2.1 Dosage for Treatment of Major Depressive Disorder

Administer CYMBALTA at a total dose of 40 mg/day (given as 20 mg twice daily) to 60 mg/day (given either once daily or as 30 mg twice daily). For some patients, it may be desirable to start at 30 mg once daily for 1 week, to allow patients to adjust to the medication before increasing to 60 mg once daily. While a 120 mg/day dose was shown to be effective, there is no evidence that doses greater than 60 mg/day confer any additional benefits. The safety of doses above 120 mg/day has not been adequately evaluated. Periodically reassess to determine the need for maintenance treatment and the appropriate dose for such treatment [see Clinical Studies (14.1)].

2.2 Dosage for Treatment of Generalized Anxiety Disorder

2.3 Dosage for Treatment of Diabetic Peripheral Neuropathic Pain

Administer CYMBALTA 60 mg once daily. There is no evidence that doses higher than 60 mg confer additional significant benefit and the higher dose is clearly less well tolerated [see Clinical Studies (14.3)]. For patients for whom tolerability is a concern, a lower starting dose may be considered.

Since diabetes is frequently complicated by renal disease, consider a lower starting dose and gradual increase in dose for patients with renal impairment [see Dosage and Administration (2.6), Use in Specific Populations (8.10), and Clinical Pharmacology (12.3)].

2.4 Dosage for Treatment of Fibromyalgia

Administer CYMBALTA 60 mg once daily. Begin treatment at 30 mg once daily for 1 week, to allow patients to adjust to the medication before increasing to 60 mg once daily. Some patients may respond to the starting dose. There is no evidence that doses greater than 60 mg/day confer additional benefit, even in patients who do not respond to a 60 mg dose, and higher doses are associated with a higher rate of adverse reactions [see Clinical Studies (14.4)].

2.5 Dosage for Treatment of Chronic Musculoskeletal Pain

Administer CYMBALTA 60 mg once daily. Begin treatment at 30 mg for one week, to allow patients to adjust to the medication before increasing to 60 mg once daily. There is no evidence that higher doses confer additional benefit, even in patients who do not respond to a 60 mg dose, and higher doses are associated with a higher rate of adverse reactions [see Clinical Studies (14.5)].

2.6 Dosing in Special Populations

2.7 Discontinuing CYMBALTA

Adverse reactions after discontinuation of CYMBALTA, after abrupt or tapered discontinuation, include: dizziness, headache, nausea, diarrhea, paresthesia, irritability, vomiting, insomnia, anxiety, hyperhidrosis, and fatigue. A gradual reduction in dosage rather than abrupt cessation is recommended whenever possible [see Warnings and Precautions (5.7)].

2.8 Switching a Patient to or from a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders

At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with CYMBALTA. Conversely, at least 5 days should be allowed after stopping CYMBALTA before starting an MAOI intended to treat psychiatric disorders [see Contraindications (4)].

2.9 Use of CYMBALTA with Other MAOIs such as Linezolid or Methylene Blue

Do not start CYMBALTA in a patient who is being treated with linezolid or intravenous methylene blue because there is an increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered [see Contraindications (4)].

In some cases, a patient already receiving CYMBALTA therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, CYMBALTA should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for 5 days or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with CYMBALTA may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue [see Warnings and Precautions (5.4)].

The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with CYMBALTA is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use [see Warnings and Precautions (5.4)].

5.1 Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults

Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment.

Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.

The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk of differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1.

No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.

It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.

All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.

The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.

Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.

If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that discontinuation can be associated with certain symptoms [see Dosage and Administration (2.7) and Warnings and Precautions (5.7) for descriptions of the risks of discontinuation of CYMBALTA].

Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for CYMBALTA should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose.

Screening Patients for Bipolar Disorder — A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that CYMBALTA is not approved for use in treating bipolar depression.

5.2 Hepatotoxicity

There have been reports of hepatic failure, sometimes fatal, in patients treated with CYMBALTA. These cases have presented as hepatitis with abdominal pain, hepatomegaly, and elevation of transaminase levels to more than twenty times the upper limit of normal with or without jaundice, reflecting a mixed or hepatocellular pattern of liver injury. CYMBALTA should be discontinued in patients who develop jaundice or other evidence of clinically significant liver dysfunction and should not be resumed unless another cause can be established.

Cases of cholestatic jaundice with minimal elevation of transaminase levels have also been reported. Other postmarketing reports indicate that elevated transaminases, bilirubin, and alkaline phosphatase have occurred in patients with chronic liver disease or cirrhosis.

CYMBALTA increased the risk of elevation of serum transaminase levels in development program clinical trials. Liver transaminase elevations resulted in the discontinuation of 0.3% (92/34,756) of CYMBALTA-treated patients. In most patients, the median time to detection of the transaminase elevation was about two months. In adult placebo-controlled trials in any indication, for patients with normal and abnormal baseline ALT values, elevation of ALT >3 times the upper limit of normal occurred in 1.25% (144/11,496) of CYMBALTA-treated patients compared to 0.45% (39/8716) of placebo-treated patients. In adult placebo-controlled studies using a fixed dose design, there was evidence of a dose response relationship for ALT and AST elevation of >3 times the upper limit of normal and >5 times the upper limit of normal, respectively.

Because it is possible that CYMBALTA and alcohol may interact to cause liver injury or that CYMBALTA may aggravate pre-existing liver disease, CYMBALTA should not be prescribed to patients with substantial alcohol use or evidence of chronic liver disease.

5.3 Orthostatic Hypotension, Falls and Syncope

Orthostatic hypotension, falls and syncope have been reported with therapeutic doses of CYMBALTA. Syncope and orthostatic hypotension tend to occur within the first week of therapy but can occur at any time during CYMBALTA treatment, particularly after dose increases. The risk of falling appears to be related to the degree of orthostatic decrease in blood pressure as well as other factors that may increase the underlying risk of falls.

In an analysis of patients from all placebo-controlled trials, patients treated with CYMBALTA reported a higher rate of falls compared to patients treated with placebo. Risk appears to be related to the presence of orthostatic decrease in blood pressure. The risk of blood pressure decreases may be greater in patients taking concomitant medications that induce orthostatic hypotension (such as antihypertensives) or are potent CYP1A2 inhibitors [see Warnings and Precautions (5.12) and Drug Interactions (7.1)] and in patients taking CYMBALTA at doses above 60 mg daily. Consideration should be given to dose reduction or discontinuation of CYMBALTA in patients who experience symptomatic orthostatic hypotension, falls and/or syncope during CYMBALTA therapy.

Risk of falling also appeared to be proportional to a patient's underlying risk for falls and appeared to increase steadily with age. As elderly patients tend to have a higher underlying risk for falls due to a higher prevalence of risk factors such as use of multiple medications, medical comorbidities and gait disturbances, the impact of increasing age by itself is unclear. Falls with serious consequences including bone fractures and hospitalizations have been reported [see Adverse Reactions (6.10) and Patient Counseling Information (17)].

5.4 Serotonin Syndrome

The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including CYMBALTA, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John's Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome.

The concomitant use of CYMBALTA with MAOIs intended to treat psychiatric disorders is contraindicated. CYMBALTA should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking CYMBALTA. CYMBALTA should be discontinued before initiating treatment with the MAOI [see Dosage and Administration (2.8, 2.9), and Contraindications (4)].

If concomitant use of CYMBALTA with other serotonergic drugs including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan and St. John's Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases. Treatment with CYMBALTA and any concomitant serotonergic agents, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.

5.5 Abnormal Bleeding

SSRIs and SNRIs, including CYMBALTA, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anti-coagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages.

Patients should be cautioned about the risk of bleeding associated with the concomitant use of CYMBALTA and NSAIDs, aspirin, or other drugs that affect coagulation.

5.6 Severe Skin Reactions

Severe skin reactions, including erythema multiforme and Stevens-Johnson Syndrome (SJS), can occur with CYMBALTA. The reporting rate of SJS associated with CYMBALTA use exceeds the general population background incidence rate for this serious skin reaction (1 to 2 cases per million person years). The reporting rate is generally accepted to be an underestimate due to underreporting.

CYMBALTA should be discontinued at the first appearance of blisters, peeling rash, mucosal erosions, or any other sign of hypersensitivity if no other etiology can be identified.

5.7 Discontinuation of Treatment with CYMBALTA

Discontinuation symptoms have been systematically evaluated in patients taking CYMBALTA. Following abrupt or tapered discontinuation in adult placebo-controlled clinical trials, the following symptoms occurred at 1% or greater and at a significantly higher rate in CYMBALTA-treated patients compared to those discontinuing from placebo: dizziness, headache, nausea, diarrhea, paresthesia, irritability, vomiting, insomnia, anxiety, hyperhidrosis, and fatigue.

During marketing of other SSRIs and SNRIs (serotonin and norepinephrine reuptake inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. Although these events are generally self-limiting, some have been reported to be severe.

Patients should be monitored for these symptoms when discontinuing treatment with CYMBALTA. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate [see Dosage and Administration (2.7)].

5.8 Activation of Mania/Hypomania

In adult placebo-controlled trials in patients with major depressive disorder, activation of mania or hypomania was reported in 0.1% (4/3779) of CYMBALTA-treated patients and 0.04% (1/2536) of placebo-treated patients. No activation of mania or hypomania was reported in DPNP, GAD, fibromyalgia, or chronic musculoskeletal pain placebo-controlled trials. Activation of mania or hypomania has been reported in a small proportion of patients with mood disorders who were treated with other marketed drugs effective in the treatment of major depressive disorder. As with these other agents, CYMBALTA should be used cautiously in patients with a history of mania.

5.9 Angle-Closure Glaucoma

The pupillary dilation that occurs following use of many antidepressant drugs including CYMBALTA may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.

5.10 Seizures

CYMBALTA has not been systematically evaluated in patients with a seizure disorder, and such patients were excluded from clinical studies. In adult placebo-controlled clinical trials, seizures/convulsions occurred in 0.02% (3/12,722) of patients treated with CYMBALTA and 0.01% (1/9513) of patients treated with placebo. CYMBALTA should be prescribed with care in patients with a history of a seizure disorder.

5.11 Effect on Blood Pressure

In adult placebo-controlled clinical trials across indications from baseline to endpoint, CYMBALTA treatment was associated with mean increases of 0.5 mm Hg in systolic blood pressure and 0.8 mm Hg in diastolic blood pressure compared to mean decreases of 0.6 mm Hg systolic and 0.3 mm Hg diastolic in placebo-treated patients. There was no significant difference in the frequency of sustained (3 consecutive visits) elevated blood pressure. In a clinical pharmacology study designed to evaluate the effects of CYMBALTA on various parameters, including blood pressure at supratherapeutic doses with an accelerated dose titration, there was evidence of increases in supine blood pressure at doses up to 200 mg twice daily. At the highest 200 mg twice daily dose, the increase in mean pulse rate was 5.0 to 6.8 beats and increases in mean blood pressure were 4.7 to 6.8 mm Hg (systolic) and 4.5 to 7 mm Hg (diastolic) up to 12 hours after dosing.

Blood pressure should be measured prior to initiating treatment and periodically measured throughout treatment [see Adverse Reactions (6.7)].

5.12 Clinically Important Drug Interactions

Both CYP1A2 and CYP2D6 are responsible for CYMBALTA metabolism.

5.13 Hyponatremia

Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including CYMBALTA. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported and appeared to be reversible when CYMBALTA was discontinued. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk [see Use in Specific Populations (8.5)]. Discontinuation of CYMBALTA should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.

Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. More severe and/or acute cases have been associated with hallucination, syncope, seizure, coma, respiratory arrest, and death.

5.14 Use in Patients with Concomitant Illness

Clinical experience with CYMBALTA in patients with concomitant systemic illnesses is limited. There is no information on the effect that alterations in gastric motility may have on the stability of CYMBALTA's enteric coating. 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).

CYMBALTA has not been systematically evaluated in patients with a recent history of myocardial infarction or unstable coronary artery disease. Patients with these diagnoses were generally excluded from clinical studies during the product's premarketing testing.

5.15 Urinary Hesitation and Retention

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.

In post marketing experience, cases of urinary retention have been observed. In some instances of urinary retention associated with CYMBALTA use, hospitalization and/or catheterization has been needed.

5.16 Laboratory Tests

No specific laboratory tests are recommended.

6.1 Clinical Trial Data Sources

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.

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.

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

6.3 Most Common Adult Adverse Reactions

6.4 Adverse Reactions Occurring at an Incidence of 5% or More Among CYMBALTA-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 CYMBALTA and with an incidence greater than placebo.

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

6.6 Effects on Male and Female Sexual Function in Adults

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 5 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.

6.7 Vital Sign Changes in Adults

In placebo-controlled clinical trials across approved indications for change from baseline to endpoint, CYMBALTA 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 (5.3, 5.11)].

CYMBALTA 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 CYMBALTA - treated patients, decrease of 0.17 beats per minute in placebo-treated patients).

6.8 Laboratory Changes in Adults

CYMBALTA treatment in placebo-controlled clinical trials across approved indications, 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 (5.2)]. High bicarbonate, cholesterol, and abnormal (high or low) potassium, were observed more frequently in CYMBALTA treated patients compared to placebo.

6.9 Electrocardiogram Changes in Adults

The effect of CYMBALTA 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. CYMBALTA appears to be associated with concentration-dependent but not clinically meaningful QT shortening.

6.10 Other Adverse Reactions Observed During the Premarketing and Postmarketing Clinical Trial Evaluation of CYMBALTA in Adults

Following is a list of treatment-emergent adverse reactions reported by patients treated with CYMBALTA in clinical trials. In clinical trials of all indications, 34,756 patients were treated with CYMBALTA. Of these, 26.9% (9337) took CYMBALTA 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.

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, dry eye, and visual impairment.

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

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

Infections and Infestations — Infrequent: gastroenteritis and laryngitis.

Investigations — Frequent: weight increased, weight decreased; 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 paraesthesia/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 — Frequent: urinary frequency; Infrequent: dysuria, micturition urgency, nocturia, polyuria, and urine odor abnormal.

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

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

Skin and Subcutaneous Tissue Disorders — Frequent: pruritus; 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.

6.11 Adverse Reactions Observed in Children and Adolescent Placebo-Controlled Clinical Trials

The adverse drug reaction profile observed in pediatric clinical trials (children and adolescents) was consistent with the adverse drug reaction profile observed in adult clinical trials. The specific adverse drug reactions observed in adult patients can be expected to be observed in pediatric patients (children and adolescents) [see Adverse Reactions (6.5)]. The most common (≥5% and twice placebo) adverse reactions observed in pediatric clinical trials include: nausea, diarrhea, decreased weight, and dizziness.

Table 6 provides the incidence of treatment-emergent adverse reactions in MDD and GAD pediatric placebo-controlled trials that occurred in greater than 2% of patients treated with CYMBALTA and with an incidence greater than placebo.

Other adverse reactions that occurred at an incidence of less than 2% but were reported by more CYMBALTA treated patients than placebo treated patients and are associated CYMBALTA treatment: abnormal dreams (including nightmare), anxiety, flushing (including hot flush), hyperhidrosis, palpitations, pulse increased, and tremor.

Discontinuation-emergent symptoms have been reported when stopping CYMBALTA. The most commonly reported symptoms following discontinuation of CYMBALTA in pediatric clinical trials have included headache, dizziness, insomnia, and abdominal pain [see Warnings and Precautions (5.7) and Adverse Reactions (6.2)].

6.12 Postmarketing Spontaneous Reports

The following adverse reactions have been identified during post approval 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 CYMBALTA 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, colitis (microscopic or unspecified), cutaneous vasculitis (sometimes associated with systemic involvement), 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.

7.1 Inhibitors of CYP1A2

When duloxetine 60 mg was co-administered with fluvoxamine 100 mg, a potent CYP1A2 inhibitor, to male subjects (n=14) duloxetine AUC was increased approximately 6-fold, the Cmax was increased about 2.5-fold, and duloxetine t1/2 was increased approximately 3-fold. Other drugs that inhibit CYP1A2 metabolism include cimetidine and quinolone antimicrobials such as ciprofloxacin and enoxacin [see Warnings and Precautions (5.12)].

7.2 Inhibitors of CYP2D6

Concomitant use of duloxetine (40 mg once daily) with paroxetine (20 mg once daily) increased the concentration of duloxetine AUC 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) [see Warnings and Precautions (5.12)].

7.3 Dual Inhibition of CYP1A2 and CYP2D6

Concomitant administration of duloxetine 40 mg twice daily with fluvoxamine 100 mg, a potent CYP1A2 inhibitor, to CYP2D6 poor metabolizer subjects (n=14) resulted in a 6-fold increase in duloxetine AUC and Cmax.

7.4 Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin)

Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs or SNRIs are co-administered with warfarin. Concomitant administration of warfarin (2-9 mg once daily) under steady state conditions with duloxetine 60 or 120 mg once daily for up to 14 days in healthy subjects (n=15) did not significantly change INR from baseline (mean INR changes ranged from 0.05 to +0.07). The total warfarin (protein bound plus free drug) pharmacokinetics (AUCτ,ss, Cmax,ss or tmax,ss) for both R- and S-warfarin were not altered by duloxetine. Because of the potential effect of duloxetine on platelets, patients receiving warfarin therapy should be carefully monitored when duloxetine is initiated or discontinued [see Warnings and Precautions (5.5)].

7.5 Lorazepam

Under steady-state conditions for duloxetine (60 mg Q 12 hours) and lorazepam (2 mg Q 12 hours), the pharmacokinetics of duloxetine were not affected by co-administration.

7.6 Temazepam

Under steady-state conditions for duloxetine (20 mg qhs) and temazepam (30 mg qhs), the pharmacokinetics of duloxetine were not affected by co-administration.

7.7 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 [see Warnings and Precautions (5.14)].

7.8 Drugs Metabolized by CYP1A2

In vitro drug interaction studies demonstrate that duloxetine does not induce CYP1A2 activity. Therefore, an increase in the metabolism of CYP1A2 substrates (e.g., theophylline, caffeine) resulting from induction is not anticipated, although clinical studies of induction have not been performed. Duloxetine is an inhibitor of the CYP1A2 isoform in in vitro studies, and in two clinical studies the average (90% confidence interval) increase in theophylline AUC was 7% (1%-15%) and 20% (13%-27%) when co-administered with duloxetine (60 mg twice daily).

7.9 Drugs Metabolized by CYP2D6

Duloxetine is a moderate inhibitor of CYP2D6. When duloxetine was administered (at a dose of 60 mg twice daily) in conjunction with a single 50 mg dose of desipramine, a CYP2D6 substrate, the AUC of desipramine increased 3-fold [see Warnings and Precautions (5.12)].

7.10 Drugs Metabolized by CYP2C9

Results of in vitro studies demonstrate that duloxetine does not inhibit activity. In a clinical study, the pharmacokinetics of S-warfarin, a CYP2C9 substrate, were not significantly affected by duloxetine [see Drug Interactions (7.4)].

7.11 Drugs Metabolized by CYP3A

Results of in vitro studies demonstrate that duloxetine does not inhibit or induce CYP3A activity. Therefore, an increase or decrease in the metabolism of CYP3A substrates (e.g., oral contraceptives and other steroidal agents) resulting from induction or inhibition is not anticipated, although clinical studies have not been performed.

7.12 Drugs Metabolized by CYP2C19

Results of in vitro studies demonstrate that duloxetine does not inhibit CYP2C19 activity at therapeutic concentrations. Inhibition of the metabolism of CYP2C19 substrates is therefore not anticipated, although clinical studies have not been performed.

7.13 Monoamine Oxidase Inhibitors (MAOIs)

[See Dosage and Administration (2.8, 2.9), Contraindications (4), and Warnings and Precautions (5.4)].

7.14 Serotonergic Drugs

[See Dosage and Administration (2.8, 2.9), Contraindications (4), and Warnings and Precautions (5.4)].

7.15 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 Warnings and Precautions (5.2, 5.12)].

7.16 CNS Drugs

[See Warnings and Precautions (5.12)].

7.17 Drugs Highly Bound to Plasma Protein

Because duloxetine is highly bound to plasma protein, administration of CYMBALTA to a patient taking another drug that is highly protein bound may cause increased free concentrations of the other drug, potentially resulting in adverse reactions. However, co-administration of duloxetine (60 or 120 mg) with warfarin (2-9 mg), a highly protein-bound drug, did not result in significant changes in INR and in the pharmacokinetics of either total S-or total R-warfarin (protein bound plus free drug) [see Drug Interactions (7.4)].

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

Of the 2,418 patients in premarketing clinical studies of CYMBALTA for MDD, 5.9% (143) were 65 years of age or over. Of the 1041 patients in CLBP premarketing studies, 21.2% (221) were 65 years of age or over. Of the 487 patients in OA premarketing studies, 40.5% (197) were 65 years of age or over. Of the 1,074 patients in the DPNP premarketing studies, 33% (357) were 65 years of age or over. Of the 1,761 patients in FM premarketing studies, 7.9% (140) were 65 years of age or over. In the MDD, GAD, DPNP, FM, OA, and CLBP studies, no overall differences in safety or effectiveness were generally observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. SSRIs and SNRIs, including CYMBALTA have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event [see Warnings and Precautions (5.13)].

In an analysis of data from all placebo-controlled-trials, patients treated with CYMBALTA reported a higher rate of falls compared to patients treated with placebo. The increased risk appears to be proportional to a patient's underlying risk for falls. Underlying risk appears to increase steadily with age. As elderly patients tend to have a higher prevalence of risk factors for falls such as medications, medical comorbidities and gait disturbances, the impact of increasing age by itself on falls during treatment with CYMBALTA is unclear. Falls with serious consequences including bone fractures and hospitalizations have been reported [see Warnings and Precautions (5.3) and Adverse Reactions (6.10)].

The pharmacokinetics of duloxetine after a single dose of 40 mg were compared in healthy elderly females (65 to 77 years) and healthy middle-age females (32 to 50 years). There was no difference in the Cmax, but the AUC of duloxetine was somewhat (about 25%) higher and the half-life about 4 hours longer in the elderly females. Population pharmacokinetic analyses suggest that the typical values for clearance decrease by approximately 1% for each year of age between 25 to 75 years of age; but age as a predictive factor only accounts for a small percentage of between-patient variability. Dosage adjustment based on the age of the patient is not necessary.

8.6 Gender

Duloxetine's half-life is similar in men and women. Dosage adjustment based on gender is not necessary.

8.7 Smoking Status

Duloxetine bioavailability (AUC) appears to be reduced by about one-third in smokers. Dosage modifications are not recommended for smokers.

8.8 Race

No specific pharmacokinetic study was conducted to investigate the effects of race.

8.9 Hepatic Impairment

Patients with clinically evident hepatic impairment have decreased duloxetine metabolism and elimination. After a single 20 mg dose of CYMBALTA, 6 cirrhotic patients with moderate liver impairment (Child-Pugh Class B) had a mean plasma duloxetine clearance about 15% that of age- and gender-matched healthy subjects, with a 5-fold increase in mean exposure (AUC). Although Cmax was similar to normals in the cirrhotic patients, the half-life was about 3 times longer [see Dosage and Administration (2.6) and Warnings and Precautions (5.14)].

8.10 Severe Renal Impairment

Limited data are available on the effects of duloxetine in patients with end-stage renal disease (ESRD). After a single 60 mg dose of duloxetine, Cmax and AUC values were approximately 100% greater in patients with end-stage renal disease receiving chronic intermittent hemodialysis than in subjects with normal renal function. The elimination half-life, however, was similar in both groups. The AUCs of the major circulating metabolites, 4-hydroxy duloxetine glucuronide and 5-hydroxy, 6-methoxy duloxetine sulfate, largely excreted in urine, were approximately 7- to 9-fold higher and would be expected to increase further with multiple dosing. Population PK analyses suggest that mild to moderate degrees of renal impairment (estimated CrCl 30-80 mL/min) have no significant effect on duloxetine apparent clearance [see Dosage and Administration (2.6) and Warnings and Precautions (5.14)].

9.2 Abuse

In animal studies, duloxetine did not demonstrate barbiturate-like (depressant) abuse potential.

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).

9.3 Dependence

In drug dependence studies, duloxetine did not demonstrate dependence-producing potential in rats.

10.1 Signs and Symptoms

In postmarketing experience, fatal outcomes have been reported for acute overdoses, primarily with mixed overdoses, but also with duloxetine only, at doses as low as 1000 mg. Signs and symptoms of overdose (duloxetine alone or with mixed drugs) included somnolence, coma, serotonin syndrome, seizures, syncope, tachycardia, hypotension, hypertension, and vomiting.

10.2 Management of Overdose

There is no specific antidote to CYMBALTA, but if serotonin syndrome ensues, specific treatment (such as with cyproheptadine and/or temperature control) may be considered. In case of acute overdose, treatment should consist of those general measures employed in the management of overdose with any drug.

An adequate airway, oxygenation, and ventilation should be assured, and cardiac rhythm and vital signs should be monitored. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion or in symptomatic patients.

Activated charcoal may be useful in limiting absorption of duloxetine from the gastrointestinal tract. Administration of activated charcoal has been shown to decrease AUC and Cmax by an average of one-third, although some subjects had a limited effect of activated charcoal. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be beneficial.

In managing overdose, the possibility of multiple drug involvement should be considered. A specific caution involves patients who are taking or have recently taken CYMBALTA and might ingest excessive quantities of a TCA. In such a case, decreased clearance of the parent tricyclic and/or its active metabolite may increase the possibility of clinically significant sequelae and extend the time needed for close medical observation [see Warnings and Precautions (5.4) and Drug Interactions (7)]. The physician should consider contacting a poison control center (1-800-222-1222 or www.poison.org) for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians' Desk Reference (PDR).

12.1 Mechanism of Action

Although the exact mechanisms of the antidepressant, central pain inhibitory and anxiolytic actions of duloxetine in humans are unknown, these actions are believed to be related to its potentiation of serotonergic and noradrenergic activity in the CNS.

12.2 Pharmacodynamics

Preclinical studies have shown that duloxetine is a potent inhibitor of neuronal serotonin and norepinephrine reuptake and a less potent inhibitor of dopamine reuptake. Duloxetine has no significant affinity for dopaminergic, adrenergic, cholinergic, histaminergic, opioid, glutamate, and GABA receptors in vitro. Duloxetine does not inhibit monoamine oxidase (MAO).

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.

12.3 Pharmacokinetics

Duloxetine has an elimination half-life of about 12 hours (range 8 to 17 hours) and its pharmacokinetics are dose proportional over the therapeutic range. Steady-state plasma concentrations are typically achieved after 3 days of dosing. Elimination of duloxetine is mainly through hepatic metabolism involving two P450 isozymes, CYP1A2 and CYP2D6.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis — Duloxetine was administered in the diet to mice and rats for 2 years.

14.1 Major Depressive Disorder

The efficacy of CYMBALTA as a treatment for depression was established in 4 randomized, double-blind, placebo-controlled, fixed-dose studies in adult outpatients (18 to 83 years) meeting DSM-IV criteria for major depression. In 2 studies, patients were randomized to CYMBALTA 60 mg once daily (N=123 and N=128, respectively) or placebo (N=122 and N=139, respectively) for 9 weeks; in the third study, patients were randomized to CYMBALTA 20 or 40 mg twice daily (N=86 and N=91, respectively) or placebo (N=89) for 8 weeks; in the fourth study, patients were randomized to CYMBALTA 40 or 60 mg twice daily (N=95 and N=93, respectively) or placebo (N=93) for 8 weeks. There is no evidence that doses greater than 60 mg/day confer additional benefits.

In all 4 studies, CYMBALTA demonstrated superiority over placebo as measured by improvement in the 17-item Hamilton Depression Rating Scale (HAMD-17) total score (Studies 1-4 in Table 7).

In all of these clinical studies, analyses of the relationship between treatment outcome and age, gender, and race did not suggest any differential responsiveness on the basis of these patient characteristics.

In another study, 533 patients meeting DSM-IV criteria for MDD received CYMBALTA 60 mg once daily during an initial 12-week open-label treatment phase. Two hundred and seventy-eight patients who responded to open label treatment (defined as meeting the following criteria at weeks 10 and 12: a HAMD-17 total score ≤9, Clinical Global Impressions of Severity (CGI-S) ≤2, and not meeting the DSM-IV criteria for MDD) were randomly assigned to continuation of CYMBALTA at the same dose (N=136) or to placebo (N=142) for 6 months. Patients on CYMBALTA experienced a statistically significantly longer time to relapse of depression than did patients on placebo (Study 5 in Figure 1). Relapse was defined as an increase in the CGI-S score of ≥2 points compared with that obtained at week 12, as well as meeting the DSM-IV criteria for MDD at 2 consecutive visits at least 2 weeks apart, where the 2-week temporal criterion had to be satisfied at only the second visit. The effectiveness of CYMBALTA in hospitalized patients with major depressive disorder has not been studied.

Figure 1: Kaplan-Meier Estimation of Cumulative Proportion of Patients with Relapse (MDD Study 5)

14.2 Generalized Anxiety Disorder

The efficacy of CYMBALTA in the treatment of generalized anxiety disorder (GAD) was established in 1 fixed-dose randomized, double-blind, placebo-controlled trial and 2 flexible-dose randomized, double-blind, placebo-controlled trials in adult outpatients between 18 and 83 years of age meeting the DSM-IV criteria for GAD.

In 1 flexible-dose study and in the fixed-dose study, the starting dose was 60 mg once daily where down titration to 30 mg once daily was allowed for tolerability reasons before increasing it to 60 mg once daily. Fifteen percent of patients were down titrated. One flexible-dose study had a starting dose of 30 mg once daily for 1 week before increasing it to 60 mg once daily.

The 2 flexible-dose studies involved dose titration with CYMBALTA doses ranging from 60 mg once daily to 120 mg once daily (N=168 and N=162) compared to placebo (N=159 and N=161) over a 10-week treatment period. The mean dose for completers at endpoint in the flexible-dose studies was 104.75 mg/day. The fixed-dose study evaluated CYMBALTA doses of 60 mg once daily (N=168) and 120 mg once daily (N=170) compared to placebo (N=175) over a 9-week treatment period. While a 120 mg/day dose was shown to be effective, there is no evidence that doses greater than 60 mg/day confer additional benefit.

In all 3 studies, CYMBALTA demonstrated superiority over placebo as measured by greater improvement in the Hamilton Anxiety Scale (HAM-A) total score (Studies 1-3 in Table 8) and by the Sheehan Disability Scale (SDS) global functional impairment score. The SDS is a composite measurement of the extent emotional symptoms disrupt patient functioning in 3 life domains: work/school, social life/leisure activities, and family life/home responsibilities.

In another study, 887 patients meeting DSM-IV-TR criteria for GAD received CYMBALTA 60 mg to 120 mg once daily during an initial 26-week open-label treatment phase. Four hundred and twenty-nine patients who responded to open-label treatment (defined as meeting the following criteria at weeks 24 and 26: a decrease from baseline HAM-A total score by at least 50% to a score no higher than 11, and a Clinical Global Impressions of Improvement [CGI-Improvement] score of 1 or 2) were randomly assigned to continuation of CYMBALTA at the same dose (N=216) or to placebo (N=213) and were observed for relapse. Of the patients randomized, 73% had been in a responder status for at least 10 weeks. Relapse was defined as an increase in CGI-Severity score at least 2 points to a score ≥4 and a MINI (Mini-International Neuropsychiatric Interview) diagnosis of GAD (excluding duration), or discontinuation due to lack of efficacy. Patients taking CYMBALTA experienced a statistically significantly longer time to relapse of GAD than did patients taking placebo (Study 4 in Figure 2).

Subgroup analyses did not indicate that there were any differences in treatment outcomes as a function of age or gender.

The efficacy of CYMBALTA in the treatment of patients ≥65 years of age with generalized anxiety disorder was established in one 10-week flexible-dose, randomized, double-blind, placebo-controlled trial in adults ≥65 years of age meeting the DSM-IV criteria for GAD. In this study, the starting dose was 30 mg once daily for 2 weeks before further dose increases in 30 mg increments at treatment weeks 2, 4, and 7 up to 120 mg once daily were allowed based on investigator judgment of clinical response and tolerability. The mean dose for patients completing the 10-week acute treatment phase was 50.95 mg. Patients treated with CYMBALTA (N=151) demonstrated significantly greater improvement compared with placebo (N=140) on mean change from baseline to endpoint as measured by the Hamilton Anxiety Rating Scale total score (Study 5 in Table 8).

The efficacy of CYMBALTA in the treatment of pediatric patients 7 to 17 years of age with generalized anxiety disorder (GAD) was established in 1 flexible-dose randomized, double-blind, placebo-controlled trial in pediatric outpatients with GAD (based on DSM-IV criteria).

In this study, the starting dose was 30 mg once daily for 2 weeks. Further dose increases in 30 mg increments up to 120 mg once daily were allowed based on investigator judgment of clinical response and tolerability. The mean dose for patients completing the 10-week treatment phase was 57.6 mg/day. In this study, CYMBALTA (N=135) demonstrated superiority over placebo (N=137) from baseline to endpoint as measured by greater improvement in the Pediatric Anxiety Rating Scale (PARS) for GAD severity score (Study 6 in Table 8).

Figure 2: Kaplan-Meier Estimation of Cumulative Proportion of Patients with Relapse (GAD Study 4)

14.3 Diabetic Peripheral Neuropathic Pain

The efficacy of CYMBALTA for the management of neuropathic pain associated with diabetic peripheral neuropathy was established in 2 randomized, 12-week, double-blind, placebo-controlled, fixed-dose studies in adult patients having diabetic peripheral neuropathic pain for at least 6 months. Study DPNP-1 and Study DPNP-2 enrolled a total of 791 patients of whom 592 (75%) completed the studies. Patients enrolled had Type I or II diabetes mellitus with a diagnosis of painful distal symmetrical sensorimotor polyneuropathy for at least 6 months. The patients had a baseline pain score of ≥4 on an 11-point scale ranging from 0 (no pain) to 10 (worst possible pain). Patients were permitted up to 4 g of acetaminophen per day as needed for pain, in addition to CYMBALTA. Patients recorded their pain daily in a diary.

Both studies compared CYMBALTA 60 mg once daily or 60 mg twice daily with placebo. DPNP-1 additionally compared CYMBALTA 20 mg with placebo. A total of 457 patients (342 CYMBALTA, 115 placebo) were enrolled in DPNP-1 and a total of 334 patients (226 CYMBALTA, 108 placebo) were enrolled in DPNP-2. Treatment with CYMBALTA 60 mg one or two times a day statistically significantly improved the endpoint mean pain scores from baseline and increased the proportion of patients with at least a 50% reduction in pain scores from baseline. For various degrees of improvement in pain from baseline to study endpoint, Figures 3 and 4 show the fraction of patients achieving that degree of improvement. The figures are cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%. Patients who did not complete the study were assigned 0% improvement. Some patients experienced a decrease in pain as early as week 1, which persisted throughout the study.

Figure 3: Percentage of Patients Achieving Various Levels of Pain Relief as Measured by 24-Hour Average Pain Severity - DPNP-1

Figure 4: Percentage of Patients Achieving Various Levels of Pain Relief as Measured by 24-Hour Average Pain Severity - DPNP-2

14.4 Fibromyalgia

The efficacy of CYMBALTA for the management of fibromyalgia was established in two randomized, double-blind, placebo-controlled, fixed-dose studies in adult patients meeting the American College of Rheumatology criteria for fibromyalgia (a history of widespread pain for 3 months, and pain present at 11 or more of the 18 specific tender point sites). Study FM-1 was three months in duration and enrolled female patients only. Study FM-2 was six months in duration and enrolled male and female patients. Approximately 25% of participants had a comorbid diagnosis of major depressive disorder (MDD). FM-1 and FM-2 enrolled a total of 874 patients of whom 541 (62%) completed the studies. The patients had a baseline pain score of 6.5 on an 11-point scale ranging from 0 (no pain) to 10 (worse possible pain).

Both studies compared CYMBALTA 60 mg once daily or 120 mg daily (given in divided doses in FM-1 and as a single daily dose in FM-2) with placebo. FM-2 additionally compared CYMBALTA 20 mg with placebo during the initial three months of a six-month study. A total of 354 patients (234 CYMBALTA, 120 placebo) were enrolled in FM-1 and a total of 520 patients (376 CYMBALTA, 144 placebo) were enrolled in FM-2 (5% male, 95% female). Treatment with CYMBALTA 60 mg or 120 mg daily statistically significantly improved the endpoint mean pain scores from baseline and increased the proportion of patients with at least a 50% reduction in pain score from baseline. Pain reduction was observed in patients both with and without comorbid MDD. However, the degree of pain reduction may be greater in patients with comorbid MDD. For various degrees of improvement in pain from baseline to study endpoint, Figures 5 and 6 show the fraction of patients achieving that degree of improvement. The figures are cumulative so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%. Patients who did not complete the study were assigned 0% improvement. Some patients experienced a decrease in pain as early as week 1, which persisted throughout the study. Improvement was also demonstrated on measures of function (Fibromyalgia Impact Questionnaires) and patient global impression of change (PGI). Neither study demonstrated a benefit of 120 mg compared to 60 mg, and a higher dose was associated with more adverse reactions and premature discontinuations of treatment.

Figure 5: Percentage of Patients Achieving Various Levels of Pain Relief as Measured by 24-Hour Average Pain Severity - FM-1

Figure 6: Percentage of Patients Achieving Various Levels of Pain Relief as Measured by 24-Hour Average Pain Severity - FM-2

Additionally, the benefit of up-titration in non-responders to CYMBALTA at 60 mg/day was evaluated in a separate study. Patients were initially treated with CYMBALTA 60 mg once daily for eight weeks in open-label fashion. Subsequently, completers of this phase were randomized to double-blind treatment with CYMBALTA at either 60 mg once daily or 120 mg once daily. Those patients who were considered non-responders, where response was defined as at least a 30% reduction in pain score from baseline at the end of the 8-week treatment, were no more likely to meet response criteria at the end of 60 weeks of treatment if blindly titrated to CYMBALTA 120 mg as compared to those who were blindly continued on CYMBALTA 60 mg.

14.5 Chronic Musculoskeletal Pain

CYMBALTA is indicated for the management of chronic musculoskeletal pain. This has been established in studies in patients with chronic low back pain and chronic pain due to osteoarthritis.

Studies in Chronic Low Back Pain

The efficacy of CYMBALTA in chronic low back pain (CLBP) was assessed in two double-blind, placebo-controlled, randomized clinical trials of 13-weeks duration (Study CLBP-1 and Study CLBP-2), and one of 12-weeks duration (CLBP-3). CLBP-1 and CLBP-3 demonstrated efficacy of CYMBALTA in the treatment of chronic low back pain. Patients in all studies had no signs of radiculopathy or spinal stenosis.

Study CLBP-1: Two hundred thirty-six adult patients (N=115 on CYMBALTA, N=121 on placebo) enrolled and 182 (77%) completed 13-week treatment phase. After 7 weeks of treatment, CYMBALTA patients with less than 30% reduction in average daily pain and who were able to tolerate CYMBALTA 60 mg once daily had their dose of CYMBALTA, in a double-blinded fashion, increased to 120 mg once daily for the remainder of the study. Patients had a mean baseline pain rating of 6 on a numerical rating scale ranging from 0 (no pain) to 10 (worst possible pain). After 13 weeks of treatment, patients taking CYMBALTA 60-120 mg daily had a significantly greater pain reduction compared to placebo. Randomization was stratified by the patients' baseline NSAIDs-use status. Subgroup analyses did not indicate that there were differences in treatment outcomes as a function of NSAIDs use.

Study CLBP-2: Four hundred and four patients were randomized to receive fixed doses of CYMBALTA daily or a matching placebo (N=59 on CYMBALTA 20 mg, N=116 on CYMBALTA 60 mg, N=112 on CYMBALTA 120 mg, N=117 on placebo) and 267 (66%) completed the entire 13-week study. After 13 weeks of treatment, none of the three CYMBALTA doses showed a statistically significant difference in pain reduction compared to placebo.

Study CLBP-3: Four hundred and one patients were randomized to receive fixed doses of CYMBALTA 60 mg daily or placebo (N=198 on CYMBALTA, N=203 on placebo), and 303 (76%) completed the study. Patients had a mean baseline pain rating of 6 on a numerical rating scale ranging from 0 (no pain) to 10 (worst possible pain). After 12 weeks of treatment, patients taking CYMBALTA 60 mg daily had significantly greater pain reduction compared to placebo.

For various degrees of improvement in pain from baseline to study endpoint, Figures 7 and 8 show the fraction of patients in CLBP-1 and CLBP-3 achieving that degree of improvement. The figures are cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%. Patients who did not complete the study were assigned the value of 0% improvement.

Figure 7: Percentage of Patients Achieving Various Levels of Pain Relief as Measured by 24-Hour Average Pain Severity – CLBP-1

Figure 8: Percentage of Patients Achieving Various Levels of Pain Relief as Measured by 24-Hour Average Pain Severity – CLBP-3

Studies in Chronic Pain Due to Osteoarthritis

The efficacy of CYMBALTA in chronic pain due to osteoarthritis was assessed in 2 double-blind, placebo-controlled, randomized clinical trials of 13-weeks duration (Study OA-1 and Study OA-2). All patients in both studies fulfilled the ACR clinical and radiographic criteria for classification of idiopathic osteoarthritis of the knee. Randomization was stratified by the patients' baseline NSAIDs-use status. Patients assigned to CYMBALTA started treatment in both studies at a dose of 30 mg once daily for one week. After the first week, the dose of CYMBALTA was increased to 60 mg once daily. After 7 weeks of treatment with CYMBALTA 60 mg once daily, in OA-1 patients with sub-optimal response to treatment (<30% pain reduction) and tolerated CYMBALTA 60 mg once daily had their dose increased to 120 mg. However, in OA-2, all patients, regardless of their response to treatment after 7 weeks, were re-randomized to either continue receiving CYMBALTA 60 mg once daily or have their dose increased to 120 mg once daily for the remainder of the study. Patients in the placebo treatment groups in both studies received a matching placebo for the entire duration of studies. For both studies, efficacy analyses were conducted using 13-week data from the combined CYMBALTA 60 mg and 120 mg once daily treatment groups compared to the placebo group.

Study OA-1: Two hundred fifty-six patients (N=128 on CYMBALTA, N=128 on placebo) enrolled and 204 (80%) completed the study. Patients had a mean baseline pain rating of 6 on a numerical rating scale ranging from 0 (no pain) to 10 (worst possible pain). After 13 weeks of treatment, patients taking CYMBALTA had significantly greater pain reduction. Subgroup analyses did not indicate that there were differences in treatment outcomes as a function of NSAIDs use.

Study OA-2: Two hundred thirty-one patients (N=111 on CYMBALTA, N=120 on placebo) enrolled and 173 (75%) completed the study. Patients had a mean baseline pain of 6 on a numerical rating scale ranging from 0 (no pain) to 10 (worst possible pain). After 13 weeks of treatment, patients taking CYMBALTA did not show a significantly greater pain reduction.

In Study OA-1, for various degrees of improvement in pain from baseline to study endpoint, Figure 7 shows the fraction of patients achieving that degree of improvement. The figure is cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%. Patients who did not complete the study were assigned the value of 0% improvement.

Figure 9: Percentage of Patients Achieving Various Levels of Pain Relief as Measured by 24-Hour Average Pain Severity – OA-1

See FDA-approved patient labeling (Medication Guide).

• Information on Medication Guide — Inform patients, their families, and their caregivers about the benefits and risks associated with treatment with CYMBALTA and counsel them in its appropriate use. A patient Medication Guide is available for CYMBALTA. Instruct patients, their families, and their caregivers to read the Medication Guide before starting CYMBALTA and each time their prescription is renewed, and assist them in understanding its contents. Give patients the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document.
  Advise patients of the following issues and ask them to alert their prescriber if these occur while taking CYMBALTA.
• Suicidal Thoughts and Behaviors — Encourage patients, their families, and their caregivers to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down.
  Advise families and caregivers of patients to observe for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication [see Boxed Warning, and Warnings and Precautions (5.1)].
• CYMBALTA should be swallowed whole and should not be chewed or crushed, nor should the capsule be opened and its contents be sprinkled on food or mixed with liquids. All of these might affect the enteric coating.
• Continuing the Therapy Prescribed — While patients may notice improvement with CYMBALTA therapy in 1 to 4 weeks, advise patients to continue therapy as directed.
• Hepatotoxicity — Inform patients that severe liver problems, sometimes fatal, have been reported in patients treated with CYMBALTA. Instruct patients to talk to their healthcare provider if they develop itching, right upper belly pain, dark urine, or yellow skin/eyes while taking CYMBALTA, which may be signs of liver problems. Instruct patients to talk to their healthcare provider about their alcohol consumption. Use of CYMBALTA with heavy alcohol intake may be associated with severe liver injury [see Warnings and Precautions (5.2)].
• Alcohol — Although CYMBALTA does not increase the impairment of mental and motor skills caused by alcohol, use of CYMBALTA concomitantly with heavy alcohol intake may be associated with severe liver injury. For this reason, CYMBALTA should not be prescribed for patients with substantial alcohol use [see Warnings and Precautions (5.2) and Drug Interactions (7.15)].
• Orthostatic Hypotension, Falls and Syncope — Advise patients of the risk of orthostatic hypotension, falls and syncope, especially during the period of initial use and subsequent dose escalation, and in association with the use of concomitant drugs that might potentiate the orthostatic effect of CYMBALTA [see Warnings and Precautions (5.3)].
• Serotonin Syndrome — Caution patients about the risk of serotonin syndrome with the concomitant use of CYMBALTA and other serotonergic agents including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan and St. John's Wort [see Contraindications (4), Warnings and Precautions (5.4), and Drug Interactions (7.14)].
  Advise patients of the signs and symptoms associated with serotonin syndrome that may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular changes (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Caution patients to seek medical care immediately if they experience these symptoms.
• Abnormal Bleeding — Caution patients about the concomitant use of CYMBALTA and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding [see Warnings and Precautions (5.5)].
• Severe Skin Reactions — Caution patients that CYMBALTA may cause serious skin reactions. This may need to be treated in a hospital and may be life-threatening. Counsel patients to call their doctor right away or get emergency help if they have skin blisters, peeling rash, sores in their mouth, hives, or any other allergic reactions [see Warnings and Precautions (5.6)].
• Discontinuation of Treatment — Instruct patients that discontinuation of CYMBALTA may be associated with symptoms such as dizziness, headache, nausea, diarrhea, paresthesia, irritability, vomiting, insomnia, anxiety, hyperhidrosis, and fatigue, and should be advised not to alter their dosing regimen, or stop taking CYMBALTA without consulting their physician [see Warnings and Precautions (5.7)].
• Activation of Mania or Hypomania — Adequately screen patients with depressive symptoms for risk of bipolar disorder (e.g. family history of suicide, bipolar disorder, and depression) prior to initiating treatment with CYMBALTA. Advise patients to report any signs or symptoms of a manic reaction such as greatly increased energy, severe trouble sleeping, racing thoughts, reckless behavior, talking more or faster than usual, unusually grand ideas, and excessive happiness or irritability [see Warnings and Precautions (5.8)].
• Angle-Closure Glaucoma — Advise patients that taking CYMBALTA can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle-closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle-closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle-closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle-closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible. [See Warnings and Precautions (5.9)].
• Seizures — Advise patients to inform their physician if they have a history of seizure disorder [see Warnings and Precautions (5.10)].
• Effects on Blood Pressure — Caution patients that CYMBALTA may cause an increase in blood pressure [see Warnings and Precautions (5.11)].
• Concomitant Medications — Advise patients to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter medications, since there is a potential for interactions [see Dosage and Administration (2.8, 2.9), Contraindications (4), Warnings and Precautions (5.4, 5.12), and Drug Interactions (7)].
• Hyponatremia — Advise patients that hyponatremia has been reported as a result of treatment with SNRIs and SSRIs, including CYMBALTA. Advise patients of the signs and symptoms of hyponatremia [see Warnings and Precautions (5.13)].
• Concomitant Illnesses — Advise patients to inform their physicians about all of their medical conditions [see Warnings and Precautions (5.14)].
• CYMBALTA is in a class of medicines that may affect urination. Instruct patients to consult with their healthcare provider if they develop any problems with urine flow [see Warnings and Precautions (5.15)].
• Pregnancy and Nursing Mothers
  Advise patients to notify their physician if they:
  • become pregnant during therapy
  • intend to become pregnant during therapy
  • are nursing [see Use in Specific Populations (8.1, 8.3)].
• Pediatric Use — Safety and efficacy of CYMBALTA in patients 7 to 17 years of age have been established for the treatment of GAD. The types of adverse reactions observed with CYMBALTA in children and adolescents were generally similar to those observed in adults. The safety and effectiveness of CYMBALTA have not been established in pediatric patients less than 18 years of age with other indications. [See Use in Specific Populations (8.4)].
• Interference with Psychomotor Performance — Any psychoactive drug may impair judgment, thinking, or motor skills. Although in controlled studies CYMBALTA has not been shown to impair psychomotor performance, cognitive function, or memory, it may be associated with sedation and dizziness. Therefore, caution patients about operating hazardous machinery including automobiles, until they are reasonably certain that CYMBALTA therapy does not affect their ability to engage in such activities.

Literature revised June 2015

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