duloxetine hcl dr 20 mg cap (generic cymbalta)

Cautions

Contraindications

Concurrent or recent (i.e., within 2 weeks) therapy with a monoamine oxidase (MAO) inhibitor.(See Drug Interactions: Monoamine Oxidase Inhibitors.)

Uncontrolled angle-closure glaucoma.

Known hypersensitivity to duloxetine or any ingredient in the formulation.

Warnings/Precautions

Warnings

Worsening of Depression and Suicidality Risk

Worsening of depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior may occur in both adult and pediatric (see Pediatric Use under Cautions: Specific Populations) patients with major depressive disorder or other psychiatric disorders, whether or not they are taking antidepressants. This risk may persist until clinically important remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. However, there has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term, placebo-controlled studies of antidepressants (i.e., selective serotonin-reuptake inhibitors and other antidepressants) have shown an increased risk of suicidality in children, adolescents, and young adults (18-24 years of age) with major depressive disorder and other psychiatric disorders. An increased suicidality risk was not demonstrated with antidepressants compared with placebo in adults older than 24 years of age and a reduced risk was observed in adults 65 years of age or older.

The US Food and Drug Administration (FDA) recommends that all patients being treated with antidepressants for any indication be appropriately monitored and closely observed for clinical worsening, suicidality, and unusual changes in behavior, particularly during initiation of therapy (i.e., the first few months) and during periods of dosage adjustments. Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, also should be advised to monitor patients on a daily basis for the emergence of agitation, irritability, or unusual changes in behavior as well as the emergence of suicidality, and to report such symptoms immediately to a health-care provider.

Although a causal relationship between the emergence of symptoms such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, and/or mania and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consequently, consideration should be given to changing the therapeutic regimen or discontinuing therapy in patients whose depression is persistently worse or in patients experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, particularly if such manifestations are severe, abrupt in onset, or were not part of the patient's presenting symptoms. FDA also recommends that the drugs be prescribed in the smallest quantity consistent with good patient management, in order to reduce the risk of overdosage.

Other Warnings and Precautions

Hepatic Effects

Hepatic failure, sometimes fatal, has been reported in duloxetine-treated patients. The cases presented as hepatitis accompanied by abdominal pain, hepatomegaly, and markedly elevated serum transaminase concentrations (more than 20 times the upper limit of normal) with or without jaundice, reflecting a mixed or hepatocellular pattern of hepatic injury. Duloxetine should be discontinued in any patient who develops jaundice or other evidence of clinically important hepatic dysfunction; therapy should not be resumed unless another cause for the hepatic dysfunction can be established.

Cases of cholestatic jaundice with minimal elevation of serum transaminase concentrations also have been reported. Postmarketing reports indicate that elevated serum transaminase, bilirubin, and alkaline phosphatase concentrations have occurred in duloxetine-treated patients with chronic hepatic disease or cirrhosis.

Duloxetine has been shown to increase the risk of serum transaminase elevations in clinical trials; such elevations resulted in discontinuance of the drug in 0.3% of patients. The median time to detection of the transaminase elevation was about 2 months. In placebo-controlled trials, elevations in serum ALT concentrations to more than 3 times the upper limit of normal occurred in 1.1% of the duloxetine-treated patients compared with 0.2% of those receiving placebo. There was evidence of a dose-response relationship for ALT (SGPT) and AST (SGOT) elevations of more than 3 times the upper limit of normal and more than 5 times the upper limit of normal, respectively.

Because of the possibility that duloxetine and alcohol may interact to cause hepatic injury or that duloxetine may aggravate preexisting hepatic disease, duloxetine should not ordinarily be prescribed to patients with a history of excessive alcohol consumption or evidence of chronic hepatic disease. Patients and clinicians should be aware of the signs and symptoms of hepatic injury (e.g., pruritus, dark urine, jaundice, right upper quadrant tenderness, unexplained flu-like symptoms), and clinicians should promptly investigate such manifestations in patients receiving the drug.

Orthostatic Hypotension and Syncope

Orthostatic hypotension and syncope reported with therapeutic dosages; although these effects tend to occur within the first week of therapy, they may occur at any time during therapy, particularly following increases in dosage. Risk of decreased blood pressure may be greater in patients concomitantly receiving other drugs that produce orthostatic hypotension (such as antihypertensive agents); in patients receiving potent inhibitors of the cytochrome P-450 (CYP) 1A2 isoenzyme (see Drug Interactions: Drugs Affecting Hepatic Microsomal Enzymes); or in those receiving duloxetine dosages exceeding 60 mg daily. Discontinuance of the drug should be considered in patients experiencing symptomatic orthostatic hypotension and/or syncope during duloxetine therapy.

Serotonin Syndrome

Potentially life-threatening serotonin syndrome reported with selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs), including duloxetine, or selective serotonin-reuptake inhibitors (SSRIs), particularly with concurrent administration of other serotonergic drugs (e.g., serotonin [5-hydroxytryptamine; 5-HT] type 1 receptor agonists [''triptans'']) or drugs that impair serotonin metabolism (e.g., monoamine oxidase [MAO] inhibitors). Symptoms of serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination), and/or GI symptoms (e.g., nausea, vomiting, diarrhea).

Concurrent therapy with MAO inhibitors used for treatment of depression is contraindicated.(See Drug Interactions: Monoamine Oxidase Inhibitors.)

If concurrent therapy with duloxetine and a 5-HT₁ receptor agonist is clinically warranted, the patient should be observed carefully, particularly during initiation of therapy, when dosage is increased, or when another serotonergic agent is initiated.

Concomitant use of duloxetine and serotonin precursors (e.g., tryptophan) is not recommended.

Abnormal Bleeding

SSRIs and SNRIs, including duloxetine, may increase the risk of bleeding events. Concurrent administration of aspirin, nonsteroidal anti-inflammatory agents, warfarin, and other anticoagulants may add to this risk. Case reports and epidemiologic studies have demonstrated an association between the use of drugs that interfere with serotonin reuptake and the occurrence of GI bleeding. Bleeding events related to SSRI and SNRI use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages. The manufacturer recommends that patients be advised of the risk of bleeding associated with the concomitant use of duloxetine and aspirin or other nonsteroidal anti-inflammatory agents, warfarin, or other drugs that affect coagulation.(See Drug Interactions: Drugs Affecting Hemostasis.)

Withdrawal Effects

Because withdrawal effects (e.g., dysphoric mood, irritability, agitation, nausea/vomiting, dizziness, sensory disturbances, anxiety, confusion, headache, lethargy, emotional lability, insomnia, nightmares, hypomania, tinnitus, seizures) may occur, abrupt discontinuance of duloxetine should be avoided.(See Dosage and Administration: Dosage.)

If intolerable symptoms occur following dosage reduction or discontinuance, reinstitute previously prescribed dosage until symptoms abate, then resume more gradual dosage reductions.

Activation of Mania/Hypomania

Activation of mania and hypomania has occurred in patients with major depressive disorder receiving duloxetine. Use with caution in patients with a history of mania.

Seizures

The risk of seizures associated with duloxetine use has not been systematically evaluated, but seizures have been reported in patients receiving the drug; therefore, use with caution in patients with a history of seizures.

Blood Pressure

May increase blood pressure. Monitor blood pressure prior to and periodically during duloxetine therapy.

Clinically Important Drug Interactions

Because both CYP1A2 and CYP2D6 are responsible for duloxetine metabolism, the potential exists for clinically important drug interactions when duloxetine is concurrently administered with CYP1A2 inhibitors, CYP2D6 inhibitors, and CYP2D6 substrates.

Concurrent therapy with MAO inhibitors used for treatment of depression is contraindicated.(See Serotonin Syndrome under Warnings/Precautions: Other Warnings and Precautions, in Cautions and also see Drug Interactions: Monoamine Oxidase Inhibitors.)

Because of the possibility that duloxetine and alcohol may interact to cause hepatic injury, duloxetine should not ordinarily be prescribed to patients with a history of excessive alcohol consumption or evidence of chronic hepatic disease.(See Hepatic Effects under Warnings/Precautions: Other Warnings and Precautions, in Cautions and also see Drug Interactions: Alcohol.)

Potential pharmacologic interaction when duloxetine is given with or substituted for other centrally acting drugs, including those with a similar mechanism of action; CNS-active drugs should be used with caution in patients receiving duloxetine.

Hyponatremia/Syndrome of Inappropriate Antidiuretic Hormone Secretion

Treatment with SSRIs and SNRIs, including duloxetine, may result in hyponatremia. In many cases, hyponatremia appears to be due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium concentrations lower than 110 mmol/L have been reported and hyponatremia appeared reversible when duloxetine was discontinued. Geriatric individuals and patients receiving diuretics or who are otherwise volume depleted may be at greater risk of developing hyponatremia. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls; more severe and/or acute cases have been associated with hallucinations, syncope, seizures, coma, respiratory arrest, and death. Initiate appropriate medical intervention and consider drug discontinuance in patients with symptomatic hyponatremia.

Concomitant Illnesses

Experience with duloxetine in patients with concomitant diseases is limited.(See Hepatic Impairment and see Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Because alterations in gastric motility may affect the stability of the enteric coating of the pellets contained in duloxetine capsules, the drug should be used with caution in patients with conditions that may slow gastric emptying (e.g., in some patients with diabetes mellitus).

Duloxetine has not been systematically evaluated in patients with a recent history of myocardial infarction or unstable coronary artery disease; such patients were generally excluded from clinical studies. The manufacturer states that duloxetine use was not associated with the development of clinically important ECG abnormalities in controlled clinical studies of up to 13 weeks' duration.

Duloxetine worsens glycemic control in some patients with diabetes. In the 12-week acute treatment phase of 3 clinical studies in patients with diabetic peripheral neuropathy, small increases in fasting blood glucose were observed in the duloxetine-treated patients compared with those receiving placebo. In the extension phase of these studies, which lasted up to 52 weeks, fasting blood glucose increased by 12 mg/dL in the duloxetine-treated patients and decreased by 11.5 mg/dL in the routine care group; increases in glycosylated hemoglobin (hemoglobin A_1c) were observed in both groups of patients although the average increase was 0.3% greater in the duloxetine-treated patients compared with those receiving routine care.

Controlled Narrow-Angle Glaucoma

Possible increased risk of mydriasis; use with caution in patients with controlled narrow-angle glaucoma. Contraindicated in patients with such glaucoma that is not controlled.

Urinary Hesitation and Retention

Duloxetine belongs to a class of drugs known to affect urethral resistance. If symptoms of urinary hesitation develop during therapy, consider possibility that they may be drug-related.(See Uses: Stress Urinary Incontinence.)

Cases of urinary retention have been reported during postmarketing experience; in some of these cases, hospitalization and/or catheterization has been necessary.

Specific Populations

Pregnancy

Category C.

Some neonates exposed to selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs) or selective serotonin-reuptake inhibitors late in the third trimester of pregnancy have developed complications that have sometimes been severe and required prolonged hospitalization, respiratory support, enteral nutrition, and other forms of supportive care in special-care nurseries. Such complications can arise immediately upon delivery and usually last several days or up to 2-4 weeks. Clinical findings reported to date in the neonates have included respiratory distress, cyanosis, apnea, seizures, temperature instability or fever, feeding difficulty, dehydration, excessive weight loss, vomiting, hypoglycemia, hypotonia, hyperreflexia, tremor, jitteriness, irritability, lethargy, reduced or lack of reaction to pain stimuli, and constant crying. These clinical features appear to be consistent with either a direct toxic effect of the SNRI or selective serotonin-reuptake inhibitor or, possibly, a drug withdrawal syndrome. It should be noted that, in some cases, the clinical picture was consistent with serotonin syndrome . When treating a pregnant woman with duloxetine during the third trimester of pregnancy, the clinician should carefully consider the potential risks and benefits of such therapy. Consideration may be given to cautiously tapering duloxetine therapy in the third trimester prior to delivery if the drug is administered during pregnancy.(See Treatment of Pregnant Women during the Third Trimester under Dosage and Administration: Special Populations.)

Lactation

Duloxetine is distributed into human milk. At steady state, concentrations in breast milk are approximately one-fourth the maternal plasma concentrations. Because the safety of duloxetine in infants is not known, use in nursing women is not recommended. However, if the clinician determines that the potential benefits of duloxetine therapy for the mother outweigh the potential risks to the infant, dosage adjustment is not required since lactation does not affect pharmacokinetics.

Pediatric Use

Safety and efficacy of duloxetine in children younger than 18 years of age have not been established.

FDA warns that a greater risk of suicidal thinking or behavior (suicidality) occurred during first few months of antidepressant treatment (4%) compared with placebo (2%) in children and adolescents with major depressive disorder, obsessive-compulsive disorder (OCD), or other psychiatric disorders based on pooled analyses of 24 short-term, placebo-controlled trials of 9 antidepressant drugs (selective serotonin-reuptake inhibitors [SSRIs] and other antidepressants). However, a more recent meta-analysis of 27 placebo-controlled trials of 9 antidepressants (SSRIs and others) in patients younger than 19 years of age with major depressive disorder, OCD, or non-OCD anxiety disorders suggests that the benefits of antidepressant therapy in treating these conditions may outweigh the risks of suicidal behavior or suicidal ideation. No suicides occurred in these pediatric trials.

Carefully consider these findings when assessing potential benefits and risks of duloxetine in a child or adolescent for any clinical use.(See Worsening of Depression and Suicidality Risk under Warnings/Precautions: Warnings, in Cautions.)

Geriatric Use

Approximately 5.9, 33, and 7.9% of patients studied in clinical trials of duloxetine for major depressive disorder, diabetic peripheral neuropathy, and fibromyalgia, respectively, were 65 years of age or older. The generalized anxiety disorder clinical trials did not include sufficient numbers of patients 65 years of age or older to determine whether they respond differently than younger adults. Although no overall differences in efficacy or safety were observed between geriatric and younger patients in the major depressive disorder, diabetic peripheral neuropathic pain, and fibromyalgia clinical trials and other clinical experience has not revealed any evidence of age-related differences, the possibility that some older patients may exhibit increased sensitivity to the drug cannot be ruled out.

Clinically important hyponatremia has been reported in geriatric patients, who may be at greater risk for this adverse effect.(See Hyponatremia/Syndrome of Inappropriate Antidiuretic Hormone Secretion under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

In pooled data analyses, a reduced risk of suicidality was observed in adults 65 years of age or older with antidepressant therapy compared with placebo.(See Worsening of Depression and Suicidality Risk under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Hepatic Impairment

Substantially increased exposure to duloxetine; use is not recommended in patients with hepatic insufficiency or with substantial alcohol use.(See Hepatic Effects under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Renal Impairment

Increased plasma concentrations of duloxetine and its metabolites; use is not recommended in patients with end-stage renal disease (requiring dialysis) or severe renal impairment (creatinine clearance less than 30 mL/minute).

Population pharmacokinetic analyses suggest that mild to moderate renal impairment has no clinically important effect on duloxetine apparent clearance.

Common Adverse Effects

Adverse effects reported in 5% or more of patients with major depressive disorder receiving duloxetine and at an incidence at least twice that reported with placebo include nausea, dry mouth, constipation, decreased appetite, fatigue, somnolence, and increased sweating.

Adverse effects reported in 5% or more of patients with generalized anxiety disorder receiving duloxetine and at an incidence at least twice that reported with placebo include nausea, fatigue, dry mouth, somnolence, constipation, insomnia, decreased appetite, vomiting, hyperhidrosis, decreased libido, delayed ejaculation, and erectile dysfunction.

Adverse effects reported in 5% or more of patients with diabetic peripheral neuropathy receiving duloxetine and at an incidence at least twice that reported with placebo include nausea, somnolence, dizziness, dry mouth, constipation, hyperhidrosis, decreased appetite, and asthenia.

Adverse effects reported in 5% or more of patients with fibromyalgia receiving duloxetine and at an incidence at least twice that reported with placebo include nausea, dry mouth, constipation, decreased appetite, somnolence, agitation, and hyperhidrosis.