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.

Cymbalta has also been evaluated for safety in 668 patients with generalized anxiety disorder representing 95 patient-years of exposure. These 668 patients participated in 9- or 10-week placebo-controlled trials at doses ranging from 60 mg once daily to 120 mg once daily. Of these 668 patients, 449 were exposed for at least 2 months to Cymbalta.

In the full cohort of placebo-controlled clinical trials for any indication, safety has been evaluated in 8504 patients treated with duloxetine and 6123 patients treated with placebo. In clinical trials, a total of 23,983 patients have been exposed to duloxetine. In duloxetine 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).

Generalized Anxiety Disorder

Approximately 16% of the 668 patients who received Cymbalta in the GAD placebo-controlled trials discontinued treatment due to an adverse event, compared with 4% of the 495 patients receiving placebo. Nausea (Cymbalta 3.7%, placebo 0.2%), vomiting (Cymbalta 1.4%, placebo 0%) and dizziness (Cymbalta 1.2%, placebo 0.2%) 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 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 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 2).

Table 2: Treatment-Emergent Adverse Events Incidence in MDD Placebo-Controlled Trials¹

Diabetic Peripheral Neuropathic Pain

Table 3 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 3).

Table 3: Treatment-Emergent Adverse Events Incidence in DPN Placebo-Controlled Trials¹

Generalized Anxiety Disorder

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 GAD placebo-controlled trials (doses of 60 to 120 mg once daily) and with an incidence greater than placebo. The most commonly observed adverse events in Cymbalta-treated GAD patients (incidence of 5% or greater and at least twice the incidence in placebo patients) were: nausea; fatigue; dry mouth; somnolence; constipation; insomnia; appetite decreased; hyperhidrosis; libido decreased; vomiting; ejaculation delayed; and erectile dysfunction (see Table 4).

Table 4: Treatment-Emergent Adverse Events Incidence in GAD Placebo-Controlled Trials¹

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 5 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 5: Treatment-Emergent Sexual Dysfunction-Related Adverse Events Incidence in MDD Placebo-Controlled Trials¹

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 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. 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 6: Mean Change in ASEX Scores by Gender in MDD Placebo-Controlled Trials

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, 9-10 weeks in GAD 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

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, averaging up to 2 mm Hg. There was no significant difference in the frequency of sustained (3 consecutive visits) elevated blood pressure (see PRECAUTIONS).

Duloxetine treatment, for up to 13-weeks in placebo-controlled trials typically caused a small increase in heart rate compared to placebo of up to 3 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.

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 BID, no prolongation of the corrected QT interval was observed.

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

Following is a list of MedDRA terms that reflect treatment-emergent adverse events as defined in the introduction to the ADVERSE REACTIONS section reported by patients treated with duloxetine at multiple doses throughout the dose range studied during any phase of a clinical trial within the premarketing and postmarketing database (23,983 patients, 10,649.5 patient-years of exposure). The events included are those not already listed in Tables 2 through 4 and not considered in the WARNINGS and PRECAUTIONS sections. The events were reported by more than one patient, are not common as background events and/or 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 and lymphadenopathy; Rare: leukopenia and thrombocytopenia.

Cardiac Disorders — Frequent: palpitations; Infrequent: atrial fibrillation, coronary artery disease, myocardial infarction, and tachycardia; Rare: bundle branch block right, cardiac failure, and cardiac failure congestive.

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

Eye Disorders — Frequent: vision blurred; Infrequent: conjunctivitis, diplopia, and visual disturbance; Rare: glaucoma, macular degeneration, maculopathy, photopsia, and retinal detachment.

Gastrointestinal Disorders —- Frequent: abdominal pain and flatulence; Infrequent: dysphagia, eructation, gastritis, halitosis, irritable bowel syndrome, and stomatitis; Rare: aphthous stomatitis, colitis,esophageal stenosis, gastric ulcer, gingivitis, hematochezia, impaired gastric emptying, and melena.

General Disorders and Administration Site Conditions — Frequent: chills/rigors; Infrequent: edema, edema peripheral, feeling abnormal, feeling hot and/or cold, influenza-like illness, malaise, and thirst; Rare: face edema and sluggishness.

Hepato-biliary Disorders — Rare: hepatic steatosis.

Infections and Infestations — Infrequent: gastroenteritis and laryngitis; Rare: diverticulitis.

Investigations —Frequent: weight decreased and weight increased; Infrequent: blood cholesterol increased; Rare: blood creatinine increased, urine output decreased, and white blood cell count increased.

Metabolism and Nutrition Disorders — Infrequent: dehydration, hypercholesterolemia, hyperlipidemia, hypoglycemia, and increased appetite; Rare: dyslipidemia and hypertriglyceridemia.

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

Nervous System Disorders — Frequent: dysgeusia, lethargy, and parasthesia/hypoesthesia; Infrequent: coordination abnormal, disturbance in attention, dyskinesia, hypersomnia, and myoclonus; Rare: dysarthria.

Psychiatric Disorders — Frequent: agitation, anxiety, libido decreased, nervousness, nightmare/abnormal dreams, and sleep disorder; Infrequent: apathy, bruxism, disorientation/confusional state, irritability, mood swings, restlessness, suicide attempt, and tension; Rare: completed suicide, mania, and pressure of speech.

Renal and Urinary Disorders — Infrequent: dysuria, micturition urgency, nocturia, urinary hesitation, urinary incontinence, urinary retention, urine flow decreased, and urine odor abnormal; Rare: nephropathy.

Reproductive System and Breast Disorders — Frequent: anorgasmia/orgasm abnormal, ejaculation delayed, and ejaculation disorder; Infrequent: menopausal symptoms.

Respiratory, Thoracic and Mediastinal Disorders — Frequent: yawning; Infrequent: throat tightness; Rare: pharyngeal edema.

Skin and Subcutaneous Tissue Disorders — Frequent: pruritus and rash; Infrequent: acne, alopecia, cold sweat, eczema, erythema, increased tendency to bruise, night sweats, photosensitivity reaction, and skin ulcer; Rare: dermatitis exfoliative, ecchymosis, and hyperkeratosis.

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

Postmarketing Spontaneous Reports

Adverse events reported since market introduction that were temporally related to duloxetine therapy and not mentioned elsewhere in labeling include: anaphylactic reaction, angioneurotic edema, erythema multiforme, extrapyramidal disorder, glaucoma, hallucinations, hyperglycemia, hypersensitivity, hypertensive crisis, rash, Stevens-Johnson Syndrome, supraventricular arrhythmia, trismus, and urticaria.

Drug Abuse And Dependence

Controlled Substance Class

Duloxetine is not a controlled substance.

Physical and Psychological Dependence

In animal studies, duloxetine did not demonstrate barbiturate-like (depressant) abuse potential. In drug dependence studies, duloxetine did not demonstrate dependence-producing potential in rats.

While Cymbalta has not been systematically studied in humans for its potential for abuse, there was no indication of drug-seeking behavior in the clinical trials. However, it is not possible to predict on the basis of premarketing experience the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for a history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of Cymbalta (e.g., development of tolerance, incrementation of dose, drug-seeking behavior).

(also see CLINICAL PHARMACOLOGY, Drug-Drug Interactions)

Potential for Other Drugs to Affect Cymbalta

Both CYP1A2 and CYP2D6 are responsible for duloxetine metabolism.

Inhibitors of CYP1A2 — Concomitant use of duloxetine with fluvoxamine, an inhibitor of CYP1A2, results in approximately a 6-fold increase in AUC and about a 2.5-fold increase in Cmax of duloxetine. Some quinolone antibiotics would be expected to have similar effects and these combinations should be avoided.

Inhibitors of CYP2D6 — Because CYP2D6 is involved in duloxetine metabolism, concomitant use of duloxetine with potent inhibitors of CYP2D6 may result in higher concentrations of duloxetine. Paroxetine (20 mg QD) increased the concentration of duloxetine (40 mg QD) by about 60%, and greater degrees of inhibition are expected with higher doses of paroxetine. Similar effects would be expected with other potent CYP2D6 inhibitors (e.g., fluoxetine, quinidine).

Potential for Duloxetine to Affect Other Drugs

Drugs Metabolized by CYP1A2 — In vitro drug interaction studies demonstrate that duloxetine does not induce CYP1A2 activity, and it is unlikely to have a clinically significant effect on the metabolism of CYP1A2 substrates (see CLINICAL PHARMACOLOGY, Drug Interactions).

Drugs Metabolized by CYP2D6 — Duloxetine is a moderate inhibitor of CYP2D6. When duloxetine was administered (at a dose of 60 mg BID) in conjunction with a single 50-mg dose of desipramine, a CYP2D6 substrate, the AUC of desipramine increased 3-fold. Therefore, co-administration of Cymbalta with other drugs that are extensively metabolized by this isozyme and which 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 Cymbalta. Because of the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, Cymbalta and thioridazine should not be co-administered.

Drugs Metabolized by CYP3A — Results of in vitro studies demonstrate that duloxetine does not inhibit or induce CYP3A activity (see CLINICAL PHARMACOLOGY, Drug Interactions).

Cymbalta May Have a Clinically Important Interaction with the Following Other Drugs:

Alcohol — When Cymbalta and ethanol were administered several hours apart so that peak concentrations of each would coincide, Cymbalta did not increase the impairment of mental and motor skills caused by alcohol.

In the Cymbalta clinical trials database, three Cymbalta-treated patients had liver injury as manifested by ALT and total bilirubin elevations, with evidence of obstruction. Substantial intercurrent ethanol use was present in each of these cases, and this may have contributed to the abnormalities seen (see PRECAUTIONS, Hepatotoxicity).

CNS Acting Drugs — Given the primary CNS effects of Cymbalta, 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.

Serotonergic Drugs — Based on the mechanism of action of SNRIs and SSRIs, including Cymbalta and the potential for serotonin syndrome, caution is advised when Cymbalta is coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, tramadol, or St. John's Wort (see WARNINGS, Serotonin Syndrome). The concomitant use of Cymbalta with other SSRIs, SNRIs or tryptophan is not recommended (see PRECAUTIONS, DRUG INTERACTIONS).

Triptans — There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of Cymbalta with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS, Serotonin Syndrome).

Potential for Interaction with Drugs that Affect Gastric Acidity — Cymbalta has an enteric coating that resists dissolution until reaching a segment of the gastrointestinal tract where the pH exceeds 5.5. In extremely acidic conditions, Cymbalta, unprotected by the enteric coating, may undergo hydrolysis to form naphthol. Caution is advised in using Cymbalta in patients with conditions that may slow gastric emptying (e.g., some diabetics). Drugs that raise the gastrointestinal pH may lead to an earlier release of duloxetine. However, co-administration of Cymbalta with aluminum- and magnesium-containing antacids (51 mEq) or Cymbalta with famotidine, had no significant effect on the rate or extent of duloxetine absorption after administration of a 40-mg oral dose. It is unknown whether the concomitant administration of proton pump inhibitors affects duloxetine absorption.

Monoamine Oxidase Inhibitors — See CONTRAINDICATIONS and WARNINGS.

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