ADVERSE REACTIONS
Cymbalta has been evaluated for safety in 2418 patients diagnosed with major depressive disorder who participated in multiple-dose premarketing trials, representing 1099 patient-years of exposure. Among these 2418 Cymbalta-treated patients, 1139 patients participated in eight 8- or 9-week, placebo-controlled trials at doses ranging from 40 to 120 mg/day, while the remaining 1279 patients were followed for up to 1 year in an open-label safety study using flexible doses from 80 to 120 mg/day. Two placebo-controlled studies with doses of 80 and 120 mg/day had 6-month maintenance extensions. Of these 2418 patients, 993 Cymbalta-treated patients were exposed for at least 180 days and 445 Cymbalta-treated patients were exposed for at least 1 year.
Cymbalta has also been evaluated for safety in 1074 patients with diabetic peripheral neuropathy representing 472 patient-years of exposure. Among these 1074 Cymbalta-treated patients, 568 patients participated in two 12- to 13-week, placebo-controlled trials at doses ranging from 20 to 120 mg/day. An additional 449 patients were enrolled in an open-label safety study using 120 mg/day for a duration of 6 months. Another 57 patients, originally treated with placebo, were exposed to Cymbalta for up to 12 months at 60 mg twice daily in an extension phase. Among these 1074 patients, 484 had 6 months of exposure to Cymbalta, and 220 had 12 months of exposure.
For both MDD and DPN clinical trials, adverse reactions were assessed by collecting adverse events, results of physical examinations, vital signs, weights, laboratory analyses, and ECGs.
Clinical investigators recorded adverse events using descriptive terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals experiencing adverse events, grouping similar types of events into a smaller number of standardized event categories is necessary. In the tables and tabulations that follow, MedDRA terminology has been used to classify reported adverse events.
The stated frequencies of adverse events represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. Events reported during the studies were not necessarily caused by the therapy, and the frequencies do not reflect investigator impression (assessment) of causality.
The cited figures provide the prescriber with some basis for estimating the relative contribution of drug and non-drug factors to the adverse event incidence rate in the population studied. The prescriber should be aware that the figures in the tables and tabulations cannot be used to predict the incidence of adverse events in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators.
Adverse Events Reported as Reasons for Discontinuation of Treatment in Placebo-Controlled Trials
Major Depressive Disorder
Approximately 10% of the 1139 patients who received Cymbalta in the MDD placebo-controlled trials discontinued treatment due to an adverse event, compared with 4% of the 777 patients receiving placebo. Nausea (Cymbalta 1.4%, placebo 0.1%) was the only common adverse event reported as reason for discontinuation and considered to be drug-related (i.e., discontinuation occurring in at least 1% of the Cymbalta-treated patients and at a rate of at least twice that of placebo).
Diabetic Peripheral Neuropathic Pain
Approximately 14% of the 568 patients who received Cymbalta in the DPN placebo-controlled trials discontinued treatment due to an adverse event, compared with 7% of the 223 patients receiving placebo. Nausea (Cymbalta 3.5%, placebo 0.4%), dizziness (Cymbalta 1.6%, placebo 0.4%), somnolence (Cymbalta 1.6%, placebo 0%) and fatigue (Cymbalta 1.1%, placebo 0%) were the common adverse events reported as reasons for discontinuation and considered to be drug-related (i.e., discontinuation occurring in at least 1% of the Cymbalta-treated patients and at a rate of at least twice that of placebo).
Adverse Events Occurring at an Incidence of 2% or More Among Cymbalta-Treated Patients in Placebo-Controlled Trials
Major Depressive Disorder
Table 1 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 MDD placebo-controlled trials and with an incidence greater than placebo. The most commonly observed adverse events in Cymbalta-treated MDD patients (incidence of 5% or greater and at least twice the incidence in placebo patients) were: nausea; dry mouth; constipation; decreased appetite; fatigue; somnolence; and increased sweating (see Table 1).
Table 1: Treatment-Emergent Adverse Events Incidence in MDD Placebo-Controlled TrialsEvents reported by at least 2% of patients treated with Cymbalta and more often with placebo. The following events were reported by at least 2% of patients treated with Cymbalta for MDD and had an incidence equal to or less than placebo: upper abdominal pain, palpitations, dyspepsia, back pain, arthralgia, headache, pharyngitis, cough, nasopharyngitis, and upper respiratory tract infection. | Percentage of Patients Reporting Event |
|---|
| System Organ Class / Adverse Event | Cymbalta
(N=1139) | Placebo
(N=777) |
|---|
| Gastrointestinal Disorders | | |
| Nausea | 20 | 7 |
| Dry mouth | 15 | 6 |
| Constipation | 11 | 4 |
| Diarrhea | 8 | 6 |
| Vomiting | 5 | 3 |
| Metabolism and Nutrition Disorders | | |
| Appetite decreasedTerm includes anorexia. | 8 | 2 |
| Investigations | | |
| Weight decreased | 2 | 1 |
| General Disorders and Administration Site Conditions | | |
| Fatigue | 8 | 4 |
| Nervous System Disorders | | |
| Dizziness | 9 | 5 |
| Somnolence | 7 | 3 |
| Tremor | 3 | 1 |
| Skin and Subcutaneous Tissue Disorders | | |
| Sweating increased | 6 | 2 |
| Vascular Disorders | | |
| Hot flushes | 2 | 1 |
| Eye Disorders | | |
| Vision blurred | 4 | 1 |
| Psychiatric Disorders | | |
| InsomniaTerm includes middle insomnia. | 11 | 6 |
| Anxiety | 3 | 2 |
| Libido decreased | 3 | 1 |
| Orgasm abnormalTerm includes anorgasmia. | 3 | 1 |
| Reproductive System and Breast Disorders | | |
| Erectile dysfunctionMale patients only. | 4 | 1 |
| Ejaculation delayed | 3 | 1 |
| Ejaculatory dysfunction,Term includes ejaculation disorder and ejaculation failure. | 3 | 1 |
Diabetic Peripheral Neuropathic Pain
Table 2 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 DPN placebo-controlled trials (doses of 20 to 120 mg/day) and with an incidence greater than placebo. The most commonly observed adverse events in Cymbalta-treated DPN patients (incidence of 5% or greater and at least twice the incidence in placebo patients) were: nausea; somnolence; dizziness; constipation; dry mouth; hyperhidrosis; decreased appetite; and asthenia (see Table 2).
Table 2: Treatment-Emergent Adverse Events Incidence in DPN Placebo-Controlled TrialsEvents reported by at least 2% of patients treated with Cymbalta and more often than placebo. The following events were reported by at least 2% of patients treated with Cymbalta for DPN and had an incidence equal to or less than placebo: edema peripheral, influenza, upper respiratory tract infection, back pain, arthralgia, pain in extremity, and pruritus. | Percentage of Patients Reporting Event |
System Organ Class /
Adverse Event | Cymbalta
60 mg BID
(N=225) | Cymbalta
60 mg QD
(N=228) | Cymbalta
20 mg QD
(N=115) | Placebo
(N=223) |
| Gastrointestinal Disorders | | | | |
| Nausea | 30 | 22 | 14 | 9 |
| Constipation | 15 | 11 | 5 | 3 |
| Diarrhea | 7 | 11 | 13 | 6 |
| Dry mouth | 12 | 7 | 5 | 4 |
| Vomiting | 5 | 5 | 6 | 4 |
| Dyspepsia | 4 | 4 | 4 | 3 |
| Loose stools | 2 | 3 | 2 | 1 |
| General Disorders and Administration Site Conditions | | | | |
| Fatigue | 12 | 10 | 2 | 5 |
| Asthenia | 8 | 4 | 2 | 1 |
| Pyrexia | 3 | 1 | 2 | 1 |
| Infections and Infestations | | | | |
| Nasopharyngitis | 9 | 7 | 9 | 5 |
| Metabolism and Nutrition Disorders | | | | |
| Decreased appetite | 11 | 4 | 3 | <1 |
| Anorexia | 5 | 3 | 3 | <1 |
| Musculoskeletal and Connective Tissue Disorders | | | | |
| Muscle cramp | 4 | 4 | 5 | 3 |
| Myalgia | 4 | 1 | 3 | <1 |
| Nervous System Disorders | | | | |
| Somnolence | 21 | 15 | 7 | 5 |
| Headache | 15 | 13 | 13 | 10 |
| Dizziness | 17 | 14 | 6 | 6 |
| Tremor | 5 | 1 | 0 | 0 |
| Psychiatric Disorders | | | | |
| Insomnia | 13 | 8 | 9 | 7 |
| Renal and Urinary Disorders | | | | |
| Pollakiuria | 5 | 1 | 3 | 2 |
| Reproductive System and Breast Disorders | | | | |
| Erectile dysfunctionMale patients only. | 4 | 1 | 0 | 0 |
| Respiratory, Thoracic and Mediastinal Disorders | | | | |
| Cough | 5 | 3 | 6 | 4 |
| Pharyngolaryngeal pain | 6 | 1 | 3 | 1 |
| Skin and Subcutaneous Tissue Disorders | | | | |
| Hyperhidrosis | 8 | 6 | 6 | 2 |
Adverse events seen in men and women were generally similar except for effects on sexual function (described below). Clinical studies of Cymbalta did not suggest a difference in adverse event rates in people over or under 65 years of age. There were too few non-Caucasian patients studied to determine if these patients responded differently from Caucasian patients.
Effects on Male and Female Sexual Function
Although changes in sexual desire, sexual performance and sexual satisfaction often occur as manifestations of a psychiatric disorder, they may also be a consequence of pharmacologic treatment. Reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance and satisfaction are difficult to obtain, however, in part because patients and physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance cited in product labeling are likely to underestimate their actual incidence. Table 3 displays the incidence of sexual side effects spontaneously reported by at least 2% of either male or female patients taking Cymbalta in MDD placebo-controlled trials.
Table 3: Treatment-Emergent Sexual Dysfunction-Related Adverse Events Incidence in MDD Placebo-Controlled TrialsEvents reported by at least 2% of patients treated with Cymbalta and more often than with placebo. |
NA=Not applicable.
|
| Percentage of Patients Reporting Event |
| % Male Patients | % Female Patients |
| Adverse Event | Cymbalta
(N=378) | Placebo
(N=247) | Cymbalta
(N=761) | Placebo
(N=530) |
| Orgasm abnormalTerm includes anorgasmia. | 4 | 1 | 2 | 0 |
| Ejaculatory dysfunctionTerm includes ejaculation disorder and ejaculation failure. | 3 | 1 | NA | NA |
| Libido decreased | 6 | 2 | 1 | 0 |
| Erectile dysfunction | 4 | 1 | NA | NA |
| Ejaculation delayed | 3 | 1 | NA | NA |
Because adverse sexual events 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 4 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. These studies did not, however, include an active control drug with known effects on female sexual dysfunction, so that there is no evidence that its effects differ from other antidepressants. 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 4: Mean Change in ASEX Scores by Gender in MDD Placebo-Controlled Trials |
n=Number of patients with non-missing change score for ASEX total.
|
| Male Patients | Female Patients |
| Cymbalta
(n=175) | Placebo
(n=83) | Cymbalta
(n=241) | Placebo
(n=126) |
| ASEX Total (Items 1-5) | 0.56p=0.013 versus placebo. | -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 | 0.40p<0.001 versus placebo. | -0.24 | -0.09 | -0.13 |
| Item 5 — Orgasm satisfaction | 0.09 | -0.13 | -0.11 | -0.17 |
Urinary Hesitation
Cymbalta is in a class of drugs known to affect urethral resistance. If symptoms of urinary hesitation develop during treatment with Cymbalta, consideration should be given to the possibility that they might be drug-related.
Laboratory Changes
Cymbalta treatment, for up to 9-weeks in MDD or 13-weeks in DPN 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 PRECAUTIONS).
Vital Sign Changes
Cymbalta treatment, for up to 9-weeks in MDD placebo-controlled clinical trials of 40 to 120 mg daily doses caused increases in blood pressure, averaging 2 mm Hg systolic and 0.5 mm Hg diastolic compared to placebo and an increase in the incidence of at least one measurement of systolic blood pressure over 140 mm Hg (see PRECAUTIONS).
Cymbalta treatment, for up to 9-weeks in MDD placebo-controlled clinical trials and for up to 13-weeks in DPN placebo-controlled trials caused a small increase in heart rate compared to placebo of about 2 beats per minute.
Weight Changes
In MDD placebo-controlled clinical trials, patients treated with Cymbalta for up to 9-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.
Electrocardiogram Changes
Electrocardiograms were obtained from 321 Cymbalta-treated patients with major depressive disorder and 169 placebo-treated patients in clinical trials lasting up to 8-weeks. The rate-corrected QT (QTc) interval in Cymbalta-treated patients did not differ from that seen in placebo-treated patients. No clinically significant differences were observed for QT, PR, and QRS intervals between Cymbalta-treated and placebo-treated patients.
Electrocardiograms were obtained from 528 Cymbalta-treated patients with DPN and 205 placebo-treated patients in clinical trials lasting up to 13-weeks. The rate-corrected QT (QTc) interval in Cymbalta-treated patients did not differ from that seen in placebo-treated patients. No clinically significant differences were observed for QT, PR, QRS, or QTc measurements between Cymbalta-treated and placebo-treated patients.
Other Adverse Events Observed During the Premarketing and Postmarketing Clinical Trial Evaluation of Cymbalta for MDD and the Pain of DPN
Following is a list of modified MedDRA terms that reflect treatment-emergent adverse events as defined in the introduction to the ADVERSE REACTIONS section reported by patients treated with Cymbalta at multiple doses throughout the dose range studied during any phase of a trial within the premarketing and postmarketing database. The events included are those not already listed in both Table 1 and Table 2 and not considered in the WARNINGS and PRECAUTIONS sections. The events were reported with an incidence of greater than or equal to 0.05% and by more than one patient, are not common as background events and were considered possibly drug related (e.g., because of the drug's pharmacology) or potentially important.
It is important to emphasize that, although the events reported occurred during treatment with Cymbalta, they were not necessarily caused by it. Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients.
Blood and Lymphatic System Disorders — Infrequent: anemia, leukopenia, increased white blood cell count, lymphadenopathy, and thrombocytopenia.
Cardiac Disorders — Frequent: palpitations; Infrequent: atrial fibrillation, bundle branch block right, cardiac failure, cardiac failure congestive, coronary artery disease, myocardial infarction, and tachycardia.
Ear and Labyrinth Disorders — Frequent: vertigo.
Eye Disorders — Frequent: vision blurred; Infrequent: diplopia, glaucoma, keroconjunctivitis sicca, macular degeneration, maculopathy, photopsia, retinal detachment, and visual disturbance.
Gastrointestinal Disorders — Frequent: dyspepsia and gastritis; Infrequent: apthous stomatitis, blood in stool, colitis, diverticulitis, dysphagia, eructation, esophageal stenosis acquired, gastric irritation, gastric ulcer, gastroenteritis, gingivitis, impaired gastric emptying, irritable bowel syndrome, lower abdominal pain, melena, and stomatitis.
General Disorders and Administration Site Conditions — Frequent: asthenia; Infrequent: edema, feeling abnormal, feeling hot and/or cold, feeling jittery, influenza-like illness, malaise, rigors, and thirst.
Hepato-biliary Disorders — Infrequent: hepatic steatosis.
Investigations — Frequent: weight decreased; Infrequent: blood cholesterol increased, blood creatinine increased, urine output decreased, and weight increased.
Metabolism and Nutrition Disorders — Frequent: hypoglycemia and increased appetite; Infrequent: dehydration, dyslipidemia, hypercholesterolemia, hyperlipidemia, and hypertriglyceridemia.
Musculoskeletal and Connective Tissue Disorders — Frequent: muscle tightness and muscle twitching; Infrequent: muscular weakness.
Nervous System Disorders — Frequent: dysgeusia and hypoesthesia; Infrequent: ataxia and dysarthria.
Psychiatric Disorders — Frequent: anorgasmia, anxiety, hypersomnia, initial insomnia, irritability, lethargy, libido decreased, middle insomnia, nervousness, nightmare, restlessness, and sleep disorder; Infrequent: agitation, bruxism, completed suicide, disorientation, loss of libido, mania, mood swings, orgasm abnormal, pressure of speech, sluggishness, suicide attempt, and tension.
Renal and Urinary Disorders — Frequent: dysuria and urinary hesitation; Infrequent: micturition urgency, nephropathy, nocturia, urinary incontinence, urinary retention, and urine flow decreased.
Reproductive System and Breast Disorders — Frequent: ejaculation delayed and ejaculation disorder.
Respiratory, Thoracic and Mediastinal Disorders — Frequent: yawning; Infrequent: oropharyngeal swelling.
Skin and Subcutaneous Tissue Disorders — Frequent: night sweats, pruritus, rash, and skin ulcer; Infrequent: acne, alopecia, cold sweat, ecchymosis, eczema, erythema, erythematous rash, exfoliative dermatitis, face edema, hyperkeratosis, increased tendency to bruise, photosensitivity reaction, and pruritic rash.
Vascular Disorders — Frequent: hot flush; Infrequent: flushing, hypertensive crisis, peripheral coldness, peripheral edema, and phlebitis.
Postmarketing Spontaneous Reports
Adverse events reported rarely since market introduction that were temporally related to Cymbalta therapy include: hallucinations, rash, and urinary retention. The following adverse events were reported very rarely: alanine aminotransferase increased, alkaline phosphatase increased, anaphylactic reaction, angioneurotic edema, aspartate aminotransferase increased, bilirubin increased, extrapyramidal disorder, glaucoma, hepatitis, hyponatremia, jaundice, orthostatic hypotension (especially at the initiation of treatment), serotonin syndrome, Stevens-Johnson Syndrome, syncope (especially at initiation of treatment), syndrome of inappropriate antidiuretic hormone secretion (SIADH), and urticaria.
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