Section Contents:- Symptoms associated with discontinuation of Cymbalta and other SSRIs and SNRIs have been reported ( see PRECAUTIONS ).(More...)
- Participating patients will be treated with Cymbalta in doses up to 60mg daily for eight (8) weeks.(More...)
Symptoms associated with discontinuation of Cymbalta and other SSRIs and SNRIs have been reported ( see PRECAUTIONS ). Patients should be monitored for these symptoms when discontinuing treatment.
[1] Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with Cymbalta and should counsel them in its appropriate use.
[1] If concomitant treatment of Cymbalta with a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases ( see PRECAUTIONS, Drug Interactions ).
[1] 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 WARNINGS, Serotonin Syndrome ).
[1] There is insufficient evidence available to answer the question of how long a patient should continue to be treated with Cymbalta. Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment.
[1] 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.
[1] Events reported by at least 2% of patients treated with Cymbalta and more often with placebo. The following events were reported by at least 2% of patients treated with Cymbalta for GAD and had an incidence equal to or less than placebo: nasopharyngitis, upper respiratory tract infection, headache, pollakiuria, and musculoskeletal pain (includes myalgia, neck pain).
[1] Events reported by at least 2% of patients treated with Cymbalta and more often with placebo. The following events were reported by at least 2% of patients treated with Cymbalta for MDD and had an incidence equal to or less than placebo: upper abdominal pain, palpitations, dyspepsia, back pain, arthralgia, headache, pharyngitis, cough, nasopharyngitis, and upper respiratory tract infection.
[1] The following events were reported by at least 2% of patients treated with Cymbalta for DPN and had an incidence equal to or less than placebo: edema peripheral, influenza, upper respiratory tract infection, back pain, arthralgia, pain in extremity, and pruritus.
[1] 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.
[1] Activation of mania/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. Seizures -- Duloxetine has not been systematically evaluated in patients with a seizure disorder, and such patients were excluded from clinical studies.
[1] 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 events.
[1] Dosage for Renally Impaired Patients -- Cymbalta is not recommended for patients with end-stage renal disease (requiring dialysis) or in severe renal impairment (estimated creatinine clearance <30 mL/min) ( see CLINICAL PHARMACOLOGY CLINICAL PHARMACOLOGY CLINICAL PHARMACOLOGY ). Dosage for Hepatically Impaired Patients -- It is recommended that Cymbalta not be administered to patients with any hepatic insufficiency ( see CLINICAL PHARMACOLOGY and PRECAUTIONS ).
[1] Use in Patients with Concomitant Illness -- Clinical experience with Cymbalta in patients with concomitant systemic illnesses is limited.
[1] 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 ordinarily not be prescribed for patients with substantial alcohol use.
[1] 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.
[1] In 2 studies, patients were randomized to Cymbalta 60 mg once daily (N123 and N128, respectively) or placebo (N122 and N139, respectively) for 9 weeks; in the third study, patients were randomized to Cymbalta 20 or 40 mg twice daily (N86 and N91, respectively) or placebo (N89) for 8 weeks; in the fourth study, patients were randomized to Cymbalta 40 or 60 mg twice daily (N95 and N93, respectively) or placebo (N93) for 8 weeks.
[1] The 2 flexible-dose studies involved dose titration with Cymbalta doses ranging from 60 mg once daily to 120 mg once daily (N168 and N162) compared to placebo (N159 and N161) over a 10-week treatment period.
[1] The fixed-dose study evaluated Cymbalta doses of 60 mg once daily (N168) and 120 mg once daily (N170) compared to placebo (N175) over a 9-week treatment period.
[1] 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.
[1] 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. 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.
[1] 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.
[1] The efficacy of Cymbalta for the management of neuropathic pain associated with diabetic peripheral neuropathy (DPN) was established in 2 randomized, 12-week, double-blind, placebo-controlled, fixed-dose studies in adult patients having diabetic peripheral neuropathy for at least 6 months.
[1] Concomitant use in patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated ( see WARNINGS WARNINGS WARNINGS WARNINGS ). In clinical trials, Cymbalta use was associated with an increased risk of mydriasis; therefore, its use should be avoided in patients with uncontrolled narrow-angle glaucoma.
[1] Controlled Narrow-Angle Glaucoma -- In clinical trials, Cymbalta was associated with an increased risk of mydriasis; therefore, it should be used cautiously in patients with controlled narrow-angle glaucoma ( see CONTRAINDICATIONS, Uncontrolled Narrow-Angle Glaucoma CONTRAINDICATIONS, Uncontrolled Narrow–Angle Glaucoma ).
[1] 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 score from baseline.
[1] The physician who elects to use Cymbalta for extended periods should periodically evaluate the long-term usefulness of the drug for the individual patient.
[1] Suicidality and Antidepressant Drugs -- Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of Cymbalta or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need.
[1] 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.
[1] 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.
[1] 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).
[1] 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. For this reason, Cymbalta is not recommended for patients with end-stage renal disease (requiring dialysis) or severe renal impairment (estimated creatinine clearance <30 mL/min) ( see DOSAGE AND ADMINISTRATION ).
[1] For most patients, the recommended starting dose for Cymbalta is 60 mg administered once daily without regard to meals.
[1] Drugs Metabolized by CYP2D6 -- Duloxetine is a moderate inhibitor of CYP2D6 and increases the AUC and C max of drugs metabolized by CYP2D6 ( see PRECAUTIONS ). Therefore, co-administration of Cymbalta with other drugs that are extensively metabolized by this isozyme and that have a narrow therapeutic index should be approached with caution ( see PRECAUTIONS, Drug Interactions ).
[1] 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 PRECAUTIONS, Drug Interactions ).
[1] The concomitant use of Cymbalta with serotonin precursors (such as tryptophan) is not recommended ( see PRECAUTIONS, Drug Interactions ).
[1] The concomitant use of Cymbalta with other SSRIs, SNRIs or tryptophan is not recommended ( see PRECAUTIONS, Drug Interactions PRECAUTIONS, Drug Interactions ).
[1] The effects of combined use of Cymbalta and MAOIs have not been evaluated in humans or animals. Therefore, because Cymbalta is an inhibitor of both serotonin and norepinephrine reuptake, it is recommended that Cymbalta not be used in combination with an MAOI, or within at least 14 days of discontinuing treatment with an MAOI. Based on the half-life of Cymbalta, at least 5 days should be allowed after stopping Cymbalta before starting an MAOI.
[1] The combination of transaminase elevations and elevated bilirubin, without evidence of obstruction, is generally recognized as an important predictor of severe liver injury. In clinical trials, three Cymbalta patients had elevations of transaminases and bilirubin, but also had elevation of alkaline phosphatase, suggesting an obstructive process; in these patients, there was evidence of heavy alcohol use and this may have contributed to the abnormalities seen.
[1] Because it is possible that duloxetine and alcohol may interact to cause liver injury or that duloxetine may aggravate pre-existing liver disease, Cymbalta should ordinarily not be prescribed to patients with substantial alcohol use or evidence of chronic liver disease.
[1] As duloxetine is rapidly hydrolyzed in acidic media to naphthol, caution is advised in using Cymbalta in patients with conditions that may slow gastric emptying (e.g., some diabetics).
[1] Cymbalta is contraindicated in patients with a known hypersensitivity to duloxetine or any of the inactive ingredients.
[1] A total of 457 patients (342 Cymbalta, 115 placebo) were enrolled in Study 1 and a total of 334 patients (226 Cymbalta, 108 placebo) were enrolled in Study 2.
[1] Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of Cymbalta and triptans, tramadol or other serotonergic agents.
[1] 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.
[1] Cymbalta should be prescribed with care in patients with a history of a seizure disorder.
[1] Caution is advised in using Cymbalta in patients with conditions that may slow gastric emptying (e.g., some diabetics).
[1] Of the 2418 patients in premarketing clinical studies of Cymbalta for MDD, 5.9% (143) were 65 years of age or over.
[1] 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.
[1] The effectiveness of Cymbalta in hospitalized patients with major depressive disorder has not been studied.
[1] The effectiveness of Cymbalta in long-term use for major depressive disorder, that is, for more than 9 weeks, has not been systematically evaluated in controlled trials.
[1] 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.
[1] The efficacy of Cymbalta has been established in 8- and 9-week placebo-controlled trials of outpatients who met DSM-IV diagnostic criteria for major depressive disorder ( see CLINICAL STUDIES CLINICAL STUDIES CLINICAL STUDIES CLINICAL STUDIES ).
[1] 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.
[1] 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.
[1] When treating pregnant women with Cymbalta during the third trimester, the physician should carefully consider the potential risks and benefits of treatment.
[1] Anyone considering the use of Cymbalta in a child or adolescent must balance the potential risks with the clinical need.
[1] Dosage for Nursing Mothers -- Because the safety of duloxetine in infants is not known, nursing while on Cymbalta is not recommended ( see CLINICAL PHARMACOLOGY ).
[1] 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.
[1] Subsequently, the physician may continue decreasing the dose but at a more gradual rate. At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with Cymbalta. At least 5 days should be allowed after stopping Cymbalta before starting an MAOI ( see CONTRAINDICATIONS and WARNINGS ).
[1] 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).
[1] In all 3 studies, Cymbalta demonstrated superiority over placebo as measured by greater improvement in the Hamilton Anxiety Scale (HAM-A) total score and by the Sheehan Disability Scale (SDS) global functional impairment score.
[1] Males treated with Cymbalta experienced more difficulty with ability to reach orgasm (ASEX Item 4) than males treated with placebo.
[1] Cymbalta ® (duloxetine hydrochloride) is a selective serotonin and norepinephrine reuptake inhibitor (SSNRI) for oral administration. Its chemical designation is (+)-( S )- N -methyl-"-(1-naphthyloxy)-2-thiophenepropylamine hydrochloride.
[1] Cymbalta ® (duloxetine hydrochloride) Delayed-release Capsules are available in 20, 30, and 60 mg strengths.
[1] Cymbalta should be administered at a total dose of 40 mg/day (given as 20 mg BID) to 60 mg/day (given either once a day or as 30 mg BID) without regard to meals.
[1] 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.
[1] Cymbalta should be administered at a total dose of 60 mg/day given once a day, without regard to meals.
[1] Cymbalta is indicated for the management of neuropathic pain associated with diabetic peripheral neuropathy ( see CLINICAL STUDIES ).
[1] As the progression of diabetic peripheral neuropathy is highly variable and management of pain is empirical, the effectiveness of Cymbalta must be assessed individually.
[1] As with other antidepressants, Cymbalta has been associated with cases of clinically significant hyponatremia ( see Hyponatremia, under PRECAUTIONS Hyponatremia, under PRECAUTIONS ).
[1] 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.
[1] Hepatotoxicity -- Cymbalta increases the risk of elevation of serum transaminase levels.
[1] 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.
[1] 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.
[1] The concomitant use of Cymbalta with MAOIs intended to treat depression is contraindicated ( see CONTRAINDICATIONS CONTRAINDICATIONS and WARNINGS, Potential for Interaction with Monoamine Oxidase Inhibitors and WARNINGS, Potential for Interaction with Monoamine Oxidase Inhibitors ).
[1] Hyponatremia -- Cases of hyponatremia (some with serum sodium lower than 110 mmol/L) have been reported and appeared to be reversible when Cymbalta was discontinued.
[1] As observed in DPNP trials, Cymbalta treatment worsens glycemic control in some patients with diabetes.
[1] Serotonin Syndrome-- The development of a potentially life-threatening serotonin syndrome may occur with SNRIs and SSRIs, including Cymbalta treatment, particularly with concomitant use of serotonergic drugs (including triptans) and with drugs which impair metabolism of serotonin (including MAOIs).
[1] A life-threatening condition called serotonin syndrome can happen when medicines called selective serotonin/norepinephrine reuptake inhibitors (SNRIs), such as Cymbalta, and medicines used to treat migraine headaches known as 5-hydroxytryptamine receptor agonists (triptans), are used together. This information reflects FDA's current analysis of data available to FDA concerning these drugs. FDA intends to update this sheet when additional information or analyses become available.
[2] SSRIs/SNRI/Triptan and Serotonin Syndrome (7/2006) A life-threatening condition called serotonin syndrome (serious changes in how your brain, muscles and digestive system work due to high levels of serotonin in the body) can happen when medicines called selective serotonin reuptake inhibitors (SSRIs), such as Cymbalta, and medicines used to treat migraine headaches known as 5-hydroxytryptamine receptor agonists (triptans), are used together.
[2] Before you take Cymbalta and a triptan together, talk to your healthcare professional. If you must take these medicines together, be aware of the possibility of serotonin syndrome, and get medical care right away if you think serotonin syndrome is happening to you.
[2] 
Participating patients will be treated with Cymbalta in doses up to 60mg daily for eight (8) weeks. The primary outcome measure for this study will be the 17-item Hamilton Rating Scale for Depression (HRSD-17). In pursuit of this objective, we will test the following hypothesis: After eight weeks of open-label treatment with Cymbalta for bereavement-associated depression, at least half of the participants will achieve remission, as measured by a score of 7 or less on the HRSD-17.
[3] Patients who tolerate and respond to Cymbalta treatment will be offered maintenance therapy with Cymbalta for up to one year at the effective dose.
[3] Concomitant use of medications known to have potential for clinically significant interaction with Cymbalta (patients can be enrolled after taper and clearance of other medications, if other medications can be safely discontinued).
[3] Cymbalta for Depression as a Complication of Bereavement This study is currently recruiting participants.
[3] Purpose The primary objective of this pilot project is to evaluate the efficacy of Cymbalta for bereavement-associated depression.
[3] We expect that Cymbalta treatment will be associated with substantial remission and response rates, as measured by HRSD-17 scores.
[3] 
