Cymbalta

— THERAPEUTIC CATEGORIES —
  • Anxiety/OCD
  • Fibromyalgia
  • Mood disorders
  • Musculoskeletal pain
  • Nonnarcotic analgesics
PAGE CONTENTS
  • Jump to Section
  • Generic Name & Formulations
  • Indications
  • Dosage and Administration
  • Contraindications
  • Boxed Warnings
  • Warnings/Precautions
  • Pharmacokinetics
  • Interactions
  • Adverse Reactions
  • Clinical Trials
  • Note
  • Patient Counseling

    • Cymbalta Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Duloxetine (as HCl) 20mg, 30mg, 60mg; del-rel caps.

    Pharmacological Class

    SNRI.

    How Supplied

    Caps 20mg—60; 30mg—30, 90; 60mg—30, 1000

    How Supplied

    20mg capsules: Green; imprint: Lilly 3235, 20mg; Capsule number: PU3235; bottles of 60.

    30mg capsules: White and blue; imprint: Lilly 3240, 30mg; Capsule number: PU3240; bottles of 30 and 90.

    60mg capsules: Green and blue; imprint: Lilly 3270, 60mg; Capsule number: PU3270; bottles of 30 and 1000.

    Storage

    Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F).

    Manufacturer

    Eli Lilly and Company

    Generic Availability

    YES

    Mechanism of Action

    The exact mechanisms of the antidepressant, central pain inhibitory and anxiolytic actions of duloxetine are unknown, however, it is believed to be related to its potentiation of serotonergic and noradrenergic activity in the CNS.

    Cymbalta Indications

    Indications

    Generalized anxiety disorder (GAD).

    Cymbalta Dosage and Administration

    Adult

    Swallow whole. Initially 60mg once daily (may start at 30mg once daily for 1 week then increase to 60mg once daily); usual target 60mg/day (doses up to 120mg/day have been given; if needed, may increase by increments of 30mg/day). Maintenance: 60–120mg once daily. Elderly: initially 30mg once daily for 2 weeks then increase to 60mg once daily; if needed, may increase by increments of 30mg/day; max 120mg/day.

    Children

    <7yrs: not established. Swallow whole. 7–17yrs: initially 30mg once daily for 2 weeks then increase to 60mg once daily; usual target 30–60mg/day; if needed, may increase by increments of 30mg/day; max 120mg/day.

    Elderly

    Start at 30mg once daily for 2 weeks before considering an increase to the target dose of 60mg/day. If increasing beyond 60mg/day, increase in increments of 30mg once daily. Max dose studied: 120mg/day.

    Renal Impairment

    Mild to moderate impairment: PK analysis suggests no significant effect on duloxetine clearance. 

    Limited data available on the effect of Cymbalta in patients with ESRD.

    Hepatic Impairment

    Patients with clinically evidence hepatic impairment have decreased duloxetine metabolism and elimination.

    Administration

    Swallow whole; do not crush or chew. Do not open the capsules and sprinkle the contents on food or liquids as these actions may affect the enteric coating.

    Missed dose: Take as soon as remembered. If it is almost time for the next dose, skip the missed dose and take the next dose at the regular time.

    Cymbalta Contraindications

    Contraindications

    During or within 14 days of MAOIs. Concomitant MAOIs within 5 days of discontinuing duloxetine. Concomitant linezolid or IV methylene blue.

    Cymbalta Boxed Warnings

    Boxed Warning

    Suicidal thoughts and behaviors.

    Cymbalta Warnings/Precautions

    Warnings/Precautions

    Increased risk of suicidal thoughts and behavior in children, adolescents and young adults; monitor for clinical worsening and unusual changes. Screen for bipolar disorder. Monitor for emergence of serotonin syndrome; discontinue if occurs. Risk of bleeding. Consider dose reduction or discontinuation if orthostatic hypotension, falls and/or syncope occur. Monitor BP prior to and during therapy. History of seizure or mania/hypomania. Angle-closure glaucoma. Volume-depleted. Hyponatremia (esp. in elderly). Decreased GI motility. Cardiac disease. Diabetes. Sexual dysfunction. Monitor weight and growth in children. Severe renal impairment (CrCl<30mL/min), end stage renal disease, hepatic insufficiency, chronic liver disease, cirrhosis, or substantial alcohol use: not recommended. Avoid abrupt cessation. Reevaluate periodically. Elderly. Pregnancy; see full labeling for effects on neonates exposed late in the 3rd trimester. Nursing mothers: monitor infants.

    Warnings/Precautions

    Suicidal Thoughts and Behavios in Children, Adolescents, and Young Adults

    • 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.
    • No suicides occurred in pediatric Cymbalta trials.
    • Monitor patients closely for clinical worsening, suicidality, unusual changes in behavior, especially during the first few months or during dosage changes.
    • In patients whose depression persistently worsens, consider changing the therapeutic regimen by tapering gradually if possible.
    • Families/caregivers: Monitor patients for emergence of agitation, irritability, unusual changes in behavior and report to health care provider.
    • Prescriptions for Cymbalta should be written for the smallest quantity of capsules consistent with good patient management in order to reduce overdose risk.
    • Screen patients with depressive symptoms prior to initiating antidepressants to determine bipolar disorder risk; Cymbalta is not indicated for bipolar depression.

    Discontinuing Cymbalta

    • Gradual reduction in dosage rather than abrupt cessation is recommended.
    • Potential adverse reactions after abrupt or tapered discontinuation: Dizziness, headache, nausea, diarrhea, paresthesia, irritability, vomiting, insomnia, anxiety, hyperhidrosis, fatigue.
    • Monitor patients for these symptoms; if intolerable symptoms occur, resuming the previously prescribed dose may be considered.
    • Subsequent decreasing of dose should be done more gradually.

    Hepatotoxicity

    • Cymbalta has been linked to cases of hepatic failure; cases have presented as hepatitis with abdominal pain, hepatomegaly, transaminase level elevations more than 20xULN with or without jaundice.
    • Discontinue Cymbalta in patients who develop jaundice or clinically significant liver dysfunction; do not resume unless another cause has been identified.
    • Cases of cholestatic jaundice with minimal elevation of transaminase levels have been reported.
    • Do not prescribe Cymbalta to patients with substantial alcohol use or evidence of chronic liver disease; Cymbalta and alcohol can interact to cause liver injury and Cymbalta may aggravate pre-existing liver disease.

    Orthostatic Hypotension, Falls and Syncope

    • Orthostatic hypotension, falls and syncope have been reported with Cymbalta.
    • Syncope and orthostatic hypotension tend to occur within the first week of treatment but can occur at any time, particularly after dose increases.
    • Risk of falling appears to be related to the presence of orthostatic decrease in BP, which is more likely to occur in patients taking concomitant drugs that induce orthostatic hypotension or are potent CYP1A2 inhibitors, as well as in patients taking doses >60mg/day.
    • Consider dose reduction or discontinuation of Cymbalta if symptomatic orthostatic hypotension, falls or syncope occur during treatment.
    • Risk of falls appears to increase with age; falls with serious consequences (eg, fractures, hospitalizations) have been reported with Cymbalta.

    Serotonin Syndrome

    • Serotonin syndrome: Mental status changes (eg, agitation, hallucinations, delirium, coma), autonomic instability (eg, tachycardia, labile BP, dizziness, diaphoresis, flushing, hyperthermia),  neuromuscular symptoms (eg, tremor, rigidity, myoclonus, hyperreflexia, incoordination), and GI symptoms (eg, nausea, vomiting, diarrhea).
    • Has been reported with SSRIs and SNRIs, including Cymbalta, and with concomitant use of serotonergic drugs (eg, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, St. John’s Wort) and with drugs that impair serotonin metabolism (eg, MOAIs, linezolid, IV methylene blue).
    • Monitor patients for the emergence of serotonin syndrome.
    • Concomitant use of MAOIs and Cymbalta is contraindicated; discontinue Cymbalta before initiating treatment with an MAOI.
    • Patients should be made aware of the potential for serotonin syndrome if concomitant use of Cymbalta and other serotonergic drugs is clinically warranted.

    Increased Risk of Bleeding

    • Drugs that interact with serotonin reuptake inhibition may increase the risk of bleeding events.
    • Concomitant aspirin, NSAIDs, warfarin, and other anticoagulants may increase this risk; inform patients about the risk of bleeding.

    Severe Skin Reactions

    • Erythema multiforme and Stevens-Johnson Syndrome have been reported with Cymbalta.
    • Discontinue treatment at the first appearance of blisters, peeling rash, mucosal erosions, or any other sign of hypersensitivity if no other etiology can be identified.

    Activation of Mania/Hypomania

    • Use Cymbalta cautiously in patients with a history of mania.
    • Activation of mania or hypomania has been reported in patients with mood disorders who were treated with other drugs for major depressive disorder.

    Angle Closure Glaucoma

    • Pupillary dilation following use of antidepressants can trigger angle closure attack in patients with anatomically narrow angles who do not have a patent iridectomy.

    Seizures

    • Patients with seizures were excluded from clinical trials.
    • Use caution when prescribing Cymbalta to patients with a history of seizure disorder.

    BP Increases

    • Across clinical trials, Cymbalta use was associated with mean increases of 0.5 mm Hg in systolic BP and 0.8 mm Hg in diastolic BP.
    • Measure BP before starting treatment and check periodically throughout treatment.

    Hyponatremia

    • Hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion.
    • Cases with serum sodium <110mmol/L have been reported with Cymbalta and appeared to be reversible when discontinued.
    • Geriatric patients, those on diuretics, and volume depleted individuals may be at greater risk.
    • Consider discontinuing Cymbalta in patients with symptomatic hyponatremia.
    • Signs/symptoms of hyponatremia: Headache, difficulty concentrating, memory impairment, confusion, weakness, unsteadiness. Severe cases: Hallucination, syncope, seizure, coma, respiratory arrest, death.

    Concomitant Illness

    • Caution advised for patients with conditions that may slow gastric emptying.
    • Patients with recent history of MI or unstable coronary artery disease were excluded from clinical studies.
    • Avoid use in patients with chronic liver disease or cirrhosis.
    • Avoid use in patients with severe renal impairment (GFR <30mL/min); increased plasma concentrations occurred in patients with end-stage renal disease.
    • Cymbalta may worsen glycemic control in some patients with diabetes.

    Urinary Hesitation and Retention

    • Cymbalta may affect urethral resistance.
    • If symptoms of urinary hesitation develop, it may be related to Cymbalta use.

    Sexual Dysfunction

    • SNRIs may cause symptoms of sexual dysfunction in males (ejaculatory delay or failure, decreased libido, erectile dysfunction) and females (decreased libido, delayed or absent orgasm).
    • Evaluate changes in sexual function; discuss potential management strategies.

    Pregnancy Considerations

    Postmarketing retrospective cohort study: Use of duloxetine in the month before delivery may be associated with an increased risk of postpartum hemorrhage.

    Neonates exposed to SNRIS, SSRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Findings were consistent with either a direct toxic effect of the drug or possibly a drug discontinuation syndrome.

    Nursing Mother Considerations

    Duloxetine is present in human milk. Sedation, poor feeding, and poor weight gain have been reported in infants exposed to duloxetine through breast milk. 

    Study findings showed that the amount of Cymbalta in breast milk was approximately 7mcg/day while on 40mg twice daily for 3.5 days. The estimated daily infant dose was approximately 2mcg/kg/day, which is <1% of the maternal dose.

    Pediatric Considerations

    Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric patients. Monitor for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of treatment or during dosage adjustments.

    Regular monitoring and weight and growth is recommended.

    Safety and effectiveness of Cymbalta has been established in patients 7 to 17 years of age with generalized anxiety disorder.

    Use of Cymbalta was supported by a 10-week placebo-controlled trial that included 272 pediatric patients with GAD. Cymbalta was found to be superior to placebo as measured by greater improvement in the Pediatric Anxiety Rating Scale for GAD severity score.

    Geriatric Considerations

    No overall differences in safety or effectiveness observed between geriatric patients and younger patients.

    SSRIs and SNRIs have been associated with clinically significant hyponatremia in geriatric patients.

    In clinical trials, Cymbalta-treated patients reported a higher rate of falls compared with those who received placebo; underlying risk appears to increase steadily with age.

    Renal Impairment Considerations

    Mild to moderate impairment: PK analysis suggests no significant effect on duloxetine clearance. 

    Limited data available on the effect of Cymbalta in patients with ESRD.

    Hepatic Impairment Considerations

    Patients with clinically evidence hepatic impairment have decreased duloxetine metabolism and elimination.

    Cymbalta Pharmacokinetics

    Absorption

    Max plasma concentrations of duloxetine occur 6 hours post dose.

    Distribution

    Duloxetine is highly protein bound (>90%).

    Metabolism

    Hepatic (CYP1A2, CYP2D6).

    Elimination

    Renal (~70%), fecal (~20%). Half-life: ~12 hours (range: 8–17 hours).

    Cymbalta Interactions

    Interactions

    See Contraindications. Concomitant thioridazine (may cause arrhythmias): not recommended. Increased risk of serotonin syndrome with other serotonergic drugs (eg, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, St. John's Wort) or with drugs that impair serotonin metabolism (eg, MAOIs, linezolid, IV methylene blue). Potentiated by CYP1A2 inhibitors (eg, cimetidine, fluvoxamine, quinolones): avoid. May potentiate or be potentiated by CYP2D6 inhibitors (eg, paroxetine, fluoxetine, quinidine) or substrates (eg, tricyclics, phenothiazines, type 1C antiarrhythmics) or other highly protein-bound drugs; caution with CYP2D6 substrates with narrow therapeutic indexes. Caution with potent CYP1A2 inhibitors, antihypertensives, other drugs that induce orthostatic hypotension. Monitor concomitant CNS-acting drugs, and with those that affect gastric pH (eg, proton pump inhibitors). Increased risk of bleeding with NSAIDs, aspirin, or others that affect coagulation.

    Cymbalta Adverse Reactions

    Adverse Reactions

    Nausea, dry mouth, somnolence, constipation, decreased appetite, hyperhidrosis; hepatotoxicity (discontinue if occurs), orthostatic hypotension, falls, syncope, mania/hypomania, increased BP, urinary hesitation/retention; rare: seizure, serious skin reactions (eg, Stevens-Johnson Syndrome). In children: also decreased weight, vomiting, fatigue, diarrhea.

    Cymbalta Clinical Trials

    Clinical Trials

    The efficacy of Cymbalta in the treatment of generalized anxiety disorder (GAD) was supported by data from 3 clinical trials. Findings showed that Cymbalta was superior to placebo as measured by greater improvement in the Hamilton Anxiety-Scale (HAM-A) total score and by the Sheehan Disability Scale global functional impairment score. 

    In Study GAD-4, 429 patients who responded to open-label treatment with Cymbalta were randomly assigned to continue 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. Cymbalta-treated patients experienced a statistically significantly longer time to relapse of GAD than those who received placebo.

    Among patients 65 years of age and older with GAD, Cymbalta demonstrated significantly greater improvement compared with placebo on mean change from baseline to endpoint as measured by the HAMA-A total score.

    In patients 7 to 17 years of age with GAD, Cymbalta demonstrated superiority over placebo from baseline to endpoint as measured by greater improvement in the Pediatric Anxiety Rating Scale for GAD severity score.

    Cymbalta Note

    Not Applicable

    Cymbalta Patient Counseling

    Patient Counseling

    Monitor for the emergence of suicidal ideation and behavior, especially during treatment and when the dose is adjusted.

    Swallow Cymbalta whole; do not chew, crush, or open the capsule because these actions might affect the enteric coating.

    Severe liver problems, sometimes fatal, have been reported in patients treated with Cymbalta; if itching, right upper belly pain, dark urine, or yellow skin/eyes occurs, contact health care provider.

    Use of Cymbalta with heavy alcohol intake may be associated with severe liver injury.  

    Risk of orthostatic hypotension, falls and syncope, especially during initial use and subsequent dose escalation, and when used with other drugs that might potentiate the orthostatic effect.

    Risk of serotonin syndrome with the concomitant use of Cymbalta and other serotonergic agents including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, amphetamines, and St. John’s Wort. 

    Concomitant use of Cymbalta and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation may increase risk of bleeding.

    Cymbalta may cause serious skin reactions. 

    Discontinuation of Cymbalta may be associated with symptoms such as dizziness, headache, nausea, diarrhea, paresthesia, irritability, vomiting, insomnia, anxiety, hyperhidrosis, and fatigue.

    Patients should report any signs or symptoms of a manic reaction.

    Cymbalta can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle-closure glaucoma.

    Cymbalta may cause an increase in blood pressure.

    Patients should report any prescription or over-the-counter medications, since there is a potential for interactions.

    Hyponatremia has been reported as a result of treatment with SNRIs and SSRIs.

    Cymbalta may affect urination.  

    Cymbalta may cause symptoms of sexual dysfunction in both male and female patients.

    Cymbalta use during the month before delivery may lead to an increased risk for postpartum hemorrhage and may increase the risk of neonatal complications requiring prolonged hospitalization, respiratory support, and tube feeding.

    Breastfeeding women on Cymbalta: Monitor infants for sedation, poor feeding and poor weight gain.  

    Cymbalta may be associated with sedation and dizziness.

    Cymbalta Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Duloxetine (as HCl) 20mg, 30mg, 60mg; del-rel caps.

    Pharmacological Class

    SNRI.

    How Supplied

    Caps 20mg—60; 30mg—30, 90; 60mg—30, 1000

    How Supplied

    20mg capsules: Green; imprint: Lilly 3235, 20mg; Capsule number: PU3235; bottles of 60.

    30mg capsules: White and blue; imprint: Lilly 3240, 30mg; Capsule number: PU3240; bottles of 30 and 90.

    60mg capsules: Green and blue; imprint: Lilly 3270, 60mg; Capsule number: PU3270; bottles of 30 and 1000.

    Storage

    Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F).

    Manufacturer

    Eli Lilly and Company

    Generic Availability

    YES

    Mechanism of Action

    The exact mechanisms of the antidepressant, central pain inhibitory and anxiolytic actions of duloxetine are unknown, however, it is believed to be related to its potentiation of serotonergic and noradrenergic activity in the CNS.

    Cymbalta Indications

    Indications

    Fibromyalgia.

    Cymbalta Dosage and Administration

    Adult

    Swallow whole. Initially 30mg once daily for 1 week, then increase to 60mg once daily.

    Children

    <13yrs: not established. Swallow whole. 13–17yrs: initially 30mg once daily; may increase to 60mg once daily based on response and tolerability.

    Renal Impairment

    Mild to moderate impairment: PK analysis suggests no significant effect on duloxetine clearance. 

    Limited data available on the effect of Cymbalta in patients with ESRD.

    Hepatic Impairment

    Patients with clinically evidence hepatic impairment have decreased duloxetine metabolism and elimination.

    Administration

    Swallow whole; do not crush or chew. Do not open the capsules and sprinkle the contents on food or liquids as these actions may affect the enteric coating.

    Missed dose: Take as soon as remembered. If it is almost time for the next dose, skip the missed dose and take the next dose at the regular time.

    Cymbalta Contraindications

    Contraindications

    During or within 14 days of MAOIs. Concomitant MAOIs within 5 days of discontinuing duloxetine. Concomitant linezolid or IV methylene blue.

    Cymbalta Boxed Warnings

    Boxed Warning

    Suicidal thoughts and behaviors.

    Cymbalta Warnings/Precautions

    Warnings/Precautions

    Increased risk of suicidal thoughts and behavior in children, adolescents and young adults; monitor for clinical worsening and unusual changes. Screen for bipolar disorder. Monitor for emergence of serotonin syndrome; discontinue if occurs. Risk of bleeding. Consider dose reduction or discontinuation if orthostatic hypotension, falls and/or syncope occur. Monitor BP prior to and during therapy. History of seizure or mania/hypomania. Angle-closure glaucoma. Volume-depleted. Hyponatremia (esp. in elderly). Decreased GI motility. Cardiac disease. Diabetes. Sexual dysfunction. Monitor weight and growth in children. Severe renal impairment (CrCl<30mL/min), end stage renal disease, hepatic insufficiency, chronic liver disease, cirrhosis, or substantial alcohol use: not recommended. Avoid abrupt cessation. Reevaluate periodically. Elderly. Pregnancy; see full labeling for effects on neonates exposed late in the 3rd trimester. Nursing mothers: monitor infants.

    Warnings/Precautions

    Suicidal Thoughts and Behavios in Children, Adolescents, and Young Adults

    • 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.
    • No suicides occurred in pediatric Cymbalta trials.
    • Monitor patients closely for clinical worsening, suicidality, unusual changes in behavior, especially during the first few months or during dosage changes.
    • In patients whose depression persistently worsens, consider changing the therapeutic regimen by tapering gradually if possible.
    • Families/caregivers: Monitor patients for emergence of agitation, irritability, unusual changes in behavior and report to health care provider.
    • Prescriptions for Cymbalta should be written for the smallest quantity of capsules consistent with good patient management in order to reduce overdose risk.
    • Screen patients with depressive symptoms prior to initiating antidepressants to determine bipolar disorder risk; Cymbalta is not indicated for bipolar depression.

    Discontinuing Cymbalta

    • Gradual reduction in dosage rather than abrupt cessation is recommended.
    • Potential adverse reactions after abrupt or tapered discontinuation: Dizziness, headache, nausea, diarrhea, paresthesia, irritability, vomiting, insomnia, anxiety, hyperhidrosis, fatigue.
    • Monitor patients for these symptoms; if intolerable symptoms occur, resuming the previously prescribed dose may be considered.
    • Subsequent decreasing of dose should be done more gradually.

    Hepatotoxicity

    • Cymbalta has been linked to cases of hepatic failure; cases have presented as hepatitis with abdominal pain, hepatomegaly, transaminase level elevations more than 20xULN with or without jaundice.
    • Discontinue Cymbalta in patients who develop jaundice or clinically significant liver dysfunction; do not resume unless another cause has been identified.
    • Cases of cholestatic jaundice with minimal elevation of transaminase levels have been reported.
    • Do not prescribe Cymbalta to patients with substantial alcohol use or evidence of chronic liver disease; Cymbalta and alcohol can interact to cause liver injury and Cymbalta may aggravate pre-existing liver disease.

    Orthostatic Hypotension, Falls and Syncope

    • Orthostatic hypotension, falls and syncope have been reported with Cymbalta.
    • Syncope and orthostatic hypotension tend to occur within the first week of treatment but can occur at any time, particularly after dose increases.
    • Risk of falling appears to be related to the presence of orthostatic decrease in BP, which is more likely to occur in patients taking concomitant drugs that induce orthostatic hypotension or are potent CYP1A2 inhibitors, as well as in patients taking doses >60mg/day.
    • Consider dose reduction or discontinuation of Cymbalta if symptomatic orthostatic hypotension, falls or syncope occur during treatment.
    • Risk of falls appears to increase with age; falls with serious consequences (eg, fractures, hospitalizations) have been reported with Cymbalta.

    Serotonin Syndrome

    • Serotonin syndrome: Mental status changes (eg, agitation, hallucinations, delirium, coma), autonomic instability (eg, tachycardia, labile BP, dizziness, diaphoresis, flushing, hyperthermia),  neuromuscular symptoms (eg, tremor, rigidity, myoclonus, hyperreflexia, incoordination), and GI symptoms (eg, nausea, vomiting, diarrhea).
    • Has been reported with SSRIs and SNRIs, including Cymbalta, and with concomitant use of serotonergic drugs (eg, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, St. John’s Wort) and with drugs that impair serotonin metabolism (eg, MOAIs, linezolid, IV methylene blue).
    • Monitor patients for the emergence of serotonin syndrome.
    • Concomitant use of MAOIs and Cymbalta is contraindicated; discontinue Cymbalta before initiating treatment with an MAOI.
    • Patients should be made aware of the potential for serotonin syndrome if concomitant use of Cymbalta and other serotonergic drugs is clinically warranted.

    Increased Risk of Bleeding

    • Drugs that interact with serotonin reuptake inhibition may increase the risk of bleeding events.
    • Concomitant aspirin, NSAIDs, warfarin, and other anticoagulants may increase this risk; inform patients about the risk of bleeding.

    Severe Skin Reactions

    • Erythema multiforme and Stevens-Johnson Syndrome have been reported with Cymbalta.
    • Discontinue treatment at the first appearance of blisters, peeling rash, mucosal erosions, or any other sign of hypersensitivity if no other etiology can be identified.

    Activation of Mania/Hypomania

    • Use Cymbalta cautiously in patients with a history of mania.
    • Activation of mania or hypomania has been reported in patients with mood disorders who were treated with other drugs for major depressive disorder.

    Angle Closure Glaucoma

    • Pupillary dilation following use of antidepressants can trigger angle closure attack in patients with anatomically narrow angles who do not have a patent iridectomy.

    Seizures

    • Patients with seizures were excluded from clinical trials.
    • Use caution when prescribing Cymbalta to patients with a history of seizure disorder.

    BP Increases

    • Across clinical trials, Cymbalta use was associated with mean increases of 0.5 mm Hg in systolic BP and 0.8 mm Hg in diastolic BP.
    • Measure BP before starting treatment and check periodically throughout treatment.

    Hyponatremia

    • Hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion.
    • Cases with serum sodium <110mmol/L have been reported with Cymbalta and appeared to be reversible when discontinued.
    • Geriatric patients, those on diuretics, and volume depleted individuals may be at greater risk.
    • Consider discontinuing Cymbalta in patients with symptomatic hyponatremia.
    • Signs/symptoms of hyponatremia: Headache, difficulty concentrating, memory impairment, confusion, weakness, unsteadiness. Severe cases: Hallucination, syncope, seizure, coma, respiratory arrest, death.

    Concomitant Illness

    • Caution advised for patients with conditions that may slow gastric emptying.
    • Patients with recent history of MI or unstable coronary artery disease were excluded from clinical studies.
    • Avoid use in patients with chronic liver disease or cirrhosis.
    • Avoid use in patients with severe renal impairment (GFR <30mL/min); increased plasma concentrations occurred in patients with end-stage renal disease.
    • Cymbalta may worsen glycemic control in some patients with diabetes.

    Urinary Hesitation and Retention

    • Cymbalta may affect urethral resistance.
    • If symptoms of urinary hesitation develop, it may be related to Cymbalta use.

    Sexual Dysfunction

    • SNRIs may cause symptoms of sexual dysfunction in males (ejaculatory delay or failure, decreased libido, erectile dysfunction) and females (decreased libido, delayed or absent orgasm).
    • Evaluate changes in sexual function; discuss potential management strategies.

    Pregnancy Considerations

    Postmarketing retrospective cohort study: Use of duloxetine in the month before delivery may be associated with an increased risk of postpartum hemorrhage.

    Neonates exposed to SNRIS, SSRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Findings were consistent with either a direct toxic effect of the drug or possibly a drug discontinuation syndrome.

    Nursing Mother Considerations

    Duloxetine is present in human milk. Sedation, poor feeding, and poor weight gain have been reported in infants exposed to duloxetine through breast milk. 

    Study findings showed that the amount of Cymbalta in breast milk was approximately 7mcg/day while on 40mg twice daily for 3.5 days. The estimated daily infant dose was approximately 2mcg/kg/day, which is <1% of the maternal dose.

    Pediatric Considerations

    Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric patients. Monitor for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of treatment or during dosage adjustments.

    Regular monitoring and weight and growth is recommended.

    The safety and effectiveness of Cymbalta have been established for the treatment of juvenile fibromyalgia syndrome in patients 13 to 17 years of age.

    Use of Cymbalta was supported by a 13-week placebo-controlled trial in 184 patients with juvenile fibromyalgia syndrome. Treatment with Cymbalta showed improvement over placebo on the primary endpoint, change from baseline to end-of-treatment on the Brief Pain Inventory-Modified Short Form: Adolescent Version 24-hour average pain severity rating.

    Geriatric Considerations

    No overall differences in safety or effectiveness observed between geriatric patients and younger patients.

    SSRIs and SNRIs have been associated with clinically significant hyponatremia in geriatric patients.

    In clinical trials, Cymbalta-treated patients reported a higher rate of falls compared with those who received placebo; underlying risk appears to increase steadily with age.

    Renal Impairment Considerations

    Mild to moderate impairment: PK analysis suggests no significant effect on duloxetine clearance. 

    Limited data available on the effect of Cymbalta in patients with ESRD.

    Hepatic Impairment Considerations

    Patients with clinically evidence hepatic impairment have decreased duloxetine metabolism and elimination.

    Cymbalta Pharmacokinetics

    Absorption

    Max plasma concentrations of duloxetine occur 6 hours post dose.

    Distribution

    Duloxetine is highly protein bound (>90%).

    Metabolism

    Hepatic (CYP1A2, CYP2D6).

    Elimination

    Renal (~70%), fecal (~20%). Half-life: ~12 hours (range: 8–17 hours).

    Cymbalta Interactions

    Interactions

    See Contraindications. Concomitant thioridazine (may cause arrhythmias): not recommended. Increased risk of serotonin syndrome with other serotonergic drugs (eg, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, St. John's Wort) or with drugs that impair serotonin metabolism (eg, MAOIs, linezolid, IV methylene blue). Potentiated by CYP1A2 inhibitors (eg, cimetidine, fluvoxamine, quinolones): avoid. May potentiate or be potentiated by CYP2D6 inhibitors (eg, paroxetine, fluoxetine, quinidine) or substrates (eg, tricyclics, phenothiazines, type 1C antiarrhythmics) or other highly protein-bound drugs; caution with CYP2D6 substrates with narrow therapeutic indexes. Caution with potent CYP1A2 inhibitors, antihypertensives, other drugs that induce orthostatic hypotension. Monitor concomitant CNS-acting drugs, and with those that affect gastric pH (eg, proton pump inhibitors). Increased risk of bleeding with NSAIDs, aspirin, or others that affect coagulation.

    Cymbalta Adverse Reactions

    Adverse Reactions

    Nausea, dry mouth, somnolence, constipation, decreased appetite, hyperhidrosis; hepatotoxicity (discontinue if occurs), orthostatic hypotension, falls, syncope, mania/hypomania, increased BP, urinary hesitation/retention; rare: seizure, serious skin reactions (eg, Stevens-Johnson Syndrome). In children: also decreased weight, vomiting, fatigue, diarrhea.

    Cymbalta Clinical Trials

    Clinical Trials

    Two randomized, double-blind, placebo-controlled trials were conducted to establish the efficacy of Cymbalta for the management of fibromyalgia in adults. Study participants met 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). 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).

    Findings showed that treatment with Cymbalta 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. Some patients experienced a decrease in pain as early as week 1. Improvement was also demonstrated on measures of function (Fibromyalgia Impact Questionnaires) and patient global impression of change. Cymbalta 120mg daily did not demonstrate a benefit over 60mg daily and was associated with more adverse reactions and premature discontinuation.

    Results from a separate trial (Study FM-3) evaluating the benefits of up-titration in nonresponders to Cymbalta showed that patients who were nonresponders at 8 weeks were no more likely to meet response criteria at the end of 60 weeks of treatment if blindly treated with Cymbalta 120mg as compared with those who received Cymbalta 60mg.

    Among pediatric patients aged 13 to 17 years with juvenile fibromyalgia syndrome (N=184), Cymbalta showed improvement over placebo on the primary endpoint (change from baseline to end-of-treatment on the Brief Pain Inventory [BPI] – Modified Short Form: Adolescent Version 24-hour average pain severity rating).

    Cymbalta Note

    Not Applicable

    Cymbalta Patient Counseling

    Patient Counseling

    Monitor for the emergence of suicidal ideation and behavior, especially during treatment and when the dose is adjusted.

    Swallow Cymbalta whole; do not chew, crush, or open the capsule because these actions might affect the enteric coating.

    Severe liver problems, sometimes fatal, have been reported in patients treated with Cymbalta; if itching, right upper belly pain, dark urine, or yellow skin/eyes occurs, contact health care provider.

    Use of Cymbalta with heavy alcohol intake may be associated with severe liver injury.  

    Risk of orthostatic hypotension, falls and syncope, especially during initial use and subsequent dose escalation, and when used with other drugs that might potentiate the orthostatic effect.

    Risk of serotonin syndrome with the concomitant use of Cymbalta and other serotonergic agents including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, amphetamines, and St. John’s Wort. 

    Concomitant use of Cymbalta and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation may increase risk of bleeding.

    Cymbalta may cause serious skin reactions. 

    Discontinuation of Cymbalta may be associated with symptoms such as dizziness, headache, nausea, diarrhea, paresthesia, irritability, vomiting, insomnia, anxiety, hyperhidrosis, and fatigue.

    Patients should report any signs or symptoms of a manic reaction.

    Cymbalta can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle-closure glaucoma.

    Cymbalta may cause an increase in blood pressure.

    Patients should report any prescription or over-the-counter medications, since there is a potential for interactions.

    Hyponatremia has been reported as a result of treatment with SNRIs and SSRIs.

    Cymbalta may affect urination.  

    Cymbalta may cause symptoms of sexual dysfunction in both male and female patients.

    Cymbalta use during the month before delivery may lead to an increased risk for postpartum hemorrhage and may increase the risk of neonatal complications requiring prolonged hospitalization, respiratory support, and tube feeding.

    Breastfeeding women on Cymbalta: Monitor infants for sedation, poor feeding and poor weight gain.  

    Cymbalta may be associated with sedation and dizziness.

    Cymbalta Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Duloxetine (as HCl) 20mg, 30mg, 60mg; del-rel caps.

    Pharmacological Class

    SNRI.

    How Supplied

    Caps 20mg—60; 30mg—30, 90; 60mg—30, 1000

    How Supplied

    20mg capsules: Green; imprint: Lilly 3235, 20mg; Capsule number: PU3235; bottles of 60.

    30mg capsules: White and blue; imprint: Lilly 3240, 30mg; Capsule number: PU3240; bottles of 30 and 90.

    60mg capsules: Green and blue; imprint: Lilly 3270, 60mg; Capsule number: PU3270; bottles of 30 and 1000.

    Storage

    Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F).

    Manufacturer

    Eli Lilly and Company

    Generic Availability

    YES

    Mechanism of Action

    The exact mechanisms of the antidepressant, central pain inhibitory and anxiolytic actions of duloxetine are unknown, however, it is believed to be related to its potentiation of serotonergic and noradrenergic activity in the CNS.

    Cymbalta Indications

    Indications

    Major depressive disorder.

    Cymbalta Dosage and Administration

    Adult

    Swallow whole. Initially 40mg/day (given as 20mg twice daily) to 60mg/day (given either once daily or as 30mg twice daily); may start at 30mg once daily for 1 week, if needed; usual target 60mg once daily (doses up to 120mg/day have been given). Maintenance: 60mg once daily.

    Children

    <18yrs: not established.

    Renal Impairment

    Mild to moderate impairment: PK analysis suggests no significant effect on duloxetine clearance. 

    Limited data available on the effect of Cymbalta in patients with ESRD.

    Hepatic Impairment

    Patients with clinically evidence hepatic impairment have decreased duloxetine metabolism and elimination.

    Administration

    Swallow whole; do not crush or chew. Do not open the capsules and sprinkle the contents on food or liquids as these actions may affect the enteric coating.

    Missed dose: Take as soon as remembered. If it is almost time for the next dose, skip the missed dose and take the next dose at the regular time.

    Cymbalta Contraindications

    Contraindications

    During or within 14 days of MAOIs. Concomitant MAOIs within 5 days of discontinuing duloxetine. Concomitant linezolid or IV methylene blue.

    Cymbalta Boxed Warnings

    Boxed Warning

    Suicidal thoughts and behaviors.

    Cymbalta Warnings/Precautions

    Warnings/Precautions

    Increased risk of suicidal thoughts and behavior in children, adolescents and young adults; monitor for clinical worsening and unusual changes. Screen for bipolar disorder. Monitor for emergence of serotonin syndrome; discontinue if occurs. Risk of bleeding. Consider dose reduction or discontinuation if orthostatic hypotension, falls and/or syncope occur. Monitor BP prior to and during therapy. History of seizure or mania/hypomania. Angle-closure glaucoma. Volume-depleted. Hyponatremia (esp. in elderly). Decreased GI motility. Cardiac disease. Diabetes. Sexual dysfunction. Monitor weight and growth in children. Severe renal impairment (CrCl<30mL/min), end stage renal disease, hepatic insufficiency, chronic liver disease, cirrhosis, or substantial alcohol use: not recommended. Avoid abrupt cessation. Reevaluate periodically. Elderly. Pregnancy; see full labeling for effects on neonates exposed late in the 3rd trimester. Nursing mothers: monitor infants.

    Warnings/Precautions

    Suicidal Thoughts and Behavios in Children, Adolescents, and Young Adults

    • 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.
    • No suicides occurred in pediatric Cymbalta trials.
    • Monitor patients closely for clinical worsening, suicidality, unusual changes in behavior, especially during the first few months or during dosage changes.
    • In patients whose depression persistently worsens, consider changing the therapeutic regimen by tapering gradually if possible.
    • Families/caregivers: Monitor patients for emergence of agitation, irritability, unusual changes in behavior and report to health care provider.
    • Prescriptions for Cymbalta should be written for the smallest quantity of capsules consistent with good patient management in order to reduce overdose risk.
    • Screen patients with depressive symptoms prior to initiating antidepressants to determine bipolar disorder risk; Cymbalta is not indicated for bipolar depression.

    Discontinuing Cymbalta

    • Gradual reduction in dosage rather than abrupt cessation is recommended.
    • Potential adverse reactions after abrupt or tapered discontinuation: Dizziness, headache, nausea, diarrhea, paresthesia, irritability, vomiting, insomnia, anxiety, hyperhidrosis, fatigue.
    • Monitor patients for these symptoms; if intolerable symptoms occur, resuming the previously prescribed dose may be considered.
    • Subsequent decreasing of dose should be done more gradually.

    Hepatotoxicity

    • Cymbalta has been linked to cases of hepatic failure; cases have presented as hepatitis with abdominal pain, hepatomegaly, transaminase level elevations more than 20xULN with or without jaundice.
    • Discontinue Cymbalta in patients who develop jaundice or clinically significant liver dysfunction; do not resume unless another cause has been identified.
    • Cases of cholestatic jaundice with minimal elevation of transaminase levels have been reported.
    • Do not prescribe Cymbalta to patients with substantial alcohol use or evidence of chronic liver disease; Cymbalta and alcohol can interact to cause liver injury and Cymbalta may aggravate pre-existing liver disease.

    Orthostatic Hypotension, Falls and Syncope

    • Orthostatic hypotension, falls and syncope have been reported with Cymbalta.
    • Syncope and orthostatic hypotension tend to occur within the first week of treatment but can occur at any time, particularly after dose increases.
    • Risk of falling appears to be related to the presence of orthostatic decrease in BP, which is more likely to occur in patients taking concomitant drugs that induce orthostatic hypotension or are potent CYP1A2 inhibitors, as well as in patients taking doses >60mg/day.
    • Consider dose reduction or discontinuation of Cymbalta if symptomatic orthostatic hypotension, falls or syncope occur during treatment.
    • Risk of falls appears to increase with age; falls with serious consequences (eg, fractures, hospitalizations) have been reported with Cymbalta.

    Serotonin Syndrome

    • Serotonin syndrome: Mental status changes (eg, agitation, hallucinations, delirium, coma), autonomic instability (eg, tachycardia, labile BP, dizziness, diaphoresis, flushing, hyperthermia),  neuromuscular symptoms (eg, tremor, rigidity, myoclonus, hyperreflexia, incoordination), and GI symptoms (eg, nausea, vomiting, diarrhea).
    • Has been reported with SSRIs and SNRIs, including Cymbalta, and with concomitant use of serotonergic drugs (eg, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, St. John’s Wort) and with drugs that impair serotonin metabolism (eg, MOAIs, linezolid, IV methylene blue).
    • Monitor patients for the emergence of serotonin syndrome.
    • Concomitant use of MAOIs and Cymbalta is contraindicated; discontinue Cymbalta before initiating treatment with an MAOI.
    • Patients should be made aware of the potential for serotonin syndrome if concomitant use of Cymbalta and other serotonergic drugs is clinically warranted.

    Increased Risk of Bleeding

    • Drugs that interact with serotonin reuptake inhibition may increase the risk of bleeding events.
    • Concomitant aspirin, NSAIDs, warfarin, and other anticoagulants may increase this risk; inform patients about the risk of bleeding.

    Severe Skin Reactions

    • Erythema multiforme and Stevens-Johnson Syndrome have been reported with Cymbalta.
    • Discontinue treatment at the first appearance of blisters, peeling rash, mucosal erosions, or any other sign of hypersensitivity if no other etiology can be identified.

    Activation of Mania/Hypomania

    • Use Cymbalta cautiously in patients with a history of mania.
    • Activation of mania or hypomania has been reported in patients with mood disorders who were treated with other drugs for major depressive disorder.

    Angle Closure Glaucoma

    • Pupillary dilation following use of antidepressants can trigger angle closure attack in patients with anatomically narrow angles who do not have a patent iridectomy.

    Seizures

    • Patients with seizures were excluded from clinical trials.
    • Use caution when prescribing Cymbalta to patients with a history of seizure disorder.

    BP Increases

    • Across clinical trials, Cymbalta use was associated with mean increases of 0.5 mm Hg in systolic BP and 0.8 mm Hg in diastolic BP.
    • Measure BP before starting treatment and check periodically throughout treatment.

    Hyponatremia

    • Hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion.
    • Cases with serum sodium <110mmol/L have been reported with Cymbalta and appeared to be reversible when discontinued.
    • Geriatric patients, those on diuretics, and volume depleted individuals may be at greater risk.
    • Consider discontinuing Cymbalta in patients with symptomatic hyponatremia.
    • Signs/symptoms of hyponatremia: Headache, difficulty concentrating, memory impairment, confusion, weakness, unsteadiness. Severe cases: Hallucination, syncope, seizure, coma, respiratory arrest, death.

    Concomitant Illness

    • Caution advised for patients with conditions that may slow gastric emptying.
    • Patients with recent history of MI or unstable coronary artery disease were excluded from clinical studies.
    • Avoid use in patients with chronic liver disease or cirrhosis.
    • Avoid use in patients with severe renal impairment (GFR <30mL/min); increased plasma concentrations occurred in patients with end-stage renal disease.
    • Cymbalta may worsen glycemic control in some patients with diabetes.

    Urinary Hesitation and Retention

    • Cymbalta may affect urethral resistance.
    • If symptoms of urinary hesitation develop, it may be related to Cymbalta use.

    Sexual Dysfunction

    • SNRIs may cause symptoms of sexual dysfunction in males (ejaculatory delay or failure, decreased libido, erectile dysfunction) and females (decreased libido, delayed or absent orgasm).
    • Evaluate changes in sexual function; discuss potential management strategies.

    Pregnancy Considerations

    Postmarketing retrospective cohort study: Use of duloxetine in the month before delivery may be associated with an increased risk of postpartum hemorrhage.

    Neonates exposed to SNRIS, SSRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Findings were consistent with either a direct toxic effect of the drug or possibly a drug discontinuation syndrome.

    Nursing Mother Considerations

    Duloxetine is present in human milk. Sedation, poor feeding, and poor weight gain have been reported in infants exposed to duloxetine through breast milk. 

    Study findings showed that the amount of Cymbalta in breast milk was approximately 7mcg/day while on 40mg twice daily for 3.5 days. The estimated daily infant dose was approximately 2mcg/kg/day, which is <1% of the maternal dose.

    Pediatric Considerations

    Safety and effectiveness of Cymbalta have not been established in pediatric patients with major depressive disorder.

    In two, 10-week trials (N=800) Cymbalta was not found to be superior to placebo in pediatric patients for the treatment of MDD. Nausea, headache, decreased weight, and abdominal pain were the most frequently observed adverse events in these trials.

    Geriatric Considerations

    No overall differences in safety or effectiveness observed between geriatric patients and younger patients.

    SSRIs and SNRIs have been associated with clinically significant hyponatremia in geriatric patients.

    In clinical trials, Cymbalta-treated patients reported a higher rate of falls compared with those who received placebo; underlying risk appears to increase steadily with age.

    Renal Impairment Considerations

    Mild to moderate impairment: PK analysis suggests no significant effect on duloxetine clearance. 

    Limited data available on the effect of Cymbalta in patients with ESRD.

    Hepatic Impairment Considerations

    Patients with clinically evidence hepatic impairment have decreased duloxetine metabolism and elimination.

    Cymbalta Pharmacokinetics

    Absorption

    Max plasma concentrations of duloxetine occur 6 hours post dose.

    Distribution

    Duloxetine is highly protein bound (>90%).

    Metabolism

    Hepatic (CYP1A2, CYP2D6).

    Elimination

    Renal (~70%), fecal (~20%). Half-life: ~12 hours (range: 8–17 hours).

    Cymbalta Interactions

    Interactions

    See Contraindications. Concomitant thioridazine (may cause arrhythmias): not recommended. Increased risk of serotonin syndrome with other serotonergic drugs (eg, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, St. John's Wort) or with drugs that impair serotonin metabolism (eg, MAOIs, linezolid, IV methylene blue). Potentiated by CYP1A2 inhibitors (eg, cimetidine, fluvoxamine, quinolones): avoid. May potentiate or be potentiated by CYP2D6 inhibitors (eg, paroxetine, fluoxetine, quinidine) or substrates (eg, tricyclics, phenothiazines, type 1C antiarrhythmics) or other highly protein-bound drugs; caution with CYP2D6 substrates with narrow therapeutic indexes. Caution with potent CYP1A2 inhibitors, antihypertensives, other drugs that induce orthostatic hypotension. Monitor concomitant CNS-acting drugs, and with those that affect gastric pH (eg, proton pump inhibitors). Increased risk of bleeding with NSAIDs, aspirin, or others that affect coagulation.

    Cymbalta Adverse Reactions

    Adverse Reactions

    Nausea, dry mouth, somnolence, constipation, decreased appetite, hyperhidrosis; hepatotoxicity (discontinue if occurs), orthostatic hypotension, falls, syncope, mania/hypomania, increased BP, urinary hesitation/retention; rare: seizure, serious skin reactions (eg, Stevens-Johnson Syndrome). In children: also decreased weight, vomiting, fatigue, diarrhea.

    Cymbalta Clinical Trials

    Clinical Trials

    Efficacy was established in 4 randomized, double-blind, placebo-controlled, fixed-dose trials in adult outpatients (18-83 years) meeting DSM-IV criteria for MDD. 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.

    In Study MDD-5, patients who responded to open-label treatment with Cymbalta were randomly assigned to continue Cymbalta at the same dose (n=136) or to placebo (n=142). Findings showed Cymbalta-treated patients experienced a statistically significantly longer time to relapse of depression than those who received placebo.

    Cymbalta Note

    Not Applicable

    Cymbalta Patient Counseling

    Patient Counseling

    Monitor for the emergence of suicidal ideation and behavior, especially during treatment and when the dose is adjusted.

    Swallow Cymbalta whole; do not chew, crush, or open the capsule because these actions might affect the enteric coating.

    Severe liver problems, sometimes fatal, have been reported in patients treated with Cymbalta; if itching, right upper belly pain, dark urine, or yellow skin/eyes occurs, contact health care provider.

    Use of Cymbalta with heavy alcohol intake may be associated with severe liver injury.  

    Risk of orthostatic hypotension, falls and syncope, especially during initial use and subsequent dose escalation, and when used with other drugs that might potentiate the orthostatic effect.

    Risk of serotonin syndrome with the concomitant use of Cymbalta and other serotonergic agents including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, amphetamines, and St. John’s Wort. 

    Concomitant use of Cymbalta and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation may increase risk of bleeding.

    Cymbalta may cause serious skin reactions. 

    Discontinuation of Cymbalta may be associated with symptoms such as dizziness, headache, nausea, diarrhea, paresthesia, irritability, vomiting, insomnia, anxiety, hyperhidrosis, and fatigue.

    Patients should report any signs or symptoms of a manic reaction.

    Cymbalta can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle-closure glaucoma.

    Cymbalta may cause an increase in blood pressure.

    Patients should report any prescription or over-the-counter medications, since there is a potential for interactions.

    Hyponatremia has been reported as a result of treatment with SNRIs and SSRIs.

    Cymbalta may affect urination.  

    Cymbalta may cause symptoms of sexual dysfunction in both male and female patients.

    Cymbalta use during the month before delivery may lead to an increased risk for postpartum hemorrhage and may increase the risk of neonatal complications requiring prolonged hospitalization, respiratory support, and tube feeding.

    Breastfeeding women on Cymbalta: Monitor infants for sedation, poor feeding and poor weight gain.  

    Cymbalta may be associated with sedation and dizziness.

    Cymbalta Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Duloxetine (as HCl) 20mg, 30mg, 60mg; del-rel caps.

    Pharmacological Class

    SNRI.

    How Supplied

    Caps 20mg—60; 30mg—30, 90; 60mg—30, 1000

    How Supplied

    20mg capsules: Green; imprint: Lilly 3235, 20mg; Capsule number: PU3235; bottles of 60.

    30mg capsules: White and blue; imprint: Lilly 3240, 30mg; Capsule number: PU3240; bottles of 30 and 90.

    60mg capsules: Green and blue; imprint: Lilly 3270, 60mg; Capsule number: PU3270; bottles of 30 and 1000.

    Storage

    Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F).

    Manufacturer

    Eli Lilly and Company

    Generic Availability

    YES

    Mechanism of Action

    The exact mechanisms of the antidepressant, central pain inhibitory and anxiolytic actions of duloxetine are unknown, however, it is believed to be related to its potentiation of serotonergic and noradrenergic activity in the CNS.

    Cymbalta Indications

    Indications

    Chronic musculoskeletal pain (eg, low back pain, osteoarthritis pain).

    Cymbalta Dosage and Administration

    Adult

    Swallow whole. Initially 30mg once daily for 1 week, then increase to 60mg once daily.

    Children

    <18yrs: not established.

    Renal Impairment

    Mild to moderate impairment: PK analysis suggests no significant effect on duloxetine clearance. 

    Limited data available on the effect of Cymbalta in patients with ESRD.

    Hepatic Impairment

    Patients with clinically evidence hepatic impairment have decreased duloxetine metabolism and elimination.

    Administration

    Swallow whole; do not crush or chew. Do not open the capsules and sprinkle the contents on food or liquids as these actions may affect the enteric coating.

    Missed dose: Take as soon as remembered. If it is almost time for the next dose, skip the missed dose and take the next dose at the regular time.

    Cymbalta Contraindications

    Contraindications

    During or within 14 days of MAOIs. Concomitant MAOIs within 5 days of discontinuing duloxetine. Concomitant linezolid or IV methylene blue.

    Cymbalta Boxed Warnings

    Boxed Warning

    Suicidal thoughts and behaviors.

    Cymbalta Warnings/Precautions

    Warnings/Precautions

    Increased risk of suicidal thoughts and behavior in children, adolescents and young adults; monitor for clinical worsening and unusual changes. Screen for bipolar disorder. Monitor for emergence of serotonin syndrome; discontinue if occurs. Risk of bleeding. Consider dose reduction or discontinuation if orthostatic hypotension, falls and/or syncope occur. Monitor BP prior to and during therapy. History of seizure or mania/hypomania. Angle-closure glaucoma. Volume-depleted. Hyponatremia (esp. in elderly). Decreased GI motility. Cardiac disease. Diabetes. Sexual dysfunction. Monitor weight and growth in children. Severe renal impairment (CrCl<30mL/min), end stage renal disease, hepatic insufficiency, chronic liver disease, cirrhosis, or substantial alcohol use: not recommended. Avoid abrupt cessation. Reevaluate periodically. Elderly. Pregnancy; see full labeling for effects on neonates exposed late in the 3rd trimester. Nursing mothers: monitor infants.

    Warnings/Precautions

    Suicidal Thoughts and Behavios in Children, Adolescents, and Young Adults

    • 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.
    • No suicides occurred in pediatric Cymbalta trials.
    • Monitor patients closely for clinical worsening, suicidality, unusual changes in behavior, especially during the first few months or during dosage changes.
    • In patients whose depression persistently worsens, consider changing the therapeutic regimen by tapering gradually if possible.
    • Families/caregivers: Monitor patients for emergence of agitation, irritability, unusual changes in behavior and report to health care provider.
    • Prescriptions for Cymbalta should be written for the smallest quantity of capsules consistent with good patient management in order to reduce overdose risk.
    • Screen patients with depressive symptoms prior to initiating antidepressants to determine bipolar disorder risk; Cymbalta is not indicated for bipolar depression.

    Discontinuing Cymbalta

    • Gradual reduction in dosage rather than abrupt cessation is recommended.
    • Potential adverse reactions after abrupt or tapered discontinuation: Dizziness, headache, nausea, diarrhea, paresthesia, irritability, vomiting, insomnia, anxiety, hyperhidrosis, fatigue.
    • Monitor patients for these symptoms; if intolerable symptoms occur, resuming the previously prescribed dose may be considered.
    • Subsequent decreasing of dose should be done more gradually.

    Hepatotoxicity

    • Cymbalta has been linked to cases of hepatic failure; cases have presented as hepatitis with abdominal pain, hepatomegaly, transaminase level elevations more than 20xULN with or without jaundice.
    • Discontinue Cymbalta in patients who develop jaundice or clinically significant liver dysfunction; do not resume unless another cause has been identified.
    • Cases of cholestatic jaundice with minimal elevation of transaminase levels have been reported.
    • Do not prescribe Cymbalta to patients with substantial alcohol use or evidence of chronic liver disease; Cymbalta and alcohol can interact to cause liver injury and Cymbalta may aggravate pre-existing liver disease.

    Orthostatic Hypotension, Falls and Syncope

    • Orthostatic hypotension, falls and syncope have been reported with Cymbalta.
    • Syncope and orthostatic hypotension tend to occur within the first week of treatment but can occur at any time, particularly after dose increases.
    • Risk of falling appears to be related to the presence of orthostatic decrease in BP, which is more likely to occur in patients taking concomitant drugs that induce orthostatic hypotension or are potent CYP1A2 inhibitors, as well as in patients taking doses >60mg/day.
    • Consider dose reduction or discontinuation of Cymbalta if symptomatic orthostatic hypotension, falls or syncope occur during treatment.
    • Risk of falls appears to increase with age; falls with serious consequences (eg, fractures, hospitalizations) have been reported with Cymbalta.

    Serotonin Syndrome

    • Serotonin syndrome: Mental status changes (eg, agitation, hallucinations, delirium, coma), autonomic instability (eg, tachycardia, labile BP, dizziness, diaphoresis, flushing, hyperthermia),  neuromuscular symptoms (eg, tremor, rigidity, myoclonus, hyperreflexia, incoordination), and GI symptoms (eg, nausea, vomiting, diarrhea).
    • Has been reported with SSRIs and SNRIs, including Cymbalta, and with concomitant use of serotonergic drugs (eg, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, St. John’s Wort) and with drugs that impair serotonin metabolism (eg, MOAIs, linezolid, IV methylene blue).
    • Monitor patients for the emergence of serotonin syndrome.
    • Concomitant use of MAOIs and Cymbalta is contraindicated; discontinue Cymbalta before initiating treatment with an MAOI.
    • Patients should be made aware of the potential for serotonin syndrome if concomitant use of Cymbalta and other serotonergic drugs is clinically warranted.

    Increased Risk of Bleeding

    • Drugs that interact with serotonin reuptake inhibition may increase the risk of bleeding events.
    • Concomitant aspirin, NSAIDs, warfarin, and other anticoagulants may increase this risk; inform patients about the risk of bleeding.

    Severe Skin Reactions

    • Erythema multiforme and Stevens-Johnson Syndrome have been reported with Cymbalta.
    • Discontinue treatment at the first appearance of blisters, peeling rash, mucosal erosions, or any other sign of hypersensitivity if no other etiology can be identified.

    Activation of Mania/Hypomania

    • Use Cymbalta cautiously in patients with a history of mania.
    • Activation of mania or hypomania has been reported in patients with mood disorders who were treated with other drugs for major depressive disorder.

    Angle Closure Glaucoma

    • Pupillary dilation following use of antidepressants can trigger angle closure attack in patients with anatomically narrow angles who do not have a patent iridectomy.

    Seizures

    • Patients with seizures were excluded from clinical trials.
    • Use caution when prescribing Cymbalta to patients with a history of seizure disorder.

    BP Increases

    • Across clinical trials, Cymbalta use was associated with mean increases of 0.5 mm Hg in systolic BP and 0.8 mm Hg in diastolic BP.
    • Measure BP before starting treatment and check periodically throughout treatment.

    Hyponatremia

    • Hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion.
    • Cases with serum sodium <110mmol/L have been reported with Cymbalta and appeared to be reversible when discontinued.
    • Geriatric patients, those on diuretics, and volume depleted individuals may be at greater risk.
    • Consider discontinuing Cymbalta in patients with symptomatic hyponatremia.
    • Signs/symptoms of hyponatremia: Headache, difficulty concentrating, memory impairment, confusion, weakness, unsteadiness. Severe cases: Hallucination, syncope, seizure, coma, respiratory arrest, death.

    Concomitant Illness

    • Caution advised for patients with conditions that may slow gastric emptying.
    • Patients with recent history of MI or unstable coronary artery disease were excluded from clinical studies.
    • Avoid use in patients with chronic liver disease or cirrhosis.
    • Avoid use in patients with severe renal impairment (GFR <30mL/min); increased plasma concentrations occurred in patients with end-stage renal disease.
    • Cymbalta may worsen glycemic control in some patients with diabetes.

    Urinary Hesitation and Retention

    • Cymbalta may affect urethral resistance.
    • If symptoms of urinary hesitation develop, it may be related to Cymbalta use.

    Sexual Dysfunction

    • SNRIs may cause symptoms of sexual dysfunction in males (ejaculatory delay or failure, decreased libido, erectile dysfunction) and females (decreased libido, delayed or absent orgasm).
    • Evaluate changes in sexual function; discuss potential management strategies.

    Pregnancy Considerations

    Postmarketing retrospective cohort study: Use of duloxetine in the month before delivery may be associated with an increased risk of postpartum hemorrhage.

    Neonates exposed to SNRIS, SSRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Findings were consistent with either a direct toxic effect of the drug or possibly a drug discontinuation syndrome.

    Nursing Mother Considerations

    Duloxetine is present in human milk. Sedation, poor feeding, and poor weight gain have been reported in infants exposed to duloxetine through breast milk. 

    Study findings showed that the amount of Cymbalta in breast milk was approximately 7mcg/day while on 40mg twice daily for 3.5 days. The estimated daily infant dose was approximately 2mcg/kg/day, which is <1% of the maternal dose.

    Pediatric Considerations

    Safety and effectiveness of Cymbalta have not been established in pediatric patients with chronic musculoskeletal pain. 

    Geriatric Considerations

    No overall differences in safety or effectiveness observed between geriatric patients and younger patients.

    SSRIs and SNRIs have been associated with clinically significant hyponatremia in geriatric patients.

    In clinical trials, Cymbalta-treated patients reported a higher rate of falls compared with those who received placebo; underlying risk appears to increase steadily with age.

    Renal Impairment Considerations

    Mild to moderate impairment: PK analysis suggests no significant effect on duloxetine clearance. 

    Limited data available on the effect of Cymbalta in patients with ESRD.

    Hepatic Impairment Considerations

    Patients with clinically evidence hepatic impairment have decreased duloxetine metabolism and elimination.

    Cymbalta Pharmacokinetics

    Absorption

    Max plasma concentrations of duloxetine occur 6 hours post dose.

    Distribution

    Duloxetine is highly protein bound (>90%).

    Metabolism

    Hepatic (CYP1A2, CYP2D6).

    Elimination

    Renal (~70%), fecal (~20%). Half-life: ~12 hours (range: 8–17 hours).

    Cymbalta Interactions

    Interactions

    See Contraindications. Concomitant thioridazine (may cause arrhythmias): not recommended. Increased risk of serotonin syndrome with other serotonergic drugs (eg, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, St. John's Wort) or with drugs that impair serotonin metabolism (eg, MAOIs, linezolid, IV methylene blue). Potentiated by CYP1A2 inhibitors (eg, cimetidine, fluvoxamine, quinolones): avoid. May potentiate or be potentiated by CYP2D6 inhibitors (eg, paroxetine, fluoxetine, quinidine) or substrates (eg, tricyclics, phenothiazines, type 1C antiarrhythmics) or other highly protein-bound drugs; caution with CYP2D6 substrates with narrow therapeutic indexes. Caution with potent CYP1A2 inhibitors, antihypertensives, other drugs that induce orthostatic hypotension. Monitor concomitant CNS-acting drugs, and with those that affect gastric pH (eg, proton pump inhibitors). Increased risk of bleeding with NSAIDs, aspirin, or others that affect coagulation.

    Cymbalta Adverse Reactions

    Adverse Reactions

    Nausea, dry mouth, somnolence, constipation, decreased appetite, hyperhidrosis; hepatotoxicity (discontinue if occurs), orthostatic hypotension, falls, syncope, mania/hypomania, increased BP, urinary hesitation/retention; rare: seizure, serious skin reactions (eg, Stevens-Johnson Syndrome). In children: also decreased weight, vomiting, fatigue, diarrhea.

    Cymbalta Clinical Trials

    Clinical Trials

    Cymbalta was evaluated in 3 clinical trials in adults with chronic low back pain. Significantly greater pain reduction was observed with Cymbalta vs placebo in 2 of these trials compared with placebo. Patients in all trials had no signs of radiculopathy or spinal stenosis.

    The efficacy of Cymbalta in chronic pain due to osteoarthritis was assessed in 2 double-blind, placebo-controlled trials. Significantly greater pain reduction was observed with Cymbalta vs placebo in 1 of these trials.

    Cymbalta Note

    Not Applicable

    Cymbalta Patient Counseling

    Patient Counseling

    Monitor for the emergence of suicidal ideation and behavior, especially during treatment and when the dose is adjusted.

    Swallow Cymbalta whole; do not chew, crush, or open the capsule because these actions might affect the enteric coating.

    Severe liver problems, sometimes fatal, have been reported in patients treated with Cymbalta; if itching, right upper belly pain, dark urine, or yellow skin/eyes occurs, contact health care provider.

    Use of Cymbalta with heavy alcohol intake may be associated with severe liver injury.  

    Risk of orthostatic hypotension, falls and syncope, especially during initial use and subsequent dose escalation, and when used with other drugs that might potentiate the orthostatic effect.

    Risk of serotonin syndrome with the concomitant use of Cymbalta and other serotonergic agents including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, amphetamines, and St. John’s Wort. 

    Concomitant use of Cymbalta and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation may increase risk of bleeding.

    Cymbalta may cause serious skin reactions. 

    Discontinuation of Cymbalta may be associated with symptoms such as dizziness, headache, nausea, diarrhea, paresthesia, irritability, vomiting, insomnia, anxiety, hyperhidrosis, and fatigue.

    Patients should report any signs or symptoms of a manic reaction.

    Cymbalta can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle-closure glaucoma.

    Cymbalta may cause an increase in blood pressure.

    Patients should report any prescription or over-the-counter medications, since there is a potential for interactions.

    Hyponatremia has been reported as a result of treatment with SNRIs and SSRIs.

    Cymbalta may affect urination.  

    Cymbalta may cause symptoms of sexual dysfunction in both male and female patients.

    Cymbalta use during the month before delivery may lead to an increased risk for postpartum hemorrhage and may increase the risk of neonatal complications requiring prolonged hospitalization, respiratory support, and tube feeding.

    Breastfeeding women on Cymbalta: Monitor infants for sedation, poor feeding and poor weight gain.  

    Cymbalta may be associated with sedation and dizziness.

    Cymbalta Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Duloxetine (as HCl) 20mg, 30mg, 60mg; del-rel caps.

    Pharmacological Class

    SNRI.

    How Supplied

    Caps 20mg—60; 30mg—30, 90; 60mg—30, 1000

    How Supplied

    20mg capsules: Green; imprint: Lilly 3235, 20mg; Capsule number: PU3235; bottles of 60.

    30mg capsules: White and blue; imprint: Lilly 3240, 30mg; Capsule number: PU3240; bottles of 30 and 90.

    60mg capsules: Green and blue; imprint: Lilly 3270, 60mg; Capsule number: PU3270; bottles of 30 and 1000.

    Storage

    Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F).

    Manufacturer

    Eli Lilly and Company

    Generic Availability

    YES

    Mechanism of Action

    The exact mechanisms of the antidepressant, central pain inhibitory and anxiolytic actions of duloxetine are unknown, however, it is believed to be related to its potentiation of serotonergic and noradrenergic activity in the CNS.

    Cymbalta Indications

    Indications

    Diabetic peripheral neuropathic pain.

    Cymbalta Dosage and Administration

    Adult

    Swallow whole. 60mg once daily (may start at lower dose if 60mg not tolerated). Renal impairment: consider lower starting dose and slow titration.

    Children

    <18yrs: not established.

    Renal Impairment

    Mild to moderate impairment: PK analysis suggests no significant effect on duloxetine clearance. 

    Limited data available on the effect of Cymbalta in patients with ESRD.

    Hepatic Impairment

    Patients with clinically evidence hepatic impairment have decreased duloxetine metabolism and elimination.

    Administration

    Swallow whole; do not crush or chew. Do not open the capsules and sprinkle the contents on food or liquids as these actions may affect the enteric coating.

    Missed dose: Take as soon as remembered. If it is almost time for the next dose, skip the missed dose and take the next dose at the regular time.

    Cymbalta Contraindications

    Contraindications

    During or within 14 days of MAOIs. Concomitant MAOIs within 5 days of discontinuing duloxetine. Concomitant linezolid or IV methylene blue.

    Cymbalta Boxed Warnings

    Boxed Warning

    Suicidal thoughts and behaviors.

    Cymbalta Warnings/Precautions

    Warnings/Precautions

    Increased risk of suicidal thoughts and behavior in children, adolescents and young adults; monitor for clinical worsening and unusual changes. Screen for bipolar disorder. Monitor for emergence of serotonin syndrome; discontinue if occurs. Risk of bleeding. Consider dose reduction or discontinuation if orthostatic hypotension, falls and/or syncope occur. Monitor BP prior to and during therapy. History of seizure or mania/hypomania. Angle-closure glaucoma. Volume-depleted. Hyponatremia (esp. in elderly). Decreased GI motility. Cardiac disease. Diabetes. Sexual dysfunction. Monitor weight and growth in children. Severe renal impairment (CrCl<30mL/min), end stage renal disease, hepatic insufficiency, chronic liver disease, cirrhosis, or substantial alcohol use: not recommended. Avoid abrupt cessation. Reevaluate periodically. Elderly. Pregnancy; see full labeling for effects on neonates exposed late in the 3rd trimester. Nursing mothers: monitor infants.

    Warnings/Precautions

    Suicidal Thoughts and Behavios in Children, Adolescents, and Young Adults

    • 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.
    • No suicides occurred in pediatric Cymbalta trials.
    • Monitor patients closely for clinical worsening, suicidality, unusual changes in behavior, especially during the first few months or during dosage changes.
    • In patients whose depression persistently worsens, consider changing the therapeutic regimen by tapering gradually if possible.
    • Families/caregivers: Monitor patients for emergence of agitation, irritability, unusual changes in behavior and report to health care provider.
    • Prescriptions for Cymbalta should be written for the smallest quantity of capsules consistent with good patient management in order to reduce overdose risk.
    • Screen patients with depressive symptoms prior to initiating antidepressants to determine bipolar disorder risk; Cymbalta is not indicated for bipolar depression.

    Discontinuing Cymbalta

    • Gradual reduction in dosage rather than abrupt cessation is recommended.
    • Potential adverse reactions after abrupt or tapered discontinuation: Dizziness, headache, nausea, diarrhea, paresthesia, irritability, vomiting, insomnia, anxiety, hyperhidrosis, fatigue.
    • Monitor patients for these symptoms; if intolerable symptoms occur, resuming the previously prescribed dose may be considered.
    • Subsequent decreasing of dose should be done more gradually.

    Hepatotoxicity

    • Cymbalta has been linked to cases of hepatic failure; cases have presented as hepatitis with abdominal pain, hepatomegaly, transaminase level elevations more than 20xULN with or without jaundice.
    • Discontinue Cymbalta in patients who develop jaundice or clinically significant liver dysfunction; do not resume unless another cause has been identified.
    • Cases of cholestatic jaundice with minimal elevation of transaminase levels have been reported.
    • Do not prescribe Cymbalta to patients with substantial alcohol use or evidence of chronic liver disease; Cymbalta and alcohol can interact to cause liver injury and Cymbalta may aggravate pre-existing liver disease.

    Orthostatic Hypotension, Falls and Syncope

    • Orthostatic hypotension, falls and syncope have been reported with Cymbalta.
    • Syncope and orthostatic hypotension tend to occur within the first week of treatment but can occur at any time, particularly after dose increases.
    • Risk of falling appears to be related to the presence of orthostatic decrease in BP, which is more likely to occur in patients taking concomitant drugs that induce orthostatic hypotension or are potent CYP1A2 inhibitors, as well as in patients taking doses >60mg/day.
    • Consider dose reduction or discontinuation of Cymbalta if symptomatic orthostatic hypotension, falls or syncope occur during treatment.
    • Risk of falls appears to increase with age; falls with serious consequences (eg, fractures, hospitalizations) have been reported with Cymbalta.

    Serotonin Syndrome

    • Serotonin syndrome: Mental status changes (eg, agitation, hallucinations, delirium, coma), autonomic instability (eg, tachycardia, labile BP, dizziness, diaphoresis, flushing, hyperthermia),  neuromuscular symptoms (eg, tremor, rigidity, myoclonus, hyperreflexia, incoordination), and GI symptoms (eg, nausea, vomiting, diarrhea).
    • Has been reported with SSRIs and SNRIs, including Cymbalta, and with concomitant use of serotonergic drugs (eg, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, St. John’s Wort) and with drugs that impair serotonin metabolism (eg, MOAIs, linezolid, IV methylene blue).
    • Monitor patients for the emergence of serotonin syndrome.
    • Concomitant use of MAOIs and Cymbalta is contraindicated; discontinue Cymbalta before initiating treatment with an MAOI.
    • Patients should be made aware of the potential for serotonin syndrome if concomitant use of Cymbalta and other serotonergic drugs is clinically warranted.

    Increased Risk of Bleeding

    • Drugs that interact with serotonin reuptake inhibition may increase the risk of bleeding events.
    • Concomitant aspirin, NSAIDs, warfarin, and other anticoagulants may increase this risk; inform patients about the risk of bleeding.

    Severe Skin Reactions

    • Erythema multiforme and Stevens-Johnson Syndrome have been reported with Cymbalta.
    • Discontinue treatment at the first appearance of blisters, peeling rash, mucosal erosions, or any other sign of hypersensitivity if no other etiology can be identified.

    Activation of Mania/Hypomania

    • Use Cymbalta cautiously in patients with a history of mania.
    • Activation of mania or hypomania has been reported in patients with mood disorders who were treated with other drugs for major depressive disorder.

    Angle Closure Glaucoma

    • Pupillary dilation following use of antidepressants can trigger angle closure attack in patients with anatomically narrow angles who do not have a patent iridectomy.

    Seizures

    • Patients with seizures were excluded from clinical trials.
    • Use caution when prescribing Cymbalta to patients with a history of seizure disorder.

    BP Increases

    • Across clinical trials, Cymbalta use was associated with mean increases of 0.5 mm Hg in systolic BP and 0.8 mm Hg in diastolic BP.
    • Measure BP before starting treatment and check periodically throughout treatment.

    Hyponatremia

    • Hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion.
    • Cases with serum sodium <110mmol/L have been reported with Cymbalta and appeared to be reversible when discontinued.
    • Geriatric patients, those on diuretics, and volume depleted individuals may be at greater risk.
    • Consider discontinuing Cymbalta in patients with symptomatic hyponatremia.
    • Signs/symptoms of hyponatremia: Headache, difficulty concentrating, memory impairment, confusion, weakness, unsteadiness. Severe cases: Hallucination, syncope, seizure, coma, respiratory arrest, death.

    Concomitant Illness

    • Caution advised for patients with conditions that may slow gastric emptying.
    • Patients with recent history of MI or unstable coronary artery disease were excluded from clinical studies.
    • Avoid use in patients with chronic liver disease or cirrhosis.
    • Avoid use in patients with severe renal impairment (GFR <30mL/min); increased plasma concentrations occurred in patients with end-stage renal disease.
    • Cymbalta may worsen glycemic control in some patients with diabetes.

    Urinary Hesitation and Retention

    • Cymbalta may affect urethral resistance.
    • If symptoms of urinary hesitation develop, it may be related to Cymbalta use.

    Sexual Dysfunction

    • SNRIs may cause symptoms of sexual dysfunction in males (ejaculatory delay or failure, decreased libido, erectile dysfunction) and females (decreased libido, delayed or absent orgasm).
    • Evaluate changes in sexual function; discuss potential management strategies.

    Pregnancy Considerations

    Postmarketing retrospective cohort study: Use of duloxetine in the month before delivery may be associated with an increased risk of postpartum hemorrhage.

    Neonates exposed to SNRIS, SSRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Findings were consistent with either a direct toxic effect of the drug or possibly a drug discontinuation syndrome.

    Nursing Mother Considerations

    Duloxetine is present in human milk. Sedation, poor feeding, and poor weight gain have been reported in infants exposed to duloxetine through breast milk. 

    Study findings showed that the amount of Cymbalta in breast milk was approximately 7mcg/day while on 40mg twice daily for 3.5 days. The estimated daily infant dose was approximately 2mcg/kg/day, which is <1% of the maternal dose.

    Pediatric Considerations

    Safety and effectiveness of Cymbalta have not been established in pediatric patients with diabetic peripheral neuropathic pain.

    Geriatric Considerations

    No overall differences in safety or effectiveness observed between geriatric patients and younger patients.

    SSRIs and SNRIs have been associated with clinically significant hyponatremia in geriatric patients.

    In clinical trials, Cymbalta-treated patients reported a higher rate of falls compared with those who received placebo; underlying risk appears to increase steadily with age.

    Renal Impairment Considerations

    Mild to moderate impairment: PK analysis suggests no significant effect on duloxetine clearance. 

    Limited data available on the effect of Cymbalta in patients with ESRD.

    Hepatic Impairment Considerations

    Patients with clinically evidence hepatic impairment have decreased duloxetine metabolism and elimination.

    Cymbalta Pharmacokinetics

    Absorption

    Max plasma concentrations of duloxetine occur 6 hours post dose.

    Distribution

    Duloxetine is highly protein bound (>90%).

    Metabolism

    Hepatic (CYP1A2, CYP2D6).

    Elimination

    Renal (~70%), fecal (~20%). Half-life: ~12 hours (range: 8–17 hours).

    Cymbalta Interactions

    Interactions

    See Contraindications. Concomitant thioridazine (may cause arrhythmias): not recommended. Increased risk of serotonin syndrome with other serotonergic drugs (eg, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, St. John's Wort) or with drugs that impair serotonin metabolism (eg, MAOIs, linezolid, IV methylene blue). Potentiated by CYP1A2 inhibitors (eg, cimetidine, fluvoxamine, quinolones): avoid. May potentiate or be potentiated by CYP2D6 inhibitors (eg, paroxetine, fluoxetine, quinidine) or substrates (eg, tricyclics, phenothiazines, type 1C antiarrhythmics) or other highly protein-bound drugs; caution with CYP2D6 substrates with narrow therapeutic indexes. Caution with potent CYP1A2 inhibitors, antihypertensives, other drugs that induce orthostatic hypotension. Monitor concomitant CNS-acting drugs, and with those that affect gastric pH (eg, proton pump inhibitors). Increased risk of bleeding with NSAIDs, aspirin, or others that affect coagulation.

    Cymbalta Adverse Reactions

    Adverse Reactions

    Nausea, dry mouth, somnolence, constipation, decreased appetite, hyperhidrosis; hepatotoxicity (discontinue if occurs), orthostatic hypotension, falls, syncope, mania/hypomania, increased BP, urinary hesitation/retention; rare: seizure, serious skin reactions (eg, Stevens-Johnson Syndrome). In children: also decreased weight, vomiting, fatigue, diarrhea.

    Cymbalta Clinical Trials

    Clinical Trials

    The efficacy of Cymbalta in the management of neuropathic pain associated with diabetic peripheral neuropathy in adults was established in 2 randomized, 12-week, double-blind, placebo-controlled studies. Study participants had type 1 or 2 diabetes mellitus with a diagnosis of painful distal symmetrical sensorimotor polyneuropathy for at least 6 months. In addition to Cymbalta, participants were allowed up to 4g of acetaminophen per day as needed for pain.

    Findings showed that treatment with Cymbalta statistically significantly improved the endpoint mean pain scores from baseline and increased the proportion of patients with at least 50% reduction in pain scores from baseline. Some patients experienced a decrease in pain as early as week 1.

    Cymbalta Note

    Not Applicable

    Cymbalta Patient Counseling

    Patient Counseling

    Monitor for the emergence of suicidal ideation and behavior, especially during treatment and when the dose is adjusted.

    Swallow Cymbalta whole; do not chew, crush, or open the capsule because these actions might affect the enteric coating.

    Severe liver problems, sometimes fatal, have been reported in patients treated with Cymbalta; if itching, right upper belly pain, dark urine, or yellow skin/eyes occurs, contact health care provider.

    Use of Cymbalta with heavy alcohol intake may be associated with severe liver injury.  

    Risk of orthostatic hypotension, falls and syncope, especially during initial use and subsequent dose escalation, and when used with other drugs that might potentiate the orthostatic effect.

    Risk of serotonin syndrome with the concomitant use of Cymbalta and other serotonergic agents including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, amphetamines, and St. John’s Wort. 

    Concomitant use of Cymbalta and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation may increase risk of bleeding.

    Cymbalta may cause serious skin reactions. 

    Discontinuation of Cymbalta may be associated with symptoms such as dizziness, headache, nausea, diarrhea, paresthesia, irritability, vomiting, insomnia, anxiety, hyperhidrosis, and fatigue.

    Patients should report any signs or symptoms of a manic reaction.

    Cymbalta can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle-closure glaucoma.

    Cymbalta may cause an increase in blood pressure.

    Patients should report any prescription or over-the-counter medications, since there is a potential for interactions.

    Hyponatremia has been reported as a result of treatment with SNRIs and SSRIs.

    Cymbalta may affect urination.  

    Cymbalta may cause symptoms of sexual dysfunction in both male and female patients.

    Cymbalta use during the month before delivery may lead to an increased risk for postpartum hemorrhage and may increase the risk of neonatal complications requiring prolonged hospitalization, respiratory support, and tube feeding.

    Breastfeeding women on Cymbalta: Monitor infants for sedation, poor feeding and poor weight gain.  

    Cymbalta may be associated with sedation and dizziness.

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