Duloxetine

Cardinal Health

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use Duloxetine Delayed-release Capsules USP safely and effectively. See full prescribing information for Duloxetine Delayed-release Capsules USP. DULOXETINE delayed-release capsules USP for oral use. Initial U.S. Approval: 2004BOXED WARNINGWARNING: SUICIDAL THOUGHTS AND BEHAVIORS See full prescribing information for complete boxed warning. •  Increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants (5.1) •  Monitor for worsening and emergence of suicidal thoughts and behaviors (5.1) •  Duloxetine delayed-release capsules are not approved for use in pediatric patients (8.4) RECENT MAJOR CHANGESDosage and Administration:         Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders (2.5)                 10/2012         Use of Duloxetine with Other MAOIs such as Linezolid or Methylene Blue (2.6)                                                         10/2012 Contraindications:        Monoamine Oxidase Inhibitors (4.1)                                                                                                         10/2012 Warnings and Precautions:         Serotonin Syndrome (5.4)                                                                                                                    10/2012         Discontinuation of Treatment with Duloxetine (5.7)                                                                                          08/2012INDICATIONS AND USAGEDuloxetine delayed-release capsules USP are a serotonin and norepinephrine reuptake inhibitor (SNRI) indicated for: •  Major Depressive Disorder (MDD) (1.1) •  Generalized Anxiety Disorder (GAD) (1.2) •  Diabetic Peripheral Neuropathic Pain (DPNP) (1.3) DOSAGE AND ADMINISTRATIONDuloxetine delayed-release capsules should generally be administered once daily without regard to meals. Duloxetine delayed-release capsules should be swallowed whole and should not be chewed or crushed, nor should the capsule be opened and its contents be sprinkled on food or mixed with liquids (2). Table 1 Indication Starting Dose Target Dose Maximum Dose MDD (2.1, 2.2) 40 mg/day to 60 mg/day  Acute Treatment: 40 mg/day (20 mg twice daily) to 60 mg/day (once daily or as 30 mg twice daily); Maintenance Treatment: 60 mg/day  120 mg/day  GAD (2.1) 60 mg/day  60 mg/day (once daily)  120 mg/day  DPNP (2.1) 60 mg/day  60 mg/day (once daily)  60 mg/day  •  Some patients may benefit from starting at 30 mg once daily (2.1) •  There is no evidence that doses greater than 60 mg/day confers additional benefit, while some adverse reactions were observed to be dose-dependent (2.1) •  Discontinuing duloxetine delayed-release capsules: A gradual dose reduction is recommended to avoid discontinuation symptoms (2.4, 5.7) DOSAGE FORMS AND STRENGTHS20 mg, 30 mg and 60 mg capsules (3).CONTRAINDICATIONS •  Serotonin Syndrome and MAOIs: Do not use MAOIs intended to treat psychiatric disorders with duloxetine or within 5 days of stopping treatment with duloxetine. Do not use duloxetine within 14 days of stopping an MAOI intended to treat psychiatric disorders. In addition, do not start duloxetine in a patient who is being treated with linezolid or intravenous methylene blue (4.1). •  Use in patients with uncontrolled narrow-angle glaucoma (4.2) WARNINGS AND PRECAUTIONS •  Suicidality: Monitor for clinical worsening and suicide risk (5.1) •  Hepatotoxicity: Hepatic failure, sometimes fatal, has been reported in patients treated with duloxetine. Duloxetine 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. Duloxetine should not be prescribed to patients with substantial alcohol use or evidence of chronic liver disease (5.2) •  Orthostatic Hypotension and Syncope: Cases have been reported with duloxetine therapy (5.3) •  Serotonin Syndrome: Serotonin syndrome has been reported with SSRIs and SNRIs, including with duloxetine, both when taken alone, but especially when co-administered with other serotonergic agents (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone and St. John's Wort). If such symptoms occur, discontinue duloxetine and initiate supportive treatment. If concomitant use of duloxetine with other serotonergic drugs is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases (5.4) •  Abnormal Bleeding: Duloxetine may increase the risk of bleeding events. Patients should be cautioned about the risk of bleeding associated with the concomitant use of duloxetine and NSAIDs, aspirin, or other drugs that affect coagulation (5.5, 7.4) •  Severe Skin Reactions: Severe skin reactions, including erythema multiforme and Stevens-Johnson Syndrome (SJS), can occur with duloxetine. Duloxetine 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. (5.6) •  Discontinuation: May result in symptoms, including dizziness, headache, nausea, diarrhea, paresthesia, irritability, vomiting, insomnia, anxiety, hyperhidrosis, and fatigue (5.7) •  Activation of mania or hypomania has occurred (5.8) •  Seizures: Prescribe with care in patients with a history of seizure disorder (5.9) •  Blood Pressure: Monitor blood pressure prior to initiating treatment and periodically throughout treatment (5.10) •  Inhibitors of CYP1A2 or Thioridazine: Should not administer with duloxetine (5.11) •  Hyponatremia: Cases of hyponatremia have been reported (5.12) •  Hepatic Insufficiency and Severe Renal Impairment: Should ordinarily not be administered to these patients (5.13) •  Controlled Narrow-Angle Glaucoma: Use cautiously in these patients (5.13) •  Glucose Control in Diabetes: In diabetic peripheral neuropathic pain patients, small increases in fasting blood glucose, and HbA1c have been observed (5.13) •  Conditions that Slow Gastric Emptying: Use cautiously in these patients (5.13) •  Urinary Hesitation and Retention (5.14) Side EffectsMost common adverse reactions (≥5% and at least twice the incidence of placebo patients): nausea, dry mouth, somnolence, constipation, decreased appetite, and hyperhidrosis (6.3). To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc. at 1-800-399-2561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS •  Potent inhibitors of CYP1A2 should be avoided (7.1). •  Potent inhibitors of CYP2D6 may increase duloxetine concentrations (7.2). •  Duloxetine is a moderate inhibitor of CYP2D6 (7.9). USE IN SPECIFIC POPULATIONS •  Pregnancy and Nursing Mothers: Use only if the potential benefit justifies the potential risk to the fetus or child (2.3, 8.1, 8.3).

FULL PRESCRIBING INFORMATION: CONTENTS*

• RECENT MAJOR CHANGES
• 1. DULOXETINE INDICATIONS AND USAGE
  • 1.1 Major Depressive Disorder
  • 1.2 Generalized Anxiety Disorder
  • 1.3 Diabetic Peripheral Neuropathic Pain
• 2. DULOXETINE DOSAGE AND ADMINISTRATION
  • 2.1 Initial Treatment
  • 2.2 Maintenance/Continuation/Extended Treatment
  • 2.3 Dosing in Special Populations
  • 2.4 Discontinuing Duloxetine Delayed-release Capsules
  • 2.5 Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders
  • 2.6 Use of Duloxetine Delayed-release Capsules with Other MAOIs such as Linezolid or Methylene Blue
• 3. DOSAGE FORMS AND STRENGTHS
• 4. DULOXETINE CONTRAINDICATIONS
  • 4.1 Monoamine Oxidase Inhibitors (MAOIs)
  • 4.2 Uncontrolled Narrow-Angle Glaucoma
• 5. WARNINGS AND PRECAUTIONS
  • 5.1 Suicidal Thoughts and Behaviors in Adolescents and Young Adults
  • 5.2 Hepatotoxicity
  • 5.3 Orthostatic Hypotension and Syncope
  • 5.5 Abnormal Bleeding
  • 5.6 Severe Skin Reactions
  • 5.7 Discontinuation of Treatment with Duloxetine
  • 5.8 Activation of Mania/Hypomania
  • 5.9 Seizures
  • 5.10 Effect on Blood Pressure
  • 5.11 Clinically Important Drug Interactions
  • 5.12 Hyponatremia
  • 5.13 Use in Patients with Concomitant Illness
  • 5.14 Urinary Hesitation and Retention
  • 5.15 Laboratory Tests
• 6. DULOXETINE ADVERSE REACTIONS
  • 6.1 Clinical Trial Data Sources
  • 6.2 Adverse Reactions Reported as Reasons for Discontinuation of Treatment in Placebo-Controlled Trials
  • 6.3 Most Common Adverse Reactions
  • 6.4 Adverse Reactions Occurring at an Incidence of 5% or More Among Duloxetine-Treated Patients in Placebo-Controlled Trials
  • 6.12 Adverse Reactions Occurring at an Incidence of 2% or More Among Duloxetine-Treated Patients in Placebo-Controlled Trials
  • 6.5 Effects on Male and Female Sexual Function
  • 6.6 Vital Sign Changes
  • 6.7 Weight Changes
  • 6.8 Laboratory Changes
  • 6.9 Electrocardiogram Changes
  • 6.10 Other Adverse Reactions Observed During the Premarketing and Postmarketing Clinical Trial Evaluation of Duloxetine
  • 6.11 Postmarketing Spontaneous Reports
• 7. DRUG INTERACTIONS
  • 7.1 Inhibitors of CYP1A2
  • 7.2 Inhibitors of CYP2D6
  • 7.3 Dual Inhibition of CYP1A2 and CYP2D6
  • 7.4 Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin)
  • 7.5 Lorazepam
  • 7.6 Temazepam
  • 7.7 Drugs that Affect Gastric Acidity
  • 7.8 Drugs Metabolized by CYP1A2
  • 7.9 Drugs Metabolized by CYP2D6
  • 7.10 Drugs Metabolized by CYP2C9
  • 7.18 Drugs Metabolized by CYP3A
  • 7.11 Drugs Metabolized by CYP2C19
  • 7.17 Drugs Metabolized by CYP3A
  • 7.12 Monoamine Oxidase Inhibitors (MAOIs)
  • 7.13 Serotonergic Drugs
  • 7.14 Alcohol
  • 7.15 CNS Drugs
  • 7.16 Drugs Highly Bound to Plasma Protein
• 8. USE IN SPECIFIC POPULATIONS
  • 8.1 Pregnancy
  • 8.2 Labor and Delivery
  • 8.3 Nursing Mothers
  • 8.4 Pediatric Use
  • 8.5 Geriatric Use
  • 8.6 Gender
  • 8.7 Smoking Status
  • 8.8 Race
  • 8.9 Hepatic Insufficiency
  • 8.10 Severe Renal Impairment
• 9. DRUG ABUSE AND DEPENDENCE
  • 9.2 Abuse
  • 9.3 Dependence
• 10. OVERDOSAGE
  • 10.1 Signs and Symptoms
  • 10.2 Management of Overdose
• 11. DULOXETINE DESCRIPTION
• 12. CLINICAL PHARMACOLOGY
  • 12.1 Mechanism of Action
  • 12.2 Pharmacodynamics
  • 12.3 Pharmacokinetics
• 13. NONCLINICAL TOXICOLOGY
  • 13.1 CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY
• 14. CLINICAL STUDIES
  • 14.1 Major Depressive Disorder
  • 14.2 Generalized Anxiety Disorder
  • 14.3 Diabetic Peripheral Neuropathic Pain
• 16. HOW SUPPLIED/STORAGE AND HANDLING
  • 16.1 How Supplied
  • 16.2 Storage
• 17. PATIENT COUNSELING INFORMATION
  • 17.1 Information on Medication Guide
  • 17.2 Suicidal Thoughts and Behaviors
  • 17.3 Medication Administration
  • 17.4 Continuing the Therapy Prescribed
  • 17.5 Hepatotoxicity
  • 17.6 Alcohol
  • 17.7 Orthostatic Hypotension and Syncope
  • 17.8 Serotonin Syndrome
  • 17.9 Abnormal Bleeding
  • 17.10 Severe Skin Reactions
  • 17.11 Discontinuation of Treatment
  • 17.12 Activation of Mania or Hypomania
  • 17.13 Seizures
  • 17.14 Effects on Blood Pressure
  • 17.15 Concomitant Medications
  • 17.16 Hyponatremia
  • 17.17 Concomitant Illnesses
  • 17.18 Urinary Hesitancy and Retention
  • 17.19 Pregnancy and Breast Feeding
  • 17.20 Interference with Psychomotor Performance
• Package/Label Display Panel
• Package/Label Display Panel

FULL PRESCRIBING INFORMATION

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS

Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24; there was a reduction in risk with antidepressant use in patients aged 65 and older [see WARNINGS AND PRECAUTIONS (5.1)].

In patients of all ages who are started on antidepressant therapy, monitor closely for worsening, and for emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication with the prescriber [see WARNINGS AND PRECAUTIONS (5.1)].

Duloxetine delayed-release capsules are not approved for use in pediatric patients [see USE IN SPECIFIC POPULATIONS (8.4)].

RECENT MAJOR CHANGES

1. INDICATIONS AND USAGE

1.1 Major Depressive Disorder

Duloxetine delayed-release capsules USP are indicated for the treatment of major depressive disorder (MDD). The efficacy of duloxetine delayed-release capsules USP was established in four short-term and one maintenance trial in adults [see CLINICAL STUDIES (14.1)].

A major depressive episode (DSM-IV) implies a prominent and relatively persistent (nearly every day for at least 2 weeks) depressed or dysphoric mood that usually interferes with daily functioning, and includes at least 5 of the following 9 symptoms: depressed mood, loss of interest in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, or a suicide attempt or suicidal ideation.

1.2 Generalized Anxiety Disorder

Duloxetine delayed-release capsules USP are indicated for the treatment of generalized anxiety disorder (GAD). The efficacy of duloxetine delayed-release capsules USP was established in three short-term trials and one maintenance trial in adults [see CLINICAL STUDIES (14.2)].

Generalized anxiety disorder is defined by the DSM-IV as excessive anxiety and worry, present more days than not, for at least 6 months. The excessive anxiety and worry must be difficult to control and must cause significant distress or impairment in normal functioning. It must be associated with at least 3 of the following 6 symptoms: restlessness or feeling keyed up or on edge, being easily fatigued, difficulty concentrating or mind going blank, irritability, muscle tension, and/or sleep disturbance.

1.3 Diabetic Peripheral Neuropathic Pain

Duloxetine delayed-release capsules USP are indicated for the management of neuropathic pain (DPNP) associated with diabetic peripheral neuropathy [see CLINICAL STUDIES (14.3)].

2. DOSAGE AND ADMINISTRATION

Duloxetine delayed-release capsules should be swallowed whole and should not be chewed or crushed, nor should the capsule be opened and its contents sprinkled on food or mixed with liquids. All of these might affect the enteric coating. Duloxetine delayed-release capsules can be given without regard to meals.

2.1 Initial Treatment

Major Depressive Disorder

Duloxetine delayed-release capsules should be administered at a total dose of 40 mg/day (given as 20 mg twice daily) to 60 mg/day (given either once daily or as 30 mg twice daily). For some patients, it may be desirable to start at 30 mg once daily for 1 week, to allow patients to adjust to the medication before increasing to 60 mg once daily. While a 120 mg/day dose was shown to be effective, there is no evidence that doses greater than 60 mg/day confer any additional benefits. The safety of doses above 120 mg/day has not been adequately evaluated [see CLINICAL STUDIES (14.1)].

Generalized Anxiety Disorder

For most patients, the recommended starting dose for duloxetine delayed-release capsules is 60 mg administered once daily. For some patients, it may be desirable to start at 30 mg once daily for 1 week, to allow patients to adjust to the medication before increasing to 60 mg once daily. While a 120 mg once daily dose was shown to be effective, there is no evidence that doses greater than 60 mg/day confer additional benefit. Nevertheless, if a decision is made to increase the dose beyond 60 mg once daily, dose increases should be in increments of 30 mg once daily. The safety of doses above 120 mg once daily has not been adequately evaluated [see CLINICAL STUDIES (14.2)].

Diabetic Peripheral Neuropathic Pain

The recommended dose for duloxetine delayed-release capsules is 60 mg administered once daily. There is no evidence that doses higher than 60 mg confer additional significant benefit and the higher dose is clearly less well tolerated [see CLINICAL STUDIES (14.3)]. For patients for whom tolerability is a concern, a lower starting dose may be considered.

Since diabetes is frequently complicated by renal disease, a lower starting dose and gradual increase in dose should be considered for patients with renal impairment [see DOSAGE AND ADMINISTRATION (2.3), USE IN SPECIFIC POPULATIONS (8.10), and CLINICAL PHARMACOLOGY (12.3)]. 

2.2 Maintenance/Continuation/Extended Treatment

Major Depressive Disorder

It is generally agreed that acute episodes of major depression require several months or longer of sustained pharmacologic therapy. Maintenance of efficacy in MDD was demonstrated with duloxetine delayed-release capsules as monotherapy. Duloxetine delayed-release capsules should be administered at a total dose of 60 mg once daily. Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment [see CLINICAL STUDIES (14.1)].

Generalized Anxiety Disorder

It is generally agreed that episodes of generalized anxiety disorder require several months or longer of sustained pharmacological therapy. Maintenance of efficacy in GAD was demonstrated with duloxetine delayed-release capsules as monotherapy. Duloxetine delayed-release capsules should be administered in a dose range of 60 to 120 mg once daily. Patients should be periodically reassessed to determine the continued need for maintenance treatment and the appropriate dose for such treatment [see CLINICAL STUDIES (14.2)].

Diabetic Peripheral Neuropathic Pain

As the progression of diabetic peripheral neuropathy is highly variable and management of pain is empirical, the effectiveness of duloxetine must be assessed individually. Efficacy beyond 12 weeks has not been systematically studied in placebo-controlled trials.

2.3 Dosing in Special Populations

Hepatic Insufficiency

It is recommended that duloxetine delayed-release capsules should ordinarily not be administered to patients with any hepatic insufficiency [see WARNINGS AND PRECAUTIONS (5.13) and USE IN SPECIFIC POPULATIONS (8.9)].

Severe Renal Impairment

Duloxetine delayed-release capsules are not recommended for patients with end-stage renal disease or severe renal impairment (estimated creatinine clearance <30 mL/min) [see WARNINGS AND PRECAUTIONS (5.13) and USE IN SPECIFIC POPULATIONS (8.10)].

Elderly Patients

No dose adjustment is recommended for elderly patients on the basis of age. As with any drug, caution should be exercised in treating the elderly. When individualizing the dosage in elderly patients, extra care should be taken when increasing the dose [see USE IN SPECIFIC POPULATIONS (8.5)].

Pregnant Women

There are no adequate and well-controlled studies in pregnant women; therefore, duloxetine delayed-release capsules should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus [see USE IN SPECIFIC POPULATIONS (8.1)].

Nursing Mothers

Because the safety of duloxetine in infants is not known, nursing while on duloxetine delayed-release capsules is not recommended [see USE IN SPECIFIC POPULATIONS (8.3)].

2.4 Discontinuing Duloxetine Delayed-release Capsules

Symptoms associated with discontinuation of duloxetine delayed-release capsules and other SSRIs and SNRIs have been reported. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible [see WARNINGS AND PRECAUTIONS (5.7)].

2.5 Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders

At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with duloxetine delayed-release capsules. Conversely, at least 5 days should be allowed after stopping duloxetine delayed-release capsules before starting an MAOI intended to treat psychiatric disorders [see CONTRAINDICATIONS (4.1)].

2.6 Use of Duloxetine Delayed-release Capsules with Other MAOIs such as Linezolid or Methylene Blue

Do not start duloxetine delayed-release capsules in a patient who is being treated with linezolid or intravenous methylene blue because there is an increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered[see CONTRAINDICATIONS (4.1)].

In some cases, a patient already receiving duloxetine delayed-release capsules therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, duloxetine delayed-release capsules should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for 5 days or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with duloxetine delayed-release capsules may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue [see WARNINGS AND PRECAUTIONS (5.4)].

The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with duloxetine delayed-release capsules is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use [see WARNINGS AND PRECAUTIONS (5.4)].

3. DOSAGE FORMS AND STRENGTHS

Duloxetine is available as delayed-release capsules:

20 mg: Size '4' capsules with green cap and green body imprinted with "LU" on cap and "Q01" in black ink on body, containing four white to off white mini tablets.

30 mg: Size '3' capsules with dark blue cap and white body imprinted with "LU" in white ink on cap and "Q02" in black ink on body, containing six white to off white mini tablets.

60 mg: Size '1' capsules with dark blue cap and green body imprinted with "LU" in white ink on cap and "Q03" in black ink on body, containing twelve white to off white mini tablets.

4. CONTRAINDICATIONS

4.1 Monoamine Oxidase Inhibitors (MAOIs)

The use of MAOIs intended to treat psychiatric disorders with duloxetine or within 5 days of stopping treatment with duloxetine is contraindicated because of an increased risk of serotonin syndrome. The use of duloxetine within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated [see DOSAGE AND ADMINISTRATION ( 2.5 ) and WARNINGS AND PRECAUTIONS ( 5.4 ) ].

Starting duloxetine in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome [see DOSAGE AND ADMINISTRATION ( 2.6 ) and WARNINGS AND PRECAUTIONS ( 5.4 ) ]. 

4.2 Uncontrolled Narrow-Angle Glaucoma

In clinical trials, duloxetine use was associated with an increased risk of mydriasis; therefore, its use should be avoided in patients with uncontrolled narrow-angle glaucoma [see WARNINGS AND PRECAUTIONS (5.13)].

5. WARNINGS AND PRECAUTIONS

5.1 Suicidal Thoughts and Behaviors in Adolescents and Young Adults

Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, 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 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 to 24) with major depressive disorder (MDD) and other psychiatric disorders. 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 with antidepressants compared to placebo in adults aged 65 and older.

The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk of differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1.

No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.

It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.

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 during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.

The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms 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.

Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.

If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that discontinuation can be associated with certain symptoms [see DOSAGE AND ADMINISTRATION (2.4) and WARNINGS AND PRECAUTIONS (5.7) for descriptions of the risks of discontinuation of duloxetine delayed-release capsules].

Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for duloxetine should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose.

Screening Patients for Bipolar Disorder

A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that duloxetine is not approved for use in treating bipolar depression.

5.2 Hepatotoxicity

There have been reports of hepatic failure, sometimes fatal, 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 with or without jaundice, reflecting a mixed or hepatocellular pattern of liver injury. Duloxetine 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.

Cases of cholestatic jaundice with minimal elevation of transaminase levels have also been reported. Other postmarketing reports indicate that elevated transaminases, bilirubin, and alkaline phosphatase have occurred in patients with chronic liver disease or cirrhosis.

Duloxetine increased the risk of elevation of serum transaminase levels in development program clinical trials. Liver transaminase elevations resulted in the discontinuation of 0.3% (89/29,435) of duloxetine -treated patients. In most patients, the median time to detection of the transaminase elevation was about two months. In placebo-controlled trials in any indication, for patients with normal and abnormal baseline ALT values, elevation of ALT >3 times the upper limit of normal occurred in 1.37% (132/9611) of duloxetine -treated patients compared to 0.49% (35/7182) of placebo-treated patients. In placebo-controlled studies using a fixed dose design, there was evidence of a dose response relationship for ALT and AST elevation of >3 times the upper limit of normal and >5 times the upper limit of normal, respectively.

Because it is possible that duloxetine and alcohol may interact to cause liver injury or that duloxetine may aggravate pre-existing liver disease, duloxetine should not be prescribed to patients with substantial alcohol use or evidence of chronic liver disease.

5.3 Orthostatic Hypotension and Syncope

Orthostatic hypotension and syncope have been reported with therapeutic doses of duloxetine. Syncope and orthostatic hypotension tend to occur within the first week of therapy but can occur at any time during duloxetine treatment, particularly after dose increases. The risk of blood pressure decreases may be greater in patients taking concomitant medications that induce orthostatic hypotension (such as antihypertensives) or are potent CYP1A2 inhibitors [see WARNINGS AND PRECAUTIONS (5.11) and DRUG INTERACTIONS (7.1)] and in patients taking duloxetine at doses above 60 mg daily. Consideration should be given to discontinuing duloxetine in patients who experience symptomatic orthostatic hypotension and/or syncope during duloxetine therapy.

The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including duloxetine, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John's Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome.

The concomitant use of duloxetine with MAOIs intended to treat psychiatric disorders is contraindicated. Duloxetine should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking duloxetine. Duloxetine should be discontinued before initiating treatment with the MAOI [see DOSAGE AND ADMINISTRATION (2.5, 2.6), and CONTRAINDICATIONS (4.1)].

If concomitant use of duloxetine with other serotonergic drugs including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan and St. John's Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases. Treatment with duloxetine and any concomitant serotonergic agents, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.

5.5 Abnormal Bleeding

SSRIs and SNRIs, including duloxetine, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anti-coagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages.

Patients should be cautioned about the risk of bleeding associated with the concomitant use of duloxetine and NSAIDs, aspirin, or other drugs that affect coagulation.

5.6 Severe Skin Reactions

Severe skin reactions, including erythema multiforme and Stevens-Johnson Syndrome (SJS), can occur with duloxetine. The reporting rate of SJS associated with duloxetine use exceeds the general population background incidence rate for this serious skin reaction (1 to 2 cases per million person years). The reporting rate is generally accepted to be an underestimate due to underreporting.

Duloxetine 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.

5.7 Discontinuation of Treatment with Duloxetine

Discontinuation symptoms have been systematically evaluated in patients taking duloxetine. Following abrupt or tapered discontinuation in placebo-controlled clinical trials, the following symptoms occurred at 1% or greater and at a significantly higher rate in duloxetine-treated patients compared to those discontinuing from placebo: dizziness, headache, nausea, diarrhea, paresthesia, irritability, vomiting, insomnia, anxiety, hyperhidrosis, and fatigue.

During marketing of other SSRIs and SNRIs (serotonin and norepinephrine reuptake inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. Although these events are generally self-limiting, some have been reported to be severe.

Patients should be monitored for these symptoms when discontinuing treatment with duloxetine. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate [see DOSAGE AND ADMINISTRATION (2.4)].

5.8 Activation of Mania/Hypomania

In placebo-controlled trials in patients with major depressive disorder, activation of mania or hypomania was reported in 0.1% (2/2489) of duloxetine-treated patients and 0.1% (1/1625) of placebo-treated patients. No activation of mania or hypomania was reported in GAD placebo-controlled trials. Activation of mania or hypomania has been reported in a small proportion of patients with mood disorders who were treated with other marketed drugs effective in the treatment of major depressive disorder. As with these other agents, duloxetine should be used cautiously in patients with a history of mania.

5.9 Seizures

Duloxetine has not been systematically evaluated in patients with a seizure disorder, and such patients were excluded from clinical studies. In placebo-controlled clinical trials, seizures/convulsions occurred in 0.03% (3/10,524) of patients treated with duloxetine and 0.01% (1/7699) of patients treated with placebo. Duloxetine should be prescribed with care in patients with a history of a seizure disorder.

5.10 Effect on Blood Pressure

In placebo-controlled clinical trials across indications from baseline to endpoint, 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 compared to mean decreases of 0.6 mm Hg systolic and 0.4 mm Hg diastolic in placebo-treated patients. There was no significant difference in the frequency of sustained (3 consecutive visits) elevated blood pressure. In a clinical pharmacology study designed to evaluate the effects of duloxetine on various parameters, including blood pressure at supratherapeutic doses with an accelerated dose titration, there was evidence of increases in supine blood pressure at doses up to 200 mg twice daily. At the highest 200 mg twice daily dose, the increase in mean pulse rate was 5.0 to 6.8 beats and increases in mean blood pressure were 4.7 to 6.8 mm Hg (systolic) and 4.5 to 7 mm Hg (diastolic) up to 12 hours after dosing.

Blood pressure should be measured prior to initiating treatment and periodically measured throughout treatment [see ADVERSE REACTIONS (6.7 )].

5.11 Clinically Important Drug Interactions

Both CYP1A2 and CYP2D6 are responsible for duloxetine metabolism.

Potential for Other   Drugs to Affect Duloxetine

CYP1A2 Inhibitors : Co-administration of duloxetine with potent CYP1A2 inhibitors should be avoided [see DRUG INTERACTIONS (7.1)].

CYP2D6 Inhibitors: Because CYP2D6 is involved in duloxetine metabolism, concomitant use of duloxetine with potent inhibitors of CYP2D6 would be expected to, and does, result in higher concentrations (on average of 60%) of duloxetine [see DRUG INTERACTIONS (7.2 )].

Potential for Duloxetine to Affect Other Drugs

Drugs Metabolized by CYP2D6: Co-administration of duloxetine with drugs that are extensively metabolized by CYP2D6 and that have a narrow therapeutic index, including certain antidepressants (tricyclic antidepressants [TCAs], such as nortriptyline, amitriptyline, and imipramine), phenothiazines and Type 1C antiarrhythmics (e.g., propafenone, flecainide), should be approached with caution. Plasma TCA concentrations may need to be monitored and the dose of the TCA may need to be reduced if a TCA is co-administered with duloxetine. Because of the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, duloxetine and thioridazine should not be co-administered [see DRUG INTERACTIONS (7.9)].

Other Clinically Important Drug Interactions

Alcohol: Use of duloxetine concomitantly with heavy alcohol intake may be associated with severe liver injury. For this reason, duloxetine should not be prescribed for patients with substantial alcohol use [see WARNINGS AND PRECAUTIONS (5.2) and DRUG INTERACTIONS (7.15)].

CNS Acting Drugs: Given the primary CNS effects of duloxetine, it should be used with caution when it is taken in combination with or substituted for other centrally acting drugs, including those with a similar mechanism of action [see WARNINGS AND PRECAUTIONS (5.11) and DRUG INTERACTIONS (7.16)].

5.12 Hyponatremia

Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including duloxetine. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported and appeared to be reversible when duloxetine was discontinued. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk [see USE IN SPECIFIC POPULATIONS (8.5)]. Discontinuation of duloxetine should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.

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 hallucination, syncope, seizure, coma, respiratory arrest, and death.

5.13 Use in Patients with Concomitant Illness

Clinical experience with duloxetine in patients with concomitant systemic illnesses is limited. There is no information on the effect that alterations in gastric motility may have on the stability of duloxetine's enteric coating. In extremely acidic conditions, duloxetine, unprotected by the enteric coating, may undergo hydrolysis to form naphthol. Caution is advised in using duloxetine in patients with conditions that may slow gastric emptying (e.g., some diabetics).

Duloxetine has not been systematically evaluated in patients with a recent history of myocardial infarction or unstable coronary artery disease. Patients with these diagnoses were generally excluded from clinical studies during the product's premarketing testing.

Hepatic Insufficiency

Duloxetine should ordinarily not be used in patients with hepatic insufficiency [see DOSAGE AND ADMINISTRATION (2.3), WARNINGS AND PRECAUTIONS (5.2), and USE IN SPECIFIC POPULATIONS (8.9)].

Severe Renal Impairment

Duloxetine should ordinarily not be used in patients with end-stage renal disease or severe renal impairment (creatinine clearance <30 mL/min). Increased plasma concentration of duloxetine, and especially of its metabolites, occur in patients with end-stage renal disease (requiring dialysis) [see DOSAGE AND ADMINISTRATION (2.3) and USE IN SPECIFIC POPULATIONS (8.10)].

Controlled Narrow-Angle Glaucoma:

In clinical trials, duloxetine was associated with an increased risk of mydriasis; therefore, it should be used cautiously in patients with controlled narrow-angle glaucoma [see CONTRAINDICATIONS (4.2)].

Glycemic Control in Patients with Diabetes

As observed in DPNP trials, duloxetine treatment worsens glycemic control in some patients with diabetes. In three clinical trials of duloxetine for the management of neuropathic pain associated with diabetic peripheral neuropathy, the mean duration of diabetes was approximately 12 years, the mean baseline fasting blood glucose was 176 mg/dL, and the mean baseline hemoglobin A_1c (HbA_1c) was 7.8%. In the 12-week acute treatment phase of these studies, duloxetine was associated with a small increase in mean fasting blood glucose as compared to placebo. In the extension phase of these studies, which lasted up to 52 weeks, mean fasting blood glucose increased by 12 mg/dL in the duloxetine group and decreased by 11.5 mg/dL in the routine care group. HbA_1c increased by 0.5% in the duloxetine and by 0.2% in the routine care groups.

5.14 Urinary Hesitation and Retention

Duloxetine is in a class of drugs known to affect urethral resistance. If symptoms of urinary hesitation develop during treatment with duloxetine, consideration should be given to the possibility that they might be drug-related. In post marketing experience, cases of urinary retention have been observed. In some instances of urinary retention associated with duloxetine use, hospitalization and/or catheterization has been needed.

5.15 Laboratory Tests

No specific laboratory tests are recommended.

6. ADVERSE REACTIONS

6.1 Clinical Trial Data Sources

The data described below reflect exposure to duloxetine in placebo-controlled trials for MDD (N=2489), GAD (N=910), and DPNP (N=906). The population studied was 17 to 91 years of age; 65.5%, 62.5% and 42.9% female; and 86.5%, 81.2%, and 74.0% Caucasian for MDD, GAD, and DPNP respectively. Most patients received doses of a total of 60 to 120 mg per day [see CLINICAL STUDIES (14)].

The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse reaction of the type listed. A reaction was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. Reactions reported during the studies were not necessarily caused by the therapy, and the frequencies do not reflect investigator impression (assessment) of causality.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

6.2 Side Effects Reported as Reasons for Discontinuation of Treatment in Placebo-Controlled Trials

Major Depressive Disorder

Approximately 9% (209/2327) of the patients who received duloxetine in placebo-controlled trials for MDD discontinued treatment due to an adverse reaction, compared with 4.7% (68/1460) of the patients receiving placebo. Nausea (duloxetine 1.3%, placebo 0.5%) was the only common adverse reaction reported as a reason for discontinuation and considered to be drug-related (i.e., discontinuation occurring in at least 1% of the duloxetinetreated patients and at a rate of at least twice that of placebo).

Generalized Anxiety Disorder

Approximately 15.3% (102/668) of the patients who received duloxetine in placebo-controlled trials for GAD discontinued treatment due to an adverse reaction, compared with 4.0% (20/495) for placebo. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine 3.7%, placebo 0.2%), and vomiting (duloxetine 1.3%, placebo 0.0%), and dizziness (duloxetine 1.0%, placebo 0.2%).

Diabetic Peripheral Neuropathic Pain

Approximately 12.9% (117/906) of the patients who received duloxetine in placebo-controlled trials for DPNP discontinued treatment due to an adverse reaction, compared with 5.1% (23/448) for placebo. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine 3.5%, placebo 0.7%), dizziness (duloxetine 1.2%, placebo 0.4%), and somnolence (duloxetine 1.1%, placebo 0.0%).

6.3 Most Common Side Effects

Pooled Trials for All Approved Indications

The most commonly observed adverse reactions in duloxetine -treated patients (incidence of at least 5% and at least twice the incidence in placebo patients) were nausea, dry mouth, somnolence, constipation, decreased appetite, and hyperhidrosis.

Diabetic Peripheral Neuropathic Pain

The most commonly observed adverse reactions in duloxetine -treated patients (as defined above) were nausea, somnolence, decreased appetite, constipation, hyperhidrosis, and dry mouth.

Chronic Pain due to Osteoarthritis

The most commonly observed adverse reactions in duloxetine -treated patients (as defined above) were nausea, fatigue, and constipation.

Chronic Low Back Pain

The most commonly observed adverse reactions in duloxetine -treated patients (as defined above) were nausea, dry mouth, insomnia, somnolence, constipation, dizziness, and fatigue.

6.4 Side Effects Occurring at an Incidence of 5% or More Among Duloxetine-Treated Patients in Placebo-Controlled Trials

Table 2 gives the incidence of treatment-emergent adverse reactions in placebo-controlled trials for approved indications that occurred in 5% or more of patients treated with duloxetine and with an incidence greater than placebo.

6.12 Side Effects Occurring at an Incidence of 2% or More Among Duloxetine-Treated Patients in Placebo-Controlled Trials

Pooled MDD and GAD Trials

Table 3 gives the incidence of treatment-emergent adverse reactions in MDD and GAD placebo-controlled trials for approved indications that occurred in 2% or more of patients treated with duloxetine and with an incidence greater than placebo.

DPNP, OA, and CLBP

Table 4 gives the incidence of treatment-emergent adverse events that occurred in 2% or more of patients treated with duloxetine (determined prior to rounding) in the premarketing acute phase of DPNP placebo-controlled trials and with an incidence greater than placebo.

6.5 Effects on Male and Female Sexual Function

Changes in sexual desire, sexual performance and sexual satisfaction often occur as manifestations of psychiatric disorders or diabetes, but they may also be a consequence of pharmacologic treatment. Because adverse sexual reactions are presumed to be voluntarily underreported, the Arizona Sexual Experience Scale (ASEX), a validated measure designed to identify sexual side effects, was used prospectively in 4 MDD placebo-controlled trials. In these trials, as shown in Table 5 below, patients treated with duloxetine experienced significantly more sexual dysfunction, as measured by the total score on the ASEX, than did patients treated with placebo. Gender analysis showed that this difference occurred only in males. Males treated with duloxetine experienced more difficulty with ability to reach orgasm (ASEX Item 4) than males treated with placebo. Females did not experience more sexual dysfunction on duloxetine than on placebo as measured by ASEX total score. Negative numbers signify an improvement from a baseline level of dysfunction, which is commonly seen in depressed patients. Physicians should routinely inquire about possible sexual side effects.

6.6 Vital Sign Changes

In placebo-controlled clinical trials across approved indications for change from baseline to endpoint, duloxetine treatment was associated with mean increases of 0.07 mm Hg in systolic blood pressure and 0.62 mm Hg in diastolic blood pressure compared to mean decreases of 1.31 mm Hg systolic and 0.73 mm Hg diastolic in placebo-treated patients. There was no significant difference in the frequency of sustained (3 consecutive visits) elevated blood pressure [see WARNINGS AND PRECAUTIONS (5.3and 5.10)]. 

Duloxetine treatment, for up to 26 weeks in placebo-controlled trials across approved indications, typically caused a small increase in heart rate for change from baseline to endpoint compared to placebo of up to 1.40 beats per minute.

6.7 Weight Changes

In placebo-controlled clinical trials, MDD and GAD patients treated with duloxetine for up to 10 weeks experienced a mean weight loss of approximately 0.5 kg, compared with a mean weight gain of approximately 0.2 kg in placebo-treated patients. In studies of DPNP, patients treated with duloxetine for up to 26 weeks experienced a mean weight loss of approximately 0.6 kg compared with a mean weight gain of approximately 0.2 kg in placebo-treated patients.

6.8 Laboratory Changes

Duloxetine treatment in placebo-controlled clinical trials across approved indications, was associated with small mean increases from baseline to endpoint in ALT, AST, CPK, and alkaline phosphatase; infrequent, modest, transient, abnormal values were observed for these analytes in duloxetine -treated patients when compared with placebo-treated patients [see WARNINGS AND PRECAUTIONS (5.2)].

6.9 Electrocardiogram Changes

The effect of duloxetine 160 mg and 200 mg administered twice daily to steady state was evaluated in a randomized, double-blinded, two-way crossover study in 117 healthy female subjects. No QT interval prolongation was detected. Duloxetine appears to be associated with concentration-dependent but not clinically meaningful QT shortening.

6.10 Other Side Effects Observed During the Premarketing and Postmarketing Clinical Trial Evaluation of Duloxetine

Following is a list of treatment-emergent adverse reactions reported by patients treated with duloxetine in clinical trials. In clinical trials of all indications, 29,435 patients were treated with duloxetine. Of these, 30.4% (8953) took duloxetine for at least 6 months, and 14.7% (4317) for at least one year. The following listing is not intended to include reactions (1) already listed in previous tables or elsewhere in labeling, (2) for which a drug cause was remote, (3) which were so general as to be uninformative, (4) which were not considered to have significant clinical implications, or (5) which occurred at a rate equal to or less than placebo.

Reactions are categorized by body system according to the following definitions: frequent adverse reactions are those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in fewer than 1/1000 patients.

Cardiac Disorders

Frequent: palpitations; Infrequent: myocardial infarction and tachycardia.

Ear and Labyrinth Disorders

Frequent: vertigo; Infrequent: ear pain and tinnitus.

Endocrine Disorders

Infrequent: hypothyroidism.

Eye Disorders

Frequent: vision blurred; Infrequent: diplopia, and visual disturbance.

Gastrointestinal Disorders

Frequent: flatulence; Infrequent: eructation, gastritis, halitosis, and stomatitis; Rare: gastric ulcer, hematochezia, and melena.

General Disorders and Administration Site Conditions

Frequent: chills/rigors; Infrequent: feeling abnormal, feeling hot and/or cold, malaise, and thirst; Rare: gait disturbance.

Infections and Infestations

Infrequent: gastroenteritis and laryngitis.

Investigations

Frequent: weight increased; Infrequent: blood cholesterol increased.

Metabolism and Nutrition Disorders

Infrequent: dehydration and hyperlipidemia; Rare: dyslipidemia.

Musculoskeletal and Connective Tissue Disorders

Frequent: musculoskeletal pain; Infrequent: muscle tightness and muscle twitching.

Nervous System Disorders

Frequent: dysgeusia, lethargy, and parasthesia/hypoesthesia; Infrequent: disturbance in attention, dyskinesia, myoclonus, and poor quality sleep; Rare: dysarthria.

Psychiatric Disorders

Frequent: abnormal dreams and sleep disorder; Infrequent: apathy, bruxism, disorientation/confusional state, irritability, mood swings, and suicide attempt; Rare: completed suicide.

Renal and Urinary Disorders

Infrequent: dysuria, micturition urgency, nocturia, polyuria, and urine odor abnormal.

Reproductive System and Breast Disorders

Frequent: anorgasmia/orgasm abnormal; Infrequent: menopausal symptoms, and sexual dysfunction.

Respiratory, Thoracic and Mediastinal Disorders

Frequent: yawning; Infrequent: throat tightness.

Skin and Subcutaneous Tissue Disorders-  Infrequent: cold sweat, dermatitis contact, erythema, increased tendency to bruise, night sweats, and photosensitivity reaction; Rare: ecchymosis.

Vascular Disorders

Frequent: hot flush; Infrequent: flushing, orthostatic hypotension, and peripheral coldness.

6.11 Postmarketing Spontaneous Reports

The following adverse reactions have been identified during postapproval use of duloxetine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Adverse reactions reported since market introduction that were temporally related to duloxetine therapy and not mentioned elsewhere in labeling include: anaphylactic reaction, aggression and anger (particularly early in treatment or after treatment discontinuation), angioneurotic edema, extrapyramidal disorder, galactorrhea, glaucoma, gynecological bleeding, hallucinations, hyperglycemia, hyperprolactinemia, hypersensitivity, hypertensive crisis, muscle spasm, rash, restless legs syndrome, seizures upon treatment discontinuation, supraventricular arrhythmia, tinnitus (upon treatment discontinuation), trismus, and urticaria.

7. DRUG INTERACTIONS

Both CYP1A2 and CYP2D6 are responsible for duloxetine metabolism.

7.1 Inhibitors of CYP1A2

When duloxetine 60 mg was co-administered with fluvoxamine 100 mg, a potent CYP1A2 inhibitor, to male subjects (n=14) duloxetine AUC was increased approximately 6-fold, the C_max was increased about 2.5-fold, and duloxetine t_1/2 was increased approximately 3-fold. Other drugs that inhibit CYP1A2 metabolism include cimetidine and quinolone antimicrobials such as ciprofloxacin and enoxacin [see WARNINGS AND PRECAUTIONS (5.11)].

7.2 Inhibitors of CYP2D6

Concomitant use of duloxetine (40 mg once daily) with paroxetine (20 mg once daily) increased the concentration of duloxetine AUC by about 60%, and greater degrees of inhibition are expected with higher doses of paroxetine. Similar effects would be expected with other potent CYP2D6 inhibitors (e.g., fluoxetine, quinidine) [see WARNINGS AND PRECAUTIONS (5.11)].

7.3 Dual Inhibition of CYP1A2 and CYP2D6

Concomitant administration of duloxetine 40 mg twice daily with fluvoxamine 100 mg, a potent CYP1A2 inhibitor, to CYP2D6 poor metabolizer subjects (n=14) resulted in a 6-fold increase in duloxetine AUC and C_max ^.

7.4 Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin)

Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs or SNRIs are co-administered with warfarin. Concomitant administration of warfarin (2 to 9 mg once daily) under steady state conditions with duloxetine 60 or 120 mg once daily for up to 14 days in healthy subjects (n=15) did not significantly change INR from baseline (mean INR changes ranged from 0.05 to +0.07). The total warfarin (protein bound plus free drug) pharmacokinetics (AUC_τ,ss, C_max,ss or t_max,ss) for both R- and S-warfarin were not altered by duloxetine. Because of the potential effect of duloxetine on platelets, patients receiving warfarin therapy should be carefully monitored when duloxetine is initiated or discontinued [see WARNINGS AND PRECAUTIONS (5.5)].

7.5 Lorazepam

Under steady-state conditions for duloxetine (60 mg Q 12 hours) and lorazepam (2 mg Q 12 hours), the pharmacokinetics of duloxetine were not affected by co-administration.

7.6 Temazepam

Under steady-state conditions for duloxetine (20 mg qhs) and temazepam (30 mg qhs), the pharmacokinetics of duloxetine were not affected by co-administration.

7.7 Drugs that Affect Gastric Acidity

Duloxetine delayed-release capsules have an enteric coating that resists dissolution until reaching a segment of the gastrointestinal tract where the pH exceeds 5.5. In extremely acidic conditions, duloxetine, unprotected by the enteric coating, may undergo hydrolysis to form naphthol. Caution is advised in using duloxetine in patients with conditions that may slow gastric emptying (e.g., some diabetics). Drugs that raise the gastrointestinal pH may lead to an earlier release of duloxetine. However, coadministration of duloxetine with aluminum- and magnesium-containing antacids (51 mEq) or duloxetine with famotidine, had no significant effect on the rate or extent of duloxetine absorption after administration of a 40 mg oral dose. It is unknown whether the concomitant administration of proton pump inhibitors affects duloxetine absorption [see WARNINGS AND PRECAUTIONS (5.13)].

7.8 Drugs Metabolized by CYP1A2

In vitro drug interaction studies demonstrate that duloxetine does not induce CYP1A2 activity. Therefore, an increase in the metabolism of CYP1A2 substrates (e.g., theophylline, caffeine) resulting from induction is not anticipated, although clinical studies of induction have not been performed. Duloxetine is an inhibitor of the CYP1A2 isoform in in vitro studies, and in two clinical studies the average (90% confidence interval) increase in theophylline AUC was 7% (1% to 15%) and 20% (13% to 27%) when co-administered with duloxetine (60 mg twice daily).

7.9 Drugs Metabolized by CYP2D6

Duloxetine is a moderate inhibitor of CYP2D6. When duloxetine was administered (at a dose of 60 mg twice daily) in conjunction with a single 50 mg dose of desipramine, a CYP2D6 substrate, the AUC of desipramine increased 3-fold [see WARNINGS AND PRECAUTIONS (5.11)].

7.10 Drugs Metabolized by CYP2C9

Results of in vitro studies demonstrate that duloxetine does not inhibit activity. In a clinical study, the pharmacokinetics of S-warfarin, a CYP2C9 substrate, were not significantly affected by duloxetine [see DRUG INTERACTIONS (7.4)].

7.18 Drugs Metabolized by CYP3A

Results of in vitro studies demonstrate that duloxetine does not inhibit or induce CYP3A activity. Therefore, an increase or decrease in the metabolism of CYP3A substrates (e.g., oral contraceptives and other steroidal agents) resulting from induction or inhibition is not anticipated, although clinical studies have not been performed.

7.11 Drugs Metabolized by CYP2C19

Results of in vitro studies demonstrate that duloxetine does not inhibit CYP2C19 activity at therapeutic concentrations. Inhibition of the metabolism of CYP2C19 substrates is therefore not anticipated, although clinical studies have not been performed.

7.17 Drugs Metabolized by CYP3A

Results of in vitro studies demonstrate that duloxetine does not inhibit or induce CYP3A activity. Therefore, an increase or decrease in the metabolism of CYP3A substrates (e.g., oral contraceptives and other steroidal agents) resulting from induction or inhibition is not anticipated, although clinical studies have not been performed.

7.12 Monoamine Oxidase Inhibitors (MAOIs)

[See DOSAGE AND ADMINISTRATION (2.5, 2.6), CONTRAINDICATIONS (4.1), and WARNINGS AND PRECAUTIONS (5.4)].

7.13 Serotonergic Drugs

[See DOSAGE AND ADMINISTRATION (2.5, 2.6), CONTRAINDICATIONS (4.1), and WARNINGS AND PRECAUTIONS (5.4)].

7.14 Alcohol

When duloxetine and ethanol were administered several hours apart so that peak concentrations of each would coincide, duloxetine did not increase the impairment of mental and motor skills caused by alcohol.

In the duloxetine clinical trials database, three duloxetine -treated patients had liver injury as manifested by ALT and total bilirubin elevations, with evidence of obstruction. Substantial intercurrent ethanol use was present in each of these cases, and this may have contributed to the abnormalities seen [see WARNINGS AND PRECAUTIONS (5.2 and 5.11)].

7.15 CNS Drugs

[See WARNINGS AND PRECAUTIONS (5.11)].

7.16 Drugs Highly Bound to Plasma Protein

Because duloxetine is highly bound to plasma protein, administration of duloxetine to a patient taking another drug that is highly protein bound may cause increased free concentrations of the other drug, potentially resulting in adverse reactions. However, co-administration of duloxetine (60 or 120 mg) with warfarin (2 to 9 mg), a highly protein-bound drug, did not result in significant changes in INR and in the pharmacokinetics of either total S-or total R-warfarin (protein bound plus free drug) [see DRUG INTERACTIONS (7.4)].

8. USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Teratogenic Effects, Pregnancy Category C

In animal reproduction studies, duloxetine has been shown to have adverse effects on embryo/fetal and postnatal development.

When duloxetine was administered orally to pregnant rats and rabbits during the period of organogenesis, there was no evidence of teratogenicity at doses up to 45 mg/kg/day (7 times the maximum recommended human dose [MRHD, 60 mg/day] and 4 times the human dose of 120 mg/day on a mg/m² basis, in rat; 15 times the MRHD and 7 times the human dose of 120 mg/day on a mg/m² basis in rabbit). However, fetal weights were decreased at this dose, with a no-effect dose of 10 mg/kg/day (2 times the MRHD and ≈1 times the human dose of 120 mg/day on a mg/m² basis in rat; 3 times the MRHD and 2 times the human dose of 120 mg/day on a mg/m² basis in rabbits).

When duloxetine was administered orally to pregnant rats throughout gestation and lactation, the survival of pups to 1 day postpartum and pup body weights at birth and during the lactation period were decreased at a dose of 30 mg/kg/day (5 times the MRHD and 2 times the human dose of 120 mg/day on a mg/m² basis); the no-effect dose was 10 mg/kg/day. Furthermore, behaviors consistent with increased reactivity, such as increased startle response to noise and decreased habituation of locomotor activity, were observed in pups following maternal exposure to 30 mg/kg/day. Post-weaning growth and reproductive performance of the progeny were not affected adversely by maternal duloxetine treatment.

There are no adequate and well-controlled studies in pregnant women; therefore, duloxetine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nonteratogenic Effects

Neonates exposed to SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs), late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome [see WARNINGS AND PRECAUTIONS (5.4)].

When treating pregnant women with duloxetine during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. The physician may consider tapering duloxetine in the third trimester [see DOSAGE AND ADMINISTRATION (2.3)].

8.2 Labor and Delivery

The effect of duloxetine on labor and delivery in humans is unknown. Duloxetine should be used during labor and delivery only if the potential benefit justifies the potential risk to the fetus.

8.3 Nursing Mothers

Duloxetine is excreted into the milk of lactating women. The estimated daily infant dose on a mg/kg basis is approximately 0.14% of the maternal dose. Because the safety of duloxetine in infants is not known, nursing while on duloxetine is not recommended. However, if the physician determines that the benefit of duloxetine therapy for the mother outweighs any potential risk to the infant, no dosage adjustment is required as lactation did not influence duloxetine pharmacokinetics.

The disposition of duloxetine was studied in 6 lactating women who were at least 12 weeks postpartum. Duloxetine 40 mg twice daily was given for 3.5 days. Like many other drugs, duloxetine is detected in breast milk, and steady state concentrations in breast milk are about one-fourth those in plasma. The amount of duloxetine in breast milk is approximately 7 mcg/day while on 40 mg BID dosing. The excretion of duloxetine metabolites into breast milk was not examined. Because the safety of duloxetine in infants is not known, nursing while on duloxetine is not recommended [see DOSAGE AND ADMINISTRATION (2.3)].

8.4 Pediatric Use

Safety and effectiveness in the pediatric population has not been established [see BOXED WARNING and WARNINGS AND PRECAUTIONS (5.1)].

Decreased appetite and weight loss have been observed in association with the use of SSRIs and SNRIs. Perform regular monitoring of weight and growth in children and adolescents treated with an SNRI such as duloxetine.

Duloxetine administration to young rats from post-natal day 21 (weaning) through post-natal day 90 (adult) resulted in decreased body weights that persisted into adulthood, but recovered when drug treatment was discontinued; slightly delayed (~1.5 days) sexual maturation in females, without any effect on fertility; and a delay in learning a complex task in adulthood, which was not observed after drug treatment was discontinued. These effects were observed at the high dose of 45 mg/kg/day; the no-effect-level was 20 mg/kg/day.

Information describing two additional clinical studies performed by Eli Lilly and Company that failed to demonstrate pediatric efficacy is approved for Eli Lilly and Company's Duloxetine Delayed-release Capsules. However, due to Eli Lilly and Company's marketing exclusivity rights, this drug product is not labelled with that pediatric information.

8.5 Geriatric Use

Of the 2,418 patients in premarketing clinical studies of duloxetine for MDD, 5.9% (143) were 65 years of age or over. Of the 1,074 patients in the DPNP premarketing studies, 33% (357) were 65 years of age or over. Premarketing clinical studies of GAD did not include sufficient numbers of subjects age 65 or over to determine whether they respond differently from younger subjects. In the MDD and DPNP studies, no overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. SSRIs and SNRIs, including duloxetine have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event [see WARNINGS AND PRECAUTIONS (5.12)].

The pharmacokinetics of duloxetine after a single dose of 40 mg were compared in healthy elderly females (65 to 77 years) and healthy middle-age females (32 to 50 years). There was no difference in the C_max, but the AUC of duloxetine was somewhat (about 25%) higher and the half-life about 4 hours longer in the elderly females. Population pharmacokinetic analyses suggest that the typical values for clearance decrease by approximately 1% for each year of age between 25 to 75 years of age; but age as a predictive factor only accounts for a small percentage of between-patient variability. Dosage adjustment based on the age of the patient is not necessary [see DOSAGE AND ADMINISTRATION (2.3)].

8.6 Gender

Duloxetine's half-life is similar in men and women. Dosage adjustment based on gender is not necessary.

8.7 Smoking Status

Duloxetine bioavailability (AUC) appears to be reduced by about one-third in smokers. Dosage modifications are not recommended for smokers.

8.8 Race

No specific pharmacokinetic study was conducted to investigate the effects of race.

8.9 Hepatic Insufficiency

Patients with clinically evident hepatic insufficiency have decreased duloxetine metabolism and elimination. After a single 20 mg dose of duloxetine, 6 cirrhotic patients with moderate liver impairment (Child-Pugh Class B) had a mean plasma duloxetine clearance about 15% that of age- and gender-matched healthy subjects, with a 5-fold increase in mean exposure (AUC). Although C_max was similar to normals in the cirrhotic patients, the half-life was about 3 times longer [see DOSAGE AND ADMINISTRATION (2.3) and WARNINGS AND PRECAUTIONS (5.13)].

8.10 Severe Renal Impairment

Limited data are available on the effects of duloxetine in patients with end-stage renal disease (ESRD). After a single 60 mg dose of duloxetine, Cmax and AUC values were approximately 100% greater in patients with end-stage renal disease receiving chronic intermittent hemodialysis than in subjects with normal renal function. The elimination half-life, however, was similar in both groups. The AUCs of the major circulating metabolites, 4-hydroxy duloxetine glucuronide and 5-hydroxy, 6-methoxy duloxetine sulfate, largely excreted in urine, were approximately 7- to 9-fold higher and would be expected to increase further with multiple dosing. Population PK analyses suggest that mild to moderate degrees of renal dysfunction (estimated CrCl 30 to 80 mL/min) have no significant effect on duloxetine apparent clearance [see DOSAGE AND ADMINISTRATION (2.3) and WARNINGS AND PRECAUTIONS (5.13)].

9. DRUG ABUSE AND DEPENDENCE

9.2 Abuse

In animal studies, duloxetine did not demonstrate barbiturate-like (depressant) abuse potential.

While duloxetine has not been systematically studied in humans for its potential for abuse, there was no indication of drug-seeking behavior in the clinical trials. However, it is not possible to predict on the basis of premarketing experience the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for a history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of duloxetine (e.g., development of tolerance, incrementation of dose, drug-seeking behavior).

9.3 Dependence

In drug dependence studies, duloxetine did not demonstrate dependence-producing potential in rats.

10. OVERDOSAGE

10.1 Signs and Symptoms

In postmarketing experience, fatal outcomes have been reported for acute overdoses, primarily with mixed overdoses, but also with duloxetine only, at doses as low as 1000 mg. Signs and symptoms of overdose (duloxetine alone or with mixed drugs) included somnolence, coma, serotonin syndrome, seizures, syncope, tachycardia, hypotension, hypertension, and vomiting.

10.2 Management of Overdose

There is no specific antidote to duloxetine, but if serotonin syndrome ensues, specific treatment (such as with cyproheptadine and/or temperature control) may be considered. In case of acute overdose, treatment should consist of those general measures employed in the management of overdose with any drug.

An adequate airway, oxygenation, and ventilation should be assured, and cardiac rhythm and vital signs should be monitored. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion or in symptomatic patients.

Activated charcoal may be useful in limiting absorption of duloxetine from the gastrointestinal tract. Administration of activated charcoal has been shown to decrease AUC and C_max by an average of one-third, although some subjects had a limited effect of activated charcoal. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be beneficial.

In managing overdose, the possibility of multiple drug involvement should be considered. A specific caution involves patients who are taking or have recently taken duloxetine and might ingest excessive quantities of a TCA. In such a case, decreased clearance of the parent tricyclic and/or its active metabolite may increase the possibility of clinically significant sequelae and extend the time needed for close medical observation [see WARNINGS AND PRECAUTIONS (5.4) and DRUG INTERACTIONS (7)]. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians' Desk Reference (PDR).

11. DESCRIPTION

Duloxetine delayed-release capsules USP are selective serotonin and norepinephrine reuptake inhibitor (SSNRI) for oral administration. Its chemical designation is (+)-(S)-N-methyl-γ-(1-naphthyloxy)-2-thiophenepropylamine hydrochloride. The empirical formula is C₁₈H₁₉NOS.HCl, which corresponds to a molecular weight of 333.88. The structural formula is: