FDA label 441a46f0-ecc8-4448-e054-00144ff88e88

5.1 Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 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 of differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1. Table 1 Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Increases Compared to Placebo <18 14 additional cases 18-24 5 additional cases Decreases Compared to Placebo 25-64 1 fewer case ≥65 6 fewer cases No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms. If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that discontinuation can be associated with certain symptoms [see DOSAGE AND ADMINISTRATION (2.7) and WARNINGS AND PRECAUTIONS (5.7) for descriptions of the risks of discontinuation of Duloxetine Delayed-release Capsules]. 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 Duloxetine Delayed-release Capsules should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose. Screening Patients for Bipolar Disorder — A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that Duloxetine Delayed-release Capsules are not approved for use in treating bipolar depression. 5.2 Hepatotoxicity There have been reports of hepatic failure, sometimes fatal, in patients treated with Duloxetine Delayed-release Capsules. 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 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 Delayed-release Capsules 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 Delayed-release Capsules-treated patients. In most patients, the median time to detection of the transaminase elevation was about two months. In adult placebo-controlled trials in any indication, for patients with normal and abnormal baseline ALT values, elevation of ALT >3 times the upper limit of normal occurred in 1.25% (144/11,496) of Duloxetine Delayed-release Capsules-treated patients compared to 0.45% (39/8716) of placebo-treated patients. In adult placebo-controlled studies using a fixed dose design, there was evidence of a dose response relationship for ALT and AST elevation of >3 times the upper limit of normal and >5 times the upper limit of normal, respectively. Because it is possible that duloxetine and alcohol may interact to cause liver injury or that duloxetine 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 with therapeutic doses of duloxetine. Syncope and orthostatic hypotension tend to occur within the first week of therapy but can occur at any time during duloxetine treatment, particularly after dose increases. The risk of falling appears to be related to the degree of orthostatic decrease in blood pressure 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 blood pressure. The risk of blood pressure decreases may be greater in patients taking concomitant medications that induce orthostatic hypotension (such as antihypertensives) or are potent CYP1A2 inhibitors [see WARNINGS AND PRECAUTIONS (5.12) and DRUG INTERACTIONS (7.1)] and in patients taking duloxetine 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 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 elderly 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 bone fractures and hospitalizations have been reported [see ADVERSE REACTIONS (6.10) and PATIENT COUNSELING INFORMATION (17)]. 5.4 Serotonin Syndrome The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including Duloxetine Delayed-release Capsules, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John's Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome. The concomitant use of Duloxetine Delayed-release Capsules with MAOIs intended to treat psychiatric disorders is contraindicated. Duloxetine Delayed-release Capsules should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking Duloxetine Delayed-release Capsules. Duloxetine Delayed-release Capsules should be discontinued before initiating treatment with the MAOI [see DOSAGE AND ADMINISTRATION (2.8, 2.9), and CONTRAINDICATIONS (4)]. If concomitant use of Duloxetine Delayed-release Capsules with other serotonergic drugs including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, 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 Duloxetine Delayed-release Capsules and any concomitant serotonergic agents, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated. 5.5 Abnormal Bleeding SSRIs and SNRIs, including duloxetine, may increase the risk of bleeding events. 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. Bleeding events related to SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages. Patients should be cautioned about the risk of bleeding associated with the concomitant use of duloxetine and NSAIDs, aspirin, or other drugs that affect coagulation. 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 Delayed-release Capsules 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 of Treatment with Duloxetine Delayed-release Capsules 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. Patients should be monitored 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 physician may continue decreasing the dose but at a more gradual rate [see DOSAGE AND ADMINISTRATION (2.7)]. 5.8 Activation of Mania/Hypomania In adult placebo-controlled trials in patients with major depressive disorder, activation of mania or hypomania was reported in 0.1% (4/3779) of duloxetine-treated patients and 0.04% (1/2536) of placebo-treated patients. No activation of mania or hypomania was reported in DPNP, GAD, or chronic musculoskeletal pain placebo-controlled trials. 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 may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. 5.10 Seizures Duloxetine 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 Effect on Blood Pressure In adult placebo-controlled clinical trials across indications 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. In a clinical pharmacology study designed to evaluate the effects of duloxetine on various parameters, including blood pressure at supratherapeutic doses with an accelerated dose titration, there was evidence of increases in supine blood pressure at doses up to 200 mg twice daily. At the highest 200 mg twice daily dose, the increase in mean pulse rate was 5.0 to 6.8 beats and increases in mean blood pressure were 4.7 to 6.8 mm Hg (systolic) and 4.5 to 7 mm Hg (diastolic) up to 12 hours after dosing. Blood pressure should be measured prior to initiating treatment and periodically measured throughout treatment [see ADVERSE REACTIONS (6.7)]. 5.12 Clinically Important Drug Interactions Both CYP1A2 and CYP2D6 are responsible for duloxetine metabolism. Potential for Other Drugs to Affect Duloxetine Delayed-release Capsules CYP1A2 Inhibitors — Co-administration of Duloxetine Delayed-release Capsules with potent CYP1A2 inhibitors should be avoided [see DRUG INTERACTIONS (7.1)]. CYP2D6 Inhibitors — Because CYP2D6 is involved in duloxetine metabolism, concomitant use of duloxetine with potent inhibitors of CYP2D6 would be expected to, and does, result in higher concentrations (on average of 60%) of duloxetine [see DRUG INTERACTIONS (7.2)]. Potential for Duloxetine Delayed-release Capsules to Affect Other Drugs Drugs Metabolized by CYP2D6 — Co-administration of Duloxetine Delayed-release Capsules with drugs that are extensively metabolized by CYP2D6 and that have a narrow therapeutic index, including certain antidepressants (tricyclic antidepressants [TCAs], such as nortriptyline, amitriptyline, and imipramine), phenothiazines and Type 1C antiarrhythmics (e.g., propafenone, flecainide), should be approached with caution. Plasma TCA concentrations may need to be monitored and the dose of the TCA may need to be reduced if a TCA is co-administered with Duloxetine Delayed-release Capsules. Because of the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, Duloxetine Delayed-release Capsules and thioridazine should not be co-administered [see DRUG INTERACTIONS (7.9)]. Other Clinically Important Drug Interactions Alcohol — Use of Duloxetine Delayed-release Capsules concomitantly with heavy alcohol intake may be associated with severe liver injury. For this reason, Duloxetine Delayed-release Capsules should not be prescribed for patients with substantial alcohol use [see WARNINGS AND PRECAUTIONS (5.2) and DRUG INTERACTIONS (7.15)]. CNS Acting Drugs — Given the primary CNS effects of Duloxetine Delayed-release Capsules, it should be used with caution when it is taken in combination with or substituted for other centrally acting drugs, including those with a similar mechanism of action [see WARNINGS AND PRECAUTIONS (5.12) and DRUG INTERACTIONS (7.16)]. 5.13 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 and appeared to be reversible when Duloxetine Delayed-release Capsules were discontinued. Elderly 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. 5.14 Use in Patients with Concomitant Illness Clinical experience with Duloxetine Delayed-release Capsules 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 Delayed-release Capsules, 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 DOSAGE AND ADMINISTRATION (2.6), WARNINGS AND PRECAUTIONS (5.2), and USE IN SPECIFIC POPULATIONS (8.9)]. Severe Renal Impairment — Avoid use in patients with severe renal impairment, GFR <30 mL/min. Increased plasma concentration of duloxetine, and especially of its metabolites, occur in patients with end-stage renal disease (requiring dialysis) [see DOSAGE AND ADMINISTRATION (2.6) and USE IN SPECIFIC POPULATIONS (8.10)]. Glycemic Control in Patients with Diabetes — As observed in DPNP trials, Duloxetine Delayed-release Capsules treatment worsens glycemic control in some patients with diabetes. In three clinical trials of Duloxetine Delayed-release Capsules for the management of neuropathic pain associated with diabetic peripheral neuropathy, the mean duration of diabetes was approximately 12 years, the mean baseline fasting blood glucose was 176 mg/dL, and the mean baseline hemoglobin A1c (HbA1c) was 7.8%. In the 12-week acute treatment phase of these studies, Duloxetine Delayed-release Capsules was associated with a small increase in mean fasting blood glucose as compared to placebo. In the extension phase of these studies, which lasted up to 52 weeks, mean fasting blood glucose increased by 12 mg/dL in the Duloxetine Delayed-release Capsules group and decreased by 11.5 mg/dL in the routine care group. HbA1c increased by 0.5% in the Duloxetine Delayed-release Capsules and by 0.2% in the routine care groups. 5.15 Urinary Hesitation and Retention Duloxetine Delayed-release Capsules are 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. 5.16 Laboratory Tests No specific laboratory tests are recommended.

The following serious adverse reactions are described below and elsewhere in the labeling: Suicidal Thoughts and Behaviors in Children, Adolescents and Young Adults [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)] Abnormal Bleeding [see WARNINGS AND PRECAUTIONS (5.5)] Severe Skin Reactions [see WARNINGS AND PRECAUTIONS (5.6)] Discontinuation of Treatment with Duloxetine Delayed-release Capsules [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)] Effect on Blood Pressure [see WARNINGS AND PRECAUTIONS (5.11)] Clinically Important Drug Interactions [see WARNINGS AND PRECAUTIONS (5.12)] Hyponatremia [see WARNINGS AND PRECAUTIONS (5.13)] Urinary Hesitation and Retention [see WARNINGS AND PRECAUTIONS (5.15)] 6.1 Clinical Trial Data Sources 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 stated frequencies of adverse reactions 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. Reactions reported during the studies were not necessarily caused by the therapy, and the frequencies do not reflect investigator impression (assessment) of causality. Adults — The data described below reflect exposure to duloxetine in placebo-controlled trials for MDD (N=3779), GAD (N=1018), OA (N=503), CLBP (N=600), DPNP (N=906), and another indication (N=1294). The population studied was 17 to 89 years of age; 65.7%, 60.8%, 60.6%, 42.9%, and 94.4% female; and 81.8%, 72.6%, 85.3%, 74.0%, and 85.7% Caucasian for MDD, GAD, OA and CLBP, DPNP, and another indication, respectively. Most patients received doses of a total of 60 to 120 mg per day [see CLINICAL STUDIES (14)]. Information describing two additional clinical studies in which efficacy was not demonstrated in patients ages 7 to 17 years is approved for Eli Lilly and Company, Inc.'s CYMBALTA® (duloxetine) delayed-release capsules. Other pediatric use information for patients ages 7 to 17 years is approved for Eli Lilly and Company, Inc.'s CYMBALTA® (duloxetine) delayed-release capsules. However, due to Eli Lilly and Company, Inc.'s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 6.2 Adverse Reactions Reported as Reasons for Discontinuation of Treatment in Adult Placebo-Controlled Trials Major Depressive Disorder — Approximately 8.4% (319/3779) of the patients who received duloxetine in placebo-controlled trials for MDD discontinued treatment due to an adverse reaction, compared with 4.6% (117/2536) of the patients receiving placebo. Nausea (duloxetine 1.1%, placebo 0.4%) was the only common 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-treated patients and at a rate of at least twice that of placebo). Generalized Anxiety Disorder — Approximately 13.7% (139/1018) of the patients who received duloxetine in placebo-controlled trials for GAD discontinued treatment due to an adverse reaction, compared with 5.0% (38/767) for placebo. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine 3.3%, placebo 0.4%), and dizziness (duloxetine 1.3%, placebo 0.4%). Diabetic Peripheral Neuropathic Pain — Approximately 12.9% (117/906) of the patients who received duloxetine in placebo-controlled trials for DPNP discontinued treatment due to an adverse reaction, compared with 5.1% (23/448) for placebo. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine 3.5%, placebo 0.7%), dizziness (duloxetine 1.2%, placebo 0.4%), and somnolence (duloxetine 1.1%, placebo 0.0%). Chronic Pain due to Osteoarthritis — Approximately 15.7% (79/503) of the patients who received duloxetine in 13-week, placebo-controlled trials for chronic pain due to OA discontinued treatment due to an adverse reaction, compared with 7.3% (37/508) for placebo. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine 2.2%, placebo 1.0%). Chronic Low Back Pain — Approximately 16.5% (99/600) of the patients who received duloxetine in 13-week, placebo-controlled trials for CLBP discontinued treatment due to an adverse reaction, compared with 6.3% (28/441) for placebo. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine 3.0%, placebo 0.7%), and somnolence (duloxetine 1.0%, placebo 0.0%). 6.3 Most Common Adult Adverse Reactions Pooled Trials for all Approved Indications — The most commonly observed adverse reactions in Duloxetine Delayed-release Capsules-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. Diabetic Peripheral Neuropathic Pain — The most commonly observed adverse reactions in Duloxetine Delayed-release Capsules-treated patients (as defined above) were nausea, somnolence, decreased appetite, constipation, hyperhidrosis, and dry mouth. Chronic Pain due to Osteoarthritis — The most commonly observed adverse reactions in Duloxetine Delayed-release Capsules-treated patients (as defined above) were nausea, fatigue, constipation, dry mouth, insomnia, somnolence, and dizziness. Chronic Low Back Pain — The most commonly observed adverse reactions in Duloxetine Delayed-release Capsules-treated patients (as defined above) were nausea, dry mouth, insomnia, somnolence, constipation, dizziness, and fatigue. 6.4 Adverse Reactions Occurring at an Incidence of 5% or More Among Duloxetine-Treated Patients in Adult Placebo-Controlled Trials Table 2 gives the incidence of treatment-emergent adverse reactions in placebo-controlled trials for approved indications that occurred in 5% or more of patients treated with duloxetine and with an incidence greater than placebo. Table 2: Treatment-Emergent Adverse Reactions: Incidence of 5% or More and Greater than Placebo in Placebo-Controlled Trials of Approved Indications* Adverse Reaction Percentage of Patients Reporting Reaction Duloxetine Delayed-release Capsules (N=8100) Placebo (N=5655) * 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. † 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. ‡ Also includes hypersomnia and sedation. § Also includes asthenia. ¶ Also includes initial insomnia, middle insomnia, and early morning awakening. # Also includes abdominal discomfort, abdominal pain lower, abdominal pain upper, abdominal tenderness, and gastrointestinal pain. Nausea† 23 8 Headache 14 12 Dry mouth 13 5 Somnolence‡ 10 3 Fatigue§,† 9 5 Insomnia¶ 9 5 Constipation† 9 4 Dizziness† 9 5 Diarrhea 9 6 Decreased appetite† 7 2 Hyperhidrosis† 6 1 Abdominal pain# 5 4 6.5 Adverse Reactions Occurring at an Incidence of 2% or More Among Duloxetine-Treated Patients in Adult Placebo-Controlled Trials Pooled MDD and GAD Trials — Table 3 gives the incidence of treatment-emergent adverse reactions in MDD and GAD placebo-controlled trials for approved indications that occurred in 2% or more of patients treated with duloxetine and with an incidence greater than placebo. Table 3: Treatment-Emergent Adverse Reactions: Incidence of 2% or More and Greater than Placebo in MDD and GAD Placebo-Controlled Trials* System Organ Class / Adverse Reaction Percentage of Patients Reporting Reaction Duloxetine Delayed-release Capsules (N=4797) Placebo (N=3303) * 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. † 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. ‡ Also includes abdominal pain upper, abdominal pain lower, abdominal tenderness, abdominal discomfort, and gastrointestinal pain § Also includes asthenia ¶ Also includes hypersomnia and sedation # Also includes initial insomnia, middle insomnia, and early morning awakening Þ Also includes feeling jittery, nervousness, restlessness, tension and psychomotor hyperactivity SS Also includes loss of libido À Also includes anorgasmia Cardiac Disorders Palpitations 2 1 Eye Disorders Vision blurred 3 1 Gastrointestinal Disorders Nausea† 23 8 Dry mouth 14 6 Constipation† 9 4 Diarrhea 9 6 Abdominal pain‡ 5 4 Vomiting 4 2 General Disorders and Administration Site Conditions Fatigue§ 9 5 Metabolism and Nutrition Disorders Decreased appetite† 6 2 Nervous System Disorders Headache 14 14 Dizziness† 9 5 Somnolence¶ 9 3 Tremor 3 1 Psychiatric Disorders Insomnia# 9 5 AgitationÞ 4 2 Anxiety 3 2 Reproductive System and Breast Disorders Erectile dysfunction 4 1 Ejaculation delayed† 2 1 Libido decreasedSS 3 1 Orgasm abnormalÀ 2 <1 Respiratory, Thoracic, and Mediastinal Disorders Yawning 2 <1 Skin and Subcutaneous Tissue Disorders Hyperhidrosis 6 2 DPNP, another indication, OA, and CLBP — Table 4 gives the incidence of treatment-emergent adverse events that occurred in 2% or more of patients treated with Duloxetine Delayed-release Capsules (determined prior to rounding) in the premarketing acute phase of DPNP, another indication, OA, and CLBP placebo-controlled trials and with an incidence greater than placebo. Table 4: Treatment-Emergent Adverse Reactions: Incidence of 2% or More and Greater than Placebo in DPNP, another indication, OA, and CLBP Placebo-Controlled Trials* System Organ Class / Adverse Reaction Percentage of Patients Reporting Reaction Duloxetine Delayed-release Capsules (N=3303) Placebo (N=2352) * 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. † Incidence of 120 mg/day is significantly greater than the incidence for 60 mg/day. ‡ Also includes abdominal discomfort, abdominal pain lower, abdominal pain upper, abdominal tenderness and gastrointestinal pain § Also includes asthenia ¶ Also includes myalgia and neck pain # Also includes hypersomnia and sedation Þ Also includes hypoaesthesia, hypoaesthesia facial, genital hypoaesthesia and paraesthesia oral SS Also includes initial insomnia, middle insomnia, and early morning awakening. À Also includes feeling jittery, nervousness, restlessness, tension and psychomotor hyperactivity È Also includes ejaculation failure Ð Also includes hot flush Ø Also includes blood pressure diastolic increased, blood pressure systolic increased, diastolic hypertension, essential hypertension, hypertension, hypertensive crisis, labile hypertension, orthostatic hypertension, secondary hypertension, and systolic hypertension Gastrointestinal Disorders Nausea 23 7 Dry Mouth† 11 3 Constipation† 10 3 Diarrhea 9 5 Abdominal Pain‡ 5 4 Vomiting 3 2 Dyspepsia 2 1 General Disorders and Administration Site Conditions Fatigue§ 11 5 Infections and Infestations Nasopharyngitis 4 4 Upper Respiratory Tract Infection 3 3 Influenza 2 2 Metabolism and Nutrition Disorders Decreased Appetite† 8 1 Musculoskeletal and Connective Tissue Musculoskeletal Pain¶ 3 3 Muscle Spasms 2 2 Nervous System Disorders Headache 13 8 Somnolence†,# 11 3 Dizziness 9 5 ParaesthesiaÞ 2 2 Tremor† 2 <1 Psychiatric Disorders Insomnia†,SS 10 5 AgitationÀ 3 1 Reproductive System and Breast Disorders Erectile Dysfunction† 4 <1 Ejaculation DisorderÈ 2 <1 Respiratory, Thoracic, and Mediastinal Disorders Cough 2 2 Skin and Subcutaneous Tissue Disorders Hyperhidrosis 6 1 Vascular Disorders FlushingÐ 3 1 Blood pressure increasedØ 2 1 6.6 Effects on Male and Female Sexual Function in Adults 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 side effects, was used prospectively in 4 MDD placebo-controlled trials. In these trials, as shown in Table 5 below, patients treated with Duloxetine Delayed-release Capsules experienced significantly more sexual dysfunction, as measured by the total score on the ASEX, than did patients treated with placebo. Gender analysis showed that this difference occurred only in males. Males treated with Duloxetine Delayed-release Capsules experienced more difficulty with ability to reach orgasm (ASEX Item 4) than males treated with placebo. Females did not experience more sexual dysfunction on Duloxetine Delayed-release Capsules than on placebo as measured by ASEX total score. Negative numbers signify an improvement from a baseline level of dysfunction, which is commonly seen in depressed patients. Physicians should routinely inquire about possible sexual side effects. Table 5: Mean Change in ASEX Scores by Gender in MDD Placebo-Controlled Trials Male Patients* Female Patients* Duloxetine Delayed-release Capsules (n=175) Placebo (n=83) Duloxetine Delayed-release Capsules (n=241) Placebo (n=126) * n=Number of patients with non-missing change score for ASEX total † p=0.013 versus placebo ‡ p<0.001 versus placebo ASEX Total (Items 1-5) 0.56† -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‡ -0.24 -0.09 -0.13 Item 5 — Orgasm satisfaction 0.09 -0.13 -0.11 -0.17 6.7 Vital Sign Changes in Adults In placebo-controlled clinical trials across approved indications for change from baseline to endpoint, duloxetine treatment was associated with mean increases of 0.23 mm Hg in systolic blood pressure and 0.73 mm Hg in diastolic blood pressure compared to mean decreases of 1.09 mm Hg systolic and 0.55 mm Hg diastolic 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 treatment, for up to 26 weeks in placebo-controlled trials across approved indications, 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-treated patients, decrease of 0.17 beats per minute in placebo-treated patients). 6.8 Laboratory Changes in Adults Duloxetine Delayed-release Capsule treatment in placebo-controlled clinical trials across approved indications, 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. 6.9 Electrocardiogram Changes in Adults The effect of duloxetine 160 mg and 200 mg administered twice daily to steady state was evaluated in a randomized, double-blinded, two-way crossover study in 117 healthy female subjects. No QT interval prolongation was detected. Duloxetine appears to be associated with concentration-dependent but not clinically meaningful QT shortening. 6.10 Other Adverse Reactions Observed During the Premarketing and Postmarketing Clinical Trial Evaluation of Duloxetine in Adults Following is a list of treatment-emergent adverse reactions reported by patients treated with duloxetine in clinical trials. In clinical trials of all indications, 34,756 patients were treated with duloxetine. Of these, 26.9% (9337) took duloxetine for at least 6 months, and 12.4% (4317) 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 and tachycardia. 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. 6.11 Adverse Reactions Observed in Children and Adolescent Placebo-Controlled Clinical Trials The adverse drug reaction profile observed in pediatric clinical trials (children and adolescents) was consistent with the adverse drug reaction profile observed in adult clinical trials. The specific adverse drug reactions observed in adult patients can be expected to be observed in pediatric patients (children and adolescents) [see ADVERSE REACTIONS (6.5)]. The most common (≥5% and twice placebo) adverse reactions observed in pediatric clinical trials include: nausea, diarrhea, decreased weight, and dizziness. Table 6 provides the incidence of treatment-emergent adverse reactions in pediatric placebo-controlled trials that occurred in greater than 2% of patients treated with Duloxetine Delayed-release Capsules and with an incidence greater than placebo. Table 6: Treatment-Emergent Adverse Reactions: Incidence of 2% or More and Greater than Placebo in three 10-week Pediatric Placebo-Controlled Trials* System Organ Class/Adverse Reaction Percentage of Pediatric Patients Reporting Reaction Duloxetine Delayed-release Capsules (N=476) Placebo (N=362) * 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. † Also includes abdominal pain upper, abdominal pain lower, abdominal tenderness, abdominal discomfort, and gastrointestinal pain. ‡ Also includes asthenia. § Frequency based on weight measurement meeting potentially clinically significant threshold of ≥3.5% weight loss (N=467 Duloxetine Delayed-release Capsules; N=354 Placebo). ¶ Also includes hypersomnia and sedation. # Also includes initial insomnia, insomnia, middle insomnia, and terminal insomnia. Gastrointestinal Disorders Nausea 18 8 Abdominal Pain† 13 10 Vomiting 9 4 Diarrhea 6 3 Dry Mouth 2 1 General Disorders and Administration Site Conditions Fatigue‡ 7 5 Investigations Decreased Weight§ 14 6 Metabolism and Nutrition Disorders Decreased Appetite 10 5 Nervous System Disorders Headache 18 13 Somnolence¶ 11 6 Dizziness 8 4 Psychiatric Disorders Insomnia# 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% but were reported by more duloxetine treated patients than placebo treated patients and are associated Duloxetine Delayed-release Capsules treatment: abnormal dreams (including nightmare), anxiety, flushing (including hot flush), hyperhidrosis, palpitations, pulse increased, and tremor. Discontinuation-emergent symptoms have been reported when stopping Duloxetine Delayed-release Capsules. The most commonly reported symptoms following discontinuation of Duloxetine Delayed-release Capsules in pediatric clinical trials have included headache, dizziness, insomnia, and abdominal pain [see WARNINGS AND PRECAUTIONS (5.7) and ADVERSE REACTIONS (6.2)]. Growth (Height and Weight) — Decreased appetite and weight loss have been observed in association with the use of SSRIs and SNRIs. 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 children [7 to 11 years of age] and 1.3 cm increase in adolescents [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 children [7 to 11 years of age] and increase of 0.3% in adolescents [12 to 17 years of age]). Weight and height should be monitored regularly in children and adolescents treated with Duloxetine Delayed-release Capsules. Information describing two additional clinical studies in which efficacy was not demonstrated in patients ages 7 to 17 years is approved for Eli Lilly and Company, Inc.'s CYMBALTA® (duloxetine) delayed-release capsules. Other pediatric use information for patients ages 7 to 17 years is approved for Eli Lilly and Company, Inc.'s CYMBALTA® (duloxetine) delayed-release capsules. However, due to Eli Lilly and Company, Inc.'s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 6.12 Postmarketing Spontaneous Reports 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: anaphylactic reaction, aggression and anger (particularly early in treatment or after treatment discontinuation), angioneurotic edema, angle-closure glaucoma, 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.