Duloxetine

1 INDICATIONS AND USAGE Duloxetine delayed-release capsules are indicated for the treatment of: Major depressive disorder in adults Generalized anxiety disorder in adults and pediatric patients 7 years of age and older Diabetic peripheral neuropathic pain in adults Fibromyalgia in adults Chronic musculoskeletal pain in adults Duloxetine delayed-release capsules are a serotonin and norepinephrine reuptake inhibitor (SNRI) indicated for the treatment of the following conditions: Major depressive disorder (MDD) in adults (1) Generalized anxiety disorder (GAD) in adults and pediatric patients 7 years of age and older (1) Diabetic peripheral neuropathic pain (DPNP) in adults (1) Fibromyalgia (FM) in adults Chronic musculoskeletal pain in adults (1)

2 DOSAGE AND ADMINISTRATION Take duloxetine delayed-release capsules once daily, with or without food. Swallow whole; do not crush, chew, or open capsule (2.1) Indication Starting Dose Target Dose Maximum Dose MDD (2.2) 40 mg/day to 60 mg/day Acute Treatment: 40 mg/day (20 mg twice daily) to 60 mg/day (once daily or as 30 mg twice daily); Maintenance Treatment: 60 mg/day 120 mg/day GAD (2.3) Adults Geriatric Pediatrics (7 to 17 years of age) 60 mg/day 30 mg/day 30 mg/day 60 mg/day (once daily) 60 mg/day (once daily) 30 to 60 mg/day (once daily) 120 mg/day 120 mg/day 120 mg/day DPNP (2.4) 60 mg/day 60 mg/day (once daily) 60 mg/day FM (2.5) Adults 30 mg/day 60 mg/day (once daily) 60 mg/day Chronic Musculoskeletal Pain (2.6) 30 mg/day 60 mg/day (once daily) 60 mg/day • Discontinuing duloxetine delayed-release capsules: Gradually reduce dosage to avoid discontinuation symptoms (2.8, 5.7) 2.1 Important Administration Instructions Administer duloxetine delayed-release capsule orally (with or without meals) and swallow whole. Do not chew or crush, and do not open the delayed-release capsule and sprinkle its contents on food or mix with liquids because these actions might affect the enteric coating. If a dose of duloxetine delayed-release capsule is missed, take the missed dose as soon as it is remembered. If it is almost time for the next dose, skip the missed dose and take the next dose at the regular time. Do not take two doses of duloxetine delayed-release capsule at the same time. 2.2 Dosage for Treatment of Major Depressive Disorder in Adults The recommended starting dosage in adults with MDD is 40 mg/day (given as 20 mg twice daily) to 60 mg/day (given either once daily or as 30 mg twice daily). For some patients, it may be desirable to start at 30 mg once daily for 1 week, to allow patients to adjust to duloxetine delayed-release capsules before increasing to 60 mg once daily. While a 120 mg/day dose was shown to be effective, there is no evidence that doses greater than 60 mg/day confer any additional benefits. Periodically reassess to determine the need for maintenance treatment and the appropriate dosage for such treatment. 2.3 Dosage for Treatment of Generalized Anxiety Disorder Recommended Dosage in Adults Less than 65 Years of Age For most adults less than 65 years of age with GAD, initiate duloxetine delayed-release capsules 60 mg once daily. For some patients, it may be desirable to start at 30 mg once daily for 1 week, to allow patients to adjust to duloxetine delayed-release capsules before increasing to 60 mg once daily. While a 120 mg once daily dosage was shown to be effective, there is no evidence that doses greater than 60 mg/day confer additional benefit. Nevertheless, if a decision is made to increase the dosage beyond 60 mg once daily, increase dosage in increments of 30 mg once daily. Periodically reassess to determine the continued need for maintenance treatment and the appropriate dosage for such treatment. Recommended Dosage in Geriatric Patients In geriatric patients with GAD, initiate duloxetine delayed-release capsules at a dosage 30 mg once daily for 2 weeks before considering an increase to the target dose of 60 mg/day. Thereafter, patients may benefit from doses above 60 mg once daily. If a decision is made to increase the dose beyond 60 mg once daily, increase dose in increments of 30 mg once daily. The maximum dose studied was 120 mg per day. Recommended Dosage in Pediatric Patients 7 to 17 Years of Age Initiate duloxetine delayed-release capsules in pediatric patients 7 to 17 years of age with GAD at a dosage of30 mg once daily for 2 weeks before considering an increase to 60 mg once daily. The recommended dosage range is 30 to 60 mg once daily. Some patients may benefit from dosages above 60 mg once daily. If a decision is made to increase the dose beyond 60 mg once daily, increase dosage in increments of 30 mg once daily. The maximum dose studied was 120 mg per day. 2.4 Dosage for Treatment of Diabetic Peripheral Neuropathic Pain in Adults Administer 60 mg once daily in adults with diabetic peripheral neuropathic pain. There is no evidence that doses higher than 60 mg once daily confer additional significant benefit and the higher dosage is clearly less well tolerated. For patients for whom tolerability is a concern, a lower starting dose may be considered. Since diabetes is frequently complicated by renal disease, consider a lower starting dosage and gradual increase in dosage for patients with renal impairment [see Dosage and Administration (2.7) and Use in Specific Populations (8.10)] . 2.5 Dosage for Treatment of Fibromyalgia Recommended Dosage in Adults The recommended duloxetine delayed-release capsules dosage is 60 mg once daily in adults with fibromyalgia. Begin treatment at 30 mg once daily for 1 week, to allow patients to adjust to duloxetine delayed-release capsulesbefore increasing to 60 mg once daily. Some patients may respond to the starting dosage. There is no evidence that dosages greater than 60 mg/day confer additional benefit, even in patients who do not respond to a 60 mg/day dosage, and higher dosages were associated with a higher rate of adverse reactions. 2.6 Dosage for Treatment of Chronic Musculoskeletal Pain in Adults The recommended duloxetine delayed-release capsules dosage is 60 mg once daily in adults with chronic musculoskeletal pain. Begin treatment at 30 mg once daily for one week, to allow patients to adjust to duloxetine delayed-release capsules before increasing to 60 mg once daily. There is no evidence that higher dosages confer additional benefit, even in patients who do not respond to a 60 mg once daily dose dosage, and higher dosages are associated with a higher rate of adverse reactions [see Clinical Studies (14.6)] . 2.7 Dosage in Patients with Hepatic Impairment or Severe Renal impairment Avoid use in patients with chronic liver disease or cirrhosis [see Warnings and Precautions (5.14) and Use in Specific Populations (8.9)] . Avoid use in patients with severe renal impairment, GFR <30 mL/minute [see Warnings and Precautions (5.14) and Use in Specific Populations (8.10)] . 2.8 Discontinuing Duloxetine Delayed-Release Capsules Adverse reactions after discontinuation of duloxetine delayed-release capsules, after abrupt or tapered discontinuation, include: dizziness, headache, nausea, diarrhea, paresthesia, irritability, vomiting, insomnia, anxiety, hyperhidrosis, and fatigue. A gradual reduction in the dosage rather than abrupt cessation is recommended whenever possible [see Warnings and Precautions (5.7)] . 2.9 Switching Patients to or from a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with duloxetine delayed-release capsules. Conversely, at least 5 days should be allowed after stopping duloxetine delayed-release capsules before starting an MAOI intended to treat psychiatric disorders [see Contraindications (4)] . 2.10 Use of Duloxetine Delayed-Release Capsules with Other MAOIs such as Linezolid or Methylene Blue Do not start duloxetine delayed-release capsule in a patient who is being treated with linezolid or intravenous methylene blue because there is an increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered [see Contraindications (4)]. In some cases, a patient already receiving duloxetine delayed-release capsule therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, duloxetine delayed-release capsule should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for 5 days or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with duloxetine delayed-release capsules may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue [see Warnings and Precautions (5.4)]. The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with duloxetine delayed-release capsule is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use [see Warnings and Precautions (5.4)] .

6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in the labeling: Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults [see Boxed Warning and Warnings and Precautions (5.1)] Hepatotoxicity [see Warnings and Precautions (5.2)] Orthostatic Hypotension, Falls and Syncope [see Warnings and Precautions (5.3)] Serotonin Syndrome [see Warnings and Precautions (5.4)] Increased Risk of Bleeding [see Warnings and Precautions (5.5)] Severe Skin Reactions [see Warnings and Precautions (5.6)] Discontinuation Syndrome [see Warnings and Precautions (5.7)] Activation of Mania/Hypomania [see Warnings and Precautions (5.8)] Angle-Closure Glaucoma [see Warnings and Precautions (5.9)] Seizures [see Warnings and Precautions (5.10)] Increases in Blood Pressure [see Warnings and Precautions (5.11)] Clinically Important Drug Interactions [see Warnings and Precautions (5.12)] Hyponatremia [see Warnings and Precautions (5.13)] Urinary Hesitation and Retention [see Warnings and Precautions (5.15)] Most common adverse reactions (≥5% and at least twice the incidence of placebo-treated patients): (6.1) Adults : nausea, dry mouth, somnolence, constipation, decreased appetite, and hyperhidrosis Pediatric Patients : decreased weight, decreased appetite, nausea, vomiting, fatigue, and diarrhea To report SUSPECTED ADVERSE REACTIONS, contact FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The stated frequencies of adverse reactions represent the proportion of patients who experienced, at least once, one treatment-emergent adverse reaction of the type listed. A reaction was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. Adverse Reactions in Adults Adult Clinical Trial Database The data described below reflect exposure to duloxetine delayed-release capsules in placebo-controlled adult trials for MDD (N=3,779), GAD (N=1,018), OA (N=503), CLBP (N=600), DPNP (N=906), and FM (N=1,294). 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 delayed-release capsules 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 delayed-release capsules 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% (319/3,779) of duloxetine delayed-release capsules-treated patients in placebo-controlled adult trials for MDD discontinued treatment due to an adverse reaction, compared with 4.6% (117/2,536) of placebo-treated patients. Nausea (duloxetine delayed-release capsules 1.1%, placebo 0.4%) was the only adverse reaction reported as a reason for discontinuation and considered to be drug-related (i.e., discontinuation occurring in at least 1% of the duloxetine delayed-release capsules-treated patients and at a rate of at least twice that of placebo-treated patients). Generalized Anxiety Disorder Approximately 13.7% (139/1,018)of the duloxetine delayed-release capsules-treated patients in placebo-controlled adult trials for GAD discontinued treatment due to an adverse reaction, compared with 5% (38/767) for placebo-treated patients. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine delayed-release capsules 3.3%, placebo 0.4%) and dizziness (duloxetine delayed-release capsules 1.3%, placebo 0.4%). Diabetic Peripheral Neuropathic Pain Approximately 12.9% (117/906) of the duloxetine delayed-release capsules-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 delayed-release capsules 3.5%, placebo 0.7%), dizziness (duloxetine delayed-release capsules 1.2%, placebo 0.4%), and somnolence (duloxetine delayed-release capsules 1.1%, placebo 0%). Fibromyalgia Approximately 17.5% (227/1294) of the duloxetine delayed-release capsules-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 delayed-release capsules 2%, placebo 0.5%), headache (duloxetine delayed-release capsules 1.2%, placebo 0.3%), somnolence (duloxetine delayed-release capsules 1.1%, placebo 0%), and fatigue (duloxetine delayed-release capsules 1.1%, placebo 0.1%). Chronic Pain due to Osteoarthritis Approximately 15.7% (79/503) of the duloxetine delayed-release capsules-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 delayed-release capsules 2.2%, placebo 1%). Chronic Low Back Pain Approximately 16.5% (99/600) of the duloxetine delayed-release capsules-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 delayed-release capsules 3%, placebo 0.7%), and somnolence (duloxetine delayed-release capsules 1%, placebo 0%). Most Common Adverse Reactions in Adult Trials The most commonly observed adverse reactions in duloxetine delayed-release capsules-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 delayed-release capsules-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 delayed-release capsules-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 Populations a Adverse Reaction Percentage of Patients Reporting Reaction Duloxetine delayed-release capsules (N= 8,100 ) Placebo (N= 5,655 ) Nausea c 23 8 Headache 14 12 Dry mouth 13 5 Somnolence e 10 3 Fatigue b,c 9 5 Insomnia d 9 5 Constipation c 9 4 Dizziness c 9 5 Diarrhea 9 6 Decreased appetite c 7 2 Hyperhidrosis c 6 1 Abdominal pain f 5 4 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. b Also includes asthenia. c Events for which there was a significant dose-dependent relationship in fixed-dose studies, excluding three MDD studies which did not have a placebo lead-in period or dose titration. d Also includes initial insomnia,middle insomnia, and early morning awakening. e Also includes hypersomnia and sedation. f Also includes abdominal discomfort, abdominal pain lower, abdominal pain upper, abdominal tenderness, and gastrointestinal pain. Adverse 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 delayed-release capsules-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 Adults a,b System Organ Class / Adverse Reaction Percentage of Patients Reporting Reaction Duloxetine delayed-release capsules (N= 4,797 ) Placebo (N= 3,303 ) Cardiac Disorders Palpitations 2 1 Eye Disorders Vision blurred 3 1 Gastrointestinal Disorders Nausea c Dry mouth Constipation c Diarrhea Abdominal pain d Vomiting 23 14 9 9 5 4 8 6 4 6 4 2 General Disorders and Administration Site Conditions Fatigue e 9 5 Metabolism and Nutrition Disorders Decreased appetite c 6 2 Nervous System Disorders Headache Dizziness c Somnolence f Tremor 14 9 9 3 14 5 3 1 Psychiatric Disorders Insomnia g Agitation h Anxiety 9 4 3 5 2 2 Reproductive System and Breast Disorders Erectile dysfunction Ejaculation delayed c Libido decreased i Orgasmabnormal j 4 2 3 2 1 1 1 <1 Respiratory, Thoracic, and Mediastinal Disorders Yawning 2 <1 Skin and Subcutaneous Tissue Disorders Hyperhidrosis 6 2 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 significantlydifferentbetweentreatments 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 psychomotorhyperactivity. i Includes loss of libido. j Includes anorgasmia. 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 delayed-release capsules 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 Trials a System Organ Class / Adverse Reaction Percentage of Patients Reporting Reaction Duloxetine delayed-release capsules (N= 3,303) Placebo (N= 2,352) Gastrointestinal Disorders Nausea Dry Mouth b Constipation b Diarrhea Abdominal Pain c Vomiting Dyspepsia 23 11 10 9 5 3 2 7 3 3 5 4 2 1 General Disorders and Administration Site Conditions Fatigue d 11 5 Infections and Infestations Nasopharyngitis Upper Respiratory Tract Infection Influenza 4 3 2 4 3 2 Metabolism and Nutrition Disorders Decreased Appetite b 8 1 Musculoskeletal and Connective Tissue Musculoskeletal Pain e Muscle Spasms 3 2 3 2 Nervous System Disorders Headache Somnolence b, f Dizziness Paraesthesia g Tremor b 13 11 9 2 2 8 3 5 2 <1 Psychiatric Disorders Insomnia b, h Agitation i 10 3 5 1 Reproductive System and Breast Disorders Erectile Dysfunction b Ejaculation Disorder j 4 2 <1 <1 Respiratory, Thoracic and Mediastinal Disorders Cough 2 2 Skin and Subcutaneous Tissue Disorders Hyperhidrosis 6 1 Vascular Disorders Flushing k Blood pressure increased l 3 2 1 1 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 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 hypoaesthesiaand 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. Effects on Male and Female Sexual Function in Adults with MDD Changes in sexual desire, sexual performance and sexual satisfaction often occur as manifestations of psychiatric disorders or diabetes, but they may also be a consequence of pharmacologic treatment. Because adverse sexual reactions are presumed to be voluntarily underreported, the Arizona Sexual Experience Scale (ASEX), a validated measure designed to identify sexual adverse reactions, was used prospectively in 4 MDD placebo-controlled adult trials (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 delayed-release capsules-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 delayed-release capsules-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 delayed-release capsules-treated patients. Table 5: Mean Change in ASEX Scores by Gender in MDD Placebo-Controlled Adult Trials Male Patients a Female Patients a Duloxetine delayed-release capsules (n=175) Placebo (n=83) Duloxetine delayed-release capsules (n=241) Placebo (n=126) ASEX Total (Items 1 to 5) 0.56 b -1.07 -1.15 -1.07 Item 1 - Sex drive -0.07 -0.12 -0.32 -0.24 Item 2 - Arousal 0.01 -0.26 -0.21 -0.18 Item 3 - Ability to achieve erection (men); Lubrication (women) 0.03 -0.25 -0.17 -0.18 Item 4 - Ease of reaching orgasm 0.4 c -0.24 -0.09 -0.13 Item 5 - Orgasm satisfaction 0.09 -0.13 -0.11 -0.17 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. Vital Sign Changes in Adults In placebo-controlled clinical trials across approved adult populations for change from baseline to endpoint, duloxetine delayed-release capsules-treated patients had mean increases of 0.23 mm Hg in systolic blood pressure (SBP) and 0.73 mm Hg in diastolic blood pressure (DBP) compared to mean decreases of 1.09 mm Hg in SBP and 0.55 mm Hg in DBP in placebo-treated patients. There was no significant difference in the frequency of sustained (3 consecutive visits) elevated blood pressure [see Warnings and Precautions (5.3, 5.11)] . Duloxetine delayed-release capsules treatment, for up to 26 weeks in placebo-controlled trials across approved adult populations, typically caused a small increase in heart rate for change from baseline to endpoint compared to placebo of up to 1.37 beats per minute (increase of 1.2 beats per minute in duloxetine delayed-release capsules-treated patients, decrease of 0.17 beats per minute in placebo-treated patients). Laboratory Changes in Adults Duloxetine delayed-release capsules treatment in placebo-controlled clinical trials across approved adult populations, was associated with small mean increases from baseline to endpoint in ALT, AST, CPK, and alkaline phosphatase; infrequent, modest, transient, abnormal values were observed for these analytes in duloxetine delayed-release capsules-treated patients when compared with placebo-treated patients [see Warnings and Precautions (5.2)] . High bicarbonate, cholesterol, and abnormal (high or low) potassium, were observed more frequently in duloxetine delayed-release capsules-treated patients compared to placebo-treated patients. Other Adverse Reactions Observed During the Clinical Trial Evaluation of Duloxetine Delayed-Release Capsules in Adults Following is a list of adverse reactions reported by patients treated with duloxetine delayed-release capsules in clinical adult trials. In clinical trials of all approved adult populations, 34,756 patients were treated with duloxetine delayed-release capsules. Of these, 27% (9,337) took duloxetine delayed-release capsules for at least 6 months, and 12% (4,317) took duloxetine delayed-release capsules for at least one year. The following listing is not intended to include reactions (1) already listed in previous tables or elsewhere in labeling, (2) for which a drug cause was remote, (3) which were so general as to be uninformative, (4) which were not considered to have significant clinical implications, or (5) which occurred at a rate equal to or less than placebo. Reactions are categorized by body system according to the following definitions: frequent adverse reactions are those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1,000 patients; rare reactions are those occurring in fewer than 1/1,000 patients. Cardiac Disorders - Frequent: palpitations; Infrequent: myocardial infarction, tachycardia, and Takotsubo cardiomyopathy. Ear and Labyrinth Disorders - Frequent: vertigo; Infrequent: ear pain and tinnitus. Endocrine Disorders - Infrequent: hypothyroidism. Eye Disorders - Frequent: vision blurred; Infrequent: diplopia, dry eye,and visual impairment. Gastrointestinal Disorders - Frequent: flatulence; Infrequent: dysphagia,eructation, gastritis, gastrointestinal hemorrhage,halitosis, and stomatitis; Rare: gastric ulcer. General Disorders and Administration Site Conditions - Frequent: chills/rigors; Infrequent: falls,feeling abnormal, feeling hot and/or cold, malaise, and thirst; Rare: gait disturbance. Infections and Infestations - Infrequent: gastroenteritis and laryngitis. Investigations - Frequent: weight increased, weight decreased; Infrequent: blood cholesterol increased. Metabolism and Nutrition Disorders - Infrequent: dehydration and hyperlipidemia; Rare: dyslipidemia. Musculoskeletal and Connective Tissue Disorders - Frequent: musculoskeletal pain; Infrequent: muscle tightness and muscle twitching. Nervous System Disorders - Frequent: dysgeusia, lethargy, and paraesthesia/hypoesthesia; Infrequent: disturbance in attention, dyskinesia, myoclonus, and poor quality sleep; Rare: dysarthria. Psychiatric Disorders - Frequent: abnormal dreams and sleep disorder; Infrequent: apathy, bruxism, disorientation/confusional state, irritability, mood swings, and suicide attempt; Rare: completed suicide. Renal and Urinary Disorders - Frequent : urinary frequency; Infrequent: dysuria, micturition urgency, nocturia, polyuria, and urine odor abnormal. Reproductive System and Breast Disorders - Frequent: anorgasmia/orgasm abnormal; Infrequent: menopausal symptoms, sexual dysfunction, and testicular pain; Rare: menstrual disorder. Respiratory, Thoracic and Mediastinal Disorders - Frequent: yawning, oropharyngeal pain; Infrequent: throat tightness. Skin and Subcutaneous Tissue Disorders - Frequent: pruritus; Infrequent: cold sweat, dermatitis contact, erythema, increased tendency to bruise, night sweats, and photosensitivity reaction; Rare: ecchymosis. Vascular Disorders - Frequent: hot flush; Infrequent: flushing, orthostatic hypotension, and peripheral coldness. Adverse Reactions Observed in Placebo-Controlled Clinical Trials in Pediatric Patients Pediatric Clinical Trial Database The data described below reflect exposure to duloxetine delayed-release capsules (N=567) in pediatric patients aged 7 to 18 years of age from two 10-week, placebo-controlled trials in patients with MDD (N=341) (Studies MDD-6 and MDD-7), one 10-week placebo-controlled trial in GAD (N=135) (Study GAD-6), and a 13-week trial in fibromyalgia (N=91). Duloxetine delayed-release capsules are not approved for the treatment of MDD in pediatric patients [see Use in Specific Populations (8.4)] . Of the duloxetine delayed-release capsules-treated patients in these studies, 36% were 7 to 11 years of age (64% were between 12 to 18 years old), 55% were female, and 69% were Caucasian. Patients received 30 to 120 mg of duloxetine delayed-release capsules per day during placebo-controlled acute treatment studies. In the pediatric MDD, GAD, and fibromyalgia trials up to 40 weeks long, there were 988 duloxetine delayed-release capsules-treated pediatric patients aged 7 to 17 years of age (most patients received 30 to 120 mg per day) – 35% were 7 to 11 years of age (65% were 12 to 17 years old) and 56% were female. Most Common Adverse Reactions in Pediatric Trials The most common adverse reactions (≥5% in duloxetine delayed-release capsules-treated patients and at least twice the incidence of placebo-treated patients) in all pooled pediatric populations (MDD, GAD, and fibromyalgia) 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 delayed-release capsules and with an incidence greater than patients treated with placebo. Duloxetine delayed-release capsulesare 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 GAD a System Organ Class / Adverse Reaction Percentage of Pediatric Patients Reporting Reaction Duloxetine delayed-release capsules (N=476) Placebo (N=362) Gastrointestinal Disorders Nausea Abdominal Pain b Vomiting Diarrhea Dry Mouth 18 13 9 6 2 8 10 4 3 1 General Disorders and Administration Site Conditions Fatigue c 7 5 Investigations Decreased Weight d 14 6 Metabolism and Nutrition Disorders Decreased Appetite 10 5 Nervous System Disorders Headache Somnolence e Dizziness 18 11 8 13 6 4 Psychiatric Disorders Insomnia f 7 4 Respiratory, Thoracic, and Mediastinal Disorders Oropharyngeal Pain Cough 4 3 2 1 a Duloxetine delayed-release capsules are not approved for the treatment of pediatric MDD [see Use in Specific Populations (8.4)] . The inclusion of an event in the table is determined based on the percentages before rounding; however, the percentages displayed in the table are rounded to the nearest integer. b Also includes abdominal pain upper, abdominal pain lower, abdominal tenderness, abdominal discomfort, and gastrointestinal pain. c Also includes asthenia. d Frequency based on weight measurement meeting potentially clinically significant threshold of ≥3.5% weight loss (N=467 duloxetine delayed-release capsules; N=354 Placebo). e Also includes hypersomnia and sedation. f Also includes initial insomnia, insomnia, middle insomnia, and terminal insomnia. Other adverse reactions that occurred at an incidence of less than 2% and were reported by more duloxetine delayed-release capsules-treated patients than placebo-treated patients in pediatric MDD and GAD clinical trials included: abnormal dreams (including nightmare), anxiety, flushing (including hot flush), hyperhidrosis, palpitations, pulse increased, and tremor (duloxetine delayed-release capsules is not approved to treat pediatric patients with MDD). The most commonly reported symptoms following discontinuation of duloxetine delayed-release capsules in pediatric MDD and GAD clinical trials included headache, dizziness, insomnia, and abdominal pain [see Warnings and Precautions (5.7)] . Growth (Height and Weight) in Pediatric Patients 7 to 17 Years Old with GAD and MDD Decreased appetite and weight loss have been observed in association with the use of SSRIs and SNRIs. Duloxetine delayed-release capsules-treated pediatric patients in clinical trials experienced a 0.1 kg mean decrease in weight at 10 weeks, compared with a mean weight gain of approximately 0.9 kg in placebo-treated pediatric patients. The proportion of patients who experienced a clinically significant decrease in weight (≥3.5%) was greater in the duloxetine delayed-release capsules group than in the placebo group (16% and 6%, respectively). Subsequently, over the 4- to 6-month uncontrolled extension periods, duloxetine delayed-release capsules-treated patients on average trended toward recovery to their expected baseline weight percentile based on population data from age- and sex-matched peers. In studies up to 9 months, duloxetine delayed-release capsules-treated pediatric patients experienced an increase in height of 1.7 cm on average (2.2 cm increase in patients 7 to 11 years of age and 1.3 cm increase in patients 12 to 17 years of age). While height increase was observed during these studies, a mean decrease of 1% in height percentile was observed (decrease of 2% in patients 7 to 11 years of age and increase of 0.3% in patients 12 to 17 years of age). Weight and height should be monitored regularly in pediatric patients treated with duloxetine delayed-release capsules [see Use in Specific Populations (8.4)]. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of duloxetine delayed-release capsules. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Adverse reactions reported since market introduction that were temporally related to duloxetine therapy and not mentioned elsewhere in labeling include: acute pancreatitis, anaphylactic reaction, aggression and anger (particularly early in treatment or after treatment discontinuation), angioneurotic edema, angle-closure glaucoma, colitis (microscopic or unspecified), cutaneous vasculitis (sometimes associated with systemic involvement), extrapyramidal disorder, galactorrhea, gynecological bleeding, hallucinations, hyperglycemia, hyperprolactinemia, hypersensitivity, hypertensive crisis, muscle spasm, rash, restless legs syndrome, seizures upon treatment discontinuation, supraventricular arrhythmia, tinnitus (upon treatment discontinuation), trismus, and urticaria.

12.3 Pharmacokinetics 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 delayed-release capsules administration, duloxetine hydrochloride is well absorbed. There is a median 2 hour lag until absorption begins (T lag ), with maximal plasma concentrations (C max ) 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 C max 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 α 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 14 C-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 agewere mostly within the concentration range observed in adult patients and did not exceed the concentration range in adults.