ADVERSE REACTIONS
Clinical Trial Data Sources
The data described below reflect exposure to duloxetine in placebo-controlled trials for MDD (N=2,327), GAD (N=668), DPNP (N=568), and FM (N=876). The population studied was 17 to 89 years of age; 64.8%, 64.7%, 38.7%, and 94.6% female; and 85.5%, 84.6%, 77.6%, and 88% Caucasian for MDD, GAD, DPNP, and FM, respectively. Most patients received doses of a total of 60 to 120 mg per day [see Clinical Studies ].
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
Major Depressive Disorder — Approximately 9% (209/2,327) of the patients who received duloxetine in placebo-controlled trials for MDD discontinued treatment due to an adverse reaction, compared with 4.7% (68/1,460) of the patients receiving placebo. Nausea (duloxetine 1.3%, placebo 0.5%) 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 15.3% (102/668) of the patients who received duloxetine in placebo-controlled trials for GAD discontinued treatment due to an adverse reaction, compared with 4.0% (20/495) for placebo. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine 3.7%, placebo 0.2%), vomiting (duloxetine 1.3%, placebo 0.0%), and dizziness (duloxetine 1.0%, placebo 0.2%).
Diabetic Peripheral Neuropathic Pain — Approximately 14.3% (81/568) of the patients who received duloxetine in placebo-controlled trials for DPNP discontinued treatment due to an adverse reaction, compared with 7.2% (16/223) for placebo. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) were nausea (duloxetine 3.5%, placebo 0.4%), dizziness (duloxetine 1.6%, placebo 0.4%), somnolence (duloxetine 1.6%, placebo 0.0%), and fatigue (duloxetine 1.1%, placebo 0.0%).
Fibromyalgia — Approximately 19.5% (171/876) 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 11.8% (63/535) for placebo. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine 1.9%, placebo 0.7%), somnolence (duloxetine 1.5%, placebo 0.0%), and fatigue (duloxetine 1.3%, placebo 0.2%).
Adverse Reactions Occurring at an Incidence of 5% or More and at least Twice Placebo Among Duloxetine-Treated Patients in Placebo-Controlled Trials
Pooled Trials for all Approved Indications — 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, constipation, somnolence, hyperhidrosis, and decreased appetite.
In addition to the adverse reactions listed above, DPNP trials also included dizziness and asthenia.
Adverse Reactions Occurring at an Incidence of 5% or More Among Duloxetine-Treated Patients in 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 in Placebo-Controlled Trials of Approved Indications |
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.
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b Also includes asthenia
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c Also includes middle insomnia, early morning awakening, and initial insomnia
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d Also includes hypersomnia and sedation
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e Also includes anorexia
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| | Percentage of Patients Reporting Reaction |
| Adverse Reaction | Cymbalta
(N=4843) | Placebo
(N=3048) |
| Nausea | 25 | 9 |
| Headache | 16 | 15 |
| Dry mouth | 14 | 6 |
| Fatigueb | 11 | 6 |
| Insomniaa,c | 11 | 7 |
| Dizziness | 11 | 6 |
| Somnolencea,d | 11 | 3 |
| Constipationa | 11 | 4 |
| Diarrhea | 10 | 7 |
| Decreased appetitea,e | 8 | 2 |
| Hyperhidrosis | 7 | 2 |
Adverse Reactions Occurring at an Incidence of 2% or More Among Duloxetine-Treated Patients in 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 in MDD and GAD Placebo-Controlled Trials |
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.
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b Also includes abdominal pain upper, abdominal pain lower, abdominal tenderness, abdominal discomfort, and gastrointestinal pain
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c Also includes asthenia
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d Also includes anorexia
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e Also includes hypersomnia and sedation
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f Also includes middle insomnia, early morning awakening, and initial insomnia
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g Also includes feeling jittery, nervousness, restlessness, tension, and psychomotor agitation
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h Also includes loss of libido
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i Also includes anorgasmia
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j Also includes nightmare
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k Male patients only
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l Also includes ejaculation failure and ejaculation dysfunction
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| | Percentage of Patients Reporting Reaction |
| System Organ Class / Adverse Reaction | Cymbalta
(N=2995) | Placebo
(N=1955) |
| Cardiac Disorders | | |
| Palpitations | 2 | 2 |
| Eye Disorders | | |
| Vision blurred | 3 | 2 |
| Gastrointestinal Disorders | | |
| Nausea | 25 | 9 |
| Dry mouth | 15 | 6 |
| Diarrhea | 10 | 7 |
| Constipationa | 10 | 4 |
| Abdominal painb | 4 | 4 |
| Vomiting | 5 | 2 |
| General Disorders and Administration Site Conditions | | |
| Fatiguec | 10 | 6 |
| Investigations | | |
| Weight decreaseda | 2 | <1 |
| Metabolism and Nutrition Disorders | | |
| Decreased appetited | 7 | 2 |
| Nervous System Disorders | | |
| Dizziness | 10 | 6 |
| Somnolencee | 10 | 4 |
| Tremor | 3 | <1 |
| Psychiatric Disorders | | |
| Insomniaf | 10 | 6 |
| Agitationg | 5 | 3 |
| Anxiety | 3 | 2 |
| Libido decreasedh | 4 | 1 |
| Orgasm abnormali | 3 | <1 |
| Abnormal dreamsj | 2 | 1 |
| Reproductive System and Breast Disorders | | |
| Erectile dysfunctionk | 5 | 1 |
| Ejaculation delayeda,k | 3 | <1 |
| Ejaculation disorderk,l | 2 | <1 |
| Respiratory, Thoracic, and Mediastinal Disorders | | |
| Yawning | 2 | <1 |
| Skin and Subcutaneous Tissue Disorders | | |
| Hyperhidrosis | 6 | 2 |
| Vascular Disorders | | |
| Hot flush | 2 | <1 |
Diabetic Peripheral Neuropathic Pain — Table 4 gives the incidence of treatment-emergent adverse events that occurred in 2% or more of patients treated with Cymbalta in the premarketing acute phase of DPNP placebo-controlled trials (doses of 20 to 120 mg/day) and with an incidence greater than placebo.
Table 4: Treatment-Emergent Adverse Reactions Incidence of 2% or More in DPNP Placebo-Controlled Trials |
a Male patients only.
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| | Percentage of Patients Reporting Reaction |
System Organ Class /
Adverse Reaction | Cymbalta
20 mg once daily
(N=115) | Cymbalta
60 mg once daily
(N=228) | Cymbalta
60 mg twice daily
(N=225) | Placebo
(N=223) |
| Gastrointestinal Disorders | | | | |
| Nausea | 14 | 22 | 30 | 9 |
| Constipation | 5 | 11 | 15 | 3 |
| Diarrhea | 13 | 11 | 7 | 6 |
| Dry mouth | 5 | 7 | 12 | 4 |
| Vomiting | 6 | 5 | 5 | 4 |
| Dyspepsia | 4 | 4 | 4 | 3 |
| Loose stools | 2 | 3 | 2 | 1 |
General Disorders and Administration
Site Conditions | | | | |
| Fatigue | 2 | 10 | 12 | 5 |
| Asthenia | 2 | 4 | 8 | 1 |
| Pyrexia | 2 | 1 | 3 | 1 |
| Infections and Infestations | | | | |
| Nasopharyngitis | 9 | 7 | 9 | 5 |
| Metabolism and Nutrition Disorders | | | | |
| Decreased appetite | 3 | 4 | 11 | <1 |
| Anorexia | 3 | 3 | 5 | <1 |
Musculoskeletal and Connective Tissue
Disorders | | | | |
| Muscle cramp | 5 | 4 | 4 | 3 |
| Myalgia | 3 | 1 | 4 | <1 |
| Nervous System Disorders | | | | |
| Somnolence | 7 | 15 | 21 | 5 |
| Headache | 13 | 13 | 15 | 10 |
| Dizziness | 6 | 14 | 17 | 6 |
| Tremor | 0 | 1 | 5 | 0 |
| Psychiatric Disorders | | | | |
| Insomnia | 9 | 8 | 13 | 7 |
| Renal and Urinary Disorders | | | | |
| Pollakiuria | 3 | 1 | 5 | 2 |
| Reproductive System and Breast Disorders | | | | |
| Erectile dysfunctiona | 0 | 1 | 4 | 0 |
Respiratory, Thoracic and Mediastinal
Disorders | | | | |
| Cough | 6 | 3 | 5 | 4 |
| Pharyngolaryngeal pain | 3 | 1 | 6 | 1 |
Skin and Subcutaneous
Tissue Disorders | | | | |
| Hyperhidrosis | 6 | 6 | 8 | 2 |
Fibromyalgia — Table 5 gives the incidence of treatment-emergent adverse events that occurred in 2% or more of patients treated with Cymbalta in the premarketing acute phase of FM placebo-controlled trials and with an incidence greater than placebo.
Table 5: Treatment-Emergent Adverse Reactions: Incidence of 2% or More in Fibromyalgia Placebo-Controlled Trials |
a Male patients only (N = 46 duloxetine-treated patients versus 26 placebo patients)
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b Also includes asthenia
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c Also includes anorexia
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d Also includes hypersomnia and sedation
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e Also includes middle insomnia, early morning awakening, and initial insomnia
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f Also includes feeling jittery, nervousness, restlessness, tension, and psychomotor agitation
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g Also includes nightmare
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h Also includes anorgasmia
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i Also includes loss of libido
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j Also includes ejaculation failure and ejaculation dysfunction
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System Organ Class / Adverse Reaction | Percentage of Patients Reporting Reaction |
Cymbalta
(N=876) | Placebo
(N=535) |
| Cardiac Disorders | | |
| Palpitations | 2 | 2 |
| Eye Disorders | | |
| Vision blurred | 2 | 1 |
| Gastrointestinal Disorders | | |
| Nausea | 29 | 11 |
| Dry mouth | 18 | 5 |
| Constipation | 15 | 4 |
| Diarrhea | 12 | 8 |
| Dyspepsia | 5 | 3 |
| General Disorders and Administration Site Conditions | | |
| Fatigueb | 15 | 8 |
| Immune System Disorders | | |
| Seasonal allergy | 3 | 2 |
| Infections and Infestations | | |
| Upper respiratory tract infection | 7 | 6 |
| Urinary tract infection | 3 | 3 |
| Influenza | 2 | 2 |
| Gastroenteritis viral | 2 | 2 |
| Investigations | | |
| Weight increased | 2 | 1 |
| Metabolism and Nutrition Disorders | | |
| Decreased appetitec | 11 | 2 |
Musculoskeletal and Connective Tissue Disorders
| | |
| Musculoskeletal pain | 5 | 4 |
| Muscle spasms | 4 | 3 |
| Nervous System Disorders | | |
| Headache | 20 | 12 |
| Dizziness | 11 | 7 |
| Somnolenced | 11 | 3 |
| Tremor | 4 | 1 |
| Paraesthesia | 4 | 4 |
| Migraine | 3 | 3 |
| Dysgeusia | 3 | 1 |
| Psychiatric Disorders | | |
| Insomniae | 16 | 10 |
| Agitationf | 6 | 2 |
| Sleep disorder | 3 | 2 |
| Abnormal dreamsg | 3 | 1 |
| Orgasm abnormalh | 3 | <1 |
| Libido decreasedi | 2 | <1 |
| Reproductive System and Breast Disorders | | |
| Ejaculation disordera,j | 4 | 0 |
| Penis disordera | 2 | 0 |
| Respiratory, Thoracic, and Mediastinal Disorders | | |
| Cough | 4 | 3 |
| Pharyngolaryngeal pain | 3 | 3 |
| Skin and Subcutaneous Tissue Disorders | | |
| Hyperhidrosis | 7 | 1 |
| Rash | 4 | 2 |
| Pruritis | 3 | 2 |
| Vascular Disorders | | |
| Hot flush | 3 | 2 |
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 Table 6 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 6: Mean Change in ASEX Scores by Gender in MDD Placebo-Controlled Trials |
a n=Number of patients with non-missing change score for ASEX total
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b p=0.013 versus placebo
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c p<0.001 versus placebo
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| | Male Patients a | Female Patients a |
| | Cymbalta
(n=175) | Placebo
(n=83) | Cymbalta
(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 |
Vital Sign Changes
In clinical trials across indications, relative to placebo, duloxetine treatment was associated with mean increases of up to 2.1 mm Hg in systolic blood pressure and up to 2.3 mm Hg in diastolic blood pressure. There was no significant difference in the frequency of sustained (3 consecutive visits) elevated blood pressure [see Warnings and Precautions (5.3 and 5.9)].
Duloxetine treatment, for up to 26 weeks in placebo-controlled trials typically caused a small increase in heart rate compared to placebo of up to 3-4 beats per minute.
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 DPN placebo-controlled clinical trials, patients treated with Cymbalta for up to 13-weeks experienced a mean weight loss of approximately 1.1 kg, compared with a mean weight gain of approximately 0.2 kg in placebo-treated patients. In fibromyalgia studies, patients treated with Cymbalta for up to 26 weeks experienced a mean weight loss of approximately 0.4 kg compared with a mean weight gain of approximately 0.3 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.
Laboratory Changes
Cymbalta treatment in placebo-controlled clinical trials, 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 Cymbalta-treated patients when compared with placebo-treated patients [see Warnings and Precautions].
Electrocardiogram Changes
Electrocardiograms were obtained from duloxetine-treated patients and placebo-treated patients in clinical trials lasting up to 13 weeks. No clinically significant differences were observed for QTc, QT, PR, and QRS intervals between duloxetine-treated and placebo-treated patients. There were no differences in clinically meaningful QTcF elevations between duloxetine and placebo. In a positive-controlled study in healthy volunteers using duloxetine up to 200 mg twice daily, no prolongation of the corrected QT interval was observed.
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, 27,229 patients were treated with duloxetine. Of these, 29% (7,886) took duloxetine for at least 6 months, and 13.3% (3,614) 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 and tachycardia.
Ear and Labyrinth Disorders — Frequent: vertigo; Infrequent: ear pain and tinnitus.
Endocrine Disorders — Infrequent: hypothyroidism.
Eye Disorders — Frequent: vision blurred; Infrequent: diplopia and visual disturbance.
Gastrointestinal Disorders — Frequent: flatulence; Infrequent: eructation, gastritis, halitosis, and stomatitis; Rare: gastric ulcer, hematochezia, and melena.
General Disorders and Administration Site Conditions — Frequent: chills/rigors; Infrequent: feeling abnormal, feeling hot and/or cold, malaise, and thirst; Rare: gait disturbance.
Infections and Infestations — Infrequent: gastroenteritis and laryngitis.
Investigations — Frequent: weight increased; 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 parasthesia/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 — Infrequent: dysuria, micturition urgency, nocturia, polyuria, and urine odor abnormal.
Reproductive System and Breast Disorders — Frequent: anorgasmia/orgasm abnormal; Infrequent: menopausal symptoms, and sexual dysfunction.
Respiratory, Thoracic and Mediastinal Disorders — Frequent: yawning; Infrequent: throat tightness.
Skin and Subcutaneous Tissue Disorders — 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.
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, erythema multiforme, extrapyramidal disorder, glaucoma, gynecological bleeding, hallucinations, hyperglycemia, hypersensitivity, hypertensive crisis, muscle spasm, rash, restless legs syndrome, seizures upon treatment discontinuation, supraventricular arrhythmia, tinnitus (upon treatment discontinuation), trismus, and urticaria.
Serious skin reactions including Stevens-Johnson Syndrome that have required drug discontinuation and/or hospitalization have been reported with duloxetine.
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