Duloxetine

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS Antidepressants increased the risk of suicidal thoughts and behavior in pediatric and young adult patients in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening, and emergence of suicidal thoughts and behaviors [see Warnings and Precautions ( 5.1 )] . WARNING: SUICIDAL THOUGHTS AND BEHAVIORS See full prescribing information for complete boxed warning. Increased risk of suicidal thoughts and behavior in pediatric and young adult patients taking antidepressants. Closely monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors. ( 5.1 )

5 WARNINGS AND PRECAUTIONS Hepatotoxicity : Hepatic failure, sometimes fatal, has been reported. Discontinue Duloxetine Delayed-Release Capsules in patients who develop jaundice or other evidence of clinically significant liver dysfunction and should not be resumed unless another cause can be established. Avoid use in patients with substantial alcohol use or evidence of chronic liver disease. ( 5.2 ) Orthostatic Hypotension, Falls and Syncope : Consider dosage reduction or discontinuation if these events occur. ( 5.3 ) Serotonin Syndrome: Increased risk when co-administered with other serotonergic agents but also when taken alone. If it occurs, discontinue Duloxetine Delayed-Release Capsules and serotonergic agents. ( 5.4 ) Increased Risk of Bleeding : May increase the risk of bleeding events. Concomitant use of antiplatelet drugs and anticoagulants may increase this risk. ( 5.5 , 7 , 8.1 ) Severe Skin Reactions: Severe skin reactions, including erythema multiforme and Stevens-Johnson Syndrome (SJS), can occur. Discontinue at the first appearance of blisters, peeling rash, mucosal erosions, or any other sign of hypersensitivity if no other etiology can be identified. ( 5.6 ) Discontinuation Syndrome : Taper dose when possible and monitor for discontinuation symptoms. ( 5.7 ) Activation of Mania or Hypomania : Prior to initiating, screen patients for personal or family history of bipolar disorder, mania, or hypomania. ( 5.8 ) Angle-Closure Glaucoma : Has occurred in patients with untreated anatomically narrow angles treated with antidepressants. ( 5.9 ) Seizures : Prescribe with care in patients with a history of seizure disorder. ( 5.10 ) Blood Pressure Increases : Monitor blood pressure prior to initiating treatment and periodically throughout treatment. ( 5.11 ) Hyponatremia : Can occur in association with SIADH; consider discontinuation. ( 5.12 ) Glucose Control in Diabetes : Worsened glycemic control has been observed. ( 5.13 ) Conditions that Slow Gastric Emptying : Use cautiously in these patients. ( 5.13 ) Sexual Dysfunction : Duloxetine Delayed-Release Capsules may cause symptoms of sexual dysfunction. ( 5.15 ) 5.1 Suicidal Thoughts and Behaviors in Pediatric and Young Adult Patients In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and 4,500 pediatric patients, the incidence of suicidal thoughts and behaviors in the antidepressant-treated patients age 24 years and younger was greater than in placebo-treated patients. There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied. There were differences in absolute risk of suicidal thoughts and behaviors across the different indications, with the highest incidence in MDD. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1000 patients treated are provided in Table 1. Table 1: Risk Differences of the Number of Patients of Suicidal Thoughts and Behavior in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Patients Age Range Drug-Placebo Difference in Number of Patients of Suicidal Thoughts or Behaviors per 1000 Patients Treated Increases Compared to Placebo <18 14 additional patients 18 to 24 5 additional patients Decreases Compared to Placebo 25 to 64 1 fewer patient ≥65 6 fewer patients It is unknown whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with MDD that antidepressants delay the recurrence of depression and that depression itself is a risk factor for suicidal thoughts and behaviors. Monitor all antidepressant-treated patients for any indication for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy, and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing Duloxetine Delayed-Release Capsules, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors. 5.2 Hepatotoxicity There have been reports of hepatic failure, sometimes fatal, in patients treated with duloxetine. These cases have presented as hepatitis with abdominal pain, hepatomegaly, and elevation of transaminase levels to more than twenty times the upper limit of normal (ULN) with or without jaundice, reflecting a mixed or hepatocellular pattern of liver injury. Duloxetine Delayed-Release Capsules should be discontinued in patients who develop jaundice or other evidence of clinically significant liver dysfunction and should not be resumed unless another cause can be established. Cases of cholestatic jaundice with minimal elevation of transaminase levels have also been reported. Other postmarketing reports indicate that elevated transaminases, bilirubin, and alkaline phosphatase have occurred in patients with chronic liver disease or cirrhosis. Duloxetine increased the risk of elevation of serum transaminase levels in development program clinical trials. Liver transaminase elevations resulted in the discontinuation of 0.3% (92/34,756) of duloxetine-treated patients. In most patients, the median time to detection of the transaminase elevation was about two months. In adult placebo-controlled trials, for patients with normal and abnormal baseline ALT values, elevation of ALT >3 times the ULN occurred in 1.25% (144/11,496) of duloxetine-treated patients compared to 0.45% (39/8,716) of placebo-treated patients. In adult placebo-controlled studies using a fixed dose design, there was evidence of a duloxetine dose response relationship for ALT and AST elevation of >3 times the ULN and >5 times the ULN, respectively. Because it is possible that Duloxetine Delayed-Release Capsules and alcohol may interact to cause liver injury or that Duloxetine Delayed-Release Capsules may aggravate pre-existing liver disease, Duloxetine Delayed-Release Capsules should not be prescribed to patients with substantial alcohol use or evidence of chronic liver disease. 5.3 Orthostatic Hypotension, Falls and Syncope Orthostatic hypotension, falls, and syncope have been reported in patients treated with recommended duloxetine dosages. Syncope and orthostatic hypotension tend to occur within the first week of therapy but can occur at any time during Duloxetine Delayed-Release Capsules treatment, particularly after dose increases. The risk of falling appears to be related to the degree of orthostatic decrease in blood pressure (BP) as well as other factors that may increase the underlying risk of falls. In an analysis of patients from all placebo-controlled trials, patients treated with duloxetine reported a higher rate of falls compared to patients treated with placebo. Risk appears to be related to the presence of orthostatic decrease in BP. The risk of BP decreases may be greater in patients taking concomitant medications that induce orthostatic hypotension (such as antihypertensives) or are potent CYP1A2 inhibitors [see Drug Interactions ( 7.1 )] and in patients taking duloxetine delayed-release capsules at doses above 60 mg daily. Consideration should be given to dose reduction or discontinuation of Duloxetine Delayed-Release Capsules in patients who experience symptomatic orthostatic hypotension, falls and/or syncope during Duloxetine Delayed-Release Capsules therapy. Risk of falling also appeared to be proportional to a patient’s underlying risk for falls and appeared to increase steadily with age. As geriatric patients tend to have a higher underlying risk for falls due to a higher prevalence of risk factors such as use of multiple medications, medical comorbidities and gait disturbances, the impact of increasing age by itself is unclear. Falls with serious consequences including fractures and hospitalizations have been reported with use of duloxetine delayed-release capsules [see Adverse Reactions ( 6.1 )] . 5.4 Serotonin Syndrome Serotonin-norepinephrine reuptake inhibitors (SNRIs), including Duloxetine Delayed-Release Capsules, can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased 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, i.e., MAOIs, [see Contraindications ( 4 ), Drug Interactions ( 7.1 )] . Serotonin syndrome can also occur when these drugs are used alone. Serotonin syndrome signs and symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The concomitant use of Duloxetine Delayed-Release Capsules with MAOIs is contraindicated. In addition, do not initiate Duloxetine Delayed-Release Capsules in a patient being treated with MAOIs such as linezolid or intravenous methylene blue. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection). If it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking Duloxetine Delayed-Release Capsules, discontinue Duloxetine Delayed-Release Capsules before initiating treatment with the MAOI [see Contraindications ( 4 ), Drug Interactions ( 7.1 )] . Monitor all patients taking Duloxetine Delayed-Release Capsules for the emergence of serotonin syndrome. Discontinue treatment with Duloxetine Delayed-Release Capsules and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of Duloxetine Delayed-Release Capsules with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms. 5.5 Increased Risk of Bleeding Drugs that interfere with serotonin reuptake inhibition, including Duloxetine Delayed-Release Capsules, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), 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. A post-marketing study showed a higher incidence of postpartum hemorrhage in mothers taking duloxetine. Other bleeding events related to SSRI and SNRI use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages. Inform patients about the increased risk of bleeding associated with the concomitant use of Duloxetine Delayed-Release Capsules and NSAIDs, aspirin, or other drugs that affect coagulation [see Drug Interactions ( 7.1 )] . 5.6 Severe Skin Reactions Severe skin reactions, including erythema multiforme and Stevens-Johnson Syndrome (SJS), can occur with Duloxetine Delayed-Release Capsules. The reporting rate of SJS associated with duloxetine use exceeds the general population background incidence rate for this serious skin reaction (1 to 2 cases per million person years). The reporting rate is generally accepted to be an underestimate due to underreporting. Duloxetine Delayed-Release Capsules should be discontinued at the first appearance of blisters, peeling rash, mucosal erosions, or any other sign of hypersensitivity if no other etiology can be identified. 5.7 Discontinuation Syndrome Discontinuation symptoms have been systematically evaluated in patients taking duloxetine. Following abrupt or tapered discontinuation in adult placebo-controlled clinical trials, the following symptoms occurred at 1% or greater and at a significantly higher rate in duloxetine-treated patients compared to those discontinuing from placebo: dizziness, headache, nausea, diarrhea, paresthesia, irritability, vomiting, insomnia, anxiety, hyperhidrosis, and fatigue. During marketing of other SSRIs and SNRIs (serotonin and norepinephrine reuptake inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. Although these events are generally self-limiting, some have been reported to be severe. Monitor patients for these symptoms when discontinuing treatment with Duloxetine Delayed-Release Capsules. 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 healthcare provider may continue decreasing the dose but at a more gradual rate. Given that Duloxetine Delayed-Release Capsules are not available in strengths below 80 mg, gradual dosage reduction will require the use of another duloxetine delayed-release capsule product [see Dosage and Administration ( 2.1 , 2.6 )] . 5.8 Activation of Mania/Hypomania In controlled clinical trials in adult patients with major depressive disorder, symptoms of mania or hypomania were reported in 0.1% of patients treated with duloxetine. No activation of mania or hypomania was reported in placebo-controlled trials for other indications. Activation of mania or hypomania has been reported in a small proportion of patients with mood disorders who were treated with other marketed drugs effective in the treatment of major depressive disorder. As with these other agents, Duloxetine Delayed-Release Capsules should be used cautiously in patients with a history of mania. 5.9 Angle-Closure Glaucoma The pupillary dilation that occurs following use of many antidepressant drugs, including Duloxetine Delayed-Release Capsules, may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. Avoid use of antidepressants, including Duloxetine Delayed-Release Capsules, in patients with anatomically narrow angles. 5.10 Seizures Duloxetine Delayed-Release Capsules has not been systematically evaluated in patients with a seizure disorder, and such patients were excluded from clinical studies. In adult placebo-controlled clinical trials, seizures/convulsions occurred in 0.02% (3/12,722) of patients treated with duloxetine and 0.01% (1/9513) of patients treated with placebo. Duloxetine Delayed-Release Capsules should be prescribed with care in patients with a history of a seizure disorder. 5.11 Increases in Blood Pressure In adult placebo-controlled clinical trials across the approved adult populations from baseline to endpoint, duloxetine treatment was associated with mean increases of 0.5 mm Hg in systolic blood pressure and 0.8 mm Hg in diastolic blood pressure compared to mean decreases of 0.6 mm Hg systolic and 0.3 mm Hg diastolic in placebo-treated patients. There was no significant difference in the frequency of sustained (3 consecutive visits) elevated blood pressure. Monitor blood pressure before initiating treatment with Duloxetine Delayed-Release Capsules and periodically during treatment [see Adverse Reactions ( 6.1 )] . Pre-existing hypertension should be controlled before initiating treatment with Duloxetine Delayed-Release Capsules. Caution should be exercised in treating patients with pre-existing hypertension, cardiovascular, or cerebrovascular conditions that might be compromised by increases in blood pressure. For patients who experience sustained increase in blood pressure while receiving Duloxetine Delayed-Release Capsules, discontinuation or other appropriate medical intervention should be considered. Given that Duloxetine Delayed-Release Capsules are not available in strengths below 80 mg, gradual dosage reduction will require the use of another duloxetine delayed-release capsule product. 5.12 Hyponatremia Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including Duloxetine Delayed-Release Capsules. 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 with duloxetine use and appeared to be reversible when duloxetine was discontinued. Geriatric patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk [see Use in Specific Populations ( 8.5 )] . Discontinuation of Duloxetine Delayed-Release Capsules 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. 5.13 Use in Patients with Concomitant Illness Clinical experience with duloxetine in patients with concomitant systemic illnesses is limited. There is no information on the effect that alterations in gastric motility may have on the stability of Duloxetine Delayed-Release Capsules' enteric coating. In extremely acidic conditions, duloxetine, unprotected by the enteric coating, may undergo hydrolysis to form naphthol. Caution is advised in using Duloxetine Delayed-Release Capsules in patients with conditions that may slow gastric emptying (e.g., some diabetics). Duloxetine Delayed-Release Capsules have not been systematically evaluated in patients with a recent history of myocardial infarction or unstable coronary artery disease. Patients with these diagnoses were generally excluded from clinical studies during the product's premarketing testing. Hepatic Impairment Avoid use in patients with chronic liver disease or cirrhosis [see Warnings and Precautions ( 5.2 ), Use in Specific Populations ( 8.6 )]. Severe Renal Impairment Avoid use in patients with severe renal impairment, GFR <30 mL/minute. Increased plasma concentration of duloxetine, and especially of its metabolites, occur in patients with end-stage renal disease (requiring dialysis) [see Use in Specific Populations ( 8.7 )]. Glycemic Control in Patients with Diabetes As observed in trials for another indication, duloxetine treatment worsened glycemic control in some patients with diabetes. 5.14 Urinary Hesitation and Retention Duloxetine Delayed-Release Capsules is in a class of drugs known to affect urethral resistance. If symptoms of urinary hesitation develop during treatment with Duloxetine Delayed-Release Capsules, consideration should be given to the possibility that they might be drug-related. In post marketing experience, cases of urinary retention have been observed. In some instances of urinary retention associated with duloxetine use, hospitalization and/or catheterization has been needed. 5.15 Sexual Dysfunction Use of SNRIs, including Duloxetine Delayed-Release Capsules, may cause symptoms of sexual dysfunction [see Adverse Reactions ( 6.1 )] . In male patients, SNRI use may result in ejaculatory delay or failure, decreased libido, and erectile dysfunction. In female patients, 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 Duloxetine Delayed-Release Capsules 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 border="0" cellpadding="0" cellspacing="0" width="100%"><caption>Table 1: Risk Differences of the Number of Patients of Suicidal Thoughts and Behavior in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Patients</caption><colgroup><col width="37.68%"/><col width="62.32%"/></colgroup><tbody><tr styleCode="Botrule"><td align="center" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Age Range</content></td><td align="center" styleCode="Rrule" valign="top"><content styleCode="bold">Drug-Placebo Difference in Number of Patients of Suicidal Thoughts or Behaviors per 1000 Patients Treated</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"/><td align="center" styleCode="Rrule" valign="top"><content styleCode="bold">Increases Compared to Placebo</content></td></tr><tr styleCode="Botrule"><td align="center" styleCode="Lrule Rrule" valign="top">&lt;18 </td><td align="center" styleCode="Rrule" valign="top">14 additional patients </td></tr><tr styleCode="Botrule"><td align="center" styleCode="Lrule Rrule" valign="top">18 to 24 </td><td align="center" styleCode="Rrule" valign="top">5 additional patients </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"/><td align="center" styleCode="Rrule" valign="top"><content styleCode="bold">Decreases Compared to Placebo </content> </td></tr><tr styleCode="Botrule"><td align="center" styleCode="Lrule Rrule" valign="top">25 to 64 </td><td align="center" styleCode="Rrule" valign="top">1 fewer patient </td></tr><tr><td align="center" styleCode="Lrule Rrule" valign="top">&#x2265;65 </td><td align="center" styleCode="Rrule" valign="top">6 fewer patients </td></tr></tbody></table>

6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in the labeling: Suicidal Thoughts and Behaviors in Pediatric and Young Adult Patients [see Boxed Warning and Warnings and Precautions ( 5.1 )] Hepatotoxicity [see Warnings and Precautions ( 5.2 )] Orthostatic Hypotension, Falls and Syncope [see Warnings and Precautions ( 5.3 )] Serotonin Syndrome [see Warnings and Precautions ( 5.4 )] Increased Risk of Bleeding [see Warnings and Precautions ( 5.5 )] Severe Skin Reactions [see Warnings and Precautions ( 5.6 )] Discontinuation Syndrome [see Warnings and Precautions ( 5.7 )] Activation of Mania/Hypomania [see Warnings and Precautions ( 5.8 )] Angle-Closure Glaucoma [see Warnings and Precautions ( 5.9 )] Seizures [see Warnings and Precautions ( 5.10 )] Increases in Blood Pressure [see Warnings and Precautions ( 5.11 )] Hyponatremia [see Warnings and Precautions ( 5.12 )] Urinary Hesitation and Retention [see Warnings and Precautions ( 5.14 )] Sexual Dysfunction [see Warnings and Precautions ( 5.15 )] Most common adverse reactions (≥5% and at least twice the incidence of placebo-treated patients): ( 6.1 ) Adults : nausea, dry mouth, somnolence, constipation, decreased appetite, and hyperhidrosis Pediatric Patients : decreased weight, decreased appetite, nausea, vomiting, fatigue, and diarrhea To report SUSPECTED ADVERSE REACTIONS, contact Almatica Pharma LLC at 1-877-447-7979 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 the rates observed in practice. The safety of Duloxetine Delayed-Release Capsules for the treatment for major depressive disorder (MDD) in adults and for the treatment of generalized anxiety disorder (GAD) in adults and pediatric patients is based upon adequate and well-controlled studies of another duloxetine delayed-release capsule product. The results of these adequate and well-controlled studies of duloxetine delayed-release capsules are presented below. The stated frequencies of adverse reactions represent the proportion of patients who experienced, at least once, one 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. Adverse Reactions in Adults Adult Clinical Trial Database The data described below reflect exposure to duloxetine delayed-release capsules in placebo-controlled trials for MDD (N=3779), GAD (N=1018), and other indications (N=3303). The population studied was 17 years to 89 years of age. 66% and 61% were female, and 82% and 73% were Caucasian in the MDD and GAD populations, respectively. Most patients received duloxetine delayed-release capsules dosages of a total of 60 mg to 120 mg per day [see Clinical Studies ( 14.1 , 14.2 )] . The data below do not include results of the trial examining the efficacy of duloxetine delayed-release capsules in patients ≥ 65 years old for the treatment of generalized anxiety disorder; however, the adverse reactions observed in this geriatric sample were generally similar to adverse reactions in the overall adult population. Adverse Reactions Reported as Reasons for Discontinuation of Treatment in Adult Placebo-Controlled Trials Major Depressive Disorder Approximately 8.4% (319/3779) of the duloxetine delayed-release capsules-treated patients in placebo-controlled adult trials for MDD discontinued treatment due to an adverse reaction, compared with 4.6% (117/2536) of placebo-treated patients. Nausea (duloxetine delayed-release capsules 1.1%, placebo 0.4%) was the only adverse reaction reported as a reason for discontinuation and considered to be drug-related (i.e., discontinuation occurring in at least 1% of the duloxetine delayed-release capsules-treated patients and at a rate of at least twice that of placebo-treated patients). Generalized Anxiety Disorder Approximately 13.7% (139/1018) of the duloxetine delayed-release capsules-treated patients in placebo-controlled adult trials for GAD discontinued treatment due to an adverse reaction, compared with 5% (38/767) for placebo-treated patients. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine delayed-release capsules 3.3%, placebo 0.4%), and dizziness (duloxetine delayed-release capsules 1.3%, placebo 0.4%). Adverse Reactions Occurring at an Incidence of 5% or More Among Duloxetine Delayed-Release Capsules Treated Patients in Adult Placebo-Controlled Trials The most commonly observed adverse reactions in duloxetine delayed-release capsule-treated patients (incidence of at least 5% and at least twice the incidence in placebo patients) were nausea, dry mouth, somnolence, constipation, decreased appetite, and hyperhidrosis. Table 2 displays the incidence of adverse reactions in placebo-controlled trials for approved indications that occurred in 5% or more of patients treated with duloxetine delayed-release capsules and with an incidence greater than placebo-treated patients. Table 2: Adverse Reactions: Incidence of 5% or More and Greater than Placebo in Placebo-Controlled Trials of Approved Adult Populations a a Includes adults with MDD, GAD, and other indications. The inclusion of an event in the table is determined based on the percentages before rounding; however, the percentages displayed in the table are rounded to the nearest integer. b Also includes asthenia. c Events for which there was a significant dose-dependent relationship in fixed-dose studies, excluding three MDD studies which did not have a placebo lead-in period or dose titration. d Also includes initial insomnia, middle insomnia, and early morning awakening. e Also includes hypersomnia and sedation. f Also includes abdominal discomfort, abdominal pain lower, abdominal pain upper, abdominal tenderness, and gastrointestinal pain. Adverse Reaction Percentage of Patients Reporting Reaction Another Duloxetine Product (N=8100) Placebo (N=5655) Nausea c 23 8 Headache 14 12 Dry mouth 13 5 Somnolence e 10 3 Fatigue b, c 9 5 Insomnia d 9 5 Constipation c 9 4 Dizziness c 9 5 Diarrhea 9 6 Decreased appetite c 7 2 Hyperhidrosis c 6 1 Abdominal pain f 5 4 Adverse Reactions in Pooled MDD and GAD Trials in Adults Table 3 displays the incidence of adverse reactions in MDD and GAD placebo-controlled trials that occurred in 2% or more of patients treated with duloxetine delayed-release capsules and with an incidence greater than placebo-treated patients. Table 3: Adverse Reactions: Incidence of 2% or More and Greater than Placebo in MDD and GAD Placebo-Controlled Trials in Adults a,b a The inclusion of an event in the table is determined based on the percentages before rounding; however, the percentages displayed in the table are rounded to the nearest integer. b For GAD, there were no adverse reactions that were significantly different between treatments in adults ≥65 years that were also not significant in the adults <65 years. c Events for which there was a significant dose-dependent relationship in fixed-dose studies, excluding three MDD studies which did not have a placebo lead-in period or dose titration. d Includes abdominal pain upper, abdominal pain lower, abdominal tenderness, abdominal discomfort, and gastrointestinal pain. e Includes asthenia. f Includes hypersomnia and sedation. g Includes initial insomnia, middle insomnia, and early morning awakening. h Includes feeling jittery, nervousness, restlessness, tension and psychomotor hyperactivity. i Includes loss of libido. j Includes anorgasmia. System Organ Class / Adverse Reaction Percentage of Patients Reporting Reaction Another Duloxetine Product (N=4797) Placebo (N=3303) Cardiac Disorders Palpitations 2 1 Eye Disorders Vision blurred 3 1 Gastrointestinal Disorders Nausea c 23 8 Dry mouth 14 6 Constipation c 9 4 Diarrhea 9 6 Abdominal pain d 5 4 Vomiting 4 2 General Disorders and Administration Site Conditions Fatigue e 9 5 Metabolism and Nutrition Disorders Decreased appetite c 6 2 Nervous System Disorders Headache 14 14 Dizziness c 9 5 Somnolence f 9 3 Tremor 3 1 Psychiatric Disorders Insomnia g 9 5 Agitation h 4 2 Anxiety 3 2 Reproductive System and Breast Disorders Erectile dysfunction 4 1 Ejaculation delayed c 2 1 Libido decreased i 3 1 Orgasm abnormal j 2 <1 Respiratory, Thoracic, and Mediastinal Disorders Yawning 2 <1 Skin and Subcutaneous Tissue Disorders Hyperhidrosis 6 2 Effects on Male and Female Sexual Function in Adults with MDD Changes in sexual desire, sexual performance and sexual satisfaction often occur as manifestations of psychiatric disorders or diabetes, but they may also be a consequence of pharmacologic treatment. Because adverse sexual reactions are presumed to be voluntarily underreported, the Arizona Sexual Experience Scale (ASEX), a validated measure designed to identify sexual adverse reactions, was used prospectively in 4 MDD placebo-controlled adult trials [see Clinical Studies ( 14.1 )] . The ASEX scale includes five questions that pertain to the following aspects of sexual function: 1) sex drive, 2) ease of arousal, 3) ability to achieve erection (men) or lubrication (women), 4) ease of reaching orgasm, and 5) orgasm satisfaction. Positive numbers signify a worsening of sexual function from baseline. Negative numbers signify an improvement from a baseline level of dysfunction, which is commonly seen in depressed patients. In these trials, male patients treated with duloxetine delayed-release capsules experienced significantly more sexual dysfunction, as measured by the total score on the ASEX and the ability to reach orgasm, than placebo-treated male patients (see Table 4). Female patients treated with duloxetine delayed-release capsules did not experience more sexual dysfunction than placebo-treated female patients as measured by ASEX total score. Healthcare providers should routinely inquire about possible sexual adverse reactions in duloxetine delayed-release capsules-treated patients. Table 4: Mean Change in ASEX Scores by Gender in MDD Placebo-Controlled Adult Trials a n=Number of patients with non-missing change score for ASEX total. b p=0.013 versus placebo. c p<0.001 versus placebo. Male Patients a Female Patients a Another Duloxetine Product (n=175) Placebo (n=83) Another Duloxetine Product (n=241) Placebo (n=126) ASEX Total (Items 1-5) 0.56 b -1.07 -1.15 -1.07 Item 1 - Sex drive -0.07 -0.12 -0.32 -0.24 Item 2 - Arousal 0.01 -0.26 -0.21 -0.18 Item 3 - Ability to achieve erection (men); Lubrication (women) 0.03 -0.25 -0.17 -0.18 Item 4 - Ease of reaching orgasm 0.40 c -0.24 -0.09 -0.13 Item 5 - Orgasm satisfaction 0.09 -0.13 -0.11 -0.17 Vital Sign Changes in Adults In placebo-controlled clinical trials across approved adult populations for change from baseline to endpoint, duloxetine delayed-release capsules-treated patients had mean increases of 0.23 mm Hg in systolic blood pressure (SBP) and 0.73 mm Hg in diastolic blood pressure (DBP) compared to mean decreases of 1.09 mm Hg in SBP and 0.55 mm Hg in DBP in placebo-treated patients. There was no significant difference in the frequency of sustained (3 consecutive visits) elevated blood pressure [see Warnings and Precautions ( 5.3 , 5.11 )] . Duloxetine delayed-release capsules treatment, for up to 26 weeks in placebo-controlled trials across approved adult populations, typically caused a small increase in heart rate for change from baseline to endpoint compared to placebo of up to 1.37 beats per minute (increase of 1.20 beats per minute in duloxetine delayed-release capsules-treated patients, decrease of 0.17 beats per minute in placebo-treated patients). Laboratory Changes in Adults Duloxetine delayed-release capsules treatment in placebo-controlled clinical trials across approved adult populations, was associated with small mean increases from baseline to endpoint in ALT, AST, CPK, and alkaline phosphatase; infrequent, modest, transient, abnormal values were observed for these analytes in duloxetine delayed-release capsules-treated patients when compared with placebo-treated patients [see Warnings and Precautions ( 5.2 )] . High bicarbonate, cholesterol, and abnormal (high or low) potassium, were observed more frequently in duloxetine delayed-release capsules-treated patients compared to placebo-treated patients. Other Adverse Reactions Observed During the Clinical Trial Evaluation of Duloxetine Delayed-Release Capsules in Adults Following is a list of adverse reactions reported by patients treated with duloxetine delayed-release capsules in clinical adult trials. In clinical trials of all approved adult populations, 34,756 patients were treated with duloxetine delayed-release capsules. Of these, 27% (9337) took duloxetine delayed-release capsules for at least 6 months, and 12% (4317) took duloxetine delayed-release capsules for at least one year. The following listing is not intended to include reactions (1) already listed in previous tables or elsewhere in labeling, (2) for which a drug cause was remote, (3) which were so general as to be uninformative, (4) which were not considered to have significant clinical implications, or (5) which occurred at a rate equal to or less than placebo. Reactions are categorized by body system according to the following definitions: frequent adverse reactions are those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in fewer than 1/1000 patients. Cardiac Disorders - Frequent: palpitations; Infrequent: myocardial infarction, tachycardia, and Takotsubo cardiomyopathy. Ear and Labyrinth Disorders - Frequent: vertigo; Infrequent: ear pain and tinnitus. Endocrine Disorders - Infrequent: hypothyroidism. Eye Disorders - Frequent: vision blurred; Infrequent: diplopia, dry eye, and visual impairment. Gastrointestinal Disorders - Frequent: flatulence; Infrequent: dysphagia, eructation, gastritis, gastrointestinal hemorrhage, halitosis, and stomatitis; Rare: gastric ulcer. General Disorders and Administration Site Conditions - Frequent: chills/rigors; Infrequent: falls, feeling abnormal, feeling hot and/or cold, malaise, and thirst; Rare: gait disturbance. Infections and Infestations - Infrequent: gastroenteritis and laryngitis. Investigations - Frequent: weight increased, weight decreased; Infrequent: blood cholesterol increased. Metabolism and Nutrition Disorders - Infrequent: dehydration and hyperlipidemia; Rare: dyslipidemia. Musculoskeletal and Connective Tissue Disorders - Frequent: musculoskeletal pain; Infrequent: muscle tightness and muscle twitching. Nervous System Disorders - Frequent: dysgeusia, lethargy, and paraesthesia/hypoesthesia; Infrequent: disturbance in attention, dyskinesia, myoclonus, and poor quality sleep; Rare: dysarthria. Psychiatric Disorders - Frequent: abnormal dreams and sleep disorder; Infrequent: apathy, bruxism, disorientation/confusional state, irritability, mood swings, and suicide attempt; Rare: completed suicide. Renal and Urinary Disorders - Frequent: urinary frequency; Infrequent: dysuria, micturition urgency, nocturia, polyuria, and urine odor abnormal. Reproductive System and Breast Disorders - Frequent: anorgasmia/orgasm abnormal; Infrequent: menopausal symptoms, sexual dysfunction, and testicular pain; Rare: menstrual disorder. Respiratory, Thoracic and Mediastinal Disorders - Frequent: yawning, oropharyngeal pain; Infrequent: throat tightness. Skin and Subcutaneous Tissue Disorders - Frequent: pruritus; Infrequent: cold sweat, dermatitis contact, erythema, increased tendency to bruise, night sweats, and photosensitivity reaction; Rare: ecchymosis . Vascular Disorders - Frequent: hot flush; Infrequent: flushing, orthostatic hypotension, and peripheral coldness. Adverse Reactions Observed in Placebo-Controlled Clinical Trials in Pediatric Patients Pediatric Clinical Trial Database The data described below reflect exposure to duloxetine delayed-release capsules (N=567) in pediatric patients 7 to 18 years of age from 10-week, placebo-controlled trials for MDD (N=341) and GAD (N=135), and a 13-week trial for another indication (N=91). Duloxetine Delayed-Release Capsules are not approved for the treatment of MDD in pediatric patients [see Use in Specific Populations ( 8.4 )] . Of the duloxetine delayed-release capsules-treated patients in these studies, 36% were 7 to 11 years of age (64% were between 12 to 18 years old), 55% were female, and 69% were Caucasian. Patients received 30 mg to 120 mg duloxetine delayed-release capsules per day during placebo-controlled acute treatment studies. In the trials up to 40 weeks long, there were 988 duloxetine delayed-release capsules-treated pediatric patients aged 7 to 17 years of age (most patients received 30 mg to 120 mg per day) – 35% were 7 to 11 years of age (65% were 12 to 17 years old) and 56% were female. Most Common Adverse Reactions in Pediatric Trials The most common adverse reactions (≥5% in duloxetine delayed-release capsules-treated patients and at least twice the incidence of placebo-treated patients) in all pooled pediatric populations (MDD, GAD, and another indication) were decreased weight, decreased appetite, nausea, vomiting, fatigue, and diarrhea. Adverse Reactions in Pediatric Patients Aged 7 to 17 Years Old with MDD and GAD The adverse reaction profile observed in clinical trials in pediatric patients aged 7 years to 18 years old with MDD and GAD was consistent with the adverse reaction profile observed in adult clinical trials. The most common (≥5% and twice placebo) adverse reactions observed in these pediatric clinical trials included: nausea, diarrhea, decreased weight, and dizziness. Table 5 provides the incidence of adverse reactions in MDD and GAD pediatric placebo-controlled trials that occurred in greater than 2% of patients treated with duloxetine delayed-release capsules and with an incidence greater than patients treated with placebo. Duloxetine Delayed-Release Capsules are not approved in the treatment of MDD in pediatric patients [see Use in Specific Populations ( 8.4 )]. Table 5: Adverse Reactions: Incidence of 2% or More and Greater than Placebo in Three 10-week Pediatric Placebo-Controlled Trials in MDD and GAD a a Duloxetine Delayed-Release Capsules are not approved for the treatment of pediatric MDD [see Use in Specific Populations (8.4)] .The inclusion of an event in the table is determined based on the percentages before rounding; however, the percentages displayed in the table are rounded to the nearest integer. b Also includes abdominal pain upper, abdominal pain lower, abdominal tenderness, abdominal discomfort, and gastrointestinal pain. c Also includes asthenia. d Frequency based on weight measurement meeting potentially clinically significant threshold of greater than or equal to 3.5% weight loss (N=467 duloxetine delayed-release capsules; N=354 Placebo). e Also includes hypersomnia and sedation. f Also includes initial insomnia, insomnia, middle insomnia, and terminal insomnia. System Organ Class/Adverse Reaction Percentage of Pediatric Patients Reporting Reaction Another Duloxetine Product Placebo (N=476) (N=362) Gastrointestinal Disorders Nausea 18 8 Abdominal Pain b 13 10 Vomiting 9 4 Diarrhea 6 3 Dry Mouth 2 1 General Disorders and Administration Site Conditions Fatigue c 7 5 Investigations Decreased Weight d 14 6 Metabolism and Nutrition Disorders Decreased Appetite 10 5 Nervous System Disorders Headache 18 13 Somnolence e 11 6 Dizziness 8 4 Psychiatric Disorders Insomnia f 7 4 Respiratory, Thoracic, and Mediastinal Disorders Oropharyngeal Pain 4 2 Cough 3 1 Other adverse reactions that occurred at an incidence of less than 2% and were reported by more duloxetine delayed-release capsules-treated patients than placebo-treated patients in pediatric MDD and GAD clinical trials included: abnormal dreams (including nightmare), anxiety, flushing (including hot flush), hyperhidrosis, palpitations, pulse increased, and tremor (Duloxetine Delayed-Release Capsules are not approved to treat pediatric patients with MDD). The most commonly reported symptoms following discontinuation of duloxetine delayed-release capsules in pediatric MDD and GAD clinical trials included headache, dizziness, insomnia, and abdominal pain [see Warnings and Precautions ( 5.7 )] . Growth (Height and Weight) in Pediatric Patients 7 to 17 Years Old with GAD and MDD Decreased appetite and weight loss have been observed in association with the use of SSRIs and SNRIs. Duloxetine delayed-release capsules-treated pediatric patients in clinical trials experienced a 0.1 kg mean decrease in weight at 10 weeks, compared with a mean weight gain of approximately 0.9 kg in placebo-treated pediatric patients. The proportion of patients who experienced a clinically significant decrease in weight (≥3.5%) was greater in the duloxetine delayed-release capsules group than in the placebo group (16% and 6%, respectively). Subsequently, over the 4- to 6-month uncontrolled extension periods, duloxetine delayed-release capsules-treated patients on average trended toward recovery to their expected baseline weight percentile based on population data from age- and sex-matched peers. In studies up to 9 months, duloxetine delayed-release capsules-treated pediatric patients experienced an increase in height of 1.7 cm on average (2.2 cm increase in patients 7 to 11 years of age and 1.3 cm increase in patients 12 to 17 years of age). While height increase was observed during these studies, a mean decrease of 1% in height percentile was observed (decrease of 2% in patients 7 to 11 years of age and increase of 0.3% in patients 12 to 17 years of age). Weight and height should be monitored regularly in pediatric patients treated with duloxetine delayed-release capsules [see Use in Specific Populations ( 8.4 )] . 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of duloxetine delayed-release capsules. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Adverse reactions reported since market introduction that were temporally related to duloxetine therapy and not mentioned elsewhere in labeling include: acute pancreatitis, anaphylactic reaction, aggression and anger (particularly early in treatment or after treatment discontinuation), angioneurotic edema, angle-closure glaucoma, colitis (microscopic or unspecified), cutaneous vasculitis (sometimes associated with systemic involvement), extrapyramidal disorder, galactorrhea, gynecological bleeding, hallucinations, hyperglycemia, hyperprolactinemia, hypersensitivity, hypertensive crisis, muscle spasm, rash, restless legs syndrome, seizures upon treatment discontinuation, supraventricular arrhythmia, tinnitus (upon treatment discontinuation), trismus, and urticaria.

<table border="0" cellpadding="0" cellspacing="0" width="100%"><caption>Table 2: Adverse Reactions: Incidence of 5% or More and Greater than Placebo in Placebo-Controlled Trials of Approved Adult Populations^a </caption><col width="29.56%"/><col width="36.3%"/><col width="34.14%"/><tfoot><tr><td align="justify" colspan="3">^aIncludes adults with MDD, GAD, and other indications. The inclusion of an event in the table is determined based on the percentages before rounding; however, the percentages displayed in the table are rounded to the nearest integer. ^bAlso includes asthenia. ^cEvents for which there was a significant dose-dependent relationship in fixed-dose studies, excluding three MDD studies which did not have a placebo lead-in period or dose titration. ^dAlso includes initial insomnia, middle insomnia, and early morning awakening. ^eAlso includes hypersomnia and sedation. ^f Also includes abdominal discomfort, abdominal pain lower, abdominal pain upper, abdominal tenderness, and gastrointestinal pain. </td></tr></tfoot><tbody><tr styleCode="Botrule"><td rowspan="2" styleCode="Lrule Rrule" valign="middle"> <content styleCode="bold">Adverse Reaction</content></td><td align="center" colspan="2" styleCode="Rrule" valign="top"> <content styleCode="bold">Percentage of Patients Reporting Reaction</content></td></tr><tr styleCode="Botrule"><td align="center" styleCode="Lrule Rrule" valign="top"> <content styleCode="bold">Another Duloxetine Product</content> <content styleCode="bold">(N=8100)</content></td><td align="center" styleCode="Rrule" valign="top"> <content styleCode="bold">Placebo</content> <content styleCode="bold">(N=5655)</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Nausea^c</td><td align="center" styleCode="Rrule" valign="top"> 23 </td><td align="center" styleCode="Rrule" valign="top"> 8 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Headache </td><td align="center" styleCode="Rrule" valign="top"> 14 </td><td align="center" styleCode="Rrule" valign="top"> 12 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Dry mouth </td><td align="center" styleCode="Rrule" valign="top"> 13 </td><td align="center" styleCode="Rrule" valign="top"> 5 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Somnolence^e</td><td align="center" styleCode="Rrule" valign="top"> 10 </td><td align="center" styleCode="Rrule" valign="top"> 3 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Fatigue^{b, c}</td><td align="center" styleCode="Rrule" valign="top"> 9 </td><td align="center" styleCode="Rrule" valign="top"> 5 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Insomnia^d</td><td align="center" styleCode="Rrule" valign="top"> 9 </td><td align="center" styleCode="Rrule" valign="top"> 5 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Constipation^c</td><td align="center" styleCode="Rrule" valign="top"> 9 </td><td align="center" styleCode="Rrule" valign="top"> 4 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Dizziness^c</td><td align="center" styleCode="Rrule" valign="top"> 9 </td><td align="center" styleCode="Rrule" valign="top"> 5 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Diarrhea </td><td align="center" styleCode="Rrule" valign="top"> 9 </td><td align="center" styleCode="Rrule" valign="top"> 6 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Decreased appetite^c</td><td align="center" styleCode="Rrule" valign="top"> 7 </td><td align="center" styleCode="Rrule" valign="top"> 2 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Hyperhidrosis^c</td><td align="center" styleCode="Rrule" valign="top"> 6 </td><td align="center" styleCode="Rrule" valign="top"> 1 </td></tr><tr><td styleCode="Lrule Rrule" valign="top"> Abdominal pain^f</td><td align="center" styleCode="Rrule" valign="top"> 5 </td><td align="center" styleCode="Rrule" valign="top"> 4 </td></tr></tbody></table>

<table border="0" cellpadding="0" cellspacing="0" width="100%"><caption>Table 3: Adverse Reactions: Incidence of 2% or More and Greater than Placebo in MDD and GAD Placebo-Controlled Trials in Adults^a,b</caption><col width="47.3%"/><col width="25.24%"/><col width="27.46%"/><tfoot><tr><td colspan="3">^aThe inclusion of an event in the table is determined based on the percentages before rounding; however, the percentages displayed in the table are rounded to the nearest integer. ^bFor GAD, there were no adverse reactions that were significantly different between treatments in adults &#x2265;65 years that were also not significant in the adults &lt;65 years. ^cEvents for which there was a significant dose-dependent relationship in fixed-dose studies, excluding three MDD studies which did not have a placebo lead-in period or dose titration. ^dIncludes abdominal pain upper, abdominal pain lower, abdominal tenderness, abdominal discomfort, and gastrointestinal pain. ^eIncludes asthenia. ^fIncludes hypersomnia and sedation. ^gIncludes initial insomnia, middle insomnia, and early morning awakening. ^hIncludes feeling jittery, nervousness, restlessness, tension and psychomotor hyperactivity. ⁱIncludes loss of libido. ^jIncludes anorgasmia. </td></tr></tfoot><tbody><tr styleCode="Botrule"><td rowspan="2" styleCode="Lrule Rrule" valign="middle"> <content styleCode="bold">System Organ Class / Adverse Reaction</content></td><td align="center" colspan="2" styleCode="Rrule" valign="top"> <content styleCode="bold">Percentage of Patients Reporting Reaction</content></td></tr><tr styleCode="Botrule"><td align="center" styleCode="Lrule Rrule" valign="top"> <content styleCode="bold">Another Duloxetine Product</content> <content styleCode="bold">(N=4797)</content></td><td align="center" styleCode="Rrule" valign="top"> <content styleCode="bold">Placebo (N=3303)</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> <content styleCode="bold">Cardiac Disorders</content> Palpitations </td><td align="center" styleCode="Rrule" valign="top"> 2 </td><td align="center" styleCode="Rrule" valign="top"> 1 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> <content styleCode="bold">Eye Disorders</content> Vision blurred </td><td align="center" styleCode="Rrule" valign="top"> 3 </td><td align="center" styleCode="Rrule" valign="top"> 1 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> <content styleCode="bold">Gastrointestinal Disorders</content></td><td styleCode="Rrule" valign="top"/><td styleCode="Rrule" valign="top"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Nausea^c</td><td align="center" styleCode="Rrule" valign="top"> 23 </td><td align="center" styleCode="Rrule" valign="top"> 8 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Dry mouth </td><td align="center" styleCode="Rrule" valign="top"> 14 </td><td align="center" styleCode="Rrule" valign="top"> 6 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Constipation^c</td><td align="center" styleCode="Rrule" valign="top"> 9 </td><td align="center" styleCode="Rrule" valign="top"> 4 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Diarrhea </td><td align="center" styleCode="Rrule" valign="top"> 9 </td><td align="center" styleCode="Rrule" valign="top"> 6 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Abdominal pain^d</td><td align="center" styleCode="Rrule" valign="top"> 5 </td><td align="center" styleCode="Rrule" valign="top"> 4 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Vomiting </td><td align="center" styleCode="Rrule" valign="top"> 4 </td><td align="center" styleCode="Rrule" valign="top"> 2 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> <content styleCode="bold">General Disorders and Administration Site Conditions</content> Fatigue^e</td><td align="center" styleCode="Rrule" valign="top"> 9 </td><td align="center" styleCode="Rrule" valign="top"> 5 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> <content styleCode="bold">Metabolism and Nutrition Disorders</content> Decreased appetite^c</td><td align="center" styleCode="Rrule" valign="top"> 6 </td><td align="center" styleCode="Rrule" valign="top"> 2 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> <content styleCode="bold">Nervous System Disorders</content></td><td styleCode="Rrule" valign="top"/><td styleCode="Rrule" valign="top"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Headache </td><td align="center" styleCode="Rrule" valign="top"> 14 </td><td align="center" styleCode="Rrule" valign="top"> 14 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Dizziness^c</td><td align="center" styleCode="Rrule" valign="top"> 9 </td><td align="center" styleCode="Rrule" valign="top"> 5 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Somnolence^f</td><td align="center" styleCode="Rrule" valign="top"> 9 </td><td align="center" styleCode="Rrule" valign="top"> 3 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Tremor </td><td align="center" styleCode="Rrule" valign="top"> 3 </td><td align="center" styleCode="Rrule" valign="top"> 1 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> <content styleCode="bold">Psychiatric Disorders</content></td><td styleCode="Rrule" valign="top"/><td styleCode="Rrule" valign="top"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Insomnia^g</td><td align="center" styleCode="Rrule" valign="top"> 9 </td><td align="center" styleCode="Rrule" valign="top"> 5 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Agitation^h</td><td align="center" styleCode="Rrule" valign="top"> 4 </td><td align="center" styleCode="Rrule" valign="top"> 2 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Anxiety </td><td align="center" styleCode="Rrule" valign="top"> 3 </td><td align="center" styleCode="Rrule" valign="top"> 2 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> <content styleCode="bold">Reproductive System and Breast Disorders</content></td><td styleCode="Rrule" valign="top"/><td styleCode="Rrule" valign="top"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Erectile dysfunction </td><td align="center" styleCode="Rrule" valign="top"> 4 </td><td align="center" styleCode="Rrule" valign="top"> 1 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Ejaculation delayed^c</td><td align="center" styleCode="Rrule" valign="top"> 2 </td><td align="center" styleCode="Rrule" valign="top"> 1 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Libido decreasedⁱ</td><td align="center" styleCode="Rrule" valign="top"> 3 </td><td align="center" styleCode="Rrule" valign="top"> 1 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Orgasm abnormal^j</td><td align="center" styleCode="Rrule" valign="top"> 2 </td><td align="center" styleCode="Rrule" valign="top"> &lt;1 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> <content styleCode="bold">Respiratory, Thoracic, and Mediastinal Disorders</content> Yawning </td><td align="center" styleCode="Rrule" valign="top"> 2 </td><td align="center" styleCode="Rrule" valign="top"> &lt;1 </td></tr><tr><td styleCode="Lrule Rrule" valign="top"> <content styleCode="bold">Skin and Subcutaneous Tissue Disorders</content> Hyperhidrosis </td><td align="center" styleCode="Rrule" valign="top"> 6 </td><td align="center" styleCode="Rrule" valign="top"> 2 </td></tr></tbody></table>

<table border="0" cellpadding="0" cellspacing="0" width="100%"><caption> Table 4: Mean Change in ASEX Scores by Gender in MDD Placebo-Controlled Adult Trials </caption><col width="39.32%"/><col width="17.08%"/><col width="13.24%"/><col width="17.08%"/><col width="13.24%"/><tfoot><tr><td colspan="5">^an=Number of patients with non-missing change score for ASEX total. ^b p=0.013 versus placebo. ^c p&lt;0.001 versus placebo. </td></tr></tfoot><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"/><td align="center" colspan="2" styleCode="Rrule" valign="top"> <content styleCode="bold">Male Patients^a</content></td><td align="center" colspan="2" styleCode="Rrule" valign="top"> <content styleCode="bold">Female Patients^a</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"/><td align="center" styleCode="Rrule" valign="top"> <content styleCode="bold">Another Duloxetine Product</content><content styleCode="bold"> (n=175)</content></td><td align="center" styleCode="Rrule" valign="top"> <content styleCode="bold">Placebo (n=83)</content></td><td align="center" styleCode="Rrule" valign="top"> <content styleCode="bold">Another Duloxetine Product</content><content styleCode="bold"> (n=241)</content></td><td align="center" styleCode="Rrule" valign="top"> <content styleCode="bold">Placebo (n=126)</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> ASEX Total (Items 1-5)</td><td align="center" styleCode="Rrule" valign="top"> 0.56^b</td><td align="center" styleCode="Rrule" valign="top"> -1.07 </td><td align="center" styleCode="Rrule" valign="top"> -1.15 </td><td align="center" styleCode="Rrule" valign="top"> -1.07 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Item 1 - Sex drive </td><td align="center" styleCode="Rrule" valign="top"> -0.07 </td><td align="center" styleCode="Rrule" valign="top"> -0.12 </td><td align="center" styleCode="Rrule" valign="top"> -0.32 </td><td align="center" styleCode="Rrule" valign="top"> -0.24 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Item 2 - Arousal </td><td align="center" styleCode="Rrule" valign="top"> 0.01 </td><td align="center" styleCode="Rrule" valign="top"> -0.26 </td><td align="center" styleCode="Rrule" valign="top"> -0.21 </td><td align="center" styleCode="Rrule" valign="top"> -0.18 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Item 3 - Ability to achieve erection (men); Lubrication (women) </td><td align="center" styleCode="Rrule" valign="top"> 0.03 </td><td align="center" styleCode="Rrule" valign="top"> -0.25 </td><td align="center" styleCode="Rrule" valign="top"> -0.17 </td><td align="center" styleCode="Rrule" valign="top"> -0.18 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Item 4 - Ease of reaching orgasm </td><td align="center" styleCode="Rrule" valign="top"> 0.40^c</td><td align="center" styleCode="Rrule" valign="top"> -0.24 </td><td align="center" styleCode="Rrule" valign="top"> -0.09 </td><td align="center" styleCode="Rrule" valign="top"> -0.13 </td></tr><tr><td styleCode="Lrule Rrule" valign="top"> Item 5 - Orgasm satisfaction </td><td align="center" styleCode="Rrule" valign="top"> 0.09 </td><td align="center" styleCode="Rrule" valign="top"> -0.13 </td><td align="center" styleCode="Rrule" valign="top"> -0.11 </td><td align="center" styleCode="Rrule" valign="top"> -0.17 </td></tr></tbody></table>