1.

INDICATIONS AND USAGE Duloxetine Delayed-release Capsules is a serotonin and norepinephrine reuptake inhibitor (SNRI) indicated for: • Major Depressive Disorder (MDD) ( 1.1 ) • Generalized Anxiety Disorder (GAD) ( 1.2 ) • Diabetic Peripheral Neuropathic Pain (DPNP) ( 1.3 ) • Chronic Musculoskeletal Pain ( 1.5 ) 1.1 Major Depressive Disorder Duloxetine Delayed-release Capsules are indicated for the treatment of major depressive disorder (MDD).

The efficacy of Duloxetine Delayed-release Capsules was established in four short-term and one maintenance trial in adults [see Clinical Studies (14.1) ] .

A major depressive episode (DSM-IV) implies a prominent and relatively persistent (nearly every day for at least 2 weeks) depressed or dysphoric mood that usually interferes with daily functioning, and includes at least 5 of the following 9 symptoms: depressed mood, loss of interest in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, or a suicide attempt or suicidal ideation.

1.2 Generalized Anxiety Disorder Duloxetine Delayed-release Capsules are indicated for the treatment of generalized anxiety disorder (GAD).

The efficacy of Duloxetine Delayed-release Capsules was established in three short-term trials and one maintenance trial in adults [see Clinical Studies (14.2) ] .

Generalized anxiety disorder is defined by the DSM-IV as excessive anxiety and worry, present more days than not, for at least 6 months.

The excessive anxiety and worry must be difficult to control and must cause significant distress or impairment in normal functioning.

It must be associated with at least 3 of the following 6 symptoms: restlessness or feeling keyed up or on edge, being easily fatigued, difficulty concentrating or mind going blank, irritability, muscle tension, and/or sleep disturbance.

1.3 Diabetic Peripheral Neuropathic Pain Duloxetine Delayed-release Capsules are indicated for the management of neuropathic pain (DPNP) associated with diabetic peripheral neuropathy [see Clinical Studies (14.3) ] .

1.5 Chronic Musculoskeletal Pain Duloxetine Delayed-release Capsules are indicated for the management of chronic musculoskeletal pain.

This has been established in studies in patients with chronic low back pain (CLBP) and chronic pain due to osteoarthritis [see Clinical Studies (14.5) ] .

6.

ADVERSE REACTIONS • Most common adverse reactions (≥5% and at least twice the incidence of placebo patients): nausea, dry mouth, somnolence, constipation, decreased appetite, and hyperhidrosis ( 6.3 ).

To report SUSPECTED ADVERSE REACTIONS, contact Breckenridge Pharmaceutical, Inc.

at 1-800-367-3395 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trial Data Sources The data described below reflect exposure to duloxetine in placebo-controlled trials for MDD (N=2489), GAD (N=910), OA (N=239), CLBP (N=600), and DPNP (N=906).

The population studied was 17 to 91 years of age; 65.5%, 62.5%, 61.5%, and 42.9% female; and 86.5%, 81.2%, 86.2%, and 74.0% Caucasian for MDD, GAD, OA and CLBP, DPNP, respectively.

Most patients received doses of a total of 60 to 120 mg per day [see Clinical Studies (14) ] .

The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse reaction of the type listed.

A reaction was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation.

Reactions reported during the studies were not necessarily caused by the therapy, and the frequencies do not reflect investigator impression (assessment) of causality.

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.

6.2 Adverse Reactions Reported as Reasons for Discontinuation of Treatment in Placebo-Controlled Trials Major Depressive Disorder — Approximately 9% (209/2327) of the patients who received duloxetine in placebo-controlled trials for MDD discontinued treatment due to an adverse reaction, compared with 4.7% (68/1460) of the patients receiving placebo.

Nausea (duloxetine 1.3%, placebo 0.5%) was the only common adverse reaction reported as a reason for discontinuation and considered to be drug-related (i.e., discontinuation occurring in at least 1% of the duloxetine-treated patients and at a rate of at least twice that of placebo).

Generalized Anxiety Disorder — Approximately 15.3% (102/668) of the patients who received duloxetine in placebo-controlled trials for GAD discontinued treatment due to an adverse reaction, compared with 4.0% (20/495) for placebo.

Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine 3.7%, placebo 0.2%), and vomiting (duloxetine 1.3%, placebo 0.0%), and dizziness (duloxetine 1.0%, placebo 0.2%).

Diabetic Peripheral Neuropathic Pain — Approximately 12.9% (117/906) of the patients who received duloxetine in placebo-controlled trials for DPNP discontinued treatment due to an adverse reaction, compared with 5.1% (23/448) for placebo.

Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine 3.5%, placebo 0.7%), dizziness (duloxetine 1.2%, placebo 0.4%), and somnolence (duloxetine 1.1%, placebo 0.0%).

Chronic Pain due to Osteoarthritis — Approximately 16.3% (39/239) of the patients who received duloxetine in 13-week, placebo-controlled trials for chronic pain due to OA discontinued treatment due to an adverse reaction, compared with 5.6% (14/248) for placebo.

Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine 2.9%, placebo 0.8%) and asthenia (duloxetine 1.3%, placebo 0.0%).

Chronic Low Back Pain — Approximately 16.5% (99/600) of the patients who received duloxetine in 13-week, placebo-controlled trials for CLBP discontinued treatment due to an adverse reaction, compared with 6.3% (28/441) for placebo.

Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine 3.0%, placebo 0.7%), and somnolence (duloxetine 1.0%, placebo 0.0%).

6.3 Most Common Adverse Reactions Pooled Trials for all Approved Indications — The most commonly observed adverse reactions in Duloxetine Delayed-release Capsules-treated patients (incidence of at least 5% and at least twice the incidence in placebo patients) were nausea, dry mouth, somnolence, constipation, decreased appetite, and hyperhidrosis.

Diabetic Peripheral Neuropathic Pain — The most commonly observed adverse reactions in Duloxetine Delayed-release Capsules-treated patients (as defined above) were nausea, somnolence, decreased appetite, constipation, hyperhidrosis, and dry mouth.

Chronic Pain due to Osteoarthritis — The most commonly observed adverse reactions in Duloxetine Delayed-release Capsules -treated patients (as defined above) were nausea, fatigue, and constipation.

Chronic Low Back Pain — The most commonly observed adverse reactions in Duloxetine Delayed-release Capsules-treated patients (as defined above) were nausea, dry mouth, insomnia, somnolence, constipation, dizziness, and fatigue.

6.4 Adverse Reactions Occurring at an Incidence of 5% or More Among Duloxetine-Treated Patients in Placebo-Controlled Trials Table 2 gives the incidence of treatment-emergent adverse reactions in placebo-controlled trials for approved indications that occurred in 5% or more of patients treated with duloxetine and with an incidence greater than placebo.

Table 1: Treatment-Emergent Adverse Reactions: Incidence of 5% or More in Placebo-Controlled Trials of Approved Indications The inclusion of an event in the table is determined based on the percentages before rounding; however, the percentages displayed in the table are rounded to the nearest integer.

Adverse Reaction Percentage of Patients Reporting Reaction Duloxetine Delayed-release Capsules (N=6020) Placebo (N=3962) Nausea 24 8 Headache 14 13 Dry mouth 13 5 Fatigue Also includes asthenia.

10 5 Somnolence Events for which there was a significant dose-dependent relationship in fixed-dose studies, excluding three MDD studies which did not have a placebo lead-in period or dose titration.

, Also includes hypersomnia and sedation.

10 3 Insomnia , Also includes middle insomnia, early morning awakening, and initial insomnia.

10 6 Dizziness 10 5 Constipation 10 4 Diarrhea 9 6 Decreased appetite , Also includes anorexia.

8 2 Hyperhidrosis 7 2 6.5 Adverse Reactions Occurring at an Incidence of 2% or More Among Duloxetine-Treated Patients in Placebo-Controlled Trials Pooled MDD and GAD Trials — Table 3 gives the incidence of treatment-emergent adverse reactions in MDD and GAD placebo-controlled trials for approved indications that occurred in 2% or more of patients treated with duloxetine and with an incidence greater than placebo.

Table 2: Treatment-Emergent Adverse Reactions: Incidence of 2% or More in MDD and GAD Placebo-Controlled Trials 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.

System Organ Class / Adverse Reaction Percentage of Patients Reporting Reaction Duloxetine Delayed-release Capsules (N=2995) Placebo (N=1955) Cardiac Disorders Palpitations 2 2 Eye Disorders Vision blurred 3 2 Gastrointestinal Disorders Nausea 25 9 Dry mouth 15 6 Diarrhea 10 7 Constipation 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.

10 4 Abdominal pain Also includes abdominal pain upper, abdominal pain lower, abdominal tenderness, abdominal discomfort, and gastrointestinal pain 4 4 Vomiting 5 2 General Disorders and Administration Site Conditions Fatigue Also includes asthenia 10 6 Investigations Weight decreased 2 <1 Metabolism and Nutrition Disorders Decreased appetite Also includes anorexia 7 2 Nervous System Disorders Dizziness 10 6 Somnolence Also includes hypersomnia and sedation 10 4 Tremor 3 <1 Psychiatric Disorders Insomnia Also includes middle insomnia, early morning awakening and initial insomnia 10 6 Agitation Also includes feeling jittery, nervousness, restlessness, tension and psychomotor agitation 5 3 Anxiety 3 2 Libido decreased Also includes loss of libido 4 1 Orgasm abnormal , Also includes anorgasmia 3 <1 Abnormal dreams Also includes nightmare 2 1 Reproductive System and Breast Disorders Erectile dysfunction Male patients only 4 1 Ejaculation delayed , 3 <1 Ejaculation disorder , Also includes ejaculation failure and ejaculation dysfunction 2 <1 Respiratory, Thoracic, and Mediastinal Disorders Yawning 2 <1 Skin and Subcutaneous Tissue Disorders Hyperhidrosis 6 2 Vascular Disorders Hot flush 2 <1 DPNP, FM, OA, and CLBP — Table 4 gives the incidence of treatment-emergent adverse events that occurred in 2% or more of patients treated with Duloxetine Delayed-release Capsules (determined prior to rounding) in the premarketing acute phase of DPNP, FM, OA, and CLBP placebo-controlled trials and with an incidence greater than placebo.

Table 3: Treatment-Emergent Adverse Reactions: Incidence of 2% or More in DPNP, FM, OA, and CLBP Placebo-Controlled Trials 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.

System Organ Class / Adverse Reaction Percentage of Patients Reporting Reaction Duloxetine Delayed-release Capsules (N=2621) Placebo (N=1672) Gastrointestinal Disorders Nausea 23 7 Dry Mouth Incidence of 120 mg/day is significantly greater than the incidence for 60 mg/day.

11 3 Constipation 10 3 Diarrhea 9 6 Abdominal Pain Also includes abdominal discomfort, abdominal pain lower, abdominal pain upper, abdominal tenderness and gastrointestinal pain 6 5 Vomiting 3 2 Dyspepsia Also includes stomach discomfort 2 1 General Disorders and Administration Site Conditions Fatigue Also includes asthenia 11 5 Infections and Infestations Nasopharyngitis 5 4 Upper Respiratory Tract Infection 4 4 Influenza 3 2 Metabolism and Nutrition Disorders Decreased Appetite , Also includes anorexia 9 1 Musculoskeletal and Connective Tissue Musculoskeletal Pain , Also includes myalgia and neck pain 4 4 Muscle Spasms 3 2 Nervous System Disorders Headache 13 9 Somnolence , Also includes hypersomnia and sedation 12 3 Dizziness 10 5 Paraesthesia Also includes hypoaesthesia, hypoaesthesia facial and paraesthesia oral 2 2 Tremor 2 <1 Psychiatric Disorders Insomnia , Also includes middle insomnia, early morning awakening and initial insomnia 10 6 Agitation Also includes feeling jittery, nervousness, restlessness, tension and psychomotor hyperactivity 3 <1 Reproductive System and Breast Disorders Erectile Dysfunction , Male patients only (N=885 for duloxetine, 494 for placebo) 4 <1 Ejaculation Disorder Male patients only (N=885 for duloxetine, 494 for placebo).

Also includes ejaculation failure 2 <1 Respiratory, Thoracic, and Mediastinal Disorders Cough 3 2 Oropharyngeal Pain 2 2 Skin and Subcutaneous Tissue Disorders Hyperhidrosis 6 1 Vascular Disorders Flushing Also includes hot flush 3 1 6.6 Effects on Male and Female Sexual Function Changes in sexual desire, sexual performance and sexual satisfaction often occur as manifestations of psychiatric disorders or diabetes, but they may also be a consequence of pharmacologic treatment.

Because adverse sexual reactions are presumed to be voluntarily underreported, the Arizona Sexual Experience Scale (ASEX), a validated measure designed to identify sexual side effects, was used prospectively in 4 MDD placebo-controlled trials.

In these trials, as shown in Table 5 below, patients treated with Duloxetine Delayed-release Capsules experienced significantly more sexual dysfunction, as measured by the total score on the ASEX, than did patients treated with placebo.

Gender analysis showed that this difference occurred only in males.

Males treated with Duloxetine Delayed-release Capsules experienced more difficulty with ability to reach orgasm (ASEX Item 4) than males treated with placebo.

Females did not experience more sexual dysfunction on Duloxetine Delayed-release Capsules than on placebo as measured by ASEX total score.

Negative numbers signify an improvement from a baseline level of dysfunction, which is commonly seen in depressed patients.

Physicians should routinely inquire about possible sexual side effects.

Table 4: Mean Change in ASEX Scores by Gender in MDD Placebo-Controlled Trials Male Patients n=Number of patients with non-missing change score for ASEX total Female Patients Duloxetine Delayed-release Capsules (n=175) Placebo (n=83) Duloxetine Delayed-release Capsules (n=241) Placebo (n=126) ASEX Total (Items 1-5) 0.56 p=0.013 versus placebo -1.07 -1.15 -1.07 Item 1 — Sex drive -0.07 -0.12 -0.32 -0.24 Item 2 — Arousal 0.01 -0.26 -0.21 -0.18 Item 3 — Ability to achieve erection (men); Lubrication (women) 0.03 -0.25 -0.17 -0.18 Item 4 — Ease of reaching orgasm 0.40 p<0.001 versus placebo -0.24 -0.09 -0.13 Item 5 — Orgasm satisfaction 0.09 -0.13 -0.11 -0.17 6.7 Vital Sign Changes In placebo-controlled clinical trials across approved indications for change from baseline to endpoint, duloxetine treatment was associated with mean increases of 0.07 mm Hg in systolic blood pressure and 0.62 mm Hg in diastolic blood pressure compared to mean decreases of 1.31 mm Hg systolic and 0.73 mm Hg diastolic in placebo-treated patients.

There was no significant difference in the frequency of sustained (3 consecutive visits) elevated blood pressure [see Warnings and Precautions (5.3 and 5.10) ] .

Duloxetine treatment, for up to 26 weeks in placebo-controlled trials across approved indications, typically caused a small increase in heart rate for change from baseline to endpoint compared to placebo of up to 1.40 beats per minute.

6.8 Weight Changes In placebo-controlled clinical trials, MDD and GAD patients treated with Duloxetine Delayed-release Capsules for up to 10 weeks experienced a mean weight loss of approximately 0.5 kg, compared with a mean weight gain of approximately 0.2 kg in placebo-treated patients.

In studies of DPNP, patients treated with Duloxetine Delayed-release Capsules for up to 26 weeks experienced a mean weight loss of approximately 0.6 kg compared with a mean weight gain of approximately 0.2 kg in placebo-treated patients.

In one long-term CLBP 54-week study (13-week, placebo-controlled acute phase and 41-week, uncontrolled extension phase), duloxetine patients had a mean weight decrease of 0.6 kg in 13 weeks of acute phase compared to study entry, then a mean weight increase of 1.4 kg in 41 weeks of extension phase compared to end of acute phase.

6.9 Laboratory Changes Duloxetine Delayed-release Capsule treatment in placebo-controlled clinical trials across approved indications, was associated with small mean increases from baseline to endpoint in ALT, AST, CPK, and alkaline phosphatase; infrequent, modest, transient, abnormal values were observed for these analytes in Duloxetine Delayed-release Capsules-treated patients when compared with placebo-treated patients [see Warnings and Precautions (5.2) ] .

6.10 Electrocardiogram Changes The effect of duloxetine 160 mg and 200 mg administered twice daily to steady state was evaluated in a randomized, double-blinded, two-way crossover study in 117 healthy female subjects.

No QT interval prolongation was detected.

Duloxetine appears to be associated with concentration-dependent but not clinically meaningful QT shortening.

6.11 Other Adverse Reactions Observed During the Premarketing and Postmarketing Clinical Trial Evaluation of Duloxetine Following is a list of treatment-emergent adverse reactions reported by patients treated with duloxetine in clinical trials.

In clinical trials of all indications, 29,435 patients were treated with duloxetine.

Of these, 30.4% (8953) took duloxetine for at least 6 months, and 14.7% (4317) for at least one year.

The following listing is not intended to include reactions (1) already listed in previous tables or elsewhere in labeling, (2) for which a drug cause was remote, (3) which were so general as to be uninformative, (4) which were not considered to have significant clinical implications, or (5) which occurred at a rate equal to or less than placebo.

Reactions are categorized by body system according to the following definitions: frequent adverse reactions are those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in fewer than 1/1000 patients.

Cardiac Disorders — Frequent: palpitations; Infrequent: myocardial infarction and tachycardia.

Ear and Labyrinth Disorders — Frequent: vertigo; Infrequent: ear pain and tinnitus.

Endocrine Disorders — Infrequent: hypothyroidism.

Eye Disorders — Frequent: vision blurred; Infrequent: diplopia, and visual disturbance.

Gastrointestinal Disorders — Frequent: flatulence; Infrequent: eructation, gastritis, halitosis, and stomatitis; Rare: gastric ulcer, hematochezia, and melena.

General Disorders and Administration Site Conditions — Frequent: chills/rigors; Infrequent: feeling abnormal, feeling hot and/or cold, malaise, and thirst; Rare: gait disturbance.

Infections and Infestations — Infrequent: gastroenteritis and laryngitis.

Investigations — Frequent: weight increased; 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 parasthesia/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 — Infrequent: dysuria, micturition urgency, nocturia, polyuria, and urine odor abnormal.

Reproductive System and Breast Disorders — Frequent: anorgasmia/orgasm abnormal; Infrequent: menopausal symptoms, and sexual dysfunction.

Respiratory, Thoracic and Mediastinal Disorders — Frequent: yawning; Infrequent: throat tightness.

Skin and Subcutaneous Tissue Disorders — Infrequent: cold sweat, dermatitis contact, erythema, increased tendency to bruise, night sweats, and photosensitivity reaction; Rare: ecchymosis.

Vascular Disorders — Frequent: hot flush; Infrequent: flushing, orthostatic hypotension, and peripheral coldness.

6.12 Postmarketing Spontaneous Reports The following adverse reactions have been identified during postapproval use of Duloxetine Delayed-release Capsules.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Adverse reactions reported since market introduction that were temporally related to duloxetine therapy and not mentioned elsewhere in labeling include: anaphylactic reaction, aggression and anger (particularly early in treatment or after treatment discontinuation), angioneurotic edema, extrapyramidal disorder, galactorrhea, glaucoma, 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.