DULOXETINE HCL DR 20 MG CAP | GREEN OBLONG LU Q01 LUPIN PHARMACEU 6818029407

Hepatotoxicity:Hepatic failure, sometimes fatal, has been reported. Discontinue duloxetine 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 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, 7.4, 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) 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) Inhibitors of CYP1A2 or Thioridazine:Avoid co-administration with duloxetine (5.12) Hyponatremia:Can occur in association with SIADH; consider discontinuation (5.13) Glucose Control in Diabetes:In DPNP patients, increases in fasting blood glucose, and HbA1chave been observed (5.14) Conditions that Slow Gastric Emptying:Use cautiously in these patients (5.14) Sexual Dysfunction: Duloxetine may cause symptoms of sexual dysfunction (5.16)

Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 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 to 24 5 additional cases Decreases Compared to Placebo 25 to 64 1 fewer case 65 6 fewer cases No suicides occurred in any of the pediatric duloxetine delayed-release capsules trials. There were suicides in the adult duloxetine delayed-release capsules trials, but the number was not sufficient to reach any conclusion about duloxetine delayed-release capsules 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 (2.8) 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 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 is not approved for use in treating bipolar depression.

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's enteric coating. In extremely acidic conditions, duloxetine, unprotected by the enteric coating, may undergo hydrolysis to form naphthol. Caution is advised in using duloxetine in patients with conditions that may slow gastric emptying (e.g., some diabetics). Duloxetine has 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 (2.7), 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/minute. Increased plasma concentration of duloxetine, and especially of its metabolites, occur in patients with end-stage renal disease (requiring dialysis) [see Dosage and Administration (2.7) and Use in Specific Populations (8.10)] . Glycemic Control in Patients with Diabetes As observed in DPNP trials, duloxetine treatment worsened glycemic control in some patients with diabetes. In three clinical trials of duloxetine for the management of neuropathic pain associated with diabetic peripheral neuropathy [see Clinical Studies (14.4)], 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 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 group and decreased by 11.5 mg/dL in the routine care group. HbA1c increased by 0.5% in the duloxetine group and by 0.2% in the routine care group.

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 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 in placebo-controlled adult trials for MDD (N=3779), GAD (N=1018), OA (N=503), CLBP (N=600), DPNP (N=906), and FM (N=1294). The age range in this pooled population was 17 to 89 years of age. In this pooled population, 66%, 61%, 61%, 43%, and 94% of adult patients were female; and 82%, 73%, 85%, 74%, and 86% of adult patients were Caucasian in the MDD, GAD, OA and CLBP, DPNP, and FM populations, respectively. Most patients received duloxetine dosages of a total of 60 to 120 mg per day [see Clinical Studies (14)]. The data below do not include results of the trial that evaluated the efficacy of duloxetine for the treatment of GAD in patients 65 years old (Study GAD-5) [see Clinical Studies (14.3)]; however, the adverse reactions observed in this geriatric population were generally similar to adverse reactions in the overall adult population. Adverse Reactions Leading to Treatment Discontinuation in Adult Placebo-Controlled Trials Major Depressive Disorder Approximately 8.4% (319/3779) of duloxetine-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 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-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-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 3.3%, placebo 0.4%), and dizziness (duloxetine 1.3%, placebo 0.4%). Diabetic Peripheral Neuropathic Pain Approximately 12.9% (117/906) of the duloxetine-treated patients in placebo-controlled adult trials for DPNP discontinued treatment due to an adverse reaction, compared with 5.1% (23/448) 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 3.5%, placebo 0.7%), dizziness (duloxetine 1.2%, placebo 0.4%), and somnolence (duloxetine 1.1%, placebo 0%). Fibromyalgia Approximately 17.5% (227/1294) of the duloxetine-treated patients in 3- to 6- month placebo-controlled adult trials for FM discontinued treatment due to an adverse reaction, compared with 10.1% (96/955) for placebo-treated patients. Adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine 2.0%, placebo 0.5%), headache (duloxetine 1.2%, placebo 0.3%), somnolence (duloxetine 1.1%, placebo 0%), and fatigue (duloxetine 1.1%, placebo 0.1%). Chronic Pain due to Osteoarthritis Approximately 15.7% (79/503) of the duloxetine-treated patients in 13-week, placebo-controlled adult trials for chronic pain due to OA discontinued treatment due to an adverse reaction, compared with 7.3% (37/508) for placebo-treated patients. Adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine 2.2%, placebo 1%). Chronic Low Back Pain Approximately 16.5% (99/600) of the duloxetine-treated patients in 13-week, placebo-controlled adult trials for CLBP discontinued treatment due to an adverse reaction, compared with 6.3% (28/441) for placebo-treated patients. Adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine 3%, placebo 0.7%), and somnolence (duloxetine 1%, placebo 0%). Most Common Adverse Reactions in Adult Trials The most commonly observed adverse reactions in duloxetine-treated patients (as defined above) were: Diabetic Peripheral Neuropathic Pain: nausea, somnolence, decreased appetite, constipation, hyperhidrosis, and dry mouth. Fibromyalgia: nausea, dry mouth, constipation, somnolence, decreased appetite, hyperhidrosis, and agitation. Chronic Pain due to Osteoarthritis: nausea, fatigue, constipation, dry mouth, insomnia, somnolence, and dizziness. Chronic Low Back Pain: nausea, dry mouth, insomnia, somnolence, constipation, dizziness, and fatigue. The most commonly observed adverse reactions in duloxetine-treated patients in all the pooled adult populations (i.e., MDD, GAD, DPNP, FM, OA, and CLBP) (incidence of at least 5% and at least twice the incidence in placebo-treated 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 adult populations (i.e., MDD, GAD, DPNP, FM, OA, and CLBP) that occurred in 5% or more of duloxetine-treated patients 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 PopulationsThe 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. a Includes adults with MDD, GAD, DPNP, FM, and chronic musculoskeletal pain. 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. Adverse Reaction Percentage of Patients Reporting Reaction Duloxetine (N=8100) Placebo (N=5655) Nauseac 23 8 Headache 14 12 Dry mouth 13 5 Somnolencee 10 3 Fatigueb,c 9 5 Insomniad 9 5 Constipationc 9 4 Dizzinessc 9 5 Diarrhea 9 6 Decreased appetitec 7 2 Hyperhidrosisc 6 1 Abdominal painf 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 adult trials that occurred in 2% or more of duloxetine-treated patients 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 Adultsa,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. Percentage of Patients Reporting Reaction System Organ Class / Adverse Reaction Duloxetine (N=4797) Placebo (N=3303) Cardiac Disorders Palpitations 2 1 Eye Disorders Vision blurred 3 1 Gastrointestinal Disorders Nauseac 23 8 Dry mouth 14 6 Constipationc 9 4 Diarrhea 9 6 Abdominal paind 5 4 Vomiting 4 2 General Disorders and Administration Site Conditions Fatiguee 9 5 Metabolism and Nutrition Disorders Decreased appetitec 6 2 Nervous System Disorders Headache 14 14 Dizzinessc 9 5 Somnolencef 9 3 Tremor 3 1 Psychiatric Disorders Insomniag 9 5 Agitationh 4 2 Anxiety 3 2 Reproductive System and Breast Disorders Erectile dysfunction 4 1 Ejaculation delayedc 2 1 Libido decreasedi 3 1 Orgasm abnormalj 2 <1 Respiratory, Thoracic, and Mediastinal Disorders Yawning 2 <1 Skin and Subcutaneous Tissue Disorders Hyperhidrosis 6 2 Adverse Reactions in the DPNP, FM, OA, and CLBP Adult Trials Table 4 displays the incidence of adverse reactions that occurred in 2% or more of duloxetine-treated patients (determined prior to rounding) in the premarketing acute phase of DPNP, FM, OA, and CLBP placebo-controlled adult trials and with an incidence greater than placebo-treated patients. Table 4: Adverse Reactions: Incidence of 2% or More and Greater than Placebo in DPNP, FM, OA, and CLBP Placebo-Controlled Trialsa a The inclusion of an event in the table is determined based on the percentages before rounding; however, the b Incidence of 120 mg/day is significantly greater than the incidence for 60 mg/day. c Includes abdominal discomfort, lower abdominal pain, upper abdominal pain, abdominal tenderness and gastrointestinal pain. d Includes asthenia. e Includes myalgia and neck pain. f Includes hypersomnia and sedation. g Includes hypoaesthesia, facial hypoaesthesia, genital hypoaesthesia and oral paraesthesia h Includes initial insomnia, middle insomnia, and early morning awakening. i Includes feeling jittery, nervousness, restlessness, tension and psychomotor hyperactivity. j Includes ejaculation failure. k Includes hot flush. l Includes increased diastolic blood pressure, increased systolic blood pressure, diastolic hypertension, essential hypertension, hypertension, hypertensive crisis, labile hypertension, orthostatic hypertension, secondary hypertension, and systolic hypertension. percentages displayed in the table are rounded to the nearest integer. Percentage of Patients Reporting Reaction System Organ Class / Adverse Reaction Duloxetine (N=3303) Placebo (N=2352) Gastrointestinal Disorders Nausea 23 7 Dry mouthb 11 3 Constipationb 10 3 Diarrhea 9 5 Abdominal Painc 5 4 Vomiting 3 2 Dyspepsia 2 1 General Disorders and Administration Site Conditions Fatigued 11 5 Infections and Infestations Nasopharyngitis 4 4 Upper Respiratory Tract Infection 3 3 Influenza 2 2 Metabolism and Nutrition Disorders Decreased Appetiteb 8 1 Musculoskeletal and Connective Tissue Musculoskeletal Paine 3 3 Muscle Spasms 2 2 Nervous System Disorders Headache 13 8 Somnolenceb,f 11 3 Dizziness 9 5 Paraesthesiag 2 2 Tremorb 2 <1 Psychiatric Disorders Insomniab,h 10 5 Agitationi 3 1 Reproductive System and Breast Disorders Erectile Dysfunctionb 4 <1 Ejaculation Disorderj 2 <1 Respiratory, Thoracic, and Mediastinal Disorders Cough 2 2 Skin and Subcutaneous Tissue Disorders Hyperhidrosis 6 1 Vascular Disorders Flushingk 3 1 Blood pressure increasedl 2 1 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 adults trials (Studies MDD-1, MDD-2, MDD-3, and MDD-4) [see Clinical Studies (14.2)]. 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, duloxetine-treated male patients 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 5). Duloxetine-treated female patients 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-treated patients. Table 5: Mean Change in ASEX Scores by Gender in MDD Placebo-Controlled 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 Patientsa Female Patientsa Duloxetine ( n = 175 ) Placebo ( n = 83 ) Duloxetine ( n = 241 ) Placebo ( n = 126 ) ASEX Total (Items 1 to 5) 0.56b -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 0.40c -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 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 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 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-treated patients, decrease of 0.17 beats per minute in placebo-treated patients). Laboratory Changes in Adults Duloxetine 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-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 treated patients compared to placebo-treated patients. Other Adverse Reactions Observed During the Clinical Trial Evaluation of Duloxetine in Adults Following is a list of adverse reactions reported by patients treated with duloxetine in clinical adult trials. In clinical trials of all approved adult populations, 34,756 patients were treated with duloxetine. Of these, 27% (9337) took duloxetine for at least 6 months, and 12% (4317) took duloxetine 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 (N=476) in pediatric patients aged 7 to 17 years of age from two 10-week, placebo-controlled trials in patients with MDD (N=341) (Studies MDD-6 and MDD-7) and one 10-week placebo-controlled trial in GAD (N=135) (Study GAD-6). Duloxetine is not approved for the treatment of MDD in pediatric patients [see Use in Specific Populations (8.4)]. Of the duloxetine-treated patients in these studies, 42% were 7 to 11 years of age (58% were between 12 to 17 years old), 51% were female, and 69% were white. Patients received 30 to 120 mg of duloxetine per day during placebo-controlled acute treatment studies. In the pediatric MDD and GAD, trials up to 36 weeks long, there were 822duloxetine-treated pediatric patients aged 7 to 17 years of age (most patients received 30 to 120 mg per day) 42% were 7 to 11 years of age (58% were 12 to 17 years old) and 52% were female. Most Common Adverse Reactions in Pediatric Trials The most common adverse reactions ( 5% in duloxetine-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 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 6 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 and with an incidence greater than patients treated with placebo. Duloxetine is not approved in the treatment of MDD in pediatric patients [see Use in Specific Populations (8.4)]. Table 6: Adverse Reactions: Incidence of 2% or More and Greater than Placebo in Three 10-week Pediatric Placebo-Controlled Trials in MDD and GADa a Duloxetine is 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 3.5% weight loss (N=467 Duloxetine; 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 Duloxetine (N=476) Placebo (N=362) Gastrointestinal Disorders Nausea Abdominal Painb Vomiting Diarrhea Dry Mouth 18 13 9 6 2 8 10 4 3 1 General Disorders and Administration Site Conditions Fatiguec 7 5 Investigations Decreased Weightd 14 6 Metabolism and Nutrition Disorders Decreased Appetite 10 5 Nervous System Disorders Headache Somnolencee Dizziness 18 11 8 13 6 4 Psychiatric Disorders Insomniaf 7 4 Respiratory, Thoracic, and Mediastinal Disorders Oropharyngeal Pain Cough 4 3 2 1 Other adverse reactions that occurred at an incidence of less than 2% and were reported by more duloxetine-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 is not approved to treat pediatric patients with MDD). The most commonly reported symptoms following discontinuation of duloxetine 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-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 group than in the placebo group (16% and 6%, respectively). Subsequently, over the 4- to 6-month uncontrolled extension periods, duloxetine -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-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 [see Use in Specific Populations (8.4)]. Adverse Reactions in Pediatric Patients Aged 13 to 17 Years Old with Fibromyalgia Table 7 provides the incidence of adverse reactions in a fibromyalgia pediatric placebo-controlled trial (Study FM-4) that occurred in greater than 5% of patients treated with duloxetine and with an incidence greater than patients treated with placebo [see Clinical Studies (14.5)]. Table 7: Adverse Reactions: Incidence of 5% or More and Greater than Placebo in a 13- week Placebo-Controlled Trial in Pediatric Patients 13 to 17 Years Old with Fibromyalgia (Study FM-4) a 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 Frequency based on weight measurement meeting potentially clinically significant threshold of 3.5% weight loss (N = 89 Duloxetine; N = 92 Placebo) Duloxetine (N=91) Placebo (N=93) Nausea 25% 15% Decreased appetite 15% 3% Vomiting 15% 5% Decreased weightb 15% 5% Headache 14% 11% Nasopharyngitis 9% 2% Somnolence 9% 3% Upper respiratory tract infection 7% 2% Viral gastroenteritis 5% 0% Fatigue 5% 2%

Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors the pregnancy outcomes in women exposed to antidepressants, including duloxetine, during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Antidepressants at 1-866-961-2388 or online at https://womensmentalhealth.org/research/pregnancyregistry/. Risk Summary Data from a postmarketing retrospective cohort study indicate that use of duloxetine in the month before delivery may be associated with an increased risk of postpartum hemorrhage. Data from published literature and from a postmarketing retrospective cohort study have not identified a clear drug-associated risk of major birth defects or other adverse developmental outcomes (see Data). There are risks associated with untreated depression and fibromyalgia in pregnancy, and with exposure to SNRIs and SSRIs, including duloxetine, during pregnancy (see Clinical Considerations). In rats and rabbits treated with duloxetine during the period of organogenesis, fetal weights were decreased but there was no evidence of developmental effects at doses up to 3 and 6 times, respectively, the maximum recommended human dose (MRHD) of 120 mg/day given to adolescents on a mg/m2 basis. When duloxetine was administered orally to pregnant rats throughout gestation and lactation, pup weights at birth and pup survival to 1 day postpartum were decreased at a dose 2 times the MRHD given to adolescents on a mg/m2 basis. At this dose, pup behaviors consistent with increased reactivity, such as increased startle response to noise and decreased habituation of locomotor activity were observed. Post-weaning growth was not adversely affected. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-associated Maternal and/or Embryo/Fetal Risk: Women who discontinue antidepressants during pregnancy are more likely to experience a relapse of major depression than women who continue antidepressants. This finding is from a prospective, longitudinal study that followed 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants at the beginning of pregnancy. Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum. Pregnant women with fibromyalgia are at increased risk for adverse maternal and infant outcomes including preterm premature rupture of membranes, preterm birth, small for gestational age, intrauterine growth restriction, placental disruption, and venous thrombosis. It is not known if these adverse maternal and fetal outcomes are a direct result of fibromyalgia or other comorbid factors. Maternal Adverse Reactions: Use of duloxetine in the month before delivery may be associated with an increased risk of postpartum hemorrhage [see Warnings and Precautions (5.5)]. Fetal/Neonatal Adverse Reaction: Neonates exposed to duloxetine and other SNRIs or SSRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These findings are consistent with either a direct toxic effect of the SNRIs or SSRIs, or possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome [see Warnings and Precautions (5.4)]. Data Human Data: Data from a postmarketing retrospective claims-based cohort study found an increased risk for postpartum hemorrhage among 955 pregnant women exposed to duloxetine in the last month of pregnancy compared to 4,128,460 unexposed pregnant women (adjusted relative risk: 1.53; 95% CI: 1.08 to 2.18). The same study did not find a clinically meaningful increase in the risk for major birth defects in the comparison of 2532 women exposed to duloxetine in the first trimester of pregnancy to 1,284,827 unexposed women after adjusting for several confounders. Methodologic limitations include possible residual confounding, misclassification of exposure and outcomes, lack of direct measures of disease severity, and lack of information about alcohol use, nutrition, and over-the-counter medication exposures. Animal Data: In animal reproduction studies, duloxetine has been shown to have adverse effects on embryo/fetal and postnatal development. When duloxetine was administered orally to pregnant rats and rabbits during the period of organogenesis, there was no evidence of malformations or developmental variations at doses up to 45 mg/kg/day [3 and 6 times, respectively, the MRHD of 120 mg/day given to adolescents on a mg/m2 basis]. However, fetal weights were decreased at this dose, with a no-effect dose of 10 mg/kg/day (approximately equal to the MRHD in rats and 2 times the MRHD in rabbits). When duloxetine was administered orally to pregnant rats throughout gestation and lactation, the survival of pups to 1 day postpartum and pup body weights at birth and during the lactation period were decreased at a dose of 30 mg/kg/day (2 times the MRHD given to adolescents on a mg/m2 basis); the no-effect dose was 10 mg/kg/day. Furthermore, behaviors consistent with increased reactivity, such as increased startle response to noise and decreased habituation of locomotor activity, were observed in pups following maternal exposure to 30 mg/kg/day. Post-weaning growth and reproductive performance of the progeny were not affected adversely by maternal duloxetine treatment.

The safety and effectiveness of duloxetine have been established for treatment of generalized anxiety disorder (GAD) in patients 7 to 17 years of age. The safety and effectiveness of duloxetine have not been established in pediatric patients with major depressive disorder (MDD), diabetic peripheral neuropathic pain, or chronic musculoskeletal pain. Antidepressants increased the risk of suicidal thoughts and behavior in pediatric patients. Monitor all pediatric patients being treated with antidepressants for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of treatment, or at times of dosage changes [see Warnings and Precautions (5.1)]. Perform regular monitoring of weight and growth in pediatric patients treated with duloxetine [see Adverse Reactions (6.1)]. Generalized Anxiety Disorder Use of duloxetine for the treatment of GAD in patients 7 to 17 years of age is supported by one 10-week, placebo-controlled trial (GAD-6). The study included 272 pediatric patients with GAD of which 47% were 7 to 11 years of age (53% were 12 to 17 years of age). Duloxetine demonstrated superiority over placebo as measured by greater improvement in the Pediatric Anxiety Rating Scale (PARS) for GAD severity score [see Clinical Studies (14.3)]. The safety and effectiveness of duloxetine for the treatment of GAD in pediatric patients less than 7 years of age have not been established. Fibromyalgia Use of duloxetine for treatment of fibromyalgia in patients 13 to 17 years of age is supported by a 13-week placebo-controlled trial in 184 patients with juvenile fibromyalgia syndrome (Study FM- 4). Duloxetine showed improvement over placebo on the primary endpoint, change from baseline to end-of-treatment on the Brief Pain Inventory (BPI) Modified Short Form: Adolescent Version 24-hour average pain severity rating [see Clinical Studies (14.5)]. The safety and effectiveness of duloxetine for the treatment of fibromyalgia in patients less than13 years of age have not been established. Major Depressive Disorder The safety and effectiveness of duloxetine have not been established in pediatric patients for the treatment of MDD. Efficacy of duloxetine was not demonstrated in two 10-week, placebo-controlled trials with 800 pediatric patients aged 7 to 17 years old with MDD (MDD-6 and MDD-7). Neither duloxetine nor an active control (approved for treatment of pediatric MDD) was superior to placebo. The most frequently observed adverse reactions in the MDD pediatric clinical trials included nausea, headache, decreased weight, and abdominal pain. Decreased appetite and weight loss have been observed in association with the use of SSRIs and SNRIs. Juvenile Animal Toxicology Data Duloxetine administration to young rats from post-natal day 21 (weaning) through post-natal day 90 (adult) resulted in decreased body weights that persisted into adulthood, but recovered when drug treatment was discontinued; slightly delayed (~1.5 days) sexual maturation in females, without any effect on fertility; and a delay in learning a complex task in adulthood, which was not observed after drug treatment was discontinued. These effects were observed at the high dose of 45 mg/kg/day (2 times the MRHD, for a child); the no-effect-level was 20 mg/kg/day ( 1 times the MRHD, for a child).

Geriatric Exposure in Premarketing Clinical Trials of Duloxetine Of the 2,418 patients in MDD trials, 6% (143) were 65 years of age or over. Of the 1041 patients in CLBP trials, 21% (221) were 65 years of age or over. Of the 487 patients in OA trials, 41% (197) were 65 years of age or over. Of the 1,074 patients in the DPNP trials, 33% (357) were 65 years of age or over. Of the 1,761 patients in FM trials, 8% (140) were 65 years of age or over. In the MDD, GAD, DPNP, FM, OA, and CLBP studies, no overall differences in safety or effectiveness were generally observed between these patients and younger adult patients, and other reported clinical experience has not identified differences in responses between these geriatric and younger adult patients, but greater sensitivity of some older patients cannot be ruled out. SSRIs and SNRIs, including duloxetine have been associated with clinically significant hyponatremia in geriatric patients, who may be at greater risk for this adverse reaction [see Warnings and Precautions (5.13)]. In an analysis of data from all placebo-controlled-trials, duloxetine-treated patients reported a higher rate of falls compared to placebo-treated patients. The increased risk appears to be proportional to a patient's underlying risk for falls. Underlying risk appears to increase steadily with age. As geriatric patients tend to have a higher prevalence of risk factors for falls such as medications, medical comorbidities and gait disturbances, the impact of increasing age by itself on falls during duloxetine treatment is unclear. Falls with serious consequences including bone fractures and hospitalizations have been reported with duloxetine use [see Warnings and Precautions (5.3) and Adverse Reactions (6.1)]. The pharmacokinetics of duloxetine after a single dose of 40 mg were compared in healthy elderly females (65 to 77 years) and healthy middle-age females (32 to 50 years). There was no difference in the Cmax, but the AUC of duloxetine was somewhat (about 25%) higher and the half-life about 4 hours longer in the elderly females. Population pharmacokinetic analyses suggest that the typical values for clearance decrease by approximately 1% for each year of age between 25 to 75 years of age; but age as a predictive factor only accounts for a small percentage of between-patient variability. Dosage adjustment based on the age of the adult patient is not necessary.

Duloxetine has an elimination half-life of about 12 hours (range 8 to 17 hours) and its pharmacokinetics are dose proportional over the therapeutic range. Steady-state plasma concentrations are typically achieved after 3 days of dosing. Elimination of duloxetine is mainly through hepatic metabolism involving two P450 isozymes, CYP1A2 and CYP2D6. Absorption After oral duloxetine administration, duloxetine hydrochloride is well absorbed. There is a median 2 hour lag until absorption begins (Tlag), with maximal plasma concentrations (Cmax) of duloxetine occurring 6 hours post dose. There is a 3 hour delay in absorption and a one-third increase in apparent clearance of duloxetine after an evening dose as compared to a morning dose. Effect of Food: Food does not affect the Cmax of duloxetine, but delays the time to reach peak concentration from 6 to 10 hours and it marginally decreases the extent of absorption (AUC) by about 10%. Distribution: The apparent volume of distribution averages about 1640 L. Duloxetine is highly bound (>90%) to proteins in human plasma, binding primarily to albumin and 1-acid glycoprotein. The interaction between duloxetine and other highly protein bound drugs has not been fully evaluated. Plasma protein binding of duloxetine is not affected by renal or hepatic impairment. Elimination Metabolism: Biotransformation and disposition of duloxetine in humans have been determined following oral administration of 14C-labeled duloxetine. Duloxetine comprises about 3% of the total radiolabeled material in the plasma, indicating that it undergoes extensive metabolism to numerous metabolites. The major biotransformation pathways for duloxetine involve oxidation of the naphthyl ring followed by conjugation and further oxidation. Both CYP1A2 and CYP2D6 catalyze the oxidation of the naphthyl ring in vitro. Metabolites found in plasma include 4-hydroxy duloxetine glucuronide and 5-hydroxy, 6-methoxy duloxetine sulfate. Excretion: Many additional metabolites have been identified in urine, some representing only minor pathways of elimination. Only trace (<1% of the dose) amounts of unchanged duloxetine are present in the urine. Most (about 70%) of the duloxetine dose appears in the urine as metabolites of duloxetine; about 20% is excreted in the feces. Duloxetine undergoes extensive metabolism, but the major circulating metabolites have not been shown to contribute significantly to the pharmacologic activity of duloxetine. Specific Populations Pediatric Patients: Duloxetine steady-state plasma concentration was comparable in pediatric patients 7 to 17 years of age and adult patients. The average steady-state duloxetine concentration was approximately 30% lower in this pediatric population relative to adult patients. The model-predicted duloxetine steady state plasma concentrations in pediatric patients 7 to 17 years of age were mostly within the concentration range observed in adult patients and did not exceed the concentration range in adults.

The efficacy of duloxetine as a treatment for MDD in adults was established in 4 randomized, double-blind, placebo-controlled, fixed-dose trials in adult outpatients (18 to 83 years) meeting DSM-IV criteria for MDD: In Studies MDD-1 and MDD-2, patients were randomized to duloxetine 60 mg once daily (N=123 and N=128, respectively) or placebo (N=122 and N=139, respectively) for 9 weeks In Study MDD-3, patients were randomized to duloxetine 20 or 40 mg twice daily (N=86 and N=91, respectively) or placebo (N=89) for 8 weeks In Study MDD-4, patients were randomized to duloxetine 40 or 60 mg twice daily (N=95 and N=93, respectively) or placebo (N=93) for 8 weeks. In all four trials, duloxetine demonstrated superiority over placebo as measured by improvement in the 17-item Hamilton Depression Rating Scale (HAMD-17) total score (see Table 8). There is no evidence that doses greater than 60 mg/day confer additional benefits. In all of these clinical trials, analyses of the relationship between treatment outcome and age, gender, and race did not suggest any differential responsiveness on the basis of these patient characteristics. Table 8: Summary of the Primary Efficacy Results for Adult Trial in MDD SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval, not adjusted for multiplicity in trials where multiple dose groups were included. aDifference (drug minus placebo) in least-squares mean change from baseline. bDoses statistically significantly superior to placebo. Study Number Treatment Group Primary Efficacy Measure: HAMD-17 Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo-subtracted Difference a (95% CI) Study MDD- 1 Duloxetine (60 mg/day)b Placebo 21.5 (4.10) 21.1 (3.71) -10.9 (0.70) -6.1 (0.69) -4.9 (-6.8, -2.9) - Study MDD- 2 Duloxetine (60 mg/day)b Placebo 20.3 (3.32) 20.5 (3.42) -10.5 (0.71) -8.3 (0.67) -2.2 (-4.0, -0.3) - Study MDD-3 Duloxetine (20 mg BID)b Duloxetine (40 mg BID)b Placebo 18.6 (5.85) 18.1 (4.52) 17.2 (5.11) -7.4 (0.80) -8.6 (0.81) -5.0 (0.81) -2.4 (-4.7, -0.2) -3.6 (-5.9, -1.4) -- Study MDD-4 Duloxetine (40 mg BID)b Duloxetine (60 mg BID)b Placebo 19.9 (3.54) 20.2 (3.41) 19.9 (3.58) -11.0 (0.49) -12.1 (0.49) -8.8 (0.50) -2.2 (-3.6, -0.9) -3.3 (-4.7, -1.9) -- In Study MDD-5, 533 adult patients meeting DSM-IV criteria for MDD received duloxetine 60 mg once daily during an initial 12-week open-label treatment phase. Two hundred and seventy-eight patients who responded to open label treatment [defined as meeting the following criteria at weeks 10 and 12: a HAMD-17 total score 9, Clinical Global Impressions of Severity (CGI-S) 2, and not meeting the DSM-IV criteria for MDD] were randomly assigned to continuation of duloxetine at the same dosage (N=136) or to placebo (N=142) for 6 months. In Study MDD-5, patients on duloxetine experienced a statistically significantly longer time to relapse of depression than did patients on placebo (see Figure 1). Relapse was defined as an increase in the CGI-S score of 2 points compared with that obtained at week 12, as well as meeting the DSM-IV criteria for MDD at 2 consecutive visits at least 2 weeks apart, where the 2-week temporal criterion had to be satisfied at only the second visit. Figure 1: Cumulative Proportiona of Adult Patients with MDD Relapse (Study MDD-5)

GAD Trials in Adults (Including Geriatric Patients) The efficacy of duloxetine in the treatment of generalized anxiety disorder (GAD) was established in 1 fixed-dose randomized, double-blind, placebo-controlled trial and 2 flexible-dose randomized, double-blind, placebo-controlled trials in adult outpatients between 18 and 83 years of age meeting the DSM-IV criteria for GAD (Studies GAD-1, GAD-2, and GAD-3, respectively). In Studies GAD-1 and GAD-2, the starting dose was 60 mg once daily (down titration to 30 mg once daily was allowed for tolerability reasons; the dosage could be increased to 60 mg once daily). Fifteen percent of patients were down titrated. Study GAD-3 had a starting dose of 30 mg once daily for 1 week before increasing it to 60 mg once daily. Studies GAD-2 and GAD-3 involved dose titration with duloxetine doses ranging from 60 mg once daily to 120 mg once daily (N=168 and N=162) compared to placebo (N=159 and N=161) over a 10-week treatment period. The mean dose for completers at endpoint in these trials was 104.8 mg/day. Study GAD-1 evaluated duloxetine dosages of 60 mg once daily (N=168) and 120 mg once daily (N=170) compared to placebo (N=175) over a 9-week treatment period. While a 120 mg/day dose was shown to be effective, there is no evidence that doses greater than 60 mg/day confer additional benefit. In all 3 trials, duloxetine demonstrated superiority over placebo as measured by greater improvement in the Hamilton Anxiety Scale (HAM-A) total score (see Table 8) and by the Sheehan Disability Scale (SDS) global functional impairment score. The SDS is a composite measurement of the extent emotional symptoms disrupt patient functioning in 3 life domains: work/school, social life/leisure activities, and family life/home responsibilities. In Study GAD-4, 887 patients meeting DSM-IV-TR criteria for GAD received duloxetine 60 mg to 120 mg once daily during an initial 26-week open-label treatment phase. Four hundred and twenty-nine patients who responded to open-label treatment [defined as meeting the following criteria at weeks 24 and 26: a decrease from baseline HAM-A total score by at least 50% to a score no higher than 11, and a Clinical Global Impressions of Improvement (CGI-Improvement) score of 1 or 2] were randomly assigned to continuation of duloxetine at the same dosage (N=216) or to placebo (N=213) and were observed for relapse. Of the patients randomized, 73% had been in a responder status for at least 10 weeks. Relapse was defined as an increase in CGI-Severity score at least 2 points to a score 4 and a MINI (Mini-International Neuropsychiatric Interview) diagnosis of GAD (excluding duration), or discontinuation due to lack of efficacy. Patients taking duloxetine experienced a statistically significantly longer time to relapse of GAD than did patients taking placebo (see Figure 2). Subgroup analyses did not indicate that there were any differences in treatment outcomes as a function of age or gender. GAD Trial in Geriatric Patients The efficacy of duloxetine in the treatment of patients 65 years of age with GAD was established in one 10-week flexible-dose, randomized, double-blind, placebo-controlled trial in adults 65 years of age meeting the DSM-IV criteria for GAD (Study GAD-5). In Study GAD-5, the starting dose was 30 mg once daily for 2 weeks before further dose increases in 30 mg increments at treatment weeks 2, 4, and 7 up to 120 mg once daily were allowed based on investigator judgment of clinical response and tolerability. The mean dosage for patients completing the 10-week acute treatment phase was 51 mg. Patients treated with duloxetine (N=151) demonstrated significantly greater improvement compared with placebo (N=140) on mean change from baseline to endpoint as measured by the HAM-A total score (see Table 8). GAD Trial in Pediatric Patients 7 to 17 Years Old The efficacy of duloxetine in the treatment of pediatric patients 7 to 17 years of age with GAD was established in 1 flexible-dose randomized, double-blind, placebo-controlled trial in pediatric outpatients with GAD (based on DSM-IV criteria) (Study GAD-6). In Study GAD-6, the starting dosage was 30 mg once daily for 2 weeks. Further dosage increases in 30 mg increments up to 120 mg once daily were allowed based on investigator judgment of clinical response and tolerability. The mean dosage for patients completing the 10-week treatment phase was 57.6 mg/day. In this study, duloxetine (N=135) demonstrated superiority over placebo (N=137) from baseline to endpoint as measured by greater improvement in the Pediatric Anxiety Rating Scale (PARS) for GAD severity score (see Table 9). Table 9: Summary of the Primary Efficacy Results for GAD Trials SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval, not adjusted for multiplicity in trials where multiple dose groups were included. a Difference (drug minus placebo) in least squares mean change from baseline. b Dose statistically significantly superior to placebo. Study Number (population) (measurement) Treatment Group Primary Efficacy Measure Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo-subtracted Differencea (95% CI) Study GAD- 1 (HAM-A) Duloxetine (60 mg/day)b 25.1 (7.18) -12.8 (0.68) -4.4 (-6.2, -2.5) Duloxetine (120 mg/day)b 25.1 (7.24) -12.5 (0.67) -4.1 (-5.9, -2.3) Placebo 25.8 (7.66) -8.4 (0.67) -- Study GAD- 2 (HAM-A) Duloxetine (60 to 120 mg/day)b 22.5 (7.44) -8.1 (0.70) -2.2 (-4.2, -0.3) Placebo 23.5 (7.91) -5.9 (0.70) -- Study GAD-3 (HAM-A) Duloxetine (60 to 120 mg/day)b 25.8 (5.66) -11.8 (0.69) -2.6 (-4.5, -0.7) Placebo 25.0 (5.82) -9.2 (0.67) -- Study GAD-5 (Geriatric) (HAM-A) Duloxetine (60 to 120 mg/day)b 24.6 (6.21) -15.9 (0.63) -4.2 (-5.9, -2.5) Placebo 24.5 (7.05) -11.7 (0.67) - Study GAD-6 (Pediatric) (PARS for GAD) Duloxetine (30 to 20 mg/day)b 17.5 (1.98) -9.7 (0.50) -2.7 (-4.0, -1.3) Placebo 17.4 (2.24) -7.1 (0.50) - Figure 2: Cumulative Proportiona of Adult Patients with GAD Relapse (Study GAD-4)

The efficacy of duloxetine for the management of neuropathic pain associated with diabetic peripheral neuropathy in adults was established in 2 randomized, 12-week, double-blind, placebo-controlled, fixed-dose trials in adult patients having diabetic peripheral neuropathic pain (DPNP) for at least 6 months (Study DPNP-1 and Study DPNP-2). These trials enrolled a total of 791 patients of whom 592 (75%) completed the trials. Patients enrolled had Type I or II diabetes mellitus with a diagnosis of painful distal symmetrical sensorimotor polyneuropathy for at least 6 months. The patients had a baseline pain score of 4 on an 11-point scale ranging from 0 (no pain) to 10 (worst possible pain). Patients were permitted up to 4 grams of acetaminophen per day as needed for pain, in addition to duloxetine. Patients recorded their pain daily in a diary. Both trials compared duloxetine 60 mg once daily or 60 mg twice daily with placebo. Study DPNP-1 additionally compared duloxetine 20 mg with placebo. A total of 457 patients (342 duloxetine, 115 placebo) were enrolled in study DPNP-1 and a total of 334 patients (226 duloxetine, 108 placebo) were enrolled in study DPNP-2. Treatment with duloxetine 60 mg one or two times a day statistically significantly improved the endpoint mean pain scores from baseline and increased the proportion of patients with at least a 50% reduction in pain scores from baseline. For various degrees of improvement in pain from baseline to study endpoint, Figures 3 and 4 show the fraction of patients achieving that degree of improvement in Studies DPNP-1 and DPNP-2, respectively. The figures are cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%. Patients who did not complete the trial were assigned 0% improvement. Some patients experienced a decrease in pain as early as week 1, which persisted throughout the trial. Figure 3: Percentage of DPNP Adult Patients Achieving Various Levels of Pain Relief as Measured by 24-Hour Average Pain Severity (Study DPNP-1) Figure 4: Percentage of DPNP Adult Patients Achieving Various Levels of Pain Relief as Measured by 24-Hour Average Pain Severity (Study DPNP-2)

Adult Trials in Fibromyalgia The efficacy of duloxetine for the management of fibromyalgia in adults was established in two randomized, double-blind, placebo-controlled, fixed-dose trials in adult patients meeting the American College of Rheumatology criteria for fibromyalgia (a history of widespread pain for 3 months, and pain present at 11 or more of the 18 specific tender point sites). Study FM-1 was three months in duration and enrolled female patients only. Study FM-2 was six months in duration and enrolled male and female patients. Approximately 25% of participants had a comorbid diagnosis of MDD. Studies FM-1 and FM-2 enrolled a total of 874 patients of whom 541 (62%) completed the trials. A total of 354 patients (234 duloxetine, 120 placebo) were enrolled in Study FM-1 and a total of 520 patients (376 duloxetine, 144 placebo) were enrolled in Study FM-2 (5% male, 95% female). The patients had a baseline pain score of 6.5 on an 11-point scale ranging from 0 (no pain) to 10 (worse possible pain). Studies FM-1 and FM-2 compared duloxetine 60 mg once daily or 120 mg daily (given in divided doses in FM-1 and as a single daily dose in Study FM-2) with placebo. Study FM-2 additionally compared duloxetine 20 mg with placebo during the initial three months of a six-month trial. Treatment with duloxetine 60 mg or 120 mg daily statistically significantly improved the endpoint mean pain scores from baseline and increased the proportion of patients with at least a 50% reduction in pain score from baseline. Pain reduction was observed in patients both with and without comorbid MDD. However, the degree of pain reduction may be greater in patients with comorbid MDD. For various degrees of improvement in pain from baseline to study endpoint, Figures 5 and 6 show the fraction of patients achieving that degree of improvement in Studies FM-1 and FM-2, respectively. The figures are cumulative so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%. Patients who did not complete the trial were assigned 0% improvement. Some patients experienced a decrease in pain as early as week 1, which persisted throughout the trial. Improvement was also demonstrated on measures of function (Fibromyalgia Impact Questionnaires) and patient global impression of change (PGI). Neither trial demonstrated a benefit of 120 mg compared to 60 mg, and a higher dosage was associated with more adverse reactions and premature discontinuations of treatment. Figure 5: Percentage of Adult Fibromyalgia Patients Achieving Various Levels of Pain Relief at Study Endpoint as Measured by 24-Hour Average Pain Severity (Study FM-1) Figure 6: Percentage of Adult Fibromyalgia Patients Achieving Various Levels of Pain Relief at Study Endpoint as Measured by 24-Hour Average Pain Severity (Study FM-2) Additionally, the benefit of up-titration in non-responders to duloxetine at 60 mg/day was evaluated in a separate trial (Study FM-3). Adult patients were initially treated with duloxetine 60 mg once daily for eight weeks in open-label fashion. Subsequently, completers of this phase were randomized to double-blind treatment with duloxetine at either 60 mg once daily or 120 mg once daily. Responders were defined as patients who had at least a 30% reduction in pain score from baseline at the end of the 8-week treatment. Patients who were non-responders at 8 weeks were no more likely to meet response criteria at the end of 60 weeks of treatment if blindly titrated to duloxetine 120 mg as compared to those who were blindly continued on duloxetine 60 mg. Pediatric Trial in Fibromyalgia Duloxetine was studied in 184 pediatric patients aged 13 to 17 years with juvenile fibromyalgia syndrome in a 13-week, placebo-controlled trial (Study FM-4). In Study FM-4, 149 (81%) patients completed the trial. Duloxetine (N=91) was initiated at a dosage of 30 mg once daily for one week and titrated to 60 mg once daily for 12 weeks, as tolerated. The mean dosage for patients completing the 12-week treatment phase was 49 mg/day. Duloxetine showed improvement over placebo on the primary endpoint [change from baseline to end-of-treatment on the Brief Pain Inventory (BPI) Modified Short Form: Adolescent Version 24-hour average pain severity rating] with a p-value of 0.052 from the prespecified primary analysis, and p-values ranging from 0.011-0.020 from sensitivity analyses which assigned baseline values to missing assessments of some patients who did not complete the trial for various reasons. The patients had a baseline BPI of 5.7. For various degrees of improvement in pain from baseline to study endpoint, Figure 7 shows the fraction of patients achieving that degree of improvement in Study FM-4.

Duloxetine is indicated for the treatment of chronic musculoskeletal pain in adults. This has been established in trials in adult patients with chronic low back pain and chronic pain due to osteoarthritis. Trials in Chronic Low Back Pain in Adults The efficacy of duloxetine in chronic low back pain (CLBP) in adults was assessed in two doubleblind, placebo-controlled, randomized clinical trials of 13-weeks duration (Studies CLBP-1 and CLBP-2), and one of 12-weeks duration (CLBP-3). Studies CLBP-1 and CLBP-3 demonstrated efficacy of duloxetine in the treatment of CLBP. Patients in all trials had no signs of radiculopathy or spinal stenosis. Study CLBP-1: Two hundred thirty-six adult patients (N=115 on duloxetine, N=121 on placebo) enrolled and 182 (77%) completed 13-week treatment phase. After 7 weeks of treatment, duloxetine-treated patients with less than 30% reduction in average daily pain and who were able to tolerate 60 mg once daily had their duloxetine dosage, in a double-blinded fashion, increased to 120 mg once daily for the remainder of the trial. Patients had a mean baseline pain rating of 6 on a numerical rating scale ranging from 0 (no pain) to 10 (worst possible pain). After 13 weeks of treatment, patients taking duloxetine 60 to 120 mg daily had a significantly greater pain reduction compared to patients taking placebo. Randomization was stratified by the patients' baseline NSAIDs use status. Subgroup analyses did not indicate that there were differences in treatment outcomes as a function of NSAIDs use. Study CLBP-2: Four hundred and four patients were randomized to receive fixed dosages of duloxetine daily or a matching placebo (N=59 on duloxetine 20 mg, N=116 on duloxetine 60 mg, N=112 on duloxetine 120 mg, N=117 on placebo) and 267 (66%) completed the entire 13-week trial. After 13 weeks of treatment, none of the three duloxetine dosages showed a statistically significant difference in pain reduction compared to placebo. Study CLBP-3: Four hundred and one patients were randomized to receive fixed doses of duloxetine 60 mg daily or placebo (N=198 on duloxetine, N=203 on placebo), and 303 (76%) completed the trial. Patients had a mean baseline pain rating of 6 on a numerical rating scale ranging from 0 (no pain) to 10 (worst possible pain). After 12 weeks of treatment, patients taking duloxetine 60 mg daily had significantly greater pain reduction compared to patients taking placebo. For various degrees of improvement in pain from baseline to study endpoint, Figures 8 and 9 show the fraction of patients in Studies CLBP-1 and CLBP-3 achieving that degree of improvement, respectively. The figures are cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%. Patients who did not complete the trial were assigned the value of 0% improvement. Figure 8: Percentage of Adult Patients with CLBP Achieving Various Levels of Pain Relief as Measured by 24-Hour Average Pain Severity (Study CLBP-1) Figure 9: Percentage of Adult Patients with CLBP Achieving Various Levels of Pain Relief as Measured by 24-Hour Average Pain Severity (Study CLBP-3) Trials in Chronic Pain Due to Osteoarthritis in Adults The efficacy of duloxetine in chronic pain due to osteoarthritis (OA) in adults was assessed in 2 double-blind, placebo-controlled, randomized clinical trials of 13-weeks duration (Study OA-1 and Study OA-2). All patients in both trials fulfilled the ACR clinical and radiographic criteria for classification of idiopathic OA of the knee. Randomization was stratified by the patients' baseline NSAIDs-use status. Patients assigned to duloxetine started treatment in both trials at a dose of 30 mg once daily for one week. After the first week, the dose of duloxetine was increased to 60 mg once daily. After 7 weeks of treatment with duloxetine 60 mg once daily, in Study OA-1 patients with sub-optimal response to treatment (<30% pain reduction) and tolerated duloxetine 60 mg once daily had their dose increased to 120 mg. However, in Study OA-2, all patients, regardless of their response to treatment after 7 weeks, were re-randomized to either continue receiving duloxetine 60 mg once daily or have their dosage increased to 120 mg once daily for the remainder of the trial. Patients in the placebo treatment groups in both trials received a matching placebo for the entire duration of trials. For both trials, efficacy analyses were conducted using 13-week data from the combined duloxetine 60 mg and 120 mg once daily treatment groups compared to the placebo group. Study OA-1: Two hundred fifty-six patients (N=128 on duloxetine, N=128 on placebo) enrolled and 204 (80%) completed the trial. Patients had a mean baseline pain rating of 6 on a numerical rating scale ranging from 0 (no pain) to 10 (worst possible pain). After 13 weeks of treatment, patients taking duloxetine had significantly greater pain reduction than patients taking placebo. Subgroup analyses did not indicate that there were differences in treatment outcomes as a function of NSAIDs use. Study OA-2: Two hundred thirty-one patients (N=111 on duloxetine, N=120 on placebo) enrolled and 173 (75%) completed the trial. Patients had a mean baseline pain of 6 on a numerical rating scale ranging from 0 (no pain) to 10 (worst possible pain). After 13 weeks of treatment, patients taking duloxetine did not show a significantly greater pain reduction than patients taking placebo. In Study OA-1, for various degrees of improvement in pain from baseline to study endpoint, Figure 10 shows the fraction of patients achieving that degree of improvement. The figure is cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%. Patients who did not complete the trial were assigned the value of 0% improvement. Figure 10: Percentage of Adult Patients with OA Achieving Various Levels of Pain Relief as Measured by 24-Hour Average Pain Severity (Study OA-1)

Advise the patient to read the FDA-approved patient labeling (Medication Guide). Suicidal Thoughts and Behaviors Advise patients, their families, and their caregivers to look for the emergence of suicidal ideation and behavior, especially during treatment and when the dose is adjusted up or down and instruct them to report such symptoms to their healthcare provider [see BOXED WARNING and Warnings and Precautions (5.1)]. Administration Advise patients to swallow duloxetine whole and to not be chew, crush, or open the capsule (do not sprinkle contents be sprinkled on food or mixed with liquids) because these actions might affect the enteric coating. Hepatotoxicity Inform patients that severe liver problems, sometimes fatal, have been reported in patients treated with duloxetine. Instruct patients to talk to their healthcare provider if they develop itching, right upper belly pain, dark urine, or yellow skin/eyes while taking duloxetine, which may be signs of liver problems. Instruct patients to talk to their healthcare provider about their alcohol consumption. Use of duloxetine with heavy alcohol intake may be associated with severe liver injury [see Warnings and Precautions (5.2)] . Alcohol Although duloxetine does not increase the impairment of mental and motor skills caused by alcohol, use of duloxetine concomitantly with heavy alcohol intake may be associated with severe liver injury. [see Warnings and Precautions (5.2) and Drug Interactions (7.15)] . Orthostatic Hypotension, Falls and Syncope Advise patients of the risk of orthostatic hypotension, falls and syncope, especially during the period of initial use and subsequent dose escalation, and in association with the use of concomitant drugs that might potentiate the orthostatic effect of duloxetine [see Warnings and Precautions (5.3)] . Serotonin Syndrome Caution patients about the risk of serotonin syndrome with the concomitant use of duloxetine and other serotonergic agents including triptans, tricyclic antidepressants, opoids, lithium, buspirone, tryptophan, amphetamines, and St. John's Wort [see Contraindications (4), Warnings and Precautions (5.4), and Drug Interactions (7.14)]. Advise patients of the signs and symptoms associated with serotonin syndrome that 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 changes (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Caution patients to seek medical care immediately if they experience these symptoms. Increased Risk of Bleeding Caution patients about the concomitant use of duloxetine and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding [see W Warnings and Precautions (5.5) and Use in Specific Populations (8.1)]. Severe Skin Reactions Caution patients that duloxetine may cause serious skin reactions. This may need to be treated in a hospital and may be life-threatening. Counsel patients to call their doctor right away or get emergency help if they have skin blisters, peeling rash, sores in their mouth, hives, or any other allergic reactions [see Warnings and Precautions (5.6)] . Discontinuation of Treatment Instruct patients that discontinuation of duloxetine may be associated with symptoms such as dizziness, headache, nausea, diarrhea, paresthesia, irritability, vomiting, insomnia, anxiety, hyperhidrosis, and fatigue, and should be advised not to alter their dosing regimen, or stop taking duloxetine without consulting their physician [see Warnings and Precautions (5.7)]. Activation of Mania or Hypomania Adequately screen patients with depressive symptoms for risk of bipolar disorder (e.g. family history of suicide, bipolar disorder, and depression) prior to initiating treatment with duloxetine. Advise patients to report any signs or symptoms of a manic reaction such as greatly increased energy, severe trouble sleeping, racing thoughts, reckless behavior, talking more or faster than usual, unusually grand ideas, and excessive happiness or irritability [see Warnings and Precautions (5.8)] . Angle-Closure Glaucoma Advise patients that taking duloxetine can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle-closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle-closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle-closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle-closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible. [See Warnings and Precautions (5.9)]. Seizures Advise patients to inform their healthcare provider if they have a history of seizure disorder [see Warnings and Precautions (5.10)] . Effects on Blood Pressure Caution patients that duloxetine may cause an increase in blood pressure [see Warnings and Precautions (5.11)] . Concomitant Medications Advise patients to inform their healthcare provider if they are taking, or plan to take, any prescription or over-the-counter medications, since there is a potential for interactions [see Dosage and Administration (2.8, 2.9), Contraindications (4), Warnings and Precautions (5.4, 5.12), and Drug Interactions (7)] . Hyponatremia Advise patients that hyponatremia has been reported as a result of treatment with SNRIs and SSRIs, including duloxetine. Advise patients of the signs and symptoms of hyponatremia [see Warnings and Precautions (5.13)]. Concomitant Illnesses Advise patients to inform their physicians about all of their medical conditions [see Warnings and Precautions (5.14)]. Urinary Hesitation and Retention Duloxetine is in a class of medicines that may affect urination. Instruct patients to consult with their healthcare provider if they develop any problems with urine flow [see Warnings and Precautions (5.15)] . Sexual Dysfunction Advise patients that use of Duloxetine may cause symptoms of sexual dysfunction in both male and female patients. Inform patients that they should discuss any changes in sexual function and potential management strategies with their healthcare provider [see Warnings and Precautions (5.16)]. Pregnancy Advise women to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with duloxetine. Advise pregnant women or patients who intend to become pregnant that duloxetine may increase the risk of neonatal complications requiring prolonged hospitalization, respiratory support, and tube feeding. Advise pregnant women that there is a risk of relapse with discontinuation of antidepressants. Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to duloxetine during pregnancy [see Use in Specific Populations (8.1)]. Lactation Advise breastfeeding women using duloxetine to monitor infants for sedation, poor feeding and poor weight gain and to seek medical care if they notice these signs [see Use in Specific Populations (8.2)]. Interference with Psychomotor Performance Duloxetine may be associated with sedation and dizziness. Therefore, caution patients about operating hazardous machinery including automobiles, until they are reasonably certain that duloxetine therapy does not affect their ability to engage in such activities. Manufactured for: Lupin Pharmaceuticals, Inc. Baltimore, Maryland 21202 United States Manufactured by: Lupin Limited Goa 403722 INDIA Revised: September 2023 ID#: 274620

Medication Guide Duloxetine ( doo-LOX-e-teen) Delayed-release Capsules Read this Medication Guide before you start taking duloxetine delayed-release capsules and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. Talk to your healthcare provider about: all risks and benefits of treatment with antidepressant medicines all treatment choices for depression or other serious mental illness What is the most important information I should know about antidepressant medicines, depression, other serious mental illnesses, and suicidal thoughts or actions? Duloxetine delayed-release capsules and other antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, or young adults within the first few months of treatment or when the dose is changed. Depression and other serious mental illnesses are the most important causes of suicidal thoughts or actions. Some people may have a particularly high risk of having suicidal thoughts or actions.These include people who have (or have a family history of) bipolar illness (also called manic-depressive illness). How can I watch for and try to prevent suicidal thoughts and actions? Pay close attention to any changes in mood, behavior, actions, thoughts, or feelings, especially sudden changes. This is very important when an antidepressant medicine is started or when the dose is changed. Call your healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings. Keep all follow-up visits with your healthcare provider as scheduled. Call your healthcare provider between visits as needed, especially if you have concerns about symptoms. Call your healthcare provider right away if you have any of the following symptoms or feelings, especially if they are new, worse, or worry you. In an emergency, call 911. attempts to commit suicide acting on dangerous impulses acting aggressive, being angry, or violent thoughts about suicide or dying new or worse depression new or worse anxiety panic attacks feeling very agitated or restless new or worse irritability trouble sleeping an extreme increase in activity or talking (mania) other unusual changes in behavior or mood What else do I need to know about antidepressant medicines? Never stop an antidepressant medicine without first talking to a healthcare provider. Stopping an antidepressant medicine suddenly can cause other symptoms. Antidepressants are medicines used to treat depression and other illnesses. It is important to discuss all the risks of treating depression and also the risks of not treating it. Patients should discuss all treatment choices with your healthcare provider, not just the use of antidepressants. Antidepressant medicines have other side effects. Talk to your healthcare provider about the side effects of the medicine prescribed for you or your family member. Antidepressant medicines can interact with other medicines. Know all of the medicines that you or your family member takes. Keep a list of all medicines to show your healthcare provider. Do not start new medicines without first checking with your healthcare provider. What is duloxetine delayed-release capsule? Duloxetine delayed-release capsule is a prescription medicine used to treat a certain type of depression called Major Depressive Disorder (MDD). Duloxetine delayed-release capsule belongs to a class of medicines known as SNRIs (or serotonin-norepinephrine reuptake inhibitors). Duloxetine delayed-release capsules are also used to treat or manage: Generalized Anxiety Disorder (GAD) Diabetic Peripheral Neuropathic Pain (DPNP) Fibromyalgia (FM) Chronic Musculoskeletal Pain Who should not take duloxetine delayed-release capsules? Do Not take duloxetine delayed-release capsules if you: take a Monoamine Oxidase Inhibitor (MAOI) . Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI, including the antibiotic linezolid or intravenous methylene blue. Do not take an MAOI within 5 days of stopping duloxetine delayed-release capsules unless directed to do so by your healthcare provider. Do not start duloxetine delayed-release capsules if you stopped taking an MAOI in the last 14 days unless directed to do so by your healthcare provider. People who take duloxetine delayed-release capsules close in time to an MAOI may have a serious problem called Serotonin Syndrome (see "What are the possible side effects of duloxetine delayed-release capsules?"). What should I tell my healthcare provider before taking duloxetine delayed-release capsules? Before starting duloxetine delayed-release capsules, tell your healthcare provider if you: have heart problems or high blood pressure have diabetes (duloxetine delayed-release capsules treatment makes it harder for some people with diabetes to control their blood sugar) have liver problems have kidney problems have glaucoma have or had seizures or convulsions have bipolar disorder or mania have low sodium levels in your blood have delayed stomach emptying have or had bleeding problems are pregnant or plan to become pregnant. Duloxetine delayed-release capsules may harm your unborn baby. Talk to your healthcare provider about the risk to your unborn baby if you take duloxetine delayed-release capsules during pregnancy. Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with duloxetine delayed-release capsules. There is a pregnancy registry for females who are exposed to duloxetine delayed release capsules during pregnancy. The purpose of the registry is to collect information about the health of females exposed to duloxetine delayed-release capsules and their baby. If you become pregnant during treatment with duloxetine delayed-release capsules, talk to your healthcare provider about registering with the National Pregnancy Registry for Antidepressants at 1-866-961-2388 or visit online at https://womensmentalhealth.org/research/pregnancyregistry/.$$$EndUnOrderedlist are breastfeeding or plan to breastfeed. Duloxetine passes into your breast milk and may harm your baby. Talk to your healthcare provider about the best way to feed your baby while taking duloxetine delayed-release capsules. Tell your healthcare provider about all the medicines that you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Duloxetine delayed-release capsules and some medicines may interact with each other, may not work as well, or may cause serious side effects. Especially tell your healthcare provider if you take: triptans used to treat migraine headache medicines used to treat mood, anxiety, psychotic or thought disorders, including tricyclics, lithium, buspirone, SSRIs, SNRIs or MAOIs tramadol, fentanyl, meperidine, methadone, or other opoids amphetamines cimetidine the antibiotics ciprofloxacin, enoxacin medicine to treat irregular heart rate (like propafenone, flecainide, quinidine) theophylline the blood thinner warfarin (Coumadin, Jantoven) non-steroidal anti-inflammatory drug (NSAID)(like ibuprofen, naproxen or aspirin). over-the-counter supplements such as tryptophan or St. John's Wort thioridazine (Mellaril). Mellaril together with duloxetine delayed-release capsules can cause serious heart rhythm problems or sudden death. Ask your healthcare provider for a list of these medicines if you are not sure. Do not take duloxetine delayed-release capsules with any other medicine that contain duloxetine. How should I take duloxetine delayed-release capsules? Take duloxetine delayed-release capsules exactly as your healthcare provider tells you to take it. Your healthcare provider may need to change the dose of duloxetine delayed-release capsules until it is the right dose for you. Swallow duloxetine delayed-release capsules whole. Do not chew or crush duloxetine delayed-release capsules. Do not open the capsule and sprinkle on food or mix with liquids. Opening the capsule may affect how well duloxetine delayed-release capsules works. Duloxetine delayed-release capsules may be taken with or without food. If you miss a dose of duloxetine delayed-release capsules, take the missed dose as soon as you remember. If it is almost time for the next dose, skip the missed dose and take your next dose at the regular time. Do not take two doses of duloxetine delayed-release capsules at the same time. If you take too much duloxetine delayed-release capsules, call your healthcare provider or poison control center at 1-800-222-1222 right away, or get emergency treatment. When switching from another antidepressant to duloxetine delayed-release capsules your healthcare provider may want to lower the dose of the initial antidepressant first to potentially avoid side effects. What should I avoid while taking duloxetine delayed-release capsules? Duloxetine delayed-release capsules can cause sleepiness or may affect your ability to make decisions, think clearly, or react quickly. You should not drive, operate heavy machinery, or do other dangerous activities until you know how duloxetine delayed-release capsules affects you. Use of duloxetine delayed-release capsules concomitantly with heavy alcohol intake may be associated with severe liver injury. Avoid heavy alcohol use while taking duloxetine delayed-release capsules. What are the possible side effects of duloxetine delayed-release capsules? Duloxetine delayed-release capsules may cause serious side effects, including: See "What is the most important information I should know about duloxetine delayed-release capsules?" Common possible side effects in people who take duloxetine delayed-release capsules include: 1. liver damage. Symptoms may include: itching right upper abdominal pain dark urine yellow skin or eyes enlarged liver increased liver enzymes 2. changes in blood pressure and falls. Monitor your blood pressure before starting and throughout treatment. Duloxetine delayed-release capsules may: increase your blood pressure. decrease your blood pressure when standing and cause dizziness or fainting, mostly when first starting duloxetine delayed-release capsules or when increasing the dose. increase risk of falls, especially in elderly. 3. Serotonin Syndrome: This condition can be life-threatening and symptoms may include: agitation, hallucinations, coma or other changes in mental status coordination problems or muscle twitching (overactive reflexes) racing heartbeat, high or low blood pressure sweating or fever nausea, vomiting, or diarrhea muscle rigidity dizziness flushing tremor seizures 4. abnormal bleeding: Duloxetine delayed-release capsules and other antidepressant medicines may increase your risk of bleeding or bruising, especially if you take the blood thinner warfarin (Coumadin, Jantoven), a non-steroidal anti-inflammatory drug (NSAIDs, like ibuprofen or naproxen), or aspirin. 5. severe skin reactions: Duloxetine delayed-release capsules may cause serious skin reactions that may require stopping its use. This may need to be treated in a hospital and may be life-threatening. Call your healthcare provider right away or get emergency help if you have skin blisters, peeling rash, sores in the mouth, hives or any other allergic reactions. 6. discontinuation symptoms: Do not stop duloxetine delayed-release capsules without first talking to your healthcare provider. Stopping duloxetine delayed-release capsules too quickly or changing from another antidepressant too quickly may result in serious symptoms including: anxiety irritability feeling tired or problems sleeping headache sweating dizziness electric shock-like sensations vomiting or nausea diarrhea 7. manic episodes: greatly increased energy severe trouble sleeping racing thoughts reckless behavior unusually grand ideas excessive happiness or irritability talking more or faster than usual 8. visual problems: eye pain changes in vision swelling or redness in or around the eye Only some people are at risk for these problems. You may want to undergo an eye examination to see if you are at risk and receive preventative treatment if you are. 9. seizures or convulsions 10. low salt (sodium) levels in the blood. Elderly people may be at greater risk for this. Symptoms may include: headache weakness or feeling unsteady confusion, problems concentrating or thinking or memory problems 11. problems with urination. Symptoms may include: decreased urine flow unable to pass any urine 12. sexual problems (dysfunction): Taking serotonin and norepinephrine reuptake inhibitors(SNRIs), including duloxetine delayed release capsules, may cause sexual problems. Symptoms in males may include: delayed ejaculation or inability to have an ejaculation decreased sex drive problems getting or keeping an erection Symptoms in females may include: decreased sex drive delayed orgasm or inability to have an orgasm. Talk to your healthcare provider if you develop any changes in your sexual function or if you have any questions or concerns about sexual problems during treatment with duloxetine delayed release capsules. There may be treatments your healthcare provider can suggest. The most common side effects of duloxetine delayed-release capsules include: nausea dry mouth sleepiness fatigue constipation loss of appetite increased sweating dizziness Common possible side effects in children and adolescents who take duloxetine delayed-release capsules include: nausea decreased weight dizziness Side effects in adults may also occur in children and adolescents who take duloxetine delayed release capsules. Children and adolescents should have height and weight monitored during treatment. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of duloxetine delayed-release capsules. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to 1-800-FDA-1088. How should I store duloxetine delayed-release capsules? Store duloxetine delayed-release capsules at room temperature between 68 F to 77 F (20 C to 25 C). Keep duloxetine delayed-release capsules and all medicines out of the reach of children. General information about the safe and effective use of duloxetine delayed-release capsules. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use duloxetine delayed-release capsules for a condition for which it was not prescribed. Do not give duloxetine delayed-release capsules to other people, even if they have the same symptoms that you have. It may harm them. This Medication Guide summarizes the most important information about duloxetine delayed-release capsules. If you would like more information, talk with your healthcare provider. You may ask your healthcare provider or pharmacist for information about duloxetine delayed-release capsules that is written for healthcare professionals. For more information about duloxetine delayed-release capsules, call 1-800-399-2561 or go to www.lupinpharmaceuticals.com. What are the ingredients in duloxetine delayed-release capsules? Active ingredient: duloxetine hydrochloride Inactive ingredients: Ammonia solution, black iron oxide, croscarmellose sodium, FD & C Blue 2, gelatin, hypromellose, hypromellose phthalate, lactose monohydrate, magnesium stearate, polysorbate 80, potassium hydroxide, pregelatinized starch, propylene glycol, shellac, sodium lauryl sulphate, talc, titanium dioxide and triethyl citrate. The 20 and 60 mg capsules also contain iron oxide yellow. This Medication Guide has been approved by the U.S. Food and Drug Administration. * The brands listed are trademarks of their respective owners and are not trademarks of Lupin Pharmaceuticals, Inc. The makers of these brands are not affiliated with and do not endorse Lupin Pharmaceuticals, Inc. or its products. Manufactured for: Lupin Pharmaceuticals, Inc. Baltimore, Maryland 21202 United States Manufactured by: Lupin Limited Goa 403722 INDIA Revised: September 2023 ID#: 274622

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