align="center" valign="top">3</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">Nervousness</td><td styleCode="Botrule Rrule" align="center" valign="top">7</td><td styleCode="Botrule Rrule" align="center" valign="top">3</td><td styleCode="Botrule Rrule" align="center" valign="top">3</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">Thinking abnormal²</td><td styleCode="Botrule Rrule" align="center" valign="top">6</td><td styleCode="Botrule Rrule" align="center" valign="top">5</td><td styleCode="Botrule Rrule" align="center" valign="top">0</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">Libido decreased</td><td styleCode="Botrule Rrule" align="center" valign="top">3</td><td styleCode="Botrule Rrule" align="center" valign="top">9</td><td styleCode="Botrule Rrule" align="center" valign="top">1</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top"><content styleCode="bold"> Respiratory System </content></td><td styleCode="Botrule Rrule" valign="top"/><td styleCode="Botrule Rrule" valign="top"/><td styleCode="Botrule Rrule" valign="top"/></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">Rhinitis</td><td styleCode="Botrule Rrule" align="center" valign="top">23</td><td styleCode="Botrule Rrule" align="center" valign="top">16</td><td styleCode="Botrule Rrule" align="center" valign="top">15</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">Pharyngitis</td><td styleCode="Botrule Rrule" align="center" valign="top">10</td><td styleCode="Botrule Rrule" align="center" valign="top">6</td><td styleCode="Botrule Rrule" align="center" valign="top">5</td></tr><tr><td styleCode="Botrule Lrule Rrule" colspan="4" align="left" valign="top"><paragraph>¹ Included in the table are adverse reactions reported by at least 5% of patients taking fluoxetine tablet 20 mg either continuously or intermittently. For additional adverse reaction terms referenced in Warnings and Precautions, reporting rates for fluoxetine tablet 20 mg continuous and intermittent were, respectively: anxiety 4.8%, 1.2% and anorexia 3.8%, 3.5%.</paragraph><paragraph>² Thinking abnormal is the COSTART term that captures concentration difficulties.</paragraph></td></tr></tbody></table>

<table ID="ID271" width="638px"><caption> Table 6: Treatment-Emergent Adverse Reactions: Incidence in Female Patients Ages 18 to 45 Years in Depression, OCD, and Bulimia Placebo-Controlled US Clinical Trials </caption><colgroup><col width="247"/><col width="196"/><col width="196"/></colgroup><tbody><tr><td styleCode="Botrule Lrule Rrule Toprule" valign="top"/><td styleCode="Botrule Rrule Toprule" colspan="2" align="center" valign="top"><content styleCode="bold"> Percentage of Patients Reporting Adverse Reaction</content></td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top"><content styleCode="bold"> Body System/Adverse Reaction¹</content></td><td styleCode="Botrule Rrule" align="center" valign="top"><content styleCode="bold"> Fluo</content><content styleCode="bold">x</content><content styleCode="bold">etine (N = 1,145)</content></td><td styleCode="Botrule Rrule" align="center" valign="top"><content styleCode="bold"> Pl</content><content styleCode="bold">a</content><content styleCode="bold">ceb</content><content styleCode="bold">o (N = 553)</content></td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top"><content styleCode="bold"> B</content><content styleCode="bold">o</content><content styleCode="bold">d</content><content styleCode="bold">y as a Whole</content></td><td styleCode="Botrule Rrule" valign="top"/><td styleCode="Botrule Rrule" valign="top"/></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">Headache</td><td styleCode="Botrule Rrule" align="center" valign="top">24</td><td styleCode="Botrule Rrule" align="center" valign="top">21</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">Asthenia</td><td styleCode="Botrule Rrule" align="center" valign="top">14</td><td styleCode="Botrule Rrule" align="center" valign="top">6</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">Flu syndrome</td><td styleCode="Botrule Rrule" align="center" valign="top">7</td><td styleCode="Botrule Rrule" align="center" valign="top">3</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">Abdominal pain</td><td styleCode="Botrule Rrule" align="center" valign="top">6</td><td styleCode="Botrule Rrule" align="center" valign="top">5</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">Accidental injury</td><td styleCode="Botrule Rrule" align="center" valign="top">4</td><td styleCode="Botrule Rrule" align="center" valign="top">3</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">Fever</td><td styleCode="Botrule Rrule" align="center" valign="top">3</td><td styleCode="Botrule Rrule" align="center" valign="top">2</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top"><content styleCode="bold"> Cardiovascular System</content></td><td styleCode="Botrule Rrule" valign="top"/><td styleCode="Botrule Rrule" valign="top"/></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">Palpitation</td><td styleCode="Botrule Rrule" align="center" valign="top">3</td><td styleCode="Botrule Rrule" align="center" valign="top">2</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">Vasodilatation</td><td styleCode="Botrule Rrule" align="center" valign="top">3</td><td styleCode="Botrule Rrule" align="center" valign="top">1</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top"><content styleCode="bold"> Digestive System</content></td><td styleCode="Botrule Rrule" valign="top"/><td styleCode="Botrule Rrule" valign="top"/></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">Nausea</td><td styleCode="Botrule Rrule" align="center" valign="top">27</td><td styleCode="Botrule Rrule" align="center" valign="top">11</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">Anorexia</td><td styleCode="Botrule Rrule" align="center" valign="top">11</td><td styleCode="Botrule Rrule" align="center" valign="top">4</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">Dry mouth</td><td styleCode="Botrule Rrule" align="center" valign="top">11</td><td styleCode="Botrule Rrule" align="center" valign="top">8</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">Diarrhea</td><td styleCode="Botrule Rrule" align="center" valign="top">10</td><td styleCode="Botrule Rrule" align="center" valign="top">7</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">Dyspepsia</td><td styleCode="Botrule Rrule" align="center" valign="top">7</td><td styleCode="Botrule Rrule" align="center" valign="top">5</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">Constipation</td><td styleCode="Botrule Rrule" align="center" valign="top">5</td><td styleCode="Botrule Rrule" align="center" valign="top">3</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">Vomiting</td><td styleCode="Botrule Rrule" align="center" valign="top">3</td><td styleCode="Botrule Rrule" align="center" valign="top">2</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top"><content styleCode="bold"> Metabolic and Nutritional</content> <content styleCode="bold"> Disorders</content></td><td styleCode="Botrule Rrule" valign="top"/><td styleCode="Botrule Rrule" valign="top"/></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">Weight loss</td><td styleCode="Botrule Rrule" align="center" valign="top">3</td><td styleCode="Botrule Rrule" align="center" valign="top">1</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top"><content styleCode="bold"> Nervous System</content></td><td styleCode="Botrule Rrule" valign="top"/><td styleCode="Botrule Rrule" valign="top"/></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">Insomnia</td><td styleCode="Botrule Rrule" align="center" valign="top">24</td><td styleCode="Botrule Rrule" align="center" valign="top">11</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">Nervousness</td><td styleCode="Botrule Rrule" align="center" valign="top">14</td><td styleCode="Botrule Rrule" align="center" valign="top">10</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">Anxiety</td><td styleCode="Botrule Rrule" align="center" valign="top">13</td><td styleCode="Botrule Rrule" align="center" valign="top">9</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">Somnolence</td><td styleCode="Botrule Rrule" align="center" valign="top">13</td><td styleCode="Botrule Rrule" align="center" valign="top">6</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">Tremor</td><td styleCode="Botrule Rrule" align="center" valign="top">12</td><td styleCode="Botrule Rrule" align="center" valign="top">1</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">Dizziness</td><td styleCode="Botrule Rrule" align="center" valign="top">11</td><td styleCode="Botrule Rrule" align="center" valign="top">5</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">Libido decreased</td><td styleCode="Botrule Rrule" align="center" valign="top">4</td><td styleCode="Botrule Rrule" align="center" valign="top">1</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">Abnormal dreams</td><td styleCode="Botrule Rrule" align="center" valign="top">3</td><td styleCode="Botrule Rrule" align="center" valign="top">2</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">Thinking abnormal²</td><td styleCode="Botrule Rrule" align="center" valign="top">3</td><td styleCode="Botrule Rrule" align="center" valign="top">2</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top"><content styleCode="bold"> Respiratory System</content></td><td styleCode="Botrule Rrule" valign="top"/><td styleCode="Botrule Rrule" valign="top"/></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">Pharyngitis</td><td styleCode="Botrule Rrule" align="center" valign="top">6</td><td styleCode="Botrule Rrule" align="center" valign="top">5</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">Yawn</td><td styleCode="Botrule Rrule" align="center" valign="top">5</td><td styleCode="Botrule Rrule" align="center" valign="top">- </td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top"><content styleCode="bold"> Skin and Appendages Skin and Subcutaneous Tissue Disorders</content></td><td styleCode="Botrule Rrule" valign="top"/><td styleCode="Botrule Rrule" valign="top"/></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">Sweating</td><td styleCode="Botrule Rrule" align="center" valign="top">8</td><td styleCode="Botrule Rrule" align="center" valign="top">3</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">Rash</td><td styleCode="Botrule Rrule" align="center" valign="top">5</td><td styleCode="Botrule Rrule" align="center" valign="top">3</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top"><content styleCode="bold"> Special Senses</content></td><td styleCode="Botrule Rrule" valign="top"/><td styleCode="Botrule Rrule" valign="top"/></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">Abnormal vision</td><td styleCode="Botrule Rrule" align="center" valign="top">3</td><td styleCode="Botrule Rrule" align="center" valign="top">1</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top"><content styleCode="bold"> Urogenital System</content></td><td styleCode="Botrule Rrule" valign="top"/><td styleCode="Botrule Rrule" valign="top"/></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top">Urinary frequency</td><td styleCode="Botrule Rrule" align="center" valign="top">2</td><td styleCode="Botrule Rrule" align="center" valign="top">1</td></tr><tr><td styleCode="Botrule Lrule Rrule" colspan="3" align="left" valign="top"><paragraph styleCode="Default First">¹Included are reactions reported by at least 2% of patients taking fluoxetine, except the following adverse reactions, which had an incidence on placebo greater than fluoxetine (depression, OCD, and bulimia combined): back pain, cough increased, depression (includes suicidal thoughts), dysmenorrhea, flatulence, infection, myalgia, pain, pruritus, rhinitis, sinusitis.</paragraph><paragraph styleCode="Default">²Thinking abnormal is the COSTART term that captures concentration difficulties.</paragraph><paragraph styleCode="Default">Incidence less than 0.5%.</paragraph></td></tr></tbody></table>