Duloxetine (Page 4 of 12)

5.12 Clinically Important Drug Interactions

Both CYP1A2 and CYP2D6 are responsible for duloxetine metabolism.

Potential for Other Drugs to Affect duloxetine

CYP1A2 Inhibitors — Co-administration of duloxetine with potent CYP1A2 inhibitors should be avoided [see Drug Interactions (7.1)].

CYP2D6 Inhibitors — Because CYP2D6 is involved in duloxetine metabolism, concomitant use of duloxetine with potent inhibitors of CYP2D6 would be expected to, and does, result in higher concentrations (on average of 60%) of duloxetine [see Drug Interactions (7.2)].

Potential for duloxetine to Affect Other Drugs

Drugs Metabolized by CYP2D6 — Co-administration of duloxetine with drugs that are extensively metabolized by CYP2D6 and that have a narrow therapeutic index, including certain antidepressants (tricyclic antidepressants [TCAs], such as nortriptyline, amitriptyline, and imipramine), phenothiazines and Type 1C antiarrhythmics (e.g., propafenone, flecainide), should be approached with caution. Plasma TCA concentrations may need to be monitored and the dose of the TCA may need to be reduced if a TCA is co-administered with duloxetine. Because of the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, duloxetine and thioridazine should not be co-administered [see Drug Interactions (7.9)].

Other Clinically Important Drug Interactions

Alcohol — Use of duloxetine concomitantly with heavy alcohol intake may be associated with severe liver injury. For this reason, duloxetine should not be prescribed for patients with substantial alcohol use [see Warnings and Precautions (5.2) and Drug Interactions (7.15)].

CNS Acting Drugs — Given the primary CNS effects of duloxetine, it should be used with caution when it is taken in combination with or substituted for other centrally acting drugs, including those with a similar mechanism of action [see Warnings and Precautions (5.12) and Drug Interactions (7.16)].

5.13 Hyponatremia

Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including duloxetine. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported and appeared to be reversible when duloxetine was discontinued. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk [see Use in Specific Populations (8.5)]. Discontinuation of duloxetine should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.
Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. More severe and/or acute cases have been associated with hallucination, syncope, seizure, coma, respiratory arrest, and death.

5.14 Use in Patients with Concomitant Illness

Clinical experience with duloxetine in patients with concomitant systemic illnesses is limited. There is no information on the effect that alterations in gastric motility may have on the stability of duloxetine’s enteric coating. In extremely acidic conditions, duloxetine, unprotected by the enteric coating, may undergo hydrolysis to form naphthol. Caution is advised in using duloxetine in patients with conditions that may slow gastric emptying (e.g., some diabetics).
Duloxetine has not been systematically evaluated in patients with a recent history of myocardial infarction or unstable coronary artery disease. Patients with these diagnoses were generally excluded from clinical studies during the product’s premarketing testing.
Hepatic Impairment — Avoid use in patients with chronic liver disease or cirrhosis [see Dosage and Administration (2.6), Warnings and Precautions (5.2), and Use in Specific Populations (8.9)].
Severe Renal Impairment — Avoid use in patients with severe renal impairment, GFR <30 mL/min. Increased plasma concentration of duloxetine, and especially of its metabolites, occur in patients with end-stage renal disease (requiring dialysis) [see Dosage and Administration (2.6) and Use in Specific Populations (8.10)].
Glycemic Control in Patients with Diabetes — As observed in DPNP trials, duloxetine treatment worsens glycemic control in some patients with diabetes. In three clinical trials of duloxetine for the management of neuropathic pain associated with diabetic peripheral neuropathy, the mean duration of diabetes was approximately 12 years, the mean baseline fasting blood glucose was 176 mg/dL, and the mean baseline hemoglobin A1c (HbA1c ) was 7.8%. In the 12-week acute treatment phase of these studies, duloxetine was associated with a small increase in mean fasting blood glucose as compared to placebo. In the extension phase of these studies, which lasted up to 52 weeks, mean fasting blood glucose increased by 12 mg/dL in the duloxetine group and decreased by 11.5 mg/dL in the routine care group. HbA1c increased by 0.5% in the duloxetine and by 0.2% in the routine care groups.

5.15 Urinary Hesitation and Retention

Duloxetine is in a class of drugs known to affect urethral resistance. If symptoms of urinary hesitation develop during treatment with duloxetine, consideration should be given to the possibility that they might be drug-related. In post marketing experience, cases of urinary retention have been observed. In some instances of urinary retention associated with duloxetine use, hospitalization and/or catheterization has been needed.

6 ADVERSE REACTIONS

The following serious adverse reactions are described below and elsewhere in the labeling:

Suicidal Thoughts and Behaviors in Children, Adolescents and Young Adults [see Boxed Warning and Warnings and Precautions (5.1)]
Hepatotoxicity [see Warnings and Precautions (5.2)]
Orthostatic Hypotension, Falls and Syncope [see Warnings and Precautions (5.3)]
Serotonin Syndrome [see Warnings and Precautions (5.4)]
Abnormal Bleeding [see Warnings and Precautions (5.5)]
Severe Skin Reactions [see Warnings and Precautions (5.6)]
Discontinuation of Treatment with duloxetine [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)]
Effect on 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)]

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)].
Information describing two additional clinical studies in which efficacy was not demonstrated in patients ages 7 to 17 years is approved for Eli Lilly and Company, Inc.’s duloxetine delayed-release capsules. Other pediatric use information for patients ages 7 to 17 years is approved for Eli Lilly and Company, Inc.’s duloxetine delayed-release capsules. However, due to Eli Lilly and Company, Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.
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-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-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-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-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 Indicationsa

Adverse Reaction

Percentage of Patients Reporting Reaction

Duloxetine(N=8100)

Placebo(N=5655)

Nauseac

23

8

Headache

14

12

Dry mouth

13

5

Somnolencee

10

3

Fatigueb,c

9

5

Insomniad

9

5

Constipationc

9

4

Dizzinessc

9

5

Diarrhea

9

6

Decreased appetitec

7

2

Hyperhidrosisc

6

1

Abdominal painf

5

4

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 Trialsa

System Organ Class / Adverse Reaction

Percentage of Patients Reporting Reaction

Duloxetine (N=4797)

Placebo (N=3303)

Cardiac Disorders Palpitations

2

1

Eye Disorders Vision blurred

3

1

Gastrointestinal Disorders Nauseac Dry mouthConstipationc DiarrheaAbdominal paind Vomiting

23149954

864642

General Disorders and Administration Site Conditions Fatiguee

9

5

Metabolism and Nutrition Disorders Decreased appetitec

6

2

Nervous System Disorders HeadacheDizzinessc Somnolencef Tremor

14993

14531

Psychiatric Disorders Insomniag Agitationh Anxiety

943

522

Reproductive System and Breast Disorders Erectile dysfunctionEjaculation delayedc Libido decreasedi Orgasm abnormalj

4232

111<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.
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 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 (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 (N=3303)

Placebo (N=2352)

Gastrointestinal Disorders NauseaDry Mouthb Constipationb DiarrheaAbdominal Painc VomitingDyspepsia

2311109532

7335421

General Disorders and Administration Site Conditions Fatigued

11

5

Infections and Infestations NasopharyngitisUpper Respiratory Tract InfectionInfluenza

432

432

Metabolism and Nutrition Disorders Decreased Appetiteb

8

1

Musculoskeletal and Connective Tissue Musculoskeletal Paine Muscle Spasms

32

32

Nervous System Disorders HeadacheSomnolenceb,f DizzinessParaesthesiag Tremorb

1311922

8352<1

Psychiatric Disorders Insomniab, h Agitationi

103

51

Reproductive System and Breast Disorders Erectile Dysfunctionb Ejaculation Disorderj

42

<1<1

Respiratory, Thoracic, and Mediastinal Disorders Cough

2

2

Skin and Subcutaneous Tissue Disorders Hyperhidrosis

6

1

Vascular Disorders Flushingk Blood pressure increasedl

32

11

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 includes 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 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 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 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 (n=175)

Placebo(n=83)

Duloxetine (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 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-treated patients when compared with placebo-treated patients [see Warnings and Precautions (5.2)]. High bicarbonate, cholesterol, and abnormal (high or low) potassium, were observed more frequently in duloxetine treated patients compared to placebo.
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 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 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 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 (N=476)

Placebo (N=362)

Gastrointestinal DisordersNauseaAbdominal Painb VomitingDiarrheaDry Mouth

1813962

810431

General Disorders and Administration Site Conditions Fatiguec

7

5

Investigations Decreased Weightd

14

6

Metabolism and Nutrition Disorders Decreased Appetite

10

5

Nervous System Disorders Headache Somnolencee Dizziness

18 11 8

13 6 4

Psychiatric Disorders Insomniaf

7

4

Respiratory, Thoracic, and Mediastinal Disorders Oropharyngeal Pain Cough

4 3

2 1

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; N=354 Placebo).

e Also includes hypersomnia and sedation.

f Also includes initial insomnia, insomnia, middle insomnia, and terminal insomnia.

Other adverse reactions that occurred at an incidence of less than 2% but were reported by more duloxetine treated patients than placebo treated patients and are associated duloxetine 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. The most commonly reported symptoms following discontinuation of duloxetine 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. In studies up to 9 months, duloxetine-treated pediatric patients experienced an increase in height of 1.7 cm on average (2.2 cm increase in 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.
Information describing two additional clinical studies in which efficacy was not demonstrated in patients ages 7 to 17 years is approved for Eli Lilly and Company, Inc.’s duloxetine delayed-release capsules. Other pediatric use information for patients ages 7 to 17 years is approved for Eli Lilly and Company, Inc.’s duloxetine delayed-release capsules. However, due to Eli Lilly and Company, Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

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