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. [see Warnings and Precautions ( 5. 15 Cardiac Electrophysiology The effect of duloxetine 160 mg and 200 mg administered twice daily (2. 7 times and 3. 3 times the maximum recommended dosage, respectively) to steady state was evaluated in a randomized, double-blinded, two-way crossover study in 117 healthy female adult subjects. No QT interval prolongation was detected. Duloxetine appears to be associated with concentration-dependent but not clinically meaningful QT shortening. Duloxetine has an elimination half-life of about 12 hours (range 8 hours 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 After oral duloxetine administration, duloxetine hydrochloride is well absorbed. There is a median 2 hours lag until absorption begins (T lag max Effect of Food: max Distribution The apparent volume of distribution averages about 1640 L. Duloxetine is highly bound (greater than 90%) to proteins in human plasma, binding primarily to albumin and alpha 1 Elimination Metabolism Biotransformation and disposition of duloxetine in humans have been determined following oral administration of 14 in vitro Excretion Many additional metabolites have been identified in urine, some representing only minor pathways of elimination. Only trace (less than 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. Specific Populations Pediatric Patients Duloxetine steady-state plasma concentration was comparable in pediatric patients 7 years to 17 years of age and adult patients. The average steady-state duloxetine concentration was approximately 30% lower in this pediatric population relative to adult patients. The model-predicted duloxetine steady state plasma concentrations in pediatric patients 7 years to 17 years of age 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 in adults Generalized anxiety disorder in adults and pediatric patients 7 years of age and older Diabetic peripheral neuropathic pain in adults Fibromyalgia in adults and pediatric patients 13 years of age and older Chronic musculoskeletal pain in adults Duloxetine delayed-release capsules are a serotonin and norepinephrine reuptake inhibitor (SNRI) indicated for the treatment of the following conditions: Major depressive disorder (MDD) in adults ( 1 Generalized anxiety disorder (GAD) in adults and pediatric patients 7 years of age and older ( 1 Diabetic peripheral neuropathic pain (DPNP) in adults ( 1 Fibromyalgia (FM) in adults and pediatric patients 13 years of age and older ( 1 Chronic musculoskeletal pain in adults ( 1.

Take duloxetine delayed-release capsules once daily, with or without food. Swallow whole; do not crush, chew, or open capsule ( 2. 1 Indication Starting Dose Target Dose Maximum Dose MDD ( 2. 2 40 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. 3 Adults 60 mg/day 60 mg/day (once daily) 120 mg/day Geriatric 30 mg/day 60 mg/day (once daily) 120 mg/day Pediatrics (7 years to 17 years of age) 30 mg/day 30 to 60 mg/day (once daily) 120 mg/day DPNP ( 2. 4 60 mg/day 60 mg/day (once daily) 60 mg/day FM ( 2. 5 30 mg/day 60 mg/day (once daily) 60 mg/day Chronic Musculoskeletal Pain ( 2. 6 30 mg/day 60 mg/day (once daily) 60 mg/day Discontinuing duloxetine delayed-release capsules: Gradually reduce dosage to avoid discontinuation symptoms ( 2. 7 Administer duloxetine delayed-release capsules orally (with or without meals) and swallow whole. Do not chew or crush, and do not open the delayed-release capsule and sprinkle its contents on food or mix with liquids because these actions might affect the enteric coating. If a dose of duloxetine delayed-release capsules 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 delayed-release capsules at the same time. The recommended starting dosage in adults with MDD is 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 duloxetine delayed-release capsules 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. Periodically reassess to determine the need for maintenance treatment and the appropriate dosage for such treatment. Recommended Dosage in Adults Less than 65 Years of Age For most adults less than 65 years of age with GAD, initiate duloxetine delayed-release capsules 60 mg once daily. While a 120 mg once daily dosage 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 dosage beyond 60 mg once daily, increase dosage in increments of 30 mg once daily. Periodically reassess to determine the continued need for maintenance treatment and the appropriate dosage for such treatment. Recommended Dosage in Geriatric Patients In geriatric patients with GAD, initiate duloxetine delayed-release capsules at a dosage of 30 mg once daily for 2 weeks before considering an increase to the target dose of 60 mg/day. 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. Recommended Dosage in Pediatric Patients 7 Years to 17 Years of Age Initiate duloxetine delayed-release capsules in pediatric patients 7 years to 17 years of age with GAD at a dosage of 30 mg once daily for 2 weeks before considering an increase to 60 mg once daily. The recommended dosages range is 30 mg to 60 mg once daily. Some patients may benefit from dosages above 60 mg once daily. If a decision is made to increase the dose beyond 60 mg once daily, increase dosage in increments of 30 mg once daily. Administer 60 mg once daily in adults with diabetic peripheral neuropathic pain. There is no evidence that doses higher than 60 mg once daily confer additional significant benefit and the higher dosage is clearly less well tolerated. Since diabetes is frequently complicated by renal disease, consider a lower starting dosage and gradual increase in dosage for patients with renal impairment [ see Dosage and Administration ( 2. 10 Recommended Dosage in Adults The recommended duloxetine delayed-release capsule dosage is 60 mg once daily in adults with fibromyalgia. Begin treatment at 30 mg once daily for 1 week, to allow patients to adjust to duloxetine delayed-release capsules before increasing to 60 mg once daily. Some patients may respond to the starting dosage. There is no evidence that dosages greater than 60 mg/day confer additional benefit, even in patients who do not respond to a 60 mg/day dosage, and higher dosages were associated with a higher rate of adverse reactions. Recommended Dosage in Pediatric Patients 13 Years to 17 Years of Age The recommended duloxetine delayed-release capsules dosage is 60 mg once daily in adults with chronic musculoskeletal pain. Begin treatment at 30 mg once daily for one week, to allow patients to adjust to duloxetine delayed-release capsules before increasing to 60 mg once daily. There is no evidence that higher dosages confer additional benefit, even in patients who do not respond to a 60 mg once daily dosage, and higher dosages are associated with a higher rate of adverse reactions [see Clinical Studies ( 14. 6 Avoid use in patients with chronic liver disease or cirrhosis [see Warnings and Precautions ( 5. 9 Avoid use in patients with severe renal impairment, GFR less than 30 mL/minute [see Warnings and Precautions ( 5. 10 Adverse reactions after discontinuation of duloxetine delayed-release capsules, 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 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 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 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.

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 Increased Risk of Bleeding [see Warnings and Precautions ( 5. 5 Severe Skin Reactions [see Warnings and Precautions ( 5. 6 Discontinuation Syndrome [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 Increases in 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 Sexual Dysfunction [see Warnings and Precautions ( 5. 16 Most common adverse reactions (greater than or equal to 5% and at least twice the incidence of placebo-treated patients): ( 6. 1 Adults: Pediatric Patients: To report SUSPECTED ADVERSE REACTIONS, contact Quallent Pharmaceuticals Health LLC at 1-877-605-7243 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 patients who experienced, at least once, one 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. Adverse Reactions in Adults Adult Clinical Trial Database The data described below reflect exposure to duloxetine delayed-release capsules in placebo-controlled adult trials for MDD (N=3779), GAD (N=1018), OA (N=503), CLBP (N=600), DPNP (N=906), and FM (N=1294). The age range in this pooled population was 17 years to 89 years of age. In this pooled population, 66%, 61%, 61%, 43%, and 94% of adult patients were female; and 82%, 73%, 85%, 74%, and 86% of adult patients were Caucasian in the MDD, GAD, OA and CLBP, DPNP, and FM populations, respectively. Most patients received duloxetine delayed-release capsules dosages of a total of 60 mg to 120 mg per day [see Clinical Studies ( 14 [see Clinical Studies ( 14. 3 Adverse Reactions Leading to Treatment Discontinuation in Adult Placebo-Controlled Trials Major Depressive Disorder Approximately 8. 4% (319/3779) of duloxetine -treated patients in placebo-controlled adult trials for MDD discontinued treatment due to an adverse reaction, compared with 4. 6% (117/2536) of placebo-treated patients. Nausea (duloxetine 1. 1%, placebo 0. 4%) was the only 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-treated patients). Generalized Anxiety Disorder Approximately 13. 7% (139/1018) of the duloxetine -treated patients in placebo-controlled adult trials for GAD discontinued treatment due to an adverse reaction, compared with 5% (38/767) for placebo-treated patients. 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 duloxetine -treated patients in placebo-controlled adult trials for DPNP discontinued treatment due to an adverse reaction, compared with 5. 1% (23/448) for placebo-treated patients. 5%, placebo 0. 7%), dizziness (duloxetine 1. 2%, placebo 0. 4%), and somnolence (duloxetine 1. 1%, placebo 0 %). Fibromyalgia Approximately 17. 5% (227/1294) of the duloxetine -treated patients in 3- to 6- month placebo-controlled adult trials for FM discontinued treatment due to an adverse reaction, compared with 10. 1% (96/955) for placebo-treated patients. Adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine 2. 0%, placebo 0. 5%), headache (duloxetine 1. 3%), somnolence (duloxetine 1. 1%, placebo 0%), and fatigue (duloxetine 1. Chronic Pain due to Osteoarthritis Approximately 15. 7% (79/503) of the duloxetine -treated patients in 13-week, placebo-controlled adult trials for chronic pain due to OA discontinued treatment due to an adverse reaction, compared with 7. 3% (37/508) for placebo-treated patients. 2%, placebo 1%). Chronic Low Back Pain Approximately 16. 5% (99/600) of the duloxetine -treated patients in 13-week, placebo-controlled adult trials for CLBP discontinued treatment due to an adverse reaction, compared with 6. 3% (28/441) for placebo-treated patients. 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 Adverse Reactions in Adult Trials The most commonly observed adverse reactions in duloxetine -treated patients (as defined above) were: Diabetic Peripheral Neuropathic Pain: nausea, somnolence, decreased appetite, constipation, hyperhidrosis, and dry mouth. Fibromyalgia: nausea, dry mouth, constipation, somnolence, decreased appetite, hyperhidrosis, and agitation. Chronic Pain due to Osteoarthritis: nausea, fatigue, constipation, dry mouth, insomnia, somnolence, and dizziness. Chronic Low Back Pain: nausea, dry mouth, insomnia, somnolence, constipation, dizziness, and fatigue. The most commonly observed adverse reactions in duloxetine -treated patients in all the pooled adult populations (i. , MDD, GAD, DPNP, FM, OA, and CLBP) (incidence of at least 5% and at least twice the incidence in placebo-treated patients) were nausea, dry mouth, somnolence, constipation, decreased appetite, and hyperhidrosis. Table 2 displays the incidence of adverse reactions in placebo-controlled trials for approved adult populations (i. , MDD, GAD, DPNP, FM, OA, and CLBP) that occurred in 5% or more of duloxetine-treated patients and with an incidence greater than placebo-treated patients. Table 2: Adverse Reactions: Incidence of 5% or More and Greater than Placebo in Placebo-Controlled Trials of Approved Adult Populations 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 in Pooled MDD and GAD Trials in Adults Table 3 displays the incidence of adverse reactions in MDD and GAD placebo-controlled adult trials that occurred in 2% or more of duloxetine -treated patients and with an incidence greater than placebo-treated patients. Table 3: Adverse Reactions: Incidence of 2% or More and Greater than Placebo in MDD and GAD Placebo-Controlled Trials in Adults 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 Cardiac Disorders Palpitations 2 1 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 Adverse Reactions in the DPNP, FM, OA, and CLBP Adult Trials Table 4 displays the incidence of adverse reactions that occurred in 2% or more of duloxetine -treated patients (determined prior to rounding) in the premarketing acute phase of DPNP, FM, OA, and CLBP placebo-controlled adult trials and with an incidence greater than placebo-treated patients. Table 4: Adverse Reactions: Incidence of 2% or More and Greater than Placebo in DPNP, FM, OA, and CLBP Placebo-Controlled Trials a a b c d e f g h i j k l System Organ Class / Adverse Reaction Percentage of Patients Reporting Reaction Duloxetine Placebo Gastrointestinal Disorders Nausea 23 7 Dry Mouth b 11 3 Constipation b 10 3 Diarrhea 9 5 Abdominal Pain c 5 4 Vomiting 3 2 Dyspepsia 2 1 General Disorders and Administration Site Conditions Fatigue d 11 5 Infections and Infestations Nasopharyngitis 4 4 Upper Respiratory Tract Infection 3 3 Influenza 2 2 Metabolism and Nutrition Disorders Decreased Appetite b 8 1 Musculoskeletal and Connective Tissue e Muscle Spasms 2 2 Nervous System Disorders Headache 13 8 Somnolence b,f 11 3 Dizziness 9 5 Paraesthesia g 2 2 Tremor b 2 <1 Psychiatric Disorders Insomnia b,h 10 5 Agitation i 3 1 Reproductive System and Breast Disorders Erectile Dysfunction b 4 <1 Ejaculation Disorder j 2 <1 Respiratory, Thoracic, and Mediastinal Disorders Cough 2 2 Skin and Subcutaneous Tissue Disorders Hyperhidrosis 6 1 Vascular Disorders Flushing k 3 1 Blood pressure increased l 2 1 Effects on Male and Female Sexual Function in Adults with MDD 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 adverse reactions, was used prospectively in 4 MDD placebo-controlled adult trials (Studies MDD-1, MDD-2, MDD-3, and MDD-4) [see Clinical Studies ( 14. 2 In these trials, duloxetine -treated male patients experienced significantly more sexual dysfunction, as measured by the total score on the ASEX and the ability to reach orgasm, than placebo-treated male patients (see Table 5). duloxetine -treated female patients did not experience more sexual dysfunction than placebo-treated female patients as measured by ASEX total score. Healthcare providers should routinely inquire about possible sexual adverse reactions in duloxetine -treated patients. Table 5: Mean Change in ASEX Scores by Gender in MDD Placebo-Controlled Adult Trials a b c Male Patients a Female Patients a Duloxetine Placebo Duloxetine Placebo ASEX Total (Items 1 to 5) 0. 07 Item 1 em dash Sex drive -0. 24 Item 2 em dash Arousal 0. 18 Item 3 em dash Ability to achieve erection (men); Lubrication (women) 0. 18 Item 4 em dash Ease of reaching orgasm 0. 13 Item 5 em dash Orgasm satisfaction 0. 17 Vital Sign Changes in Adults In placebo-controlled clinical trials across approved adult populations for change from baseline to endpoint, duloxetine treated patients had mean increases of 0. 23 mm Hg in systolic blood pressure (SBP) and 0. 73 mm Hg in diastolic blood pressure (DBP) compared to mean decreases of 1. 09 mm Hg in SBP and 0. 55 mm Hg in DBP 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 adult populations, 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 adult populations, 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 Other Adverse Reactions Observed During the Clinical Trial Evaluation of Duloxetine in Adults Following is a list of adverse reactions reported by patients treated with duloxetine in clinical adult trials. In clinical trials of all approved adult populations, 34,756 patients were treated with duloxetine. Of these, 27% (9337) took duloxetine for at least 6 months, and 12% (4317) took duloxetine 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 Placebo-Controlled Clinical Trials in Pediatric Patients Pediatric Clinical Trial Database The data described below reflect exposure to duloxetine (N=567) in pediatric patients aged 7 years to 18 years of age from two 10-week, placebo-controlled trials in patients with MDD (N=341) (Studies MDD-6 and MDD-7), one 10-week placebo-controlled trial in GAD (N=135) (Study GAD-6), and a 13-week trial in fibromyalgia (N=91). Duloxetine is not approved for the treatment of MDD in pediatric patients [see Use in Specific Populations ( 8. 4 Most Common Adverse Reactions in Pediatric Trials The most common adverse reactions (greater than or equal to 5% in duloxetine -treated patients and at least twice the incidence of placebo-treated patients) in all pooled pediatric populations (MDD, GAD, and fibromyalgia) were decreased weight, decreased appetite, nausea, vomiting, fatigue, and diarrhea. Adverse Reactions in Pediatric Patients Aged 7 Years to 17 Years Old with MDD and GAD The adverse reaction profile observed in clinical trials in pediatric patients aged 7 years to 18 years old with MDD and GAD was consistent with the adverse reaction profile observed in adult clinical trials. The most common (greater than or equal to 5% and twice placebo) adverse reactions observed in these pediatric clinical trials included: nausea, diarrhea, decreased weight, and dizziness. Table 6 provides the incidence of 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 patients treated with placebo. Duloxetine is not approved in the treatment of MDD in pediatric patients [see Use in Specific Populations ( 8. 4 Table 6: Adverse Reactions: Incidence of 2% or More and Greater than Placebo in Three 10-week Pediatric Placebo-Controlled Trials in MDD and GAD a a [see Use in Specific Populations ( 8. 4 b c d e f System Organ Class/Adverse Reaction Percentage of Pediatric Patients Reporting Reaction Duloxetine Placebo (N=476) (N=362) Gastrointestinal Disorders Nausea 18 8 Abdominal Pain b 13 10 Vomiting 9 4 Diarrhea 6 3 Dry Mouth 2 1 General Disorders and Administration Site Conditions Fatigue c 7 5 Investigations Decreased Weight d 14 6 Metabolism and Nutrition Disorders Decreased Appetite 10 5 Nervous System Disorders Headache 18 13 Somnolence e 11 6 Dizziness 8 4 Psychiatric Disorders Insomnia f 7 4 Respiratory, Thoracic, and Mediastinal Disorders Oropharyngeal Pain 4 2 Cough 3 1 Other adverse reactions that occurred at an incidence of less than 2% and were reported by more duloxetine-treated patients than placebo-treated patients in pediatric MDD and GAD clinical trials included: abnormal dreams (including nightmare), anxiety, flushing (including hot flush), hyperhidrosis, palpitations, pulse increased, and tremor (duloxetine is not approved to treat pediatric patients with MDD). The most commonly reported symptoms following discontinuation of duloxetine in pediatric MDD and GAD clinical trials included headache, dizziness, insomnia, and abdominal pain [see Warnings and Precautions ( 5. 7 Growth (Height and Weight) in Pediatric Patients 7 Years to 17 Years Old with GAD and MDD Decreased appetite and weight loss have been observed in association with the use of SSRIs and SNRIs. Duloxetine -treated pediatric patients 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 pediatric patients. The proportion of patients who experienced a clinically significant decrease in weight (greater than or equal to 3. 5%) was greater in the duloxetine group than in the placebo group (16% 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 patients 7 years to 11 years of age and 1. 3 cm increase in patients 12 years 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 patients 7 years to 11 years of age and increase of 0. 3% in patients 12 years to 17 years of age). Weight and height should be monitored regularly in pediatric patients treated with duloxetine [see Use in Specific Populations ( 8. 4 Adverse Reactions in Pediatric Patients Aged 13 Years to 17 Years Old with Fibromyalgia Table 7 provides the incidence of adverse reactions in a fibromyalgia pediatric placebo-controlled trial (Study FM-4) that occurred in greater than 5% of patients treated with duloxetine and with an incidence greater than patients treated with placebo [see Clinical Studies ( 14. 5 Table 7: Adverse Reactions: Incidence of 5% or More and Greater than Placebo in a 13-week Placebo-Controlled Trial in Pediatric Patients 13 Years to 17 Years Old with Fibromyalgia (Study FM-4) a a b Duloxetine (N=91) Placebo (N=93) Nausea 25% 15% Decreased appetite 15% 3% Vomiting 15% 5% Decreased weight b 15% 5% Headache 14% 11% Nasopharyngitis 9% 2% Somnolence 9% 3% Upper respiratory tract infection 7% 2% Viral gastroenteritis 5% 0% Fatigue 5% 2% 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.

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 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. 4 Concomitant use of an MAOI antidepressant with duloxetine is contraindicated Use of duloxetine within 14 days of stopping an MAOI antidepressant is contraindicated In linezolid-or intravenous methylene blue-treated patients, initiation of duloxetine is contraindicated ( 4.

Pregnancy: 8. 1 Hepatic Impairment: 5. 14 Renal Impairment: 5. 14 Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors the pregnancy outcomes in women exposed to antidepressants, including duloxetine, during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Antidepressants at 1-866-961-2388 or online at https://womensmentalhealth. org/research/pregnancyregistry/. 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 times 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. Pregnant women with fibromyalgia are at increased risk for adverse maternal and infant outcomes including preterm premature rupture of membranes, preterm birth, small for gestational age, intrauterine growth restriction, placental disruption, and venous thrombosis. It is not known if these adverse maternal and fetal outcomes are a direct result of fibromyalgia or other comorbid factors. 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 [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 2532 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 times 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 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. The safety and effectiveness of duloxetine have been established for treatment of generalized anxiety disorder (GAD) in patients 7 years to 17 years of age and for treatment of juvenile fibromyalgia syndrome in patients 13 years to 17 years of age. The safety and effectiveness of duloxetine have not been established in pediatric patients with major depressive disorder (MDD), diabetic peripheral neuropathic pain, or chronic musculoskeletal pain. Antidepressants increased the risk of suicidal thoughts and behavior in pediatric patients. Monitor all pediatric patients being treated with antidepressants for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of treatment, or at times of dosage changes [see Warnings and Precautions ( 5. 1 [see Adverse Reactions ( 6. 1 Generalized Anxiety Disorder Use of duloxetine for the treatment of GAD in patients 7 years to 17 years of age is supported by one 10-week, placebo-controlled trial (GAD-6). The study included 272 pediatric patients with GAD of which 47% were 7 years to 11 years of age (53% were 12 years to 17 years of age). Duloxetine [see Clinical Studies ( 14. 3 The safety and effectiveness of duloxetine for the treatment of GAD in pediatric patients less than 7 years of age have not been established. Fibromyalgia [see Clinical Studies ( 14. 5 Major Depressive Disorder The safety and effectiveness of duloxetine have not been established in pediatric patients for the treatment of MDD. Efficacy of duloxetine was not demonstrated in two 10-week, placebo-controlled trials with 800 pediatric patients aged 7 years to 17 years old with MDD (MDD-6 and MDD-7). Neither duloxetine nor an active control (approved for treatment of pediatric MDD) was superior to placebo. The most frequently observed adverse reactions in the MDD pediatric 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. Juvenile Animal Toxicology 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). Geriatric Exposure in Premarketing Clinical Trials of Duloxetine Of the 2,418 patients in MDD trials, 6% (143) were 65 years of age or over. Of the 1,041 patients in CLBP trials, 21% (221) were 65 years of age or over. Of the 487 patients in OA trials, 41% (197) were 65 years of age or over. Of the 1,074 patients in the DPNP trials, 33% (357) were 65 years of age or over. Of the 1,761 patients in FM trials, 8% (140) were 65 years of age or over. In the MDD, GAD, DPNP, FM, OA, and CLBP studies, no overall differences in safety or effectiveness were generally observed between these patients and younger adult patients, and other reported clinical experience has not identified differences in responses between these geriatric and younger adult patients, but greater sensitivity of some older patients cannot be ruled out. SSRIs and SNRIs, including duloxetine have been associated with clinically significant hyponatremia in geriatric patients, who may be at greater risk for this adverse reaction [see Warnings and Precautions ( 5. 13 In an analysis of data from all placebo-controlled-trials, duloxetine -treated patients reported a higher rate of falls compared to placebo-treated patients. The increased risk appears to be proportional to a patient’s underlying risk for falls. Underlying risk appears to increase steadily with age. As geriatric 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 duloxetine treatment is unclear. Falls with serious consequences including bone fractures and hospitalizations have been reported with duloxetine use [see Warnings and Precautions ( 5. 1 The pharmacokinetics of duloxetine after a single dose of 40 mg were compared in healthy elderly females (65 years to 77 years) and healthy middle-age females (32 years 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.

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 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 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 co-administered with warfarin. Concomitant administration of warfarin (2 mg to 9 mg once daily) under steady state conditions with duloxetine 60 mg 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 T,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 co-administration. Under steady-state conditions for duloxetine (20 mg qhs) and temazepam (30 mg qhs), the pharmacokinetics of duloxetine were not affected by co-administration. 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, co-administration 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 The concomitant use of serotonergic drugs (including other SNRIs, SSRIs, triptans, tricyclic antidepressants, opioids, lithium, buspirone, amphetamines, tryptophan, and St. John's Wort) with duloxetine increases the risk of serotonin syndrome. Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of duloxetine and/or concomitant serotonergic drugs [see Warnings and Precautions ( 5. 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, co-administration of duloxetine (60 mg or 120 mg) with warfarin (2 mg 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 duloxetine overdoses, primarily with mixed overdoses, but also with duloxetine only, including 1000 mg of duloxetine (approximately 8. 3 times the maximum recommended dosage). 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 a duloxetine overdosage, but if serotonin syndrome ensues, specific treatment (such as with cyproheptadine and/or temperature control) may be considered. In case of acute overdose with duloxetine, treatment should consist of those general measures employed in the management of overdose with any drug, such as assuring an adequate airway, oxygenation, and ventilation and monitoring cardiac rhythm and vital signs. 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. Induction of emesis is not recommended. Activated charcoal may be useful in limiting absorption of duloxetine from the gastrointestinal tract. Administration of activated charcoal has been shown to decrease duloxetine AUC and C max In managing overdose, the possibility of multiple drug involvement should be considered. A specific caution involves patients who overdose with duloxetine and tricyclic antidepressants. 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 Consider contacting a poison control center (1-800-222-1222 or www. org) for additional information on the treatment of overdosage.
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 MRHDgiven to children) and up to 36 mg/kg/day in males (1.4 time 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 populations in adequate and well-controlled trials: Major Depressive Disorder (MDD): [see Clinical Studies ( 14. 2 Generalized Anxiety Disorder (GAD): [see Clinical Studies ( 14. 3 Diabetic Peripheral Neuropathic Pain (DPNP): [see Clinical Studies ( 14. 4 Fibromyalgia (FM): [see Clinical Studies ( 14. 5 Chronic Musculoskeletal Pain: [see Clinical Studies ( 14. 6 Additionally, a summary of the following trials that did not demonstrate efficacy are presented below: Study FM-3 (a 16-week trial in adult patients with fibromyalgia), Study CLBP-2 (a 13-week trial in adult patients with CLBP), and Study OA-2 (a 13-week trial in adult patients with chronic pain due to OA). The efficacy of duloxetine as a treatment for MDD in adults was established in 4 randomized, double-blind, placebo-controlled, fixed-dose trials in adult outpatients (18 years to 83 years) meeting DSM-IV criteria for MDD: In Studies MDD-1 and MDD-2, 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 Study MDD-3, patients were randomized to duloxetine 20 mg or 40 mg twice daily (N=86 and N=91, respectively) or placebo (N=89) for 8 weeks In Study MDD-4, patients were randomized to duloxetine 40 mg or 60 mg twice daily (N=95 and N=93, respectively) or placebo (N=93) for 8 weeks. In all four trials, duloxetine demonstrated superiority over placebo as measured by improvement in the 17-item Hamilton Depression Rating Scale (HAMD-17) total score (see Table 8). There is no evidence that doses greater than 60 mg/day confer additional benefits. In all of these clinical trials, 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 8: Summary of the Primary Efficacy Results for Adult Trials in MDD Study Number Treatment Group Primary Efficacy Measure: HAMD-17 Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo-Subtracted Difference a (95% CI) Study Duloxetine b 21. 9) Placebo 21. 69) -- Study Duloxetine b 20. 3) Placebo 20. 67) -- Study Duloxetine b 18. 2) Duloxetine b 18. 4) Placebo 17. 81) -- Study Duloxetine b 19. 9) Duloxetine b 20. 9) Placebo 19. 50) -- 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 In Study MDD-5, 533 adult 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 less than or equal to 9, Clinical Global Impressions of Severity (CGI-S) less than or equal to 2, and not meeting the DSM-IV criteria for MDD] were randomly assigned to continuation of duloxetine at the same dosage (N=136) or to placebo (N=142) for 6 months. In Study MDD-5, patients on duloxetine experienced a statistically significantly longer time to relapse of depression than did patients on placebo (see Figure 1). Relapse was defined as an increase in the CGI-S score of greater than or equal to 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. Figure 1: Cumulative Proportion a a figure1 GAD Trials in Adults (Including Geriatric Patients) 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 years and 83 years of age meeting the DSM-IV criteria for GAD (Studies GAD-1, GAD-2, and GAD-3, respectively). In Studies GAD-1 and GAD-2, the starting dose was 60 mg once daily (down titration to 30 mg once daily was allowed for tolerability reasons; the dosage could be increased to 60 mg once daily). Fifteen percent of patients were down titrated. Study GAD-3 had a starting dose of 30 mg once daily for 1 week before increasing it to 60 mg once daily. Studies GAD-2 and GAD-3 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 dosage for completers at endpoint in these trials was 104. Study GAD-1 evaluated duloxetine dosages 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 trials, duloxetine demonstrated superiority over placebo as measured by greater improvement in the Hamilton Anxiety Scale (HAM-A) total score (see 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 Study GAD-4, 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 dosage (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 greater than or equal to 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 (see Figure 2). Subgroup analyses did not indicate that there were any differences in treatment outcomes as a function of age or gender. GAD Trial in Geriatric Patients The efficacy of duloxetine in the treatment of patients greater than or equal to 65 years of age with GAD was established in one 10-week flexible-dose, randomized, double-blind, placebo-controlled trial in adults greater than or equal to 65 years of age meeting the DSM-IV criteria for GAD (Study GAD-5). In Study GAD-5, 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 dosage for patients completing the 10-week acute treatment phase was 51 mg. 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 HAM-A total score (see Table 8). GAD Trial in Pediatric Patients 7 Years to 17 Years Old The efficacy of duloxetine in the treatment of pediatric patients 7 years to 17 years of age with GAD was established in 1 flexible-dose randomized, double-blind, placebo-controlled trial in pediatric outpatients with GAD (based on DSM-IV criteria) (Study GAD-6). In Study GAD-6, the starting dosage was 30 mg once daily for 2 weeks. Further dosage increases in 30 mg increments up to 120 mg once daily were allowed based on investigator judgment of clinical response and tolerability. The mean dosage 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 (see Table 9). Table 9: Summary of the Primary Efficacy Results for GAD Trials Study Number (population) (measurement) Treatment Group Primary Efficacy Measure Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo-Subtracted Difference a (95% CI) Study Duloxetine b 25. 5) Duloxetine b 25. 3) Placebo 25. 67) -- Study GAD-2 Duloxetine b 22. 3) Placebo 23. 70) -- Study GAD-3 Duloxetine b 25. 7) Placebo 25. 67) -- Study GAD-5 Duloxetine b 24. 5) Placebo 24. 67) -- Study GAD-6 (Pediatric) (PARS for GAD) Duloxetine b 17. 3) Placebo 17. a b Figure 2: Cumulative Proportion a a figure2 The efficacy of duloxetine for the management of neuropathic pain associated with diabetic peripheral neuropathy in adults was established in 2 randomized, 12-week, double-blind, placebo-controlled, fixed-dose trials in adult patients having diabetic peripheral neuropathic pain (DPNP) for at least 6 months (Study DPNP-1 and Study DPNP-2). These trials enrolled a total of 791 patients of whom 592 (75%) completed the trials. 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 greater than or equal to 4 on an 11-point scale ranging from 0 (no pain) to 10 (worst possible pain). Patients were permitted up to 4 grams of acetaminophen per day as needed for pain, in addition to duloxetine. Patients recorded their pain daily in a diary. Both trials compared duloxetine 60 mg once daily or 60 mg twice daily with placebo. Study DPNP-1 additionally compared duloxetine 20 mg with placebo. A total of 457 patients (342 duloxetine, 115 placebo) were enrolled in Study DPNP-1 and a total of 334 patients (226 duloxetine, 108 placebo) were enrolled in Study 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 in Studies DPNP-1 and DPNP-2, respectively. 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 trial were assigned 0% improvement. Some patients experienced a decrease in pain as early as week 1, which persisted throughout the trial. Figure 3: Percentage of DPNP Adult Patients Achieving Various Levels of Pain Relief as Measured by 24-Hour Average Pain Severity (Study DPNP-1) Figure 4: Percentage of DPNP Adult Patients Achieving Various Levels of Pain Relief as Measured by 24-Hour Average Pain Severity (Study DPNP-2) figure3 figure4 Adult Trials in Fibromyalgia The efficacy of duloxetine for the management of fibromyalgia in adults was established in two randomized, double-blind, placebo-controlled, fixed-dose trials in adult patients meeting the American College of Rheumatology criteria for fibromyalgia (a history of widespread pain for 3 months, and pain present at 11 or more of the 18 specific tender point sites). Study FM-1 was three months in duration and enrolled female patients only. Study FM-2 was six months in duration and enrolled male and female patients. Approximately 25% of participants had a comorbid diagnosis of MDD. Studies FM-1 and FM-2 enrolled a total of 874 patients of whom 541 (62%) completed the trials. A total of 354 patients (234 duloxetine, 120 placebo) were enrolled in Study FM-1 and a total of 520 patients (376 duloxetine, 144 placebo) were enrolled in Study FM-2 (5% male, 95% female). The patients had a baseline pain score of 6. 5 on an 11-point scale ranging from 0 (no pain) to 10 (worse possible pain). Studies FM-1 and FM-2 compared duloxetine 60 mg once daily or 120 mg daily (given in divided doses in Study FM-1 and as a single daily dose in Study FM-2) with placebo. Study FM-2 additionally compared duloxetine 20 mg with placebo during the initial three months of a six-month trial. Treatment with duloxetine 60 mg or 120 mg daily statistically significantly improved the endpoint mean pain scores from baseline and increased the proportion of patients with at least a 50% reduction in pain score from baseline. Pain reduction was observed in patients both with and without comorbid MDD. However, the degree of pain reduction may be greater in patients with comorbid MDD. For various degrees of improvement in pain from baseline to study endpoint, Figures 5 and 6 show the fraction of patients achieving that degree of improvement in Studies FM-1 and FM-2, respectively. 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%. Improvement was also demonstrated on measures of function (Fibromyalgia Impact Questionnaires) and patient global impression of change (PGI). Neither trial demonstrated a benefit of 120 mg compared to 60 mg, and a higher dosage was associated with more adverse reactions and premature discontinuations of treatment. Figure 5: Percentage of Adult Fibromyalgia Patients Achieving Various Levels of Pain Relief at Study Endpoint as Measured by 24-Hour Average Pain Severity (Study FM-1) Figure 6: Percentage of Adult Fibromyalgia Patients Achieving Various Levels of Pain Relief at Study Endpoint as Measured by 24-Hour Average Pain Severity (Study FM-2) Additionally, the benefit of up-titration in non-responders to duloxetine delayed-release capsules at 60 mg/day was evaluated in a separate trial (Study FM-3). Adult patients were initially treated with duloxetine delayed-release capsules 60 mg once daily for eight weeks in open-label fashion. Subsequently, completers of this phase were randomized to double-blind treatment with duloxetine delayed-release capsules at either 60 mg once daily or 120 mg once daily. Responders were defined as patients who had at least a 30% reduction in pain score from baseline at the end of the 8 week treatment. Patients who were non-responders at 8 weeks were no more likely to meet response criteria at the end of 60 weeks of treatment if blindly titrated to duloxetine delayed-release capsules 120 mg as compared to those who were blindly continued on duloxetine delayed-release capsules 60 mg. Pediatric Trial in Fibromyalgia Figure 7: Percentage of Pediatric Patients Aged 13 Years to 17 Years Old with Juvenile Fibromyalgia Syndrome Achieving Various Levels of Pain Relief at Week 12 (Study FM-4) a a b figure5 figure6 figure7 Duloxetine delayed-release capsules are indicated for the treatment of chronic musculoskeletal pain in adults. This has been established in trials in adult patients with chronic low back pain and chronic pain due to osteoarthritis. Trials in Chronic Low Back Pain in Adults The efficacy of duloxetine delayed-release capsules in chronic low back pain (CLBP) in adults was assessed in two double-blind, placebo-controlled, randomized clinical trials of 13-weeks duration (Studies CLBP-1 and CLBP-2), and one of 12-weeks duration (CLBP-3). Studies CLBP-1 and CLBP-3 demonstrated efficacy of duloxetine delayed-release capsules in the treatment of CLBP. Patients in all trials had no signs of radiculopathy or spinal stenosis. Study CLBP-1 Study CLBP-2 Study CLBP-3 For various degrees of improvement in pain from baseline to study endpoint, Figures 8 and 9 show the fraction of patients in Studies CLBP-1 and CLBP-3 achieving that degree of improvement, respectively. Patients who did not complete the trial were assigned the value of 0% improvement. Figure 8: Percentage of Adult Patients with CLBP Achieving Various Levels of Pain Relief as Measured by 24-Hour Average Pain Severity (Study CLBP-1) Figure 9: Percentage of Adult Patients with CLBP Achieving Various Levels of Pain Relief as Measured by 24-Hour Average Pain Severity (Study CLBP-3) Trials in Chronic Pain Due to Osteoarthritis in Adults The efficacy of duloxetine delayed-release capsules in chronic pain due to osteoarthritis (OA) in adults 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 trials fulfilled the ACR clinical and radiographic criteria for classification of idiopathic OA of the knee. Randomization was stratified by the patients’ baseline NSAIDs-use status. Patients assigned to duloxetine delayed-release capsules started treatment in both trials at a dose of 30 mg once daily for one week. After the first week, the dose of duloxetine delayed-release capsules was increased to 60 mg once daily. After 7 weeks of treatment with duloxetine delayed-release capsules 60 mg once daily, in Study OA-1 patients with sub-optimal response to treatment (less than 30% pain reduction) and tolerated duloxetine delayed-release capsules 60 mg once daily had their doseincreased to 120 mg. However, in Study OA-2, all patients, regardless of their response to treatment after 7 weeks, were re-randomized to either continue receiving duloxetine delayed-release capsules 60 mg once daily or have their dosage increased to 120 mg once daily for the remainder of the trial. Patients in the placebo treatment groups in both trials received a matching placebo for the entire duration of trials. For both trials, efficacy analyses were conducted using 13-week data from the combined duloxetine delayed-release capsules 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 10 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 10: Percentage of Adult Patients with OA Achieving Various Levels of Pain Relief as Measured by 24-Hour Average Pain Severity (Study OA-1) figure8 figure9 figure10.
Medication Guide
Duloxetine Delayed-Release Capsules Read this Medication Guide before you start taking duloxetine delayed-release capsules and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. Talk to your healthcare provider about: all risks and benefits of treatment with antidepressant medicines all treatment choices for depression or other serious mental illness What is the most important information I should know about antidepressant medicines, depression, other serious mental illnesses, and suicidal thoughts or actions? Duloxetine delayed-release capsules and other antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, or young adults within the first few months of treatment or when the dose is changed. Depression and other serious mental illnesses are the most important causes of suicidal thoughts or actions. Some people may have a particularly high risk of having suicidal thoughts or actions. How can I watch for and try to prevent suicidal thoughts and actions? Pay close attention to any changes in mood, behavior, actions, thoughts, or feelings, especially sudden changes. This is very important when an antidepressant medicine is started or when the dose is changed. Call your healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings. Keep all follow-up visits with your healthcare provider as scheduled. Call your healthcare provider between visits as needed, especially if you have concerns about symptoms. Call your healthcare provider right away if you have any of the following symptoms, or feelings, especially if they are new, worse, or worry you. In an emergency, call 911. attempts to commit suicide acting on dangerous impulses acting aggressive, being angry, or violent thoughts about suicide or dying new or worse depression new or worse anxiety panic attacks feeling very agitated or restless new or worse irritability trouble sleeping an extreme increase in activity or talking (mania) other unusual changes in behavior or mood What else do I need to know about antidepressant medicines? Never stop an antidepressant medicine without first talking to a healthcare provider. Stopping an antidepressant medicine suddenly can cause other symptoms. Antidepressants are medicines used to treat depression and other illnesses. It is important to discuss all the risks of treating depression and also the risks of not treating it. Patients should discuss all treatment choices with your healthcare provider, not just the use of antidepressants. Antidepressant medicines have other side effects. Talk to your healthcare provider about the side effects of the medicine prescribed for you or your family member. Antidepressant medicines can interact with other medicines. Know all of the medicines that you or your family member takes. Keep a list of all medicines to show your healthcare provider. Do not start new medicines without first checking with your healthcare provider. What are duloxetine delayed-release capsules? Generalized Anxiety Disorder (GAD) Diabetic Peripheral Neuropathic Pain (DPNP) Fibromyalgia (FM) Chronic Musculoskeletal Pain Who should not take duloxetine delayed-release capsules? Do Not take duloxetine delayed-release capsules if you: take a Monoamine Oxidase Inhibitor (MAOI). Do not take an MAOI within 5 days of stopping duloxetine delayed-release capsules unless directed to do so by your healthcare provider. Do not start duloxetine delayed-release capsules if you stopped taking an MAOI in the last 14 days unless directed to do so by your healthcare provider. People who take duloxetine delayed-release capsules close in time to an MAOI may have a serious problem called Serotonin Syndrome (see “What are the possible side effects of duloxetine delayed-release capsules?”). What should I tell my healthcare provider before taking duloxetine delayed-release capsules? have heart problems or high blood pressure have diabetes (duloxetine delayed-release capsules treatment makes it harder for some people with diabetes to control their blood sugar) have liver problems have kidney problems have glaucoma have or had seizures or convulsions have bipolar disorder or mania have low sodium levels in your blood have delayed stomach emptying have or had bleeding problems are pregnant or plan to become pregnant. Duloxetine delayed-release capsules may harm your unborn baby. Talk to your healthcare provider about the risk to your unborn baby if you take duloxetine delayed-release capsules during pregnancy. Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with duloxetine delayed-release capsules. There is a pregnancy registry for females who are exposed to duloxetine delayed-release capsules during pregnancy. The purpose of the registry is to collect information about the health of females exposed to duloxetine delayed-release capsules and their baby. If you become pregnant during treatment with duloxetine delayed-release capsules, talk to your healthcare provider about registering with the National Pregnancy Registry for Antidepressants at 1-866-961-2388 or visit online at https://womensmentalhealth. org/research/pregnancyregistry/. are breastfeeding or plan to breastfeed. Duloxetine passes into your breast milk and may harm your baby. Talk to your healthcare provider about the best way to feed your baby while taking duloxetine delayed-release capsules. Tell your healthcare provider about all the medicines that you take, Especially tell your healthcare provider if you take: triptans used to treat migraine headache medicines used to treat mood, anxiety, psychotic or thought disorders, including tricyclics, lithium, buspirone, SSRIs, SNRIs or MAOIs tramadol, fentanyl, meperidine, methadone, or other opioids amphetamines cimetidine the antibiotics ciprofloxacin, enoxacin medicine to treat irregular heart rate (like propafenone, flecainide, quinidine) theophylline the blood thinner warfarin (Coumadin, Jantoven) non-steroidal anti-inflammatory drug (NSAID) (like ibuprofen, naproxen or aspirin). over-the-counter supplements such as tryptophan or St. John''s Wort thioridazine (Mellaril). Mellaril together with duloxetine delayed-release capsules can cause serious heart rhythm problems or sudden death. Ask your healthcare provider for a list of these medicines if you are not sure. How should I take duloxetine delayed-release capsules? Take duloxetine delayed-release capsules exactly as your healthcare provider tells you to take it. Your healthcare provider may need to change the dose of duloxetine delayed-release capsules until it is the right dose for you. Swallow duloxetine delayed-release capsules whole. Do not chew or crush duloxetine delayed-release capsules. Do not open the capsule and sprinkle on food or mix with liquids. Opening the capsule may affect how well duloxetine delayed-release capsules work. Duloxetine delayed-release capsules may be taken with or without food. If you miss a dose of duloxetine delayed-release capsules, take the missed dose as soon as you remember. If it is almost time for the next dose, skip the missed dose and take your next dose at the regular time. Do not take two doses of duloxetine delayed-release capsules at the same time. If you take too much duloxetine delayed-release capsules, call your healthcare provider or poison control center at 1-800-222-1222 right away, or get emergency treatment. When switching from another antidepressant to duloxetine delayed-release capsules your healthcare provider may want to lower the dose of the initial antidepressant first to potentially avoid side effects. What should I avoid while taking duloxetine delayed-release capsules? Duloxetine delayed-release capsules can cause sleepiness or may affect your ability to make decisions, think clearly, or react quickly. You should not drive, operate heavy machinery, or do other dangerous activities until you know how duloxetine delayed-release capsules affects you. Use of duloxetine delayed-release capsules concomitantly with heavy alcohol intake may be associated with severe liver injury. Avoid heavy alcohol use while taking duloxetine delayed-release capsules. What are the possible side effects of duloxetine delayed-release capsules? Common possible side effects in people who take duloxetine delayed-release capsules include: 1. liver damage. Symptoms may include: itching right upper abdominal pain dark urine yellow skin or eyes enlarged liver increased liver enzymes 2. changes in blood pressure and falls. Monitor your blood pressure before starting and throughout treatment. Duloxetine delayed-release capsules may: increase your blood pressure. decrease your blood pressure when standing and cause dizziness or fainting, mostly when first starting duloxetine delayed-release capsules or when increasing the dose. increase risk of falls, especially in elderly. Serotonin Syndrome: This condition can be life-threatening and symptoms may include: agitation, hallucinations, coma or other changes in mental status coordination problems or muscle twitching (overactive reflexes) racing heartbeat, high or low blood pressure sweating or fever nausea, vomiting, or diarrhea muscle rigidity dizziness flushing tremor seizures 4. abnormal bleeding: 5. severe skin reactions: 6. discontinuation symptoms: anxiety irritability feeling tired or problems sleeping headache sweating dizziness electric shock-like sensations vomiting or nausea diarrhea 7. manic episodes: greatly increased energy severe trouble sleeping racing thoughts reckless behavior unusually grand ideas excessive happiness or irritability talking more or faster than usual 8. visual problems: eye pain changes in vision swelling or redness in or around the eye 9. seizures or convulsions 10. low salt (sodium) levels in the blood. headache weakness or feeling unsteady confusion, problems concentrating or thinking or memory problems 11. problems with urination. Symptoms may include: decreased urine flow unable to pass any urine 12. sexual problems (dysfunction). delayed ejaculation or inability to have an ejaculation decreased sex drive problems getting or keeping an erection Symptoms in females may include: decreased sex drive delayed orgasm or inability to have an orgasm Talk to your healthcare provider if you develop any changes in your sexual function or if you have any questions or concerns about sexual problems during treatment with duloxetine delayed-release capsules. There may be treatments your healthcare provider can suggest. The most common side effects of duloxetine delayed-release capsules include: nausea dry mouth sleepiness fatigue constipation loss of appetite increased sweating dizziness Common possible side effects in children and adolescents who take duloxetine delayed-release capsules include: nausea decreased weight dizziness Side effects in adults may also occur in children and adolescents who take duloxetine delayed-release capsules. Children and adolescents should have height and weight monitored during treatment. Call your doctor for medical advice about side effects. You may report side effects to 1-800-FDA-1088 How should I store duloxetine delayed-release capsules? Keep duloxetine delayed-release capsules and all medicines out of the reach of children. General information about the safe and effective use of duloxetine delayed-release capsules Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use duloxetine delayed-release capsules for a condition for which it was not prescribed. Do not give duloxetine delayed-release capsules to other people, even if they have the same symptoms that you have. It may harm them. This Medication Guide summarizes the most important information about duloxetine delayed-release capsules. If you would like more information, talk with your healthcare provider. You may ask your healthcare provider or pharmacist for information about duloxetine delayed-release capsules that is written for healthcare professionals. What are the ingredients in duloxetine delayed-release capsules? Active ingredient: Inactive ingredients: This Medication Guide has been approved by the U. Food and Drug Administration All trademarks are the properties of their respective owners. Medication Guide revised: 03/2025 Manufactured by: Manufactured for: logo.

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