Important Safety Information on Cymbalta^® (duloxetine HCl)

Cymbalta is indicated in adults for:

• The acute and maintenance treatment of major depressive disorder (MDD)
• The acute treatment of generalized anxiety disorder (GAD)
• The management of diabetic peripheral neuropathic pain (DPNP)
• The management of fibromyalgia (FM)

Suicidality and Antidepressant Drugs—Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of Cymbalta or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Cymbalta is not approved for use in pediatric patients.

Contraindications

• Cymbalta should not be used in combination with MAOIs and is contraindicated for at least 14 days after discontinuation of an MAOI. After stopping therapy on Cymbalta, at least 5 days should be allowed before starting an MAOI.
• Cymbalta was associated with an increased risk of mydriasis; therefore, it should not be used in patients with uncontrolled narrow-angle glaucoma and used cautiously in patients with controlled narrow-angle glaucoma.

Warnings and Precautions

• Clinical Worsening and Suicide Risk
  All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially within the first few months of treatment and when changing the dose. Consider changing the therapeutic regimen, including possibly discontinuing the medication in patients whose depression is persistently worse or includes symptoms of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, or suicidality that are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. If discontinuing treatment, the medication should be tapered. Families and caregivers of patients being treated with antidepressants for any indication should be alerted about the need to monitor patients.
• Hepatic failure, sometimes fatal, has been reported in patients treated with Cymbalta. Cymbalta should be discontinued in patients who develop jaundice or other evidence of clinically significant liver dysfunction and should not be resumed unless another cause can be established.
• Because it is possible that Cymbalta and alcohol may interact to cause liver injury or that Cymbalta may aggravate pre-existing liver disease, Cymbalta should ordinarily not be prescribed to patients with substantial alcohol use or evidence of chronic liver disease.
• Orthostatic hypotension and syncope have been reported with therapeutic doses of Cymbalta. Consideration should be given to discontinuing Cymbalta in patients who experience symptomatic orthostatic hypotension and/or syncope.
• Development of a potentially life-threatening serotonin syndrome may occur with SNRIs and SSRIs, including Cymbalta treatment, particularly with concomitant use of serotonergic drugs, including triptans. Concomitant use is not recommended.
• SSRIs and SNRIs, including Cymbalta, may increase the risk of bleeding events. Patients should be cautioned about the risk of bleeding associated with concomitant use of Cymbalta and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation.
• On abrupt or tapered discontinuation, spontaneous reports of adverse events, some of which may be serious, have been reported during the marketing of SSRIs and SNRIs. A gradual reduction in dose rather than abrupt cessation is recommended when possible.
• As with many antidepressants, Cymbalta should be used cautiously in patients with a history of mania or with a history of a seizure disorder.
• In clinical trials across indications relative to placebo, treatment with Cymbalta was associated with mean increases of up to 2.3 mm Hg systolic and diastolic blood pressure. There was no significant difference in the frequency of sustained (3 consecutive visits) elevated blood pressure. Blood pressure should be measured prior to initiating treatment and periodically measured throughout treatment.
• Co-administration of Cymbalta with potent CYP1A2 inhibitors or thioridazine should be avoided.
• SSRIs and SNRIs, including Cymbalta, have been associated with cases of clinically significant hyponatremia that appeared to be reversible when Cymbalta was discontinued. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs.
• The effect that alterations in gastric motility may have on the stability of the enteric coating of Cymbalta is unknown. As duloxetine is rapidly hydrolyzed in acidic media to naphthol, caution is advised in using Cymbalta in patients with conditions that may slow gastric emptying (eg, some diabetics).
• Cymbalta should ordinarily not be administered to patients with any hepatic insufficiency or patients with end-stage renal disease (requiring dialysis) or severe renal impairment (creatinine clearance <30 mL/min).
• As observed in DPNP trials, Cymbalta treatment worsens glycemic control in some patients with diabetes. In the extension phases (up to 52 weeks) of the DPNP studies, an increase in HbA_1c in both the Cymbalta (0.5%) and the routine care groups (0.2%) was noted.
• Cymbalta is in a class of drugs known to affect urethral resistance. If symptoms of urinary hesitation develop during Cymbalta treatment, this effect may be drug-related. In postmarketing experience, urinary retention has been observed.

Use in Specific Populations

• Pregnancy and Nursing Mothers: Use only if the potential benefit justifies the potential risk to the fetus or child.

Adverse Events

• The most commonly reported adverse events (≥5% and at least twice placebo) for Cymbalta vs placebo in controlled clinical trials (N=4843 vs 3048) were: nausea (25% vs 9%), dry mouth (14% vs 6%), somnolence* (11% vs 3%), constipation* (11% vs 4%), decreased appetite* (8% vs 2%), and increased sweating (7% vs 2%).
  *Events for which there was a significant dose-dependent relationship in fixed-dose studies, excluding three MDD studies that did not have a placebo lead-in period or dose titration.
• In placebo-controlled clinical trials, the overall discontinuation rates due to adverse events were:
  MDD: 9% vs 5%; GAD: 15% vs 4%; DPNP: 14% vs 7%; FM: 20% vs 12%.
  
  The common adverse events reported as a reason for discontinuation and considered to be drug related were:
  MDD: nausea (1.3% vs 0.5%). GAD: nausea (3.7% vs 0.2%), vomiting (1.3% vs 0%), dizziness (1.0% vs 0.2%). DPNP: nausea (3.5% vs 0.4%), dizziness (1.6% vs 0.4%), somnolence (1.6% vs 0%), fatigue (1.1% vs 0%). FM: nausea (1.9% vs 0.7%), somnolence (1.5% vs 0%), fatigue (1.3% vs 0.2%).
  

References:

1. Cymbalta full Prescribing Information. Eli Lilly and Company (2008).
2. Bymaster FP, Lee TC, Knadler MP, et al. The dual transporter inhibitor duloxetine: A review of its preclinical pharmacology, pharmacokinetic profile, and clinical results in depression. Curr Pharm Des. 2005;11:1475-1493.
3. Data on file, Lilly Research Laboratories: a: CYM20050902A; b: CYM20051007B; c: CYM20080508C; d: CYM20080508F.
4. Papakostas GI. Limitations of contemporary antidepressants: tolerability. J Clin Psychiatry. 2007;68(suppl 10):11-17.
5. Ashton AK, Jamerson BD, Weinstein WL, et al. Antidepressant-related adverse effects impacting treatment compliance: results of a patient survey. Curr Ther Res. 2005;66:96-106.
6. Goldenberg DL, Simms R, Geiger A, et al. High frequency of fibromyalgia in patients with chronic fatigue seen in primary care practice. Arthritis Rheum. 1990;33:381-387.