Duloxetine Hydrochloride (Page 5 of 15)

6.2 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%).

6.3 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.

6.4 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

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.
	Percentage of Patients	Reporting Reaction
Adverse 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

6.5 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}

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 <65 years.
c Events for which there was a significant dose-dependent relationship in fixed-dose studies, excluding three MDD studies which did not have a placebo lead-in period or dose titration.
d 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
	Percentage of Patients	Reporting Reaction
System Organ Class / Adverse Reaction	Duloxetine ( N = 4797 )	Placebo ( N = 3303 )
Cardiac Disorders Palpitations	2	1
Eye Disorders Vision blurred	3	1
Gastrointestinal Disorders
Nauseac	25	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

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

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
	Percentage of Patients	Reporting Reaction
System Organ Class / Adverse Reaction	Duloxetine ( 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	0
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