DULOXETINE- duloxetine_capsule, delayed release

Although the exact mechanisms of the antidepressant, central pain inhibitory and anxiolytic actions of duloxetine in humans are unknown, these actions are believed to be related to its potentiation of serotonergic and noradrenergic activity in the CNS. Preclinical studies have shown that duloxetine is a potent inhibitor of neuronal serotonin and norepinephrine reuptake and a less potent inhibitor of dopamine reuptake. Duloxetine has no significant affinity for dopaminergic, adrenergic, cholinergic, histaminergic, opioid, glutamate, and GABA receptors in vitro 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. Duloxetine has an elimination half-life of about 12 hours (range 8 to 17 hours) and its pharmacokinetics are dose proportional over the therapeutic range. Steady-state plasma concentrations are typically achieved after 3 days of dosing. Elimination of duloxetine is mainly through hepatic metabolism involving two P450 isozymes, CYP1A2 and CYP2D6. Absorption and Distribution Orally administered duloxetine hydrochloride is well absorbed. There is a median 2 hour lag until absorption begins (Tlag), with maximal plasma concentrations (Cmax) of duloxetine occurring 6 hours post dose. Food does not affect the Cmax of duloxetine, but delays the time to reach peak concentration from 6 to 10 hours and it marginally decreases the extent of absorption (AUC) by about 10%. There is a 3 hour delay in absorption and a one-third increase in apparent clearance of duloxetine after an evening dose as compared to a morning dose. The apparent volume of distribution averages about 1640 L. Duloxetine is highly bound (>90%) to proteins in human plasma, binding primarily to albumin and alpha1-acid glycoprotein. The interaction between duloxetine and other highly protein bound drugs has not been fully evaluated. Plasma protein binding of duloxetine is not affected by renal or hepatic impairment. Metabolism and Elimination Biotransformation and disposition of duloxetine in humans have been determined following oral administration of 14C-labeled duloxetine. Duloxetine comprises about 3% of the total radiolabeled material in the plasma, indicating that it undergoes extensive metabolism to numerous metabolites. The major biotransformation pathways for duloxetine involve oxidation of the naphthyl ring followed by conjugation and further oxidation. Both CYP1A2 and CYP2D6 catalyze the oxidation of the naphthyl ring in vitro. Metabolites found in plasma include 4-hydroxy duloxetine glucuronide and 5-hydroxy, 6-methoxy duloxetine sulfate. Many additional metabolites have been identified in urine, some representing only minor pathways of elimination. Only trace (< 1% of the dose) amounts of unchanged duloxetine are present in the urine. Most (about 70%) of the duloxetine dose appears in the urine as metabolites of duloxetine; about 20% is excreted in the feces. Duloxetine undergoes extensive metabolism, but the major circulating metabolites have not been shown to contribute significantly to the pharmacologic activity of duloxetine. Children and Adolescents (ages 7 to 17 years) Duloxetine steady-state plasma concentration was comparable in children (7 to 12 years of age), adolescents (13 to 17 years of age) and adults. The average steady-state duloxetine concentration was approximately 30% lower in the pediatric population (children and adolescents) relative to the adults. The model-predicted duloxetine steady state plasma concentrations in children and adolescents were mostly within the concentration range observed in adult patients and did not exceed the concentration range in adults.

Duloxetine delayed-release capsules are indicated for the treatment of: Major Depressive Disorder [see Clinical Studies ( 14. 1 Generalized Anxiety Disorder [see Clinical Studies ( 14. 2 Diabetic Peripheral Neuropathy [see Clinical Studies ( 14. 3 Chronic Musculoskeletal Pain [see Clinical Studies ( 14. 5 Duloxetine Major Depressive Disorder (MDD) ( 1 Generalized Anxiety Disorder (GAD) ( 1 Diabetic Peripheral Neuropathic Pain (DPNP) ( 1 Chronic Musculoskeletal Pain ( 1.

Swallow duloxetine delayed-release capsules whole. Do not chew or crush. Do not open the capsule and sprinkle its contents on food or mix with liquids. All of these might affect the enteric coating. Duloxetine delayed-release capsules can be given without regard to meals. If a dose of duloxetine is missed, take the missed dose as soon as it is remembered. If it is almost time for the next dose, skip the missed dose and take the next dose at the regular time. Do not take two doses of duloxetine at the same time. Take duloxetine delayed-release capsules once daily, with or without food. Swallow duloxetine delayed-release capsules whole; do not crush or chew, do not open capsule. Take a missed dose as soon as it is remembered. ( 2 Indication Starting Dose Target Dose Maximum Dose MDD (2. 1) 40 mg/day to 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. 2) 60 mg/day 60 mg/day (once daily) 120 mg/day Elderly 30 mg/day 60 mg/day (once daily) 120 mg/day Children and Adolescents (7 to 17 years of age) 30 mg/day 30 to 60 mg/day (once daily) 120 mg/day DPNP (2. 3) 60 mg/day 60 mg/day (once daily) 60 mg/day Chronic Musculoskeletal Pain (2. 5) 30 mg/day 60 mg/day (once daily) 60 mg/day Some patients may benefit from starting at 30 mg once daily ( 2 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 Discontinuing duloxetine delayed-release capsules: Gradually reduce dosage to avoid discontinuation symptoms ( 2. 7 Hepatic Impairment: Avoid use in patients with chronic liver disease or cirrhosis ( 5. 14 Renal Impairment: Avoid use in patients with severe renal impairment, GFR < 30 mL/min ( 5. 14 Administer duloxetine 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. Periodically reassess to determine the need for maintenance treatment and the appropriate dose for such treatment [see Clinical Studies ( 14. 1 Adults For most patients, initiate duloxetine 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, increase dose in increments of 30 mg once daily. The safety of doses above 120 mg once daily has not been adequately evaluated. Periodically reassess to determine the continued need for maintenance treatment and the appropriate dose for such treatment [see Clinical Studies ( 14. 2 Elderly Initiate duloxetine at a dose of 30 mg once daily for 2 weeks before considering an increase to the target dose of 60 mg. Thereafter, patients may benefit from doses above 60 mg once daily. If a decision is made to increase the dose beyond 60 mg once daily, increase dose in increments of 30 mg once daily. The maximum dose studied was 120 mg per day. Safety of doses above 120 mg once daily has not been adequately evaluated [see Clinical Studies ( 14. 2 Children and Adolescents (7 to 17 years of age) Initiate duloxetine at a dose of 30 mg once daily for 2 weeks before considering an increase to 60 mg. The recommended dose range is 30 to 60 mg once daily. Some patients may benefit from doses above 60 mg once daily. The safety of doses above 120 mg once daily has not been evaluated [see Clinical Studies ( 14. 2 Administer duloxetine 60 mg 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 Since diabetes is frequently complicated by renal disease, consider a lower starting dose and gradual increase in dose for patients with renal impairment [see Dosage and Administration ( 2. 3 Administer duloxetine 60 mg once daily. Begin treatment at 30 mg for one week, to allow patients to adjust to the medication before increasing to 60 mg once daily. There is no evidence that higher doses confer additional benefit, even in patients who do not respond to a 60 mg dose, and higher doses are associated with a higher rate of adverse reactions [see Clinical Studies ( 14. 5 Hepatic Impairment Avoid use in patients with chronic liver disease or cirrhosis [see Warnings and Precautions ( 5. 9 Severe Renal Impairment Avoid use in patients with severe renal impairment, GFR < 30 mL/min [see Warnings and Precautions ( 5. 10 Adverse reactions after discontinuation of duloxetine, after abrupt or tapered discontinuation, include: dizziness, headache, nausea, diarrhea, paresthesia, irritability, vomiting, insomnia, anxiety, hyperhidrosis, and fatigue. A gradual reduction in dosage rather than abrupt cessation is recommended whenever possible [see Warnings and Precautions ( 5. 7 At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with duloxetine. Conversely, at least 5 days should be allowed after stopping duloxetine before starting an MAOI intended to treat psychiatric disorders [see Contraindications ( 4 Do not start duloxetine 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 In some cases, a patient already receiving duloxetine 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 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 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 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.

The following serious adverse reactions are described below and elsewhere in the labeling: Suicidal Thoughts and Behaviors in Children, Adolescents and Young Adults [see Boxed Warning and Warnings and Precautions ( 5. 1 Hepatotoxicity [see Warnings and Precautions ( 5. 2 Orthostatic Hypotension, Falls and Syncope [see Warnings and Precautions ( 5. 3 Serotonin Syndrome [see Warnings and Precautions ( 5. 4 Abnormal Bleeding [see Warnings and Precautions ( 5. 5 Severe Skin Reactions [see Warnings and Precautions ( 5. 6 Discontinuation of Treatment with duloxetine [see Warnings and Precautions ( 5. 7 Activation of Mania/Hypomania [see Warnings and Precautions ( 5. 8 Angle-Closure Glaucoma [see Warnings and Precautions ( 5. 9 Seizures [see Warnings and Precautions ( 5. 10 Effect on Blood Pressure [see Warnings and Precautions ( 5. 11 Clinically Important Drug Interactions [see Warnings and Precautions ( 5. 12 Hyponatremia [see Warnings and Precautions ( 5. 13 Urinary Hesitation and Retention [see Warnings and Precautions ( 5. 15 Most common adverse reactions (>=5% and at least twice the incidence of placebo patients): nausea, dry mouth, somnolence, constipation, decreased appetite, and hyperhidrosis ( 6 To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals (USA) Inc. at 1-877-993-8779 or FDA at 1-800-FDA-1088 or www. gov/medwatch. 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. 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. Adults The data described below reflect exposure to duloxetine in placebo-controlled trials for MDD (N=3779), GAD (N=1018), OA (N=503), CLBP (N=600), DPNP (N=906) and another indication (N=1294). The population studied was 17 to 89 years of age; 65. 4% female; and 81. 3%, 74% and 85. 7% Caucasian for MDD, GAD, OA, CLBP, DPNP and another indication, respectively. Most patients received doses of a total of 60 to 120 mg per day [see Clinical Studies ( 14 Children and Adolescents The data described below reflect exposure to duloxetine in pediatric, 10-week, placebo-controlled trials for MDD (N=341) and GAD (N=135). The population studied (N=476) was 7 to 17 years of age with 42. 4% children age 7 to 11 years of age, 50. 6% female, and 68. Patients received 30 to 120 mg per day during placebo-controlled acute treatment studies. Additional data come from the overall total of 822 pediatric patients (age 7 to 17 years of age) with 41. 7% children age 7 to 11 years of age and 51. 8% female exposed to duloxetine in MDD and GAD clinical trials up to 36-weeks in length, in which most patients received 30 to 120 mg per day. Adverse Reactions Reported as Reasons for Discontinuation of Treatment in Adult Placebo-Controlled Trials Major Depressive Disorder Approximately 8. 4% (319/3779) of the patients who received duloxetine in placebo-controlled trials for MDD discontinued treatment due to an adverse reaction, compared with 4. 6% (117/2536) of the patients receiving placebo. Nausea (duloxetine 1. 1%, placebo 0. 4%) was the only common adverse reaction reported as a reason for discontinuation and considered to be drug-related (i. , discontinuation occurring in at least 1% of the duloxetine-treated patients and at a rate of at least twice that of placebo). Generalized Anxiety Disorder Approximately 13. 7% (139/1018) of the patients who received duloxetine in placebo-controlled trials for GAD discontinued treatment due to an adverse reaction, compared with 5% (38/767) for placebo. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine 3. 3%, placebo 0. 4%), and dizziness (duloxetine 1. 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. 5%, placebo 0. 7%), dizziness (duloxetine 1. 2%, placebo 0. 4%), and somnolence (duloxetine 1. 1%, placebo 0%). Chronic Pain due to Osteoarthritis Approximately 15. 7% (79/503) of the patients who received duloxetine in 13-week, placebo-controlled trials for chronic pain due to OA discontinued treatment due to an adverse reaction, compared with 7. 3% (37/508) for placebo. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine 2. 2%, placebo 1%). Chronic Low Back Pain Approximately 16. 5% (99/600) of the patients who received duloxetine in 13-week, placebo-controlled trials for CLBP discontinued treatment due to an adverse reaction, compared with 6. 3% (28/441) for placebo. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine 3%, placebo 0. 7%), and somnolence (duloxetine 1%, placebo 0%). Most Common Adult Adverse Reactions 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, constipation, dry mouth, insomnia, somnolence and dizziness. 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. Adverse Reactions Occurring at an Incidence of 5% or More Among Duloxetine-Treated Patients in Adult 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. Table 2 Treatment-Emergent Adverse Reactions: Incidence of 5% or More and Greater than Placebo in Placebo-Controlled Trials of Approved Indications a a b c d e f Adverse Reaction Percentage of Patients Reporting Reaction Duloxetine (N=8100) Placebo (N=5655) Nausea c 23 8 Headache 14 12 Dry mouth 13 5 Somnolence e 10 3 Fatigue b,c 9 5 Insomnia d 9 5 Constipation c 9 4 Dizziness c 9 5 Diarrhea 9 6 Decreased appetite c 7 2 Hyperhidrosis c 6 1 Abdominal pain f 5 4 Adverse Reactions Occurring at an Incidence of 2% or More Among Duloxetine-Treated Patients in Adult 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. Table 3 Treatment-Emergent Adverse Reactions: Incidence of 2% or More and Greater than Placebo in MDD and GAD Placebo-Controlled Trials a,b a b c d e f g h i j System Organ Class / Adverse Reaction Percentage of Patients Reporting Reaction Duloxetine (N=4797) Placebo (N=3303) Cardiac Disorders Palpitations 2 2 Eye Disorders Vision blurred 3 1 Gastrointestinal Disorders Nausea c 23 8 Dry mouth 14 6 Constipation c 9 4 Diarrhea 9 6 Abdominal pain d 5 4 Vomiting 4 2 General Disorders and Administration Site Conditions Fatigue e 9 5 Metabolism and Nutrition Disorders Decreased appetite c 6 2 Nervous System Disorders Headache 14 14 Dizziness c 9 5 Somnolence f 9 3 Tremor 3 1 Psychiatric Disorders Insomnia g 9 5 Agitation h 4 2 Anxiety 3 2 Reproductive System and Breast Disorders Erectile dysfunction 4 1 Ejaculation delayed c 2 1 Libido decreased i 3 1 Orgasm abnormal j 2 <1 Respiratory, Thoracic, and Mediastinal Disorders Yawning 2 <1 Skin and Subcutaneous Tissue Disorders Hyperhidrosis 6 2 DPNP, another indication, 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, another indication, OA, and CLBP placebo-controlled trials and with an incidence greater than placebo. Table 4 Treatment-Emergent Adverse Reactions: Incidence of 2% or More and Greater than Placebo in DPNP, Another indication, OA, and CLBP Placebo-Controlled Trials a a b c gastrointestinal pain d e f g h i j k l System Organ Class / Adverse Reaction Percentage of Patients Reporting Reaction Duloxetine (N=3303) Placebo (N=2352) Gastrointestinal Disorders b b c 23 7 General Disorders and Administration Site Conditions d 11 5 Infections and Infestations 4 4 Metabolism and Nutrition Disorders b 8 1 Musculoskeletal and Connective Tissue e 3 3 Nervous System Disorders b,f g b 13 8 Psychiatric Disorders b,h i 10 5 Reproductive System and Breast Disorders b j 4 <1 Respiratory, Thoracic, and Mediastinal Disorders 2 2 Skin and Subcutaneous Tissue Disorders 6 1 Vascular Disorders k l 3 1 Effects on Male and Female Sexual Function in Adults 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. Table 5 Mean Change in ASEX Scores by Gender in MDD Placebo-Controlled Trials a b c Male Patients a Female Patients a Duloxetine (n=175) Placebo (n=83) Duloxetine (n=241) Placebo (n=126) ASEX Total (Items 1 to 5) 0. 07 Vital Sign Changes in Adults In placebo-controlled clinical trials across approved indications for change from baseline to endpoint, duloxetine treatment was associated with mean increases of 0. 23 mm Hg in systolic blood pressure and 0. 73 mm Hg in diastolic blood pressure compared to mean decreases of 1. 09 mm Hg systolic and 0. 55 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. 11 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. 37 beats per minute (increase of 1. 20 beats per minute in duloxetine-treated patients, decrease of 0. 17 beats per minute in placebo-treated patients). Laboratory Changes in Adults 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 Electrocardiogram Changes in Adults 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. Other Adverse Reactions Observed During the Premarketing and Postmarketing Clinical Trial Evaluation of Duloxetine in Adults Following is a list of treatment-emergent adverse reactions reported by patients treated with duloxetine in clinical trials. In clinical trials of all indications, 34,756 patients were treated with duloxetine. Of these, 26. 9% (9337) took duloxetine for at least 6 months, and 12. 4% (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: Infrequent: Ear and Labyrinth Disorders Frequent: Infrequent: Endocrine Disorders Infrequent: Eye Disorders Frequent: Infrequent: Gastrointestinal Disorders Frequent: Infrequent: Rare: General Disorders and Administration Site Conditions Frequent: Infrequent: , Rare: Infections and Infestations Infrequent: Investigations Frequent: Infrequent: Metabolism and Nutrition Disorders Infrequent: Rare: Musculoskeletal and Connective Tissue Disorders Frequent: Infrequent: Nervous System Disorders Frequent: Infrequent: Rare: Psychiatric Disorders Frequent: Infrequent: Rare: Renal and Urinary Disorders Frequent: Infrequent: Reproductive System and Breast Disorders Frequent: Infrequent: Rare: Respiratory, Thoracic and Mediastinal Disorders Frequent: Infrequent: Skin and Subcutaneous Tissue Disorders Frequent: Infrequent: Rare: Vascular Disorders Frequent: Infrequent: Adverse Reactions Observed in Children and Adolescent Placebo-Controlled Clinical Trials The adverse drug reaction profile observed in pediatric clinical trials (children and adolescents) was consistent with the adverse drug reaction profile observed in adult clinical trials. The specific adverse drug reactions observed in adult patients can be expected to be observed in pediatric patients (children and adolescents) [see Adverse Reactions ( 6 Table 6 provides the incidence of treatment-emergent adverse reactions in MDD and GAD pediatric placebo-controlled trials that occurred in greater than 2% of patients treated with duloxetine and with an incidence greater than placebo. Table 6 Treatment-Emergent Adverse Reactions: Incidence of 2% or More and Greater than Placebo in three 10- week Pediatric Placebo-Controlled Trials a a b c d (N=467 duloxetine; N=354 Placebo). e f System Organ Class/Adverse Reaction Percentage of Pediatric Patients Reporting Reaction Duloxetine (N=476) Placebo (N=362) Gastrointestinal Disorders b 18 8 General Disorders and Administration Site Conditions c 7 5 Investigations d 14 6 Metabolism and Nutrition Disorders 10 5 Nervous System Disorders e 18 13 Psychiatric Disorders f 7 4 Respiratory, Thoracic, and Mediastinal Disorders 4 2 Other adverse reactions that occurred at an incidence of less than 2% but were reported by more duloxetine treated patients than placebo treated patients and are associated duloxetine treatment: abnormal dreams (including nightmare), anxiety, flushing (including hot flush), hyperhidrosis, palpitations, pulse increased, and tremor. Discontinuation-emergent symptoms have been reported when stopping duloxetine. The most commonly reported symptoms following discontinuation of duloxetine in pediatric clinical trials have included headache, dizziness, insomnia, and abdominal pain [see Warnings and Precautions ( 5. 2 Growth (Height and Weight) Decreased appetite and weight loss have been observed in association with the use of SSRIs and SNRIs. Pediatric patients treated with duloxetine in clinical trials experienced a 0. 1kg mean decrease in weight at 10 weeks, compared with a mean weight gain of approximately 0. 9 kg in placebo-treated patients. The proportion of patients who experienced a clinically significant decrease in weight (>=3. 5%) was greater in the duloxetine group than in the placebo group (14% and 6%, respectively). Subsequently, over the 4- to 6-month uncontrolled extension periods, duloxetine-treated patients on average trended toward recovery to their expected baseline weight percentile based on population data from age- and sex-matched peers. In studies up to 9 months, duloxetine-treated pediatric patients experienced an increase in height of 1. 7 cm on average (2. 2 cm increase in children [7 to 11 years of age] and 1. 3 cm increase in adolescents [12 to 17 years of age]). While height increase was observed during these studies, a mean decrease of 1% in height percentile was observed (decrease of 2% in children [7 to 11 years of age] and increase of 0. 3% in adolescents [12 to 17 years of age]). Weight and height should be monitored regularly in children and adolescents treated with duloxetine. The following adverse reactions have been identified during post approval 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: acute pancreatitis, anaphylactic reaction, aggression and anger (particularly early in treatment or after treatment discontinuation), angioneurotic edema, angle-closure glaucoma, colitis (microscopic or unspecified), cutaneous vasculitis (sometimes associated with systemic involvement), extrapyramidal disorder, galactorrhea, 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.

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. 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. 9 Warnings and Precautions ( 5. 4 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.

Pregnancy: Third trimester use may increase risk for symptoms of poor adaptation (respiratory distress, temperature instability, feeding difficulty, hypotonia, tremor, irritability) in the neonate ( 8. 1 Pregnancy: Third trimester use may increase risk for symptoms of poor adaptation (respiratory distress, temperature instability, feeding difficulty, hypotonia, tremor, irritability) in the neonate ( 8. 1 Risk Summary Data from a postmarketing retrospective cohort study indicate that use of duloxetine in the month before delivery may be associated with an increased risk of postpartum hemorrhage. Data from published literature and from a postmarketing retrospective cohort study have not identified a clear drug-associated risk of major birth defects or other adverse developmental outcomes (see Data) (see Clinical Considerations) In rats and rabbits treated with duloxetine during the period of organogenesis, fetal weights were decreased but there was no evidence of developmental effects at doses up to 3 and 6 times, respectively, the maximum recommended human dose (MRHD) of 120 mg/day given to adolescents on a mg/m 2 2 The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-associated Maternal and/or Embryo/Fetal Risk Women who discontinue antidepressants during pregnancy are more likely to experience a relapse of major depression than women who continue antidepressants. This finding is from a prospective, longitudinal study that followed 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants at the beginning of pregnancy. Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum. Maternal Adverse Reactions Use of duloxetine in the month before delivery may be associated with an increased risk of postpartum hemorrhage [see Warnings and Precautions ( 5. 5 Fetal/Neonatal Adverse Reaction Neonates exposed to duloxetine and other SNRIs or SSRIs 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 findings are consistent with either a direct toxic effect of the SNRIs or SSRIs, 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 Data Human Data Data from a postmarketing retrospective claims-based cohort study found an increased risk for postpartum hemorrhage among 955 pregnant women exposed to duloxetine in the last month of pregnancy compared to 4,128,460 unexposed pregnant women (adjusted relative risk: 1. 53; 95% CI: 1. The same study did not find a clinically meaningful increase in the risk for major birth defects in the comparison of 2,532 women exposed to duloxetine in the first trimester of pregnancy to 1,284,827 unexposed women after adjusting for several confounders. Methodologic limitations include possible residual confounding, misclassification of exposure and outcomes, lack of direct measures of disease severity, and lack of information about alcohol use, nutrition, and over-the-counter medication exposures. Animal Data 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 malformations or developmental variations at doses up to 45 mg/kg/day [3 and 6 times, respectively, the MRHD of 120 mg/day given to adolescents on a mg/m 2 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 (2 times the MRHD given to adolescents on a mg/m 2 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. Risk Summary Data from published literature report the presence of duloxetine in human milk (see Data) (see Clinical Considerations) The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for duloxetine and any potential adverse effects on the breastfed child from duloxetine or from the underlying maternal condition. Clinical Considerations Infants exposed to duloxetine should be monitored for sedation, poor feeding and poor weight gain. Data Disposition of duloxetine was studied in 6 lactating women who were at least 12 weeks postpartum and had elected to wean their infants. The women were given 40 mg of duloxetine twice daily for 3. The peak concentration measured in breast milk occurred at a median of 3 hours after the dose. The amount of duloxetine in breast milk was approximately 7 mcg/day while on that dose; the estimated daily infant dose was approximately 2 mcg/kg/day, which is less than 1% of the maternal dose. The presence of duloxetine metabolites in breast milk was not examined. Generalized Anxiety Disorder In pediatric patients aged 7 to 17 years, efficacy was demonstrated in one 10-week, placebo-controlled trial. The study included 272 pediatric patients with GAD of which 47% were 7 to 11 years of age. Duloxetine demonstrated superiority over placebo as measured by greater improvement in the Pediatric Anxiety Rating Scale (PARS) for GAD severity score [see Clinical Studies ( 14. 2 Major Depressive Disorder Efficacy was not demonstrated in two 10-week, placebo-controlled trials with 800 pediatric patients with MDD, age 7 to 17. Neither duloxetine nor an active control (indicated for treatment of pediatric depression) was superior to placebo. The safety and effectiveness in pediatric patients less than 7 years of age have not been established. The most frequently observed adverse reactions in the clinical trials included nausea, headache, decreased weight, and abdominal pain. 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 [see Adverse Reactions ( 6 Use of duloxetine in a child or adolescent must balance the potential risks with the clinical need [see Boxed Warning and Warnings and Precautions ( 5. 1 Animal Data 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 (2 times the MRHD, for a child); the no-effect-level was 20 mg/kg/day (approximately1 times the MRHD, for a child). 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 1041 patients in CLBP premarketing studies, 21. 2% (221) were 65 years of age or over. Of the 487 patients in OA premarketing studies, 40. 5% (197) 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. In the MDD, GAD, DPNP, OA, CLBP and other studies, no overall differences in safety or effectiveness were generally 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. 13 In an analysis of data from all placebo-controlled-trials, patients treated with duloxetine reported a higher rate of falls compared to patients treated with placebo. The increased risk appears to be proportional to a patient's underlying risk for falls. Underlying risk appears to increase steadily with age. As elderly patients tend to have a higher prevalence of risk factors for falls such as medications, medical comorbidities and gait disturbances, the impact of increasing age by itself on falls during treatment with duloxetine is unclear. Falls with serious consequences including bone fractures and hospitalizations have been reported [see Warnings and Precautions ( 5. 3 6 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 Duloxetine's half-life is similar in men and women. Dosage adjustment based on gender is not necessary. Duloxetine bioavailability (AUC) appears to be reduced by about one-third in smokers. Dosage modifications are not recommended for smokers. No specific pharmacokinetic study was conducted to investigate the effects of race. Patients with clinically evident hepatic impairment 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 [see Dosage and Administration ( 2. 14 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, C max [see Dosage and Administration ( 2.

RECENT MAJOR CHANGES
Warnings and Precautions ( 5.5 10/2019
DRUG INTERACTIONS
Both CYP1A2 and CYP2D6 are responsible for duloxetine metabolism. 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 When duloxetine 60 mg was coadministered with fluvoxamine 100 mg, a potent CYP1A2 inhibitor, to male subjects (n=14) duloxetine AUC was increased approximately 6-fold, the C max 1/2 [see Warnings and Precautions ( 5. 12 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. , fluoxetine, quinidine) [see Warnings and Precautions ( 5. 12 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 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 coadministered 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. The total warfarin (protein bound plus free drug) pharmacokinetics (AUC tau,ss max,ss max,ss [see Warnings and Precautions ( 5. 5 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 coadministration. Under steady-state conditions for duloxetine (20 mg qhs) and temazepam (30 mg qhs), the pharmacokinetics of duloxetine were not affected by coadministration. Duloxetine has an enteric coating that resists dissolution until reaching a segment of the gastrointestinal tract where the pH exceeds 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. , 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. 14 In vitro in vitro 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. 12 Results of in vitro [see Drug Interactions ( 7. 4 Results of in vitro Results of in vitro [See Dosage and Administration ( 2. 4 [See Dosage and Administration ( 2. 4 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. 12 [See Warnings and Precautions ( 5. 12 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, coadministration 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.

OVERDOSAGE
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. 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 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 7 Physicians'' Desk Reference.
NONCLINICAL TOXICOLOGY
Carcinogenesis Duloxetine was administered in the diet to mice and rats for 2 years. In female mice receiving duloxetine at 140 mg/kg/day (3 times the maximum recommended human dose (MRHD) of 120 mg/day given to children on a mg/m 2 In rats, dietary doses of duloxetine up to 27 mg/kg/day in females (1 time the MRHD given to children) and up to 36 mg/kg/day in males (1.4 times the MRHD given to children) did not increase the incidence of tumors. Mutagenesis Duloxetine was not mutagenic in the in vitro in vivo in vitro in vitro in vivo Impairment of Fertility Duloxetine administered orally to either male or female rats prior to and throughout mating at doses up to 45 mg/kg/day (3 times the MRHD given to adolescents on a mg/m 2
CLINICAL STUDIES
The efficacy of duloxetine has been established in the following adequate and well-controlled trials: Major Depressive Disorder (MDD): 4 short-term and 1 maintenance trial in adults [see Clinical Studies ( 14. 1 Generalized Anxiety Disorder (GAD): 3 short-term trials in adults, 1 maintenance trial in adults and 1 short-term trial in children and adolescents [see Clinical Studies ( 14. 2 Diabetic Peripheral Neuropathic Pain (DPNP): Two 12-week trials in adults [see Clinical Studies ( 14. 3 Chronic Musculoskeletal Pain: Two 12- to 13-week trials in adult patients with chronic low back pain (CLBP) and one 13-week trial in adult patients with chronic pain due to osteoarthritis [see Clinical Studies ( 14. 5 The efficacy of duloxetine as a treatment for depression was established in 4 randomized, double-blind, placebo-controlled, fixed-dose studies in adult outpatients (18 to 83 years) meeting DSM-IV criteria for major depression. In 2 studies, patients were randomized to duloxetine 60 mg once daily (N=123 and N=128, respectively) or placebo (N=122 and N=139, respectively) for 9 weeks; in the third study, patients were randomized to duloxetine 20 or 40 mg twice daily (N=86 and N=91, respectively) or placebo (N=89) for 8 weeks; in the fourth study, patients were randomized to duloxetine 40 or 60 mg twice daily (N=95 and N=93, respectively) or placebo (N=93) for 8 weeks. There is no evidence that doses greater than 60 mg/day confer additional benefits. In all 4 studies, duloxetine demonstrated superiority over placebo as measured by improvement in the 17-item Hamilton Depression Rating Scale (HAMD-17) total score (Studies 1 to 4 in Table 7). In all of these clinical studies, analyses of the relationship between treatment outcome and age, gender, and race did not suggest any differential responsiveness on the basis of these patient characteristics. Table 7 Summary of the Primary Efficacy Results for Studies in Major Depressive Disorder SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval, not adjusted for multiplicity in trials where multiple dose groups were included. a b Study Number Treatment Group Primary Efficacy Measure: HAMD-17 Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo-subtracted Difference a Study 1 Duloxetine (60 mg/day) b 21. 9) Study 2 Duloxetine (60 mg/day) b 20. 3) Study 3 Duloxetine (20 mg BID) b b 18. 2) Study 4 Duloxetine (40 mg BID) b b 19. 9) In another study, 533 patients meeting DSM-IV criteria for MDD received duloxetine 60 mg once daily during an initial 12-week open-label treatment phase. Two hundred and seventy-eight patients who responded to open label treatment (defined as meeting the following criteria at weeks 10 and 12: a HAMD-17 total score <=9, Clinical Global Impressions of Severity (CGI-S) <=2, and not meeting the DSM-IV criteria for MDD) were randomly assigned to continuation of duloxetine at the same dose (N=136) or to placebo (N=142) for 6 months. Patients on duloxetine experienced a statistically significantly longer time to relapse of depression than did patients on placebo (Study 5 in Figure 1). Relapse was defined as an increase in the CGI-S score of >=2 points compared with that obtained at week 12, as well as meeting the DSM-IV criteria for MDD at 2 consecutive visits at least 2 weeks apart, where the 2-week temporal criterion had to be satisfied at only the second visit. The effectiveness of duloxetine in hospitalized patients with major depressive disorder has not been studied. Figure 1 Kaplan-Meier Estimation of Cumulative Proportion of Patients with Relapse (MDD Study 5) The efficacy of duloxetine in the treatment of generalized anxiety disorder (GAD) was established in 1 fixed-dose randomized, double-blind, placebo-controlled trial and 2 flexible-dose randomized, double-blind, placebo-controlled trials in adult outpatients between 18 and 83 years of age meeting the DSM-IV criteria for GAD. In 1 flexible-dose study and in the fixed-dose study, the starting dose was 60 mg once daily where down titration to 30 mg once daily was allowed for tolerability reasons before increasing it to 60 mg once daily. Fifteen percent of patients were down titrated. One flexible-dose study had a starting dose of 30 mg once daily for 1 week before increasing it to 60 mg once daily. The 2 flexible-dose studies involved dose titration with duloxetine doses ranging from 60 mg once daily to 120 mg once daily (N=168 and N=162) compared to placebo (N=159 and N=161) over a 10-week treatment period. The mean dose for completers at endpoint in the flexible-dose studies was 104. The fixed-dose study evaluated duloxetine doses of 60 mg once daily (N=168) and 120 mg once daily (N=170) compared to placebo (N=175) over a 9 week treatment period. While a 120 mg/day dose was shown to be effective, there is no evidence that doses greater than 60 mg/day confer additional benefit. In all 3 studies, duloxetine demonstrated superiority over placebo as measured by greater improvement in the Hamilton Anxiety Scale (HAM-A) total score (Studies 1 to 3 in Table 8) and by the Sheehan Disability Scale (SDS) global functional impairment score. The SDS is a composite measurement of the extent emotional symptoms disrupt patient functioning in 3 life domains: work/school, social life/leisure activities, and family life/home responsibilities. In another study, 887 patients meeting DSM-IV-TR criteria for GAD received duloxetine 60 mg to 120 mg once daily during an initial 26-week open-label treatment phase. Four hundred and twenty-nine patients who responded to open-label treatment (defined as meeting the following criteria at weeks 24 and 26: a decrease from baseline HAM-A total score by at least 50% to a score no higher than 11, and a Clinical Global Impressions of Improvement [CGI-Improvement] score of 1 or 2) were randomly assigned to continuation of duloxetine at the same dose (N=216) or to placebo (N=213) and were observed for relapse. Of the patients randomized, 73% had been in a responder status for at least 10 weeks. Relapse was defined as an increase in CGI-Severity score at least 2 points to a score >=4 and a MINI (Mini-International Neuropsychiatric Interview) diagnosis of GAD (excluding duration), or discontinuation due to lack of efficacy. Patients taking duloxetine experienced a statistically significantly longer time to relapse of GAD than did patients taking placebo (Study 4 in Figure 2). Subgroup analyses did not indicate that there were any differences in treatment outcomes as a function of age or gender. The efficacy of duloxetine in the treatment of patients >=65 years of age with generalized anxiety disorder was established in one 10-week flexible-dose, randomized, double-blind, placebo-controlled trial in adults >=65 years of age meeting the DSM-IV criteria for GAD. In this study, the starting dose was 30 mg once daily for 2 weeks before further dose increases in 30 mg increments at treatment weeks 2, 4, and 7 up to 120 mg once daily were allowed based on investigator judgment of clinical response and tolerability. The mean dose for patients completing the 10-week acute treatment phase was 50. Patients treated with duloxetine (N=151) demonstrated significantly greater improvement compared with placebo (N=140) on mean change from baseline to endpoint as measured by the Hamilton Anxiety Rating Scale total score (Study 5 in Table 8). The efficacy of duloxetine in the treatment of pediatric patients 7 to 17 years of age with generalized anxiety disorder (GAD) was established in 1 flexible-dose randomized, double-blind, placebo-controlled trial in pediatric outpatients with GAD (based on DSM-IV criteria). In this study, the starting dose was 30 mg once daily for 2 weeks. Further dose increases in 30 mg increments up to 120 mg once daily were allowed based on investigator judgment of clinical response and tolerability. The mean dose for patients completing the 10-week treatment phase was 57. In this study, duloxetine (N=135) demonstrated superiority over placebo (N=137) from baseline to endpoint as measured by greater improvement in the Pediatric Anxiety Rating Scale (PARS) for GAD severity score (Study 6 in Table 8). Table 8 Summary of the Primary Efficacy Results for Studies in General Anxiety Disorder SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: confidence interval, not adjusted for multiplicity in trials where multiple dose groups were included. a b Study Number Treatment Group Primary Efficacy Measure Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo-subtracted Difference a Study 1 Duloxetine (60 mg/day) b 25. 5) Duloxetine (120 mg/day) b 25. 3) Placebo 25. 67) -- Study 2 Duloxetine (60 to 120 mg/day) b 22. 3) Placebo 23. 70) -- Study 3 Duloxetine (60 to 120 mg/day) b 25. 7) Placebo 25 (5. 67) -- Study 5 Duloxetine (60 to 120 mg/day) b 24. 5) Placebo 24. 67) -- Study 6 (Pediatric) (PARS for GAD) Duloxetine (30 to 120 mg/day) b 17. 3) Placebo 17. 50) -- Figure 2 Kaplan-Meier Estimation of Cumulative Proportion of Patients with Relapse (GAD Study 4) The efficacy of duloxetine for the management of neuropathic pain associated with diabetic peripheral neuropathy was established in 2 randomized, 12-week, double-blind, placebo-controlled, fixed-dose studies in adult patients having diabetic peripheral neuropathic pain for at least 6 months. Study DPNP-1 and Study DPNP-2 enrolled a total of 791 patients of whom 592 (75%) completed the studies. Patients enrolled had Type I or II diabetes mellitus with a diagnosis of painful distal symmetrical sensorimotor polyneuropathy for at least 6 months. The patients had a baseline pain score of >=4 on an 11-point scale ranging from 0 (no pain) to 10 (worst possible pain). Patients were permitted up to 4 g of acetaminophen per day as needed for pain, in addition to duloxetine. Patients recorded their pain daily in a diary. Both studies compared duloxetine 60 mg once daily or 60 mg twice daily with placebo. DPNP-1 additionally compared duloxetine 20 mg with placebo. A total of 457 patients (342 duloxetine, 115 placebo) were enrolled in DPNP-1 and a total of 334 patients (226 duloxetine, 108 placebo) were enrolled in DPNP-2. Treatment with duloxetine 60 mg one or two times a day statistically significantly improved the endpoint mean pain scores from baseline and increased the proportion of patients with at least a 50% reduction in pain scores from baseline. For various degrees of improvement in pain from baseline to study endpoint, Figures 3 and 4 show the fraction of patients achieving that degree of improvement. The figures are cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%. Patients who did not complete the study were assigned 0% improvement. Some patients experienced a decrease in pain as early as week 1, which persisted throughout the study. Figure 3 Percentage of Patients Achieving Various Levels of Pain Relief as Measured by 24-Hour Average Pain Severity - DPNP-1 DLX=Duloxetine Figure 4 Percentage of Patients Achieving Various Levels of Pain Relief as Measured by 24-Hour Average Pain Severity - DPNP-2 DLX=Duloxetine Duloxetine is indicated for the management of chronic musculoskeletal pain. This has been established in studies in patients with chronic low back pain and chronic pain due to osteoarthritis. Studies in Chronic Low Back Pain The efficacy of duloxetine in chronic low back pain (CLBP) was assessed in two double-blind, placebo-controlled, randomized clinical trials of 13-weeks duration (Study CLBP-1 and Study CLBP-2), and one of 12-weeks duration (CLBP-3). CLBP-1 and CLBP-3 demonstrated efficacy of duloxetine in the treatment of chronic low back pain. Patients in all studies had no signs of radiculopathy or spinal stenosis. Study CLBP-1: Two hundred thirty-six adult patients (N=115 on duloxetine, N=121 on placebo) enrolled and 182 (77%) completed 13-week treatment phase. After 7 weeks of treatment, duloxetine patients with less than 30% reduction in average daily pain and who were able to tolerate duloxetine 60 mg once daily had their dose of duloxetine, in a double-blinded fashion, increased to 120 mg once daily for the remainder of the study. Patients had a mean baseline pain rating of 6 on a numerical rating scale ranging from 0 (no pain) to 10 (worst possible pain). After 13 weeks of treatment, patients taking duloxetine 60 to 120 mg daily had a significantly greater pain reduction compared to placebo. Randomization was stratified by the patients'' baseline NSAIDs-use status. Subgroup analyses did not indicate that there were differences in treatment outcomes as a function of NSAIDs use. Study CLBP-2: Four hundred and four patients were randomized to receive fixed doses of duloxetine daily or a matching placebo (N=59 on duloxetine 20 mg, N=116 on duloxetine 60 mg, N=112 on duloxetine 120 mg, N=117 on placebo) and 267 (66%) completed the entire 13-week study. After 13 weeks of treatment, none of the three duloxetine doses showed a statistically significant difference in pain reduction compared to placebo. Study CLBP-3: Four hundred and one patients were randomized to receive fixed doses of duloxetine 60 mg daily or placebo (N=198 on duloxetine, N=203 on placebo), and 303 (76%) completed the study. After 12 weeks of treatment, patients taking duloxetine 60 mg daily had significantly greater pain reduction compared to placebo. For various degrees of improvement in pain from baseline to study endpoint, Figures 7 and 8 show the fraction of patients in CLBP-1 and CLBP-3 achieving that degree of improvement. Patients who did not complete the study were assigned the value of 0% improvement. Figure 7 Percentage of Patients Achieving Various Levels of Pain Relief as Measured by 24-Hour Average Pain Severity en dash CLBP-1 DLX=Duloxetine Figure 8 Percentage of Patients Achieving Various Levels of Pain Relief as Measured by 24-Hour Average Pain Severity en dash CLBP-3 DLX=Duloxetine Studies in Chronic Pain Due to Osteoarthritis The efficacy of duloxetine in chronic pain due to osteoarthritis was assessed in 2 double-blind, placebo-controlled, randomized clinical trials of 13-weeks duration (Study OA-1 and Study OA-2). All patients in both studies fulfilled the ACR clinical and radiographic criteria for classification of idiopathic osteoarthritis of the knee. Patients assigned to duloxetine started treatment in both studies at a dose of 30 mg once daily for one week. After the first week, the dose of duloxetine was increased to 60 mg once daily. After 7 weeks of treatment with duloxetine 60 mg once daily, in OA-1 patients with sub-optimal response to treatment (< 30% pain reduction) and tolerated duloxetine 60 mg once daily had their dose increased to 120 mg. However, in OA-2, all patients, regardless of their response to treatment after 7 weeks, were re-randomized to either continue receiving duloxetine 60 mg once daily or have their dose increased to 120 mg once daily for the remainder of the study. Patients in the placebo treatment groups in both studies received a matching placebo for the entire duration of studies. For both studies, efficacy analyses were conducted using 13-week data from the combined duloxetine 60 mg and 120 mg once daily treatment groups compared to the placebo group. Study OA-1 Study OA-2 In Study OA-1, for various degrees of improvement in pain from baseline to study endpoint, Figure 7 shows the fraction of patients achieving that degree of improvement. The figure is cumulative, so that patients whose change from baseline is, for example, 50%, are also included at every level of improvement below 50%. Figure 9 Percentage of Patients Achieving Various Levels of Pain Relief as Measured by 24-Hour Average Pain Severity en dash OA-1 DLX=Duloxetine Image Image Image Image Image Image Image.

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