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Important Safety Information

CONTRAINDICATIONS

Duloxetine Delayed-Release Capsules are contraindicated in patients

  • who are using or within 14 days of stopping an MAOI intended to treat psychiatric disorders because of an increased risk of serotonin syndrome. Allow at least 5 days after stopping Duloxetine Delayed-Release Capsules prior to initiation of an MAOI to treat psychiatric disorders.
  • who are using other MAOIs such as linezolid or intravenous methylene blue because of an increased risk of serotonin syndrome.

WARNINGS AND PRECAUTIONS

Suicidal Thoughts and Behaviors in Pediatric and Young Adult Patients

There was an increased incidence of suicidal thoughts and behaviors in antidepressant-treated patients age 24 years and younger. Across indications, the highest incidence was in major depressive disorder (MDD). Monitor for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial months of drug therapy and at times of dosage changes. Consider changing the therapeutic regimen, including possibly discontinuing Duloxetine Delayed-Release Capsules, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.

Hepatotoxicity

Hepatic failure, sometimes fatal, has been reported in patients treated with duloxetine. These cases have presented as hepatitis with abdominal pain, hepatomegaly, and elevation of transaminase levels to more than twenty times the upper limit of normal (ULN) with or without jaundice, reflecting a mixed or hepatocellular pattern of liver injury. Discontinue treatment in patients who develop jaundice or other evidence of clinically significant liver dysfunction. Duloxetine increased the risk of elevation of serum transaminase levels in clinical trials. Because it is possible that alcohol may interact to cause liver injury or that Duloxetine Delayed-Release Capsules may aggravate pre-existing liver disease, do not prescribe to patients with substantial alcohol use or evidence of chronic liver disease.

Orthostatic Hypotension, Falls and Syncope

Orthostatic hypotension, falls, and syncope have been reported and tend to occur within the first week of therapy but can occur at any time during treatment, particularly after dose increases. The risk of falling appears to be related to the degree of orthostatic decrease in blood pressure (BP) as well as other factors. The risk of BP decreases may be greater in patients taking concomitant medications that induce orthostatic hypotension (such as antihypertensives) or are potent CYP1A2 inhibitors and in patients taking duloxetine delayed-release capsules at doses above 60 mg daily. Consider dose reduction or discontinuation in patients who experience symptomatic orthostatic hypotension, falls and/or syncope.

Serotonin Syndrome

Duloxetine Delayed-Release Capsules can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased with concomitant use of other serotonergic drugs and with drugs that impair metabolism of serotonin, i.e., MAOIs. Signs and symptoms may include mental status changes, autonomic instability, neuromuscular symptoms, seizures, and gastrointestinal symptoms. Do not initiate in a patient being treated with MAOIs such as linezolid or intravenous methylene blue. If it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue, discontinue Duloxetine Delayed-Release Capsules before initiating treatment with the MAOI. Monitor all patients for the emergence of serotonin syndrome. Discontinue treatment if the above symptoms occur and initiate supportive symptomatic treatment.

Increased Risk of Bleeding

Duloxetine Delayed-Release Capsules may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin, and other anti-coagulants may add to this risk. There is evidence of an association between drugs that interfere with serotonin reuptake and gastrointestinal bleeding. A post-marketing study showed a higher incidence of postpartum hemorrhage in mothers taking duloxetine. Other bleeding events have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages.

Severe Skin Reactions

Severe skin reactions, including erythema multiforme and Stevens-Johnson Syndrome (SJS), can occur. Duloxetine Delayed-Release Capsules should be discontinued at the first appearance of blisters, peeling rash, mucosal erosions, or any other sign of hypersensitivity if no other etiology can be identified.

Discontinuation Syndrome

Following abrupt or tapered discontinuation in adult placebo-controlled clinical trials, duloxetine-treated patients experienced: dizziness, headache, nausea, diarrhea, paresthesia, irritability, vomiting, insomnia, anxiety, hyperhidrosis, and fatigue. Monitor patients for symptoms when discontinuing treatment. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. Given Duloxetine Delayed-Release Capsules are not available in strengths below 80 mg, gradual dosage reduction will require the use of another duloxetine delayed-release capsule product.

Activation of Mania/Hypomania

In controlled clinical trials in adult patients with major depressive disorder, symptoms of mania or hypomania were reported in 0.1% of patients treated with duloxetine. Duloxetine Delayed-Release Capsules should be used cautiously in patients with a history of mania.

Angle-Closure Glaucoma

Duloxetine Delayed-Release Capsules may cause pupillary dilation that may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. Avoid use in patients with anatomically narrow angles.

Seizures

Duloxetine Delayed-Release Capsules should be prescribed with care in patients with a history of a seizure disorder.

Increases in Blood Pressure

Duloxetine treatment was associated with mean increases of 0.5 mm Hg in systolic blood pressure and 0.8 mm Hg in diastolic blood pressure. Monitor blood pressure and pre-existing hypertension should be controlled before initiating treatment. Caution should be exercised in treating patients with pre-existing hypertension, cardiovascular, or cerebrovascular conditions that might be compromised by increases in blood pressure. For patients who experience sustained increase in blood pressure, consider discontinuation or other appropriate medical intervention.

Hyponatremia

Hyponatremia may occur. Geriatric patients and those taking diuretics or who are otherwise volume depleted may be at greater risk. Consider discontinuation in patients with symptomatic hyponatremia and institute appropriate medical intervention.

Use in Patients with Concomitant Illness

Clinical experience with duloxetine in patients with concomitant systemic illnesses is limited. In extremely acidic conditions, duloxetine, unprotected by the enteric coating, may undergo hydrolysis to form naphthol. Caution is advised in treating patients with conditions that may slow gastric emptying (e.g., some diabetics). Duloxetine Delayed-Release Capsules have not been systematically evaluated in patients with a recent history of myocardial infarction or unstable coronary artery disease.

Avoid use in patients with chronic liver disease or cirrhosis.

Avoid use in patients with severe renal impairment, GFR <30 mL/minute.

Duloxetine treatment worsened glycemic control in some patients with diabetes.

Urinary Hesitation and Retention

Duloxetine Delayed-Release Capsules is in a class of drugs known to affect urethral resistance. If symptoms of urinary hesitation develop, it might be drug-related. In some instances of urinary retention associated with duloxetine use, hospitalization and/or catheterization has been needed.

Sexual Dysfunction

Duloxetine Delayed-Release Capsules may cause symptoms of sexual dysfunction resulting in ejaculatory delay or failure, decreased libido, and erectile dysfunction in men and decreased libido and delayed or absent orgasm in women.

ADVERSE REACTIONS

The most common adverse reactions (≥5% and at least twice the incidence of placebo-treated patients):

Adults – nausea, dry mouth, somnolence, constipation, decreased appetite, and hyperhidrosis

Pediatric Patients – decreased weight, decreased appetite, nausea, vomiting, fatigue, and diarrhea

DRUG INTERACTIONS

Strong CYP1A2 inhibitors: Avoid concomitant use. 

Potent inhibitors of CYP2D6 may increase Duloxetine Delayed-Release Capsule concentrations. Duloxetine Delayed-Release Capsule is a moderate inhibitor of CYP2D6. 

SELECT USE IN SPECIFIC POPULATIONS

Pregnancy: Third trimester use may increase risk for symptoms of poor adaptation (respiratory distress, temperature instability, feeding difficulty, hypotonia, tremor, irritability) in the neonate.

Hepatic Impairment: Avoid use in patients with chronic liver disease or cirrhosis.

Renal Impairment: Avoid use in patients with severe renal impairment, GFR <30 mL/minute.

INDICATIONS FOR USE

Duloxetine Delayed-Release Capsules are indicated for the treatment of major depressive disorder in adults and generalized anxiety disorder in adults and pediatric patients 7 years and older.

For additional safety information about Duloxetine Delayed-Release Capsules, see the Full Prescribing Information, including BOXED WARNING, and Medication Guide.