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Cymbalta (Duloxetine Hydrochloride) - Side Effects and Adverse Reactions

 
 



ADVERSE REACTIONS

Clinical Trial Data Sources

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

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

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

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

— 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). Major Depressive 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%). Generalized Anxiety Disorder

— 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%). Diabetic Peripheral Neuropathic Pain

— Approximately 17.5% (227/1294) of the patients who received duloxetine in 3 to 6 month placebo-controlled trials for FM discontinued treatment due to an adverse reaction, compared with 10.1% (96/955) for placebo. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine 2.0%, placebo 0.5%), headache (duloxetine 1.2%, placebo 0.3%), somnolence (duloxetine 1.1%, placebo 0.0%), and fatigue (duloxetine 1.1%, placebo 0.1%). Fibromyalgia

— 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 Pain due to Osteoarthritis

— 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%). Chronic Low Back Pain

Most Common Adverse Reactions

— The most commonly observed adverse reactions in Cymbalta-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. Pooled Trials for all Approved Indications

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

— The most commonly observed adverse reactions in Cymbalta-treated patients (as defined above) were nausea, dry mouth, constipation, somnolence, decreased appetite, hyperhidrosis, and agitation. Fibromyalgia

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

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

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

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

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

Also includes asthenia. b

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. c

Also includes initial insomnia, middle insomnia, and early morning awakening. d

Also includes hypersomnia and sedation. e

Also includes abdominal discomfort, abdominal pain lower, abdominal pain upper, abdominal tenderness, and gastrointestinal pain. f

Percentage of Patients Reporting Reaction
Adverse Reaction Cymbalta (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
Insomnia d 9 5
Constipation c 9 4
Dizziness c 9 5
Diarrhea 9 6
Decreased appetite c 7 2
Hyperhidrosis c 6 1
Abdominal pain f 5 4

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

— 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. Pooled MDD and GAD Trials Table 3

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

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. b

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

Also includes asthenia d

Also includes hypersomnia and sedation e

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

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

Also includes loss of libido h

Also includes anorgasmia i

Percentage of Patients Reporting Reaction
System Organ Class / Adverse Reaction Cymbalta (N=4797)
Placebo (N=3303)
Cardiac Disorders
Palpitations 2 1
Eye Disorders
Vision blurred 3 1
Gastrointestinal Disorders
Nausea b 23 8
Dry mouth 14 6
Constipation b 9 4
Diarrhea 9 6
Abdominal pain c 5 4
Vomiting 4 2
General Disorders and Administration Site Conditions
Fatigue d 9 5
Metabolism and Nutrition Disorders
Decreased appetite b 6 2
Nervous System Disorders
Headache 14 14
Dizziness b 9 5
Somnolence e 9 3
Tremor 3 1
Psychiatric Disorders
Insomnia f 9 5
Agitation g 4 2
Libido decreased h 3 1
Anxiety 3 2
Orgasm abnormal i 2 <1
Reproductive System and Breast Disorders
Erectile dysfunction 4 1
Ejaculation delayed b 2 1
Respiratory, Thoracic, and Mediastinal Disorders
Yawning 2 <1
Skin and Subcutaneous Tissue Disorders
Hyperhidrosis 6 2

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

Table 4: Treatment-Emergent Adverse Reactions: Incidence of 2% or More and Greater than Placebo in DPNP, FM, OA, and CLBP Placebo-Controlled Trials 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. a

Incidence of 120 mg/day is significantly greater than the incidence for 60 mg/day. b

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

Also includes asthenia d

Also includes myalgia and neck pain e

Also includes hypersomnia and sedation f

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

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

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

Also includes ejaculation failure j

Also includes hot flush k

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 l

System Organ Class / Adverse Reaction Percentage of Patients Reporting Reaction
Cymbalta (N=3303)
Placebo
(N=2352)
Gastrointestinal Disorders
Nausea 23 7
Dry Mouth b 11 3
Constipation b 10 3
Diarrhea 9 5
Abdominal Pain c 5 4
Vomiting 3 2
Dyspepsia 2 1
General Disorders and Administration Site Conditions
Fatigue d 11 5
Infections and Infestations
Nasopharyngitis 4 4
Upper Respiratory Tract Infection 3 3
Influenza 2 2
Metabolism and Nutrition Disorders
Decreased Appetite b 8 1
Musculoskeletal Pain Musculoskeletal and Connective Tissue
e
3
3
Muscle Spasms 2 2
Back Pain 3 3
Nervous System Disorders
Headache 13 8
Somnolence b,f 11 3
Dizziness 9 5
Paraesthesia g 2 2
Tremor b 2 <1
Psychiatric Disorders
Insomnia b,h 10 5
Agitation i 3 <1
Reproductive System and Breast Disorders
Erectile Dysfunction b 4 <1
Ejaculation Disorder j 2 <1
Respiratory, Thoracic, and Mediastinal Disorders
Cough 2 2
Oropharyngeal Pain b 2 2
Skin and Subcutaneous Tissue Disorders
Hyperhidrosis 6 1
Vascular Disorders
Flushing k 3 <1
Blood pressure increased l 2 1

Effects on Male and Female Sexual Function

Changes in sexual desire, sexual performance and sexual satisfaction often occur as manifestations of psychiatric disorders or diabetes, but they may also be a consequence of pharmacologic treatment. Because adverse sexual reactions are presumed to be voluntarily underreported, the Arizona Sexual Experience Scale (ASEX), a validated measure designed to identify sexual side effects, was used prospectively in 4 MDD placebo-controlled trials. In these trials, as shown in below, patients treated with Cymbalta 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 Cymbalta experienced more difficulty with ability to reach orgasm (ASEX Item 4) than males treated with placebo. Females did not experience more sexual dysfunction on Cymbalta 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

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

n=Number of patients with non-missing change score for ASEX total a

p=0.013 versus placebo b

p<0.001 versus placebo c

Male Patients a Female Patients a
Cymbalta (n=175)
Placebo (n=83)
Cymbalta (n=241)
Placebo (n=126)
ASEX Total (Items 1-5) 0.56 b -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 c -0.24 -0.09 -0.13
Item 5 — Orgasm satisfaction 0.09 -0.13 -0.11 -0.17

Vital Sign Changes

In placebo-controlled clinical trials across approved indications for change from baseline to endpoint, duloxetine treatment was associated with mean increases of 0.23 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 (and)] 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).

Weight Changes

In placebo-controlled clinical trials, MDD and GAD patients treated with Cymbalta for up to 10 weeks experienced a mean weight loss of approximately 0.5 kg, compared with a mean weight gain of approximately 0.2 kg in placebo-treated patients. In studies of DPNP, FM, OA, and CLBP, patients treated with Cymbalta for up to 26 weeks experienced a mean weight loss of approximately 0.6 kg compared with a mean weight gain of approximately 0.2 kg in placebo-treated patients. In one long-term fibromyalgia 60-week uncontrolled study, duloxetine patients had a mean weight increase of 0.7 kg. In one long-term CLBP 54-week study (13-week, placebo-controlled acute phase and 41-week, uncontrolled extension phase), duloxetine patients had a mean weight decrease of 0.6 kg in 13 weeks of acute phase compared to study entry, then a mean weight increase of 1.4 kg in 41 weeks of extension phase compared to end of acute phase.

Laboratory Changes

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

Electrocardiogram Changes

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

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

Following is a list of treatment-emergent adverse reactions reported by patients treated with duloxetine in clinical trials. In clinical trials of all indications, 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.

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

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

— hypothyroidism. Endocrine Disorders Infrequent:

— vision blurred; diplopia, dry eye, and visual impairment. Eye Disorders Frequent: Infrequent:

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

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

— gastroenteritis and laryngitis. Infections and Infestations Infrequent:

— weight increased, weight decreased; blood cholesterol increased. Investigations Frequent: Infrequent:

— dehydration and hyperlipidemia; dyslipidemia. Metabolism and Nutrition Disorders Infrequent: Rare:

— musculoskeletal pain; muscle tightness and muscle twitching. Musculoskeletal and Connective Tissue Disorders Frequent: Infrequent:

— dysgeusia, lethargy, and parasthesia/hypoesthesia; disturbance in attention, dyskinesia, myoclonus, and poor quality sleep; dysarthria. Nervous System Disorders Frequent: Infrequent: Rare:

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

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

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

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

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

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

Postmarketing Spontaneous Reports

The following adverse reactions have been identified during postapproval use of Cymbalta. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

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



REPORTS OF SUSPECTED CYMBALTA SIDE EFFECTS / ADVERSE REACTIONS

Below is a sample of reports where side effects / adverse reactions may be related to Cymbalta. The information is not vetted and should not be considered as verified clinical evidence.

Possible Cymbalta side effects / adverse reactions in 63 year old female

Reported by a consumer/non-health professional from United States on 2011-10-03

Patient: 63 year old female

Reactions: Nightmare

Suspect drug(s):
Cymbalta



Possible Cymbalta side effects / adverse reactions in 47 year old male

Reported by a physician from United States on 2011-10-03

Patient: 47 year old male

Reactions: Anaphylactic Reaction

Suspect drug(s):
Cymbalta

Other drugs received by patient: Zoloft



Possible Cymbalta side effects / adverse reactions in 45 year old female

Reported by a consumer/non-health professional from United States on 2011-10-03

Patient: 45 year old female

Reactions: Drug Ineffective, Brain Neoplasm, Convulsion

Suspect drug(s):
Prozac
    Dosage: unk unk, unknown

Cymbalta
    Dosage: 30 mg, qd
    Indication: Depression
    Start date: 2011-09-01
    End date: 2011-09-01

Prozac
    Dosage: unk, unknown
    Start date: 2011-09-01
    End date: 2011-09-01



See index of all Cymbalta side effect reports >>

Drug label data at the top of this Page last updated: 2014-07-17

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