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AJANTA PHARMA L
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27241009990

duloxetine hcl dr 60 mg cap (generic cymbalta)

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Uses

Major Depressive Disorder

Duloxetine hydrochloride is used for the acute and maintenance treatment of major depressive disorder in adults.

Efficacy of duloxetine for the acute treatment of major depression has principally been established by 4 double-blind, placebo-controlled studies of 8-9 weeks' duration in outpatient settings in adults. In these studies, patients receiving duloxetine (40-120 mg daily) had greater improvements in the 17-item Hamilton depression rating scale (HAMD-17) total score than did patients receiving placebo. No age-, race-, or gender-related differences in efficacy were noted in these studies.

Efficacy of duloxetine for the maintenance treatment of major depressive disorder has been established in a randomized, placebo-controlled relapse prevention study in which 533 adult outpatients who met DSM-IV criteria for major depressive disorder initially received duloxetine 60 mg once daily in a 12-week, open-label acute phase. Patients who responded to treatment during the acute phase were then randomized to continue receiving duloxetine at the same dosage or to receive placebo for 26 weeks in the continuation phase. The duloxetine-treated patients experienced a longer time to relapse of depression compared with the placebo recipients. In addition, more placebo recipients relapsed compared with patients receiving duloxetine (approximately 29% and 17%, respectively).

The manufacturer states that if duloxetine is used for extended periods, the need for continued therapy should be reassessed periodically.

Antidepressant efficacy of duloxetine in hospital settings has not been adequately studied to date.

For further information on treatment of major depressive disorder and considerations in choosing the most appropriate antidepressant for a particular patient, including considerations related to patient tolerance, patient age, and cardiovascular, sedative, and suicidal risk, .

Generalized Anxiety Disorder

Duloxetine hydrochloride is used for the acute management of generalized anxiety disorder in adults. Efficacy of duloxetine for this indication has been established by 3 placebo-controlled trials of 9-10 weeks' duration in outpatient settings in adults who met DSM-IV criteria for generalized anxiety disorder. In these studies, patients receiving duloxetine (60-120 mg daily) had greater improvements in the Hamilton anxiety scale (HAM-A) total score and the Sheehan Disability Scale (SDS) global functional impairment score than did patients receiving placebo. No age- or gender-related differences in efficacy were noted in these studies.

The manufacturer states that the anxiolytic efficacy of duloxetine for long-term use (i.e., exceeding 10 weeks) has not been established by controlled studies to date. If duloxetine is used for extended periods, the need for continued therapy should be reassessed periodically.

Neuropathic Pain

Duloxetine hydrochloride is used for the management of neuropathic pain associated with diabetic peripheral neuropathy in adults. Efficacy of duloxetine for this indication has been established by 2 controlled studies of 12 weeks' duration in adults with type 1 or 2 diabetes mellitus and a diagnosis of painful distal symmetrical sensorimotor polyneuropathy for at least 6 months. Patients were excluded from the studies if they met DSM-IV-TR criteria for major depressive disorder and dysthymia. In these studies, 51% of patients receiving duloxetine (60-120 mg daily) and up to 4 g of acetaminophen daily (as needed) reported at least a 30% sustained reduction in pain compared with 31% of those receiving placebo plus acetaminophen (as needed). Some patients in the study experienced a decrease in pain as early as week 1, which persisted throughout the study.

Fibromyalgia

Duloxetine hydrochloride is used for the management of fibromyalgia in adults. Efficacy of duloxetine for this indication has been established by 2 randomized, double-blind, placebo-controlled, fixed-dose studies in adults with a diagnosis of fibromyalgia based on the American College of Rheumatology (ACR) criteria (i.e., history of widespread pain for 3 months and pain present in 11 or more of the 18 specific tender point sites). The first study was of 3 months' duration and enrolled female patients only while the second study was of 6 months' duration and enrolled both male and female patients. Approximately 25% of the patients had concurrent major depressive disorder. Both of these studies compared duloxetine 60 mg once daily or 120 mg daily (given in divided doses in study 1 and as a single daily dose in study 2) with placebo. In addition, Study 2 compared duloxetine 20 mg daily with placebo during the initial 3 months of the 6-month study; after 3 months, the duloxetine dosage was titrated up to 60 mg once daily for the remainder of the study. In these studies, duloxetine therapy in dosages of 60 or 120 mg daily significantly improved the endpoint mean pain scores from baseline and increased the number of patients who had at least a 50% reduction in pain score compared with baseline. Although pain reduction was observed in patients both with and without major depressive disorder, the degree of pain reduction may be greater in patients with major depressive disorder. Some patients experienced a reduction in pain as early as week 1, which persisted throughout the study. Improvement also was noted on measures of function as well as on the Patient Global Impression of Improvement (PGI) scale. Neither study demonstrated an additional therapeutic benefit of 120 mg daily compared with 60 mg daily, and the higher dosage was associated with more frequent adverse effects and early discontinuance of therapy.

The manufacturer states that the efficacy of duloxetine for long-term use (i.e., exceeding 3 months) has not been established by controlled studies to date. However, longer-term efficacy of the drug has been demonstrated for up to 6 months in extension phases of 2 controlled studies to date. The manufacturer recommends that the decision to continue therapy with the drug be based on individual patient response.

Stress Urinary Incontinence

Duloxetine has been used for the management of moderate to severe stress urinary incontinence (SUI) in women. In a number of placebo-controlled clinical trials involving women with predominantly SUI receiving duloxetine or placebo for up to 12 weeks, duloxetine was significantly better than placebo in reducing the frequency of incontinence episodes (which were reduced by approximately 50% in patients receiving duloxetine) and improving patients' quality of life (as assessed by Incontinence Quality of Life questionnaire scores). Therapy with the drug generally was well tolerated in these studies, with nausea being the most commonly reported adverse effect.

Data from one subsequent analysis suggest that the beneficial effects of duloxetine in women with SUI are maintained for up to 30 months. In addition, some data suggest that combining duloxetine and pelvic floor muscle training exercises may be more effective than either treatment alone. The potential role of duloxetine therapy relative to other forms of treatment (including pelvic floor muscle training, management of fluid intake and voiding, weight loss, devices, and surgery) remains to be established and requires additional study.

Dosage and Administration

Administration

Duloxetine hydrochloride is administered orally without regard to meals. Duloxetine hydrochloride delayed-release capsules should be swallowed whole and should not be chewed or crushed, nor should the contents be sprinkled on food or mixed with liquids.

Dosage

Dosage of duloxetine hydrochloride is expressed in terms of duloxetine.

Patients receiving duloxetine should be monitored for possible worsening of depression, suicidality, or unusual changes in behavior, especially at the beginning of therapy or during periods of dosage adjustment.(See Worsening of Depression and Suicidality Risk under Warnings/Precautions: Warnings, in Cautions.)

The manufacturer recommends that an interval of at least 2 weeks elapse when switching a patient from a monoamine oxidase (MAO) inhibitor to duloxetine. In addition, an interval of at least 5 days should elapse when switching from duloxetine to an MAO inhibitor.

Because withdrawal effects may occur (see Withdrawal Effects under Warnings/Precautions: Other Warnings and Precautions in Cautions), abrupt discontinuance of duloxetine should be avoided. When duloxetine therapy is discontinued, dosage should be tapered gradually and the patient carefully monitored to reduce the risk of withdrawal symptoms. If intolerable symptoms occur following dosage reduction or upon discontinuance of treatment, duloxetine therapy may be reinstituted at the previously prescribed dosage until such symptoms abate. Clinicians may resume dosage reductions at that time but at a more gradual rate.

Major Depressive Disorder

For the management of major depressive disorder, the recommended initial dosage of duloxetine in adults is 40 mg daily (given as 20 mg twice daily) to 60 mg daily (given either as 60 mg once daily or 30 mg twice daily). In some patients, it may be desirable to initiate therapy with a dosage of 30 mg once daily given for 1 week, followed by an increase to 60 mg once daily. Although duloxetine dosages of 120 mg daily have been effective, there is no evidence that dosages exceeding 60 mg daily provide additional therapeutic benefit. Safety of dosages exceeding 120 mg daily has not been adequately evaluated.

While the optimum duration of duloxetine therapy has not been established, it generally is agreed that acute depressive episodes require several months or longer of sustained antidepressant therapy. Systematic evaluation of duloxetine has shown that its antidepressant efficacy is maintained for periods of up to 26 weeks in patients receiving 60 mg daily. The manufacturer recommends a maintenance dosage of 60 mg once daily in adults. The manufacturer also recommends that the usefulness of duloxetine be reevaluated periodically in patients receiving long-term therapy.

Generalized Anxiety Disorder

For the management of generalized anxiety disorder, the recommended initial adult dosage of duloxetine is 60 mg once daily. In some patients, it may be desirable to initiate therapy with a dosage of 30 mg once daily given for 1 week, followed by an increase to 60 mg once daily. Dosage may be increased in increments of 30 mg once daily (up to a maximum dosage of 120 mg once daily). However, no additional benefit has been demonstrated from duloxetine dosages exceeding 60 mg once daily.

While the optimum duration of duloxetine therapy has not been established, it generally is agreed that generalized anxiety disorder is a chronic condition. The manufacturer states that the efficacy of duloxetine for long-term use (i.e., exceeding 10 weeks) has not been established by controlled studies and that the usefulness of the drug in patients receiving prolonged therapy should be reevaluated periodically.

Neuropathic Pain

For the management of neuropathic pain associated with diabetic peripheral neuropathy, the recommended adult dosage of duloxetine is 60 mg once daily. Duloxetine dosages exceeding 60 mg daily do not appear to provide substantially greater therapeutic benefit and clearly are less well tolerated. For patients for whom tolerability is a concern, a lower initial dosage may be considered. Because progression of diabetic peripheral neuropathy is highly variable and management of pain is empirical, efficacy of the drug must be assessed individually. The manufacturer states that the efficacy of duloxetine for long-term use (i.e., exceeding 12 weeks) has not been established by controlled studies.

Fibromyalgia

For the management of fibromyalgia, the recommended adult dosage of duloxetine is 60 mg once daily. The manufacturer states that treatment should be initiated at 30 mg once daily for one week to allow patients to adjust to the drug before increasing the dosage to 60 mg once daily. Some patients may respond to the initial dosage of 30 mg once daily. Duloxetine dosages exceeding 60 mg daily do not appear to provide greater therapeutic benefit, even in patients not responding to a dosage of 60 mg daily, and are associated with a higher incidence of adverse effects.

Fibromyalgia is recognized as a chronic condition. The manufacturer states that efficacy of duloxetine in the management of fibromyalgia has been demonstrated in placebo-controlled studies lasting up to 3 months, and that the efficacy of the drug for longer-term use (i.e., exceeding 3 months) has not been established in controlled studies. However, efficacy of the drug has been demonstrated for up to 6 months in extension phases of 2 controlled studies. The manufacturer recommends that the decision to continue therapy with the drug be based on individual patient response.

Stress Urinary Incontinence

Although the optimum dosage and duration of duloxetine therapy for the treatment of stress urinary incontinence in women remain to be established, the most commonly used dosage in controlled trials has been 80 mg daily, usually given as 40 mg twice daily (dosage range: 20-120 mg daily). Some patients may benefit (i.e., reduced risk of nausea and dizziness) from initiating therapy with a duloxetine dosage of 20 mg twice daily for 2 weeks before increasing to the usual dosage of 40 mg twice daily. If adverse effects are bothersome during the first few weeks of therapy at the usual dosage, the dosage may be reduced to 20 mg twice daily. The safety of higher dosages (i.e., 120 mg daily), which have been used in a limited number of women with more severe cases of stress urinary incontinence, requires additional study.

Special Populations

Although there are no specific dosage recommendations for geriatric patients, extra caution is recommended when the duloxetine dosage is increased in elderly patients.

Although the manufacturer makes no specific dosage recommendation for smoking patients, some clinicians recommend a slightly increased duloxetine dosage (by about 15%) in patients who smoke.(See Drug Interactions: Smoking.)

In patients with mild to moderate renal impairment (creatinine clearance 30-80 mL/minute), a lower initial dosage and gradual increase in dosage may be considered. The manufacturer recommends that duloxetine not be administered to patients with end-stage renal disease (requiring dialysis), severe renal impairment (creatinine clearance less than 30 mL/minute), or any hepatic insufficiency.(See Specific Populations under Cautions: Warnings/Precautions.)

Treatment of Pregnant Women during the Third Trimester

Because some neonates exposed to duloxetine and other selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs) or selective serotonin-reuptake inhibitors late in the third trimester of pregnancy have developed severe complications, consideration may be given to cautiously tapering duloxetine therapy in the third trimester prior to delivery if the drug is administered during pregnancy.(See Pregnancy under Warnings/Precautions: Specific Populations, in Cautions.)

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 A1c) 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.

Drug Interactions

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of cytochrome P-450 (CYP) 2D6 isoenzyme (e.g., tricyclic antidepressants [TCAs; amitriptyline, desipramine, imipramine, nortriptyline], phenothiazines, class IC antiarrhythmics [flecainide, propafenone]): potential pharmacokinetic (increased AUC of the substrate) interactions. Use with caution. Consider monitoring plasma TCA concentrations and reducing the TCA dosage if a TCA is administered concurrently with duloxetine.

Substrates of CYP1A2, CYP3A, CYP2C9, or CYP2C19 isoenzymes: clinically important pharmacokinetic interaction generally is considered unlikely.

Drugs Affecting Hepatic Microsomal Enzymes

Potent inhibitors of CYP1A2 (e.g., fluvoxamine, some quinolone anti-infective agents [e.g., ciprofloxacin, enoxacin]): potential pharmacokinetic (increased plasma duloxetine concentrations) interaction. Avoid concomitant use.

Potent inhibitors of CYP2D6 (e.g., fluoxetine, paroxetine, quinidine) isoenzymes: potential pharmacokinetic interaction (increased plasma duloxetine concentrations).

Concomitant administration of duloxetine and fluvoxamine, a potent CYP1A2 inhibitor, in poor CYP2D6 metabolizers resulted in a sixfold increase in duloxetine area under the plasma concentration-time curve (AUC) and peak plasma concentrations.

Drugs Affecting Hemostasis

Altered anticoagulant effects, including increased bleeding, have been reported when selective serotonin-reuptake inhibitors (SSRIs) or selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs), including duloxetine, were concurrently administered with warfarin or other anticoagulants. The manufacturer recommends carefully monitoring patients receiving warfarin during initiation and discontinuance of duloxetine therapy.

Potential pharmacologic (increased risk of bleeding) interaction with aspirin or other nonsteroidal anti-inflammatory agents; use with caution.

Drugs that Affect Gastric Acidity

Theoretical risk of altered duloxetine bioavailability if administered with drugs that increase gastric pH. However, no clinically important effect was demonstrated when duloxetine was administered with aluminum- and magnesium-containing antacids or famotidine.

Whether the concomitant administration of proton-pump inhibitors affects duloxetine absorption is currently unknown.

Alcohol

Potential pharmacologic (increased risk of hepatotoxicity) interaction; avoid concomitant use in patients with substantial alcohol use.(See Hepatic Effects under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Duloxetine has not been shown to potentiate the impairment of mental and motor skills caused by alcohol.

Antihypertensive Agents

Potential pharmacologic (increased risk of hypotension and syncope) interaction.

Benzodiazepines

Lorazepam does not appear to affect the pharmacokinetics of duloxetine.

Temazepam does not appear to affect the pharmacokinetics of duloxetine.

CNS-active Drugs

Potential pharmacologic interaction when given with or substituted for other centrally acting drugs, including those with a similar mechanism of action; use with caution.

5-HT1 Receptor Agonists (''Triptans'')

Pharmacologic interaction (potentially life-threatening serotonin syndrome) if used concurrently with 5-HT1 receptor agonists (e.g., almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan). If concomitant use is clinically warranted, the patient should be observed carefully, particularly during treatment initiation, when dosage is increased, or when another serotonergic agent is initiated.(See Serotonin Syndrome under Warnings/Precautions:Other Warnings and Precautions, in Cautions.)

Monoamine Oxidase (MAO) Inhibitors

Pharmacologic interaction (potentially fatal serotonin syndrome); concomitant use is contraindicated. The manufacturer recommends that at least 2 weeks should elapse between discontinuance of an MAO inhibitor and initiation of duloxetine and that at least 5 days elapse between discontinuance of duloxetine therapy and initiation of MAO inhibitor therapy.(See Serotonin Syndrome under Warnings/Precautions:Other Warnings and Precautions, in Cautions.)

Selective Serotonin-reuptake Inhibitors and Selective Serotonin- and Norepinephrine-reuptake Inhibitors

Potential pharmacologic interaction (potentially life-threatening serotonin syndrome); concurrent administration not recommended.(See Serotonin Syndrome under Warnings/Precautions:Other Warnings and Precautions, in Cautions.)

Concomitant administration of duloxetine and fluvoxamine, a potent CYP1A2 inhibitor, in poor CYP2D6 metabolizers resulted in a six-fold increase in duloxetine AUCs and peak plasma concentrations.

Serotonergic Drugs

Potential pharmacologic interaction (potentially life-threatening serotonin syndrome) with drugs affecting serotonergic neurotransmission, including linezolid (an anti-infective agent that is a nonselective, reversible MAO inhibitor), lithium, tramadol, and St. John's wort (Hypericum perforatum); use with caution. Concurrent administration of serotonin precursors (such as tryptophan) is not recommended.(See Serotonin Syndrome under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Smoking

Potential pharmacokinetic interaction (reduced duloxetine bioavailability and plasma concentrations). The manufacturer states that routine dosage adjustment is not necessary. However, some clinicians recommend a small increase in duloxetine dosage (about 15%) in patients who smoke.

Theophylline

Although small increases (averaging from 7-20%) in theophylline AUCs have been reported during concurrent administration of theophylline and duloxetine, combined use of these drugs reportedly has been well tolerated and routine theophylline dosage adjustment does not appear to be necessary during concomitant administration.

Thioridazine

Potential pharmacokinetic (increased plasma thioridazine concentrations) interaction with resulting increased risk of serious ventricular arrhythmias and sudden death; concomitant use is not recommended by manufacturer of duloxetine.

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