Duloxetine Delayed-Release (Page 5 of 13)

6.1 Clinical Studies 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 individuals who experienced, at least once, a treatment-emergent adverse reaction of the type listed. A reaction was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. Reactions reported during the studies were not necessarily caused by the therapy, and the frequencies do not reflect investigator impression (assessment) of causality.

Adults — The data described below reflect exposure to duloxetine in placebo-controlled trials for MDD (N=3779), GAD (N=1018), OA (N=503), CLBP (N=600), DPNP (N=906), and another indication (N=1294). The population studied was 17 to 89 years of age; 65.7%, 60.8%, 60.6%, 42.9%, and 94.4% female; and 81.8%, 72.6%, 85.3%, 74.0%, and 85.7% Caucasian for MDD, GAD, OA and CLBP, DPNP, and another indication, respectively. Most patients received doses of a total of 60 to 120 mg per day [see Clinical Studies (14)]. The data below do not include results of the trial examining the efficacy of Duloxetine delayed-release capsules in patients ≥ 65 years old for the treatment of generalized anxiety disorder; however, the adverse reactions observed in this geriatric sample were generally similar to adverse reactions in the overall adult population.

Children and Adolescents — The data described below reflect exposure to Duloxetine delayed-release capsules in pediatric, 10-week, placebo-controlled trials for MDD (N=341) and GAD (N=135). The population studied (N=476) was 7 to 17 years of age with 42.4% children age 7 to 11 years of age, 50.6% female, and 68.6% white. Patients received 30-120 mg per day during placebo-controlled acute treatment studies. Additional data come from the overall total of 822 pediatric patients (age 7 to 17 years of age) with 41.7% children age 7 to 11 years of age and 51.8% female exposed to Duloxetine delayed-release capsules in MDD and GAD clinical trials up to 36-weeks in length, in which most patients received 30-120 mg per day.

Adverse Reactions Reported as Reasons for Discontinuation of Treatment in Adult Placebo-Controlled Trials

Major Depressive Disorder — Approximately 8.4% (319/3779) of the patients who received duloxetine in placebo-controlled trials for MDD discontinued treatment due to an adverse reaction, compared with 4.6% (117/2536) of the patients receiving placebo. Nausea (duloxetine 1.1%, placebo 0.4%) was the only common adverse reaction reported as a reason for discontinuation and considered to be drug-related (i.e., discontinuation occurring in at least 1% of the duloxetine-treated patients and at a rate of at least twice that of placebo).

Generalized Anxiety Disorder — Approximately 13.7% (139/1018) of the patients who received duloxetine in placebo-controlled trials for GAD discontinued treatment due to an adverse reaction, compared with 5.0% (38/767) for placebo. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine 3.3%, placebo 0.4%), and dizziness (duloxetine 1.3%, placebo 0.4%).

Diabetic Peripheral Neuropathic Pain — Approximately 12.9% (117/906) of the patients who received duloxetine in placebo-controlled trials for DPNP discontinued treatment due to an adverse reaction, compared with 5.1% (23/448) for placebo. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine 3.5%, placebo 0.7%), dizziness (duloxetine 1.2%, placebo 0.4%), and somnolence (duloxetine 1.1%, placebo 0.0%).

Chronic Pain due to Osteoarthritis — Approximately 15.7% (79/503) of the patients who received duloxetine in 13-week, placebo-controlled trials for chronic pain due to OA discontinued treatment due to an adverse reaction, compared with 7.3% (37/508) for placebo. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine 2.2%, placebo 1.0%).

Chronic Low Back Pain — Approximately 16.5% (99/600) of the patients who received duloxetine in 13-week, placebo-controlled trials for CLBP discontinued treatment due to an adverse reaction, compared with 6.3% (28/441) for placebo. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine 3.0%, placebo 0.7%), and somnolence (duloxetine 1.0%, placebo 0.0%).

Most Common Adult Adverse Reactions

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

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

Chronic Pain due to Osteoarthritis — The most commonly observed adverse reactions in Duloxetine delayed-release capsules-treated patients (as defined above) were nausea, fatigue, constipation, dry mouth, insomnia, somnolence, and dizziness.

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

Adverse Reactions Occurring at an Incidence of 5% or More Among Duloxetine-Treated Patients in Adult Placebo-Controlled Trials

Table 2 gives the incidence of treatment-emergent adverse reactions in placebo-controlled trials for approved indications that occurred in 5% or more of patients treated with duloxetine and with an incidence greater than placebo.

Table 2: Treatment-Emergent Adverse Reactions: Incidence of 5% or More and Greater than Placebo in Placebo-Controlled Trials of Approved Indications a

Adverse Reaction Percentage of Patients Reporting Reaction
Duloxetine delayed-release capsules (N=8100) Placebo (N=5655)

Nausea c

23

8

Headache

14

12

Dry mouth

13

5

Somnolence e

10

3

Fatigue b,c

9

5

Insomniad

9

5

Constipationc

9

4

Dizzinessc

9

5

Diarrhea

9

6

Decreased appetitec

7

2

Hyperhidrosisc

6

1

Abdominal painf

5

4

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 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 Occurring at an Incidence of 2% or More Among Duloxetine-Treated Patients in Adult Placebo-Controlled Trials

Pooled MDD and GAD Trials — Table 3 gives the incidence of treatment-emergent adverse reactions in MDD and GAD placebo-controlled trials for approved indications that occurred in 2% or more of patients treated with duloxetine and with an incidence greater than placebo.

Table 3: Treatment-Emergent Adverse Reactions: Incidence of 2% or More and Greater than Placebo in MDD and GAD Placebo-Controlled Trials a,b

System Organ Class / Adverse Reaction Percentage of Patients Reporting Reaction
Duloxetine delayed-release capsules (N=4797) Placebo (N=3303)

Cardiac Disorders

Palpitations

2

1

Eye Disorders

Vision blurred

3

1

Gastrointestinal Disorders

Nauseac

23

8

Dry mouth

14

6

Constipationc

9

4

Diarrhea

9

6

Abdominal paind

5

4

Vomiting

4

2

General Disorders and Administration Site Conditions

Fatiguee

9

5

Metabolism and Nutrition Disorders

Decreased appetitec

6

2

Nervous System Disorders

Headache

14

14

Dizzinessc

9

5

Somnolencef

9

3

Tremor

3

1

Psychiatric Disorders

Insomniag

9

5

Agitationh

4

2

Anxiety

3

2

Reproductive System and Breast Disorders

Erectile dysfunction

4

1

Ejaculation delayedc

2

1

Libido decreasedi

3

1

Orgasm abnormalj

2

<1

Respiratory, Thoracic, and Mediastinal Disorders

Yawning

2

<1

Skin and Subcutaneous Tissue Disorders

Hyperhidrosis

6

2

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 events that were significantly different between treatments in adults ≥65 years that were also not significant in the adults <65years.

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

d Also includes abdominal pain upper, abdominal pain lower, abdominal tenderness, abdominal discomfort, and gastrointestinal pain

e Also includes asthenia

f Also includes hypersomnia and sedation

g Also includes initial insomnia, middle insomnia, and early morning awakening

h Also includes feeling jittery, nervousness, restlessness, tension and psychomotor hyperactivity

i Also includes loss of libido

j Also includes anorgasmia

DPNP, another indication, OA, and CLBP — Table 4 gives the incidence of treatment-emergent adverse events that occurred in 2% or more of patients treated with Duloxetine delayed-release capsules (determined prior to rounding) in the premarketing acute phase of DPNP, another indication, OA, and CLBP placebo-controlled trials and with an incidence greater than placebo.

Table 4: Treatment-Emergent Adverse Reactions: Incidence of 2% or More and Greater than Placebo in DPNP, another indication, OA, and CLBP Placebo-Controlled Trialsa

System Organ Class / Adverse Reaction Percentage of Patients Reporting Reaction
Duloxetine delayed-release capsules (N=3303) Placebo (N=2352)

Gastrointestinal Disorders

Nausea

23

7

Dry Mouthb

11

3

Constipationb

10

3

Diarrhea

9

5

Abdominal Painc

5

4

Vomiting

3

2

Dyspepsia

2

1

General Disorders and Administration Site Conditions

Fatigued

11

5

Infections and Infestations

Nasopharyngitis

4

4

Upper Respiratory Tract Infection

3

3

Influenza

2

2

Metabolism and Nutrition Disorders

Decreased Appetiteb

8

1

Musculoskeletal and Connective Tissue

Musculoskeletal Paine

3

3

Muscle Spasms

2

2

Nervous System Disorders

Headache

13

8

Somnolenceb,f

11

3

Dizziness

9

5

Paraesthesiag

2

2

Tremorb

2

<1

Psychiatric Disorders

Insomniab,h

10

5

Agitationi

3

1

Reproductive System and Breast Disorders

Erectile Dysfunctionb

4

<1

Ejaculation Disorderj

2

<1

Respiratory, Thoracic, and Mediastinal Disorders

Cough

2

2

Skin and Subcutaneous Tissue Disorders

Hyperhidrosis

6

1

Vascular Disorders

Flushingk

3

1

Blood pressure increasedl

2

1

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 Also included abdominal discomfort, abdominal pain lower, abdominal pain upper, abdominal tenderness and gastrointestinal pain

d Also includes asthenia

e Also includes myalgia and neck pain

f Also includes hypersomnia and sedation

g Also includes hypoaesthesia, hypoaesthesia facial, genital hypoaesthesia and paraesthesia oral

h Also includes initial insomnia, middle insomnia, and early morning awakening

i Also includes feeling jittery, nervousness, restlessness, tension and psychomotor hyperactivity

j Also includes ejaculation failure

k Also includes hot flush

l Also includes blood pressure diastolic increased, blood pressure systolic increased, diastolic hypertension, essential hypertension, hypertension, hypertensive crisis, labile hypertension, orthostatic hypertension, secondary hypertension, and systolic hypertension.

Effects on Male and Female Sexual Function in Adults

Changes in sexual desire, sexual performance and sexual satisfaction often occur as manifestations of psychiatric disorders or diabetes, but they may also be a consequence of pharmacologic treatment. Because adverse sexual reactions are presumed to be voluntarily underreported, the Arizona Sexual Experience Scale (ASEX), a validated measure designed to identify sexual side effects, was used prospectively in 4 MDD placebo-controlled trials. In these trials, as shown in Table 5 below, patients treated with Duloxetine delayed-release capsules experienced significantly more sexual dysfunction, as measured by the total score on the ASEX, than did patients treated with placebo. Gender analysis showed that this difference occurred only in males. Males treated with Duloxetine delayed-release capsules experienced more difficulty with ability to reach orgasm (ASEX Item 4) than males treated with placebo. Females did not experience more sexual dysfunction on Duloxetine delayed-release capsules than on placebo as measured by ASEX total score. Negative numbers signify an improvement from a baseline level of dysfunction, which is commonly seen in depressed patients. Physicians should routinely inquire about possible sexual side effects.

Table 5: Mean Change in ASEX Scores by Gender in MDD Placebo-Controlled Trials

Male Patientsa Female Patientsa
Duloxetine delayed-release capsules (n=175) Placebo (n=83) Duloxetine delayed-release capsules (n=241) Placebo (n=126)

ASEX Total (Items 1-5)

0.56b

-1.07

-1.15

-1.07

Item 1- Sex drive

-0.07

-0.12

-0.32

-0.24

Item 2 — Arousal

0.01

-0.26

-0.21

-0.18

Item 3 — Ability to achieve erection (men); Lubrication (women)

0.03

-0.25

-0.17

-0.18

Item 4 -Ease of reaching orgasm

0.40c

-0.24

-0.09

-0.13

Item 5 — Orgasm satisfaction

0.09

-0.13

-0.11

-0.17

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 indications for change from baseline to endpoint, duloxetine treatment was associated with mean increases of 0.23 mm Hg in systolic blood pressure and 0.73 mm Hg in diastolic blood pressure compared to mean decreases of 1.09 mm Hg systolic and 0.55 mm Hg diastolic in placebo-treated patients. There was no significant difference in the frequency of sustained (3 consecutive visits) elevated blood pressure [see Warnings and Precautions (5.3, 5.11)].

Duloxetine treatment, for up to 26 weeks in placebo-controlled trials across approved indications, typically caused a small increase in heart rate for change from baseline to endpoint compared to placebo of up to 1.37 beats per minute (increase of 1.20 beats per minute in duloxetine-treated patients, decrease of 0.17 beats per minute in placebo-treated patients).

Laboratory Changes in Adults

Duloxetine delayed-release capsule treatment in placebo-controlled clinical trials across approved indications, was associated with small mean increases from baseline to endpoint in ALT, AST, CPK, and alkaline phosphatase; infrequent, modest, transient, abnormal values were observed for these analytes in Duloxetine delayed-release capsules-treated patients when compared with placebo-treated patients [see Warnings and Precautions (5.2)]. High bicarbonate, cholesterol, and abnormal (high or low) potassium, were observed more frequently in Duloxetine delayed-release capsules treated patients compared to placebo.

Electrocardiogram Changes in Adults

The effect of duloxetine 160 mg and 200 mg administered twice daily to steady state was evaluated in a randomized, double-blinded, two-way crossover study in 117 healthy female subjects. No QT interval prolongation was detected. Duloxetine appears to be associated with concentration-dependent but not clinically meaningful QT shortening.

Other Adverse Reactions Observed During the Premarketing and Postmarketing Clinical Trial Evaluation of Duloxetine in Adults

Following is a list of treatment-emergent adverse reactions reported by patients treated with duloxetine in clinical trials. In clinical trials of all indications, 34,756 patients were treated with duloxetine. Of these, 26.9% (9337) took duloxetine for at least 6 months, and 12.4% (4317) for at least one year. The following listing is not intended to include reactions (1) already listed in previous tables or elsewhere in labeling, (2) for which a drug cause was remote, (3) which were so general as to be uninformative, (4) which were not considered to have significant clinical implications, or (5) which occurred at a rate equal to or less than placebo.

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

Cardiac DisordersFrequent: palpitations; Infrequent: myocardial infarction, tachycardia, and Takotsubo cardiomyopathy.

Ear and Labyrinth DisordersFrequent: vertigo; Infrequent: ear pain and tinnitus.

Endocrine DisordersInfrequent: hypothyroidism.

Eye DisordersFrequent: vision blurred; Infrequent: diplopia, dry eye, and visual impairment.

Gastrointestinal DisordersFrequent: flatulence; Infrequent: dysphagia, eructation, gastritis, gastrointestinal hemorrhage, halitosis, and stomatitis; Rare: gastric ulcer.

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

Infections and InfestationsInfrequent: gastroenteritis and laryngitis.

InvestigationsFrequent: weight increased, weight decreased; Infrequent: blood cholesterol increased.

Metabolism and Nutrition DisordersInfrequent: dehydration and hyperlipidemia; Rare: dyslipidemia.

Musculoskeletal and Connective Tissue DisordersFrequent: musculoskeletal pain; Infrequent: muscle tightness and muscle twitching.

Nervous System DisordersFrequent: dysgeusia, lethargy, and paraesthesia/hypoesthesia; Infrequent: disturbance in attention, dyskinesia, myoclonus, and poor quality sleep; Rare: dysarthria.

Psychiatric DisordersFrequent: abnormal dreams and sleep disorder; Infrequent: apathy, bruxism, disorientation/confusional state, irritability, mood swings, and suicide attempt; Rare: completed suicide.

Renal and Urinary DisordersFrequent: urinary frequency; Infrequent: dysuria, micturition urgency, nocturia, polyuria, and urine odor abnormal.

Reproductive System and Breast DisordersFrequent: anorgasmia/orgasm abnormal; Infrequent: menopausal symptoms, sexual dysfunction, and testicular pain; Rare: menstrual disorder.

Respiratory, Thoracic and Mediastinal DisordersFrequent: yawning, oropharyngeal pain; Infrequent: throat tightness.

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

Vascular DisordersFrequent: hot flush; Infrequent: flushing, orthostatic hypotension, and peripheral coldness.

Adverse Reactions Observed in Children and Adolescent Placebo-Controlled Clinical Trials

The adverse drug reaction profile observed in pediatric clinical trials (children and adolescents) was consistent with the adverse drug reaction profile observed in adult clinical trials. The specific adverse drug reactions observed in adult patients can be expected to be observed in pediatric patients (children and adolescents) [see Adverse Reactions (6.5)]. The most common (≥5% and twice placebo) adverse reactions observed in pediatric clinical trials include: nausea, diarrhea, decreased weight, and dizziness.

Table 6 provides the incidence of treatment-emergent adverse reactions in 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 placebo.

Table 6: Treatment-Emergent Adverse Reactions: Incidence of 2% or More and Greater than Placebo in three 10 — week Pediatric Placebo-Controlled Trialsa

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 Painb

13

10

Vomiting

9

4

Diarrhea

6

3

Dry Mouth

2

1

General Disorders and Administration Site Conditions

Fatiguec

7

5

Investigations

Decreased Weightd

14

6

Metabolism and Nutrition Disorders

Decreased Appetite

10

5

Nervous System Disorders

Headache

18

13

Somnolencee

11

6

Dizziness

8

4

Psychiatric Disorders

Insomniaf

7

4

Respiratory, Thoracic, and Mediastinal Disorders

Oropharyngeal Pain

4

2

Cough

3

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 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 insomnia, middle insomnia, and terminal insomnia.

Other adverse reactions that occurred at an incidence of less than 2% but were reported by more duloxetine treated patients than placebo treated patients and are associated Duloxetine delayed-release capsules treatment: abnormal dreams (including nightmare), anxiety, flushing (including hot flush), hyperhidrosis, palpitations, pulse increased, and tremor.

Discontinuation-emergent symptoms have been reported when stopping Duloxetine delayed-release capsules. The most commonly reported symptoms following discontinuation of Duloxetine delayed-release capsules in pediatric clinical trials have included headache, dizziness, insomnia, and abdominal pain [see Warnings and Precautions (5.7) and Adverse Reactions (6.2)].

Growth (Height and Weight) — Decreased appetite and weight loss have been observed in association with the use of SSRIs and SNRIs. Pediatric patients treated with Duloxetine delayed-release capsules in clinical trials experienced a 0.1kg mean decrease in weight at 10 weeks, compared with a mean weight gain of approximately 0.9 kg in placebo-treated 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 (14% 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 children [7 to 11 years of age] and 1.3 cm increase in adolescents [12 to 17 years of age]). While height increase was observed during these studies, a mean decrease of 1% in height percentile was observed (decrease of 2% in children [7 to 11 years of age] and increase of 0.3% in adolescents [12 to 17 years of age]). Weight and height should be monitored regularly in children and adolescents treated with Duloxetine delayed-release capsules.

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