Duloxetine (duloxetine hydrochloride 30 mg) Dailymed

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 Warningand 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)]
• Sexual Dysfunction [see Warnings and Precautions (5.16)]

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 Breckenridge Pharmaceutical, Inc. at 1-800-367-3395 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The stated frequencies of adverse reactions represent the proportion of patients who experienced, at least once, one treatment-emergent adverse reaction of the type uled. 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 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

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-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 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.

Adverse Reaction	Percentage of Patients Reporting Reaction
	Duloxetine delayed-release capsules (N=8100)	Placebo (N=5655)
Nausea 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.	23	8
Headache	14	12
Dry mouth	13	5
Somnolence Also includes hypersomnia and sedation.	10	3
Fatigue Also includes asthenia. ,	9	5
Insomnia Also includes initial insomnia, middle insomnia, and early morning awakening.	9	5
Constipation	9	4
Dizziness	9	5
Diarrhea	9	6
Decreased appetite	7	2
Hyperhidrosis	6	1
Abdominal pain Also includes abdominal discomfort, abdominal pain lower, abdominal pain upper, abdominal tenderness, and gastrointestinal pain.	5	4

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 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

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 in placebo-treated patients. There was no significant difference in the frequency of sustained (3 consecutive visits) elevated blood pressure [see Warnings and Precautions (5.3, 5.11)].

Duloxetine treatment, for up to 26 weeks in placebo-controlled trials across approved 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 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 in Adults

Following is a ul 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 at least one year. The following uling is not intended to include reactions (1) already uled 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=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-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-treated pediatric patients aged 7 to 17 years of age (most patients received 30-120 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-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 capsules are 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 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.

System Organ Class / Adverse Reaction	Percentage of Pediatric Patients Reporting Reaction
	Duloxetine delayed-release capsules (N=476)	Placebo (N=362)
Gastrointestinal Disorders
Nausea	18	8
Abdominal Pain Also includes abdominal pain upper, abdominal pain lower, abdominal tenderness, abdominal discomfort, and gastrointestinal pain.	13	10
Vomiting	9	4
Diarrhea	6	3
Dry Mouth	2	1
General Disorders and Administration Site Conditions
Fatigue Also includes asthenia.	7	5
Investigations
Decreased Weight Frequency based on weight measurement meeting potentially clinically significant threshold of ≥3.5% weight loss (N=467 Duloxetine delayed-release capsules; N=354 Placebo).	14	6
Metabolism and Nutrition Disorders
Decreased Appetite	10	5
Nervous System Disorders
Headache	18	13
Somnolence Also includes hypersomnia and sedation.	11	6
Dizziness	8	4
Psychiatric Disorders
Insomnia Also includes initial insomnia, insomnia, middle insomnia, and terminal insomnia.	7	4
Respiratory, Thoracic, and Mediastinal Disorders
Oropharyngeal Pain	4	2
Cough	3	1

Other adverse reactions that occurred at an incidence of less than 2% 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 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)].

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 delayed-release capsules 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) 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.

	Duloxetine delayed-release capsules (N=91)	Placebo (N=93)
Nausea	25%	15%
Decreased appetite	15%	3%
Vomiting	15%	5%
Decreased weight Frequency based on weight measurement meeting potentially clinically significant threshold of ≥3.5% weight loss (N=89 Duloxetine delayed-release capsules; N=92 Placebo).	15%	5%
Headache	14%	11%
Nasopharyngitis	9%	2%
Somnolence	9%	3%
Upper respiratory tract infection	7%	2%
Viral gastroenteritis	5%	0%
Fatigue	5%	2%

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 delayed-release capsules 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.

14.1 Overview of the Clinical Trials

The efficacy of duloxetine has been established in the following populations in adequate and well-controlled trials:

• Major Depressive Disorder (MDD):4 short-term (Studies MDD-1, MDD-2, MDD-3, and MDD-4) and 1 maintenance trial (Study MDD-5) in adults [see Clinical Studies (14.2)].
• Generalized Anxiety Disorder (GAD):3 short-term trials in adults (Studies GAD-1, GAD-2, and GAD-3), 1 maintenance trial in adults (Study GAD-4), 1 short-term trial in geriatric patients (Study GAD-5), and 1 short-term trial in pediatric patients 7 to 17 years of age (Study GAD-6) [see Clinical Studies (14.3)].
• Diabetic Peripheral Neuropathic Pain (DPNP):Two 12-week trials in adults (Studies DPNP-1 and DPNP-2) [see Clinical Studies (14.4)].
• Fibromyalgia (FM):Two trials in adults (one of 3 months duration and one of 6 months duration) (Studies FM-1 and FM-2) and one 13-week trial in pediatric patients 13 to 17 years of age (Study FM-4) [see Clinical Studies (14.5)].
• Chronic Musculoskeletal Pain:Two 12- to 13-week trials in adult patients with chronic low back pain (CLBP) (Studies CLBP-1 and CLBP-3) and one 13-week trial in adult patients with chronic pain due to osteoarthritis (OA) (Study OA-1) [see Clinical Studies (14.6)].

Additionally, a summary of the following trials that did not demonstrate efficacy are presented below: Study FM-3 (a 16-week trial in adult patients with fibromyalgia), Study CLBP-2 (a 13-week trial in adult patients with CLBP), and Study OA-2 (a 13-week trial in adult patients with chronic pain due to OA).

14.2 Major Depressive Disorder in Adults

The efficacy of Duloxetine delayed-release capsules 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 delayed-release capsules 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 delayed-release capsules 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 delayed-release capsules 40 or 60 mg twice daily (N=95 and N=93, respectively) or placebo (N=93) for 8 weeks.

In all four trials, Duloxetine delayed-release capsules demonstrated superiority over placebo as measured by improvement in the 17-li 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 Trials in MDD

Study Number	Treatment Group	Primary Efficacy Measure: HAMD-17
		Mean Baseline Score (SD)	LS Mean Change from Baseline (SE)	Placebo-subtracted Difference Difference (drug minus placebo) in least-squares mean change from baseline.(95% CI)
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.
Study MDD-1	Duloxetine delayed-release capsules (60 mg/day) Doses statistically significantly superior to placebo.	21.5 (4.10)	-10.9 (0.70)	-4.9 (-6.8, -2.9)
	Placebo	21.1 (3.71)	-6.1 (0.69)	--
Study MDD-2	Duloxetine delayed-release capsules (60 mg/day)	20.3 (3.32)	-10.5 (0.71)	-2.2 (-4.0, -0.3)
	Placebo	20.5 (3.42)	-8.3 (0.67)	--
Study MDD-3	Duloxetine delayed-release capsules (20 mg BID)	18.6 (5.85)	-7.4 (0.80)	-2.4 (-4.7, -0.2)
	Duloxetine delayed-release capsules (40 mg BID)	18.1 (4.52)	-8.6 (0.81)	-3.6 (-5.9, -1.4)
	Placebo	17.2 (5.11)	-5.0 (0.81)	--
Study MDD-4	Duloxetine delayed-release capsules (40 mg BID)	19.9 (3.54)	-11.0 (0.49)	-2.2 (-3.6, -0.9)
	Duloxetine delayed-release capsules (60 mg BID)	20.2 (3.41)	-12.1 (0.49)	-3.3 (-4.7, -1.9)
	Placebo	19.9 (3.58)	-8.8 (0.50)	--

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 delayed-release capsules 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 Proportion Kaplan-Meier estimator methodof Adult Patients with MDD Relapse (Study MDD-5)

14.3 Generalized Anxiety Disorder

GAD Trials in Adults (Including Geriatric Patients)

The efficacy of Duloxetine delayed-release capsules 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 delayed-release capsules 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 dosage for completers at endpoint in these trials was 104.8 mg/day. Study GAD-1 evaluated Duloxetine delayed-release capsules 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 delayed-release capsules demonstrated superiority over placebo as measured by greater improvement in the Hamilton Anxiety Scale (HAM-A) total score (see Table 9) 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 delayed-release capsules 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 delayed-release capsules 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 delayed-release capsules 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 delayed-release capsules 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 9).

GAD Trial in Pediatric Patients 7 to 17 Years Old

The efficacy of Duloxetine delayed-release capsules 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 delayed-release capsules (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

Study Number (population) (measurement)	Treatment Group	Primary Efficacy Measure
		Mean Baseline Score (SD)	LS Mean Change from Baseline (SE)	Placebo-subtracted Difference Difference (drug minus placebo) in least squares mean change from baseline.(95% CI)
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.
Study GAD-1 (Adult) (HAM-A)	Duloxetine delayed-release capsules (60 mg/day) Dose statistically significantly superior to placebo.	25.1 (7.18)	-12.8 (0.68)	-4.4 (-6.2, -2.5)
	Duloxetine delayed-release capsules (120 mg/day)	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 (Adult) (HAM-A)	Duloxetine delayed-release capsules (60-120 mg/day)	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 (Adult) (HAM-A)	Duloxetine delayed-release capsules (60-120 mg/day)	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 delayed-release capsules (60-120 mg/day)	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 delayed-release capsules (30-120 mg/day)	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 Proportion Kaplan-Meier estimator methodof Adult Patients with GAD Relapse (Study GAD-4)

14.4 Diabetic Peripheral Neuropathic Pain in Adults

The efficacy of Duloxetine delayed-release capsules 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 delayed-release capsules. Patients recorded their pain daily in a diary.

Both trials compared Duloxetine delayed-release capsules 60 mg once daily or 60 mg twice daily with placebo. Study DPNP-1 additionally compared Duloxetine delayed-release capsules 20 mg with placebo. A total of 457 patients (342 Duloxetine delayed-release capsules, 115 placebo) were enrolled in Study DPNP-1 and a total of 334 patients (226 Duloxetine delayed-release capsules, 108 placebo) were enrolled in Study DPNP-2.

Treatment with Duloxetine delayed-release capsules 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)

14.5 Fibromyalgia

Adult Trials in Fibromyalgia

The efficacy of Duloxetine delayed-release capsules 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 delayed-release capsules, 120 placebo) were enrolled in Study FM-1 and a total of 520 patients (376 Duloxetine delayed-release capsules, 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 delayed-release capsules 60 mg once daily or 120 mg daily (given in divided doses in Study FM-1 and as a single daily dose in Study FM-2) with placebo. Study FM-2 additionally compared Duloxetine delayed-release capsules 20 mg with placebo during the initial three months of a six-month trial.

Treatment with Duloxetine delayed-release capsules 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 delayed-release capsules at 60 mg/day was evaluated in a separate trial (Study FM-3). Adult patients were initially treated with Duloxetine delayed-release capsules 60 mg once daily for eight weeks in open-label fashion. Subsequently, completers of this phase were randomized to double-blind treatment with Duloxetine delayed-release capsules 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 delayed-release capsules 120 mg as compared to those who were blindly continued on Duloxetine delayed-release capsules 60 mg.

Pediatric Trial in Fibromyalgia

Duloxetine delayed-release capsules were 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 delayed-release capsules (N=91) were 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 delayed-release capsules 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 pre- specified 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.

Figure 7: Percentage of Pediatric Patients Aged 13 to 17 Years Old with Juvenile Fibromyalgia Syndrome Achieving Various Levels of Pain Relief at Week 12 (Study FM-4) ^a

14.6 Chronic Musculoskeletal Pain in Adults

Duloxetine delayed-release capsules are 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 delayed-release capsules in chronic low back pain (CLBP) in adults was assessed in two double-blind, 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 delayed-release capsules 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 delayed-release capsules, N=121 on placebo) enrolled and 182 (77%) completed 13-week treatment phase. After 7 weeks of treatment, Duloxetine delayed-release capsules-treated patients with less than 30% reduction in average daily pain and who were able to tolerate 60 mg once daily had their Duloxetine delayed-release capsules 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 delayed-release capsules 60-120 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 delayed-release capsules daily or a matching placebo (N=59 on Duloxetine delayed-release capsules 20 mg, N=116 on Duloxetine delayed-release capsules 60 mg, N=112 on Duloxetine delayed-release capsules 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 delayed-release capsules 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 delayed-release capsules 60 mg daily or placebo (N=198 on Duloxetine delayed-release capsules, 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 delayed-release capsules 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 delayed-release capsules 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 delayed-release capsules started treatment in both trials at a dose of 30 mg once daily for one week. After the first week, the dose of Duloxetine delayed-release capsules was increased to 60 mg once daily. After 7 weeks of treatment with Duloxetine delayed-release capsules 60 mg once daily, in Study OA-1 patients with sub-optimal response to treatment (<30% pain reduction) and tolerated Duloxetine delayed-release capsules 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 delayed-release capsules 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 delayed-release capsules 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 delayed-release capsules, 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 delayed-release capsules 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 delayed-release capsules, 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 delayed-release capsules 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)