DULOXETINE- duloxetine hydrochloride_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 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 lag max max The apparent volume of distribution averages about 1640 L. Duloxetine is highly bound (>90%) to proteins in human plasma, binding primarily to albumin and alpha 1 Metabolism and Elimination 14 in vitro Children and Adolescents (ages 7 to 17 years).

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 delayed-release capsules are a serotonin and norepinephrine reuptake inhibitor (SNRI) indicated for: 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 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. 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 60 mg/day Acute Treatment: 40 mg/day (20 mg twice daily) to 60 mg/day (once daily or as 30 mg twice daily); Maintenance Treatment: 60 mg/day 120 mg/day GAD ( 2. 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 delayed-release capsules 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 [see Clinical Studies (14. 2) see Clinical Studies ( 14. 2 ) Children and Adolescents (7 to 17 years of age) see Clinical Studies ( 14. 2 ) Administer duloxetine delayed-release capsules 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. 6) Use in Specific Populations (8. 10) Clinical Pharmacology (12. 3) Administer duloxetine delayed-release capsules 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 [see Warnings and Precautions (5. 14) Use in Specific Populations (8. 9) Severe Renal Impairment [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)] Abnormal Bleeding [see Warnings and Precautions (5. 5)] Severe Skin Reactions [see Warnings and Precautions (5. 6) Discontinuation of Treatment with duloxetine delayed-release capsules [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. 3 To report SUSPECTED ADVERSE REACTIONS, contact Prasco Laboratories at 1-866-525-0688 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. [see Clinical Studies (14) ]. Major Depressive Disorder Generalized Anxiety Disorder Diabetic Peripheral Neuropathic Pain Chronic Pain due to Osteoarthritis Chronic Low Back Pain Pooled Trials for all Approved Indications 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 delayed-release capsules 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 Delayed- Release Capsules (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 Pooled MDD and GAD Trials Table 3: Treatment-Emergent Adverse Reactions: Incidence of 2% or More and Greater than Placebo in MDD and GAD Placebo-Controlled Trials a,b System Organ Class / Adverse Reaction Percentage of Patients Reporting Reaction Duloxetine Delayed-Release Capsules ( N=4797) Placebo (N=3303) 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 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 a b c d e f g h i j DPNP, another indication, OA, and CLBP 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 System Organ Class / Adverse Reaction Percentage of Patients Reporting Reaction Duloxetine Delayed-Release Capsules (N=3303) Placebo (N=2352) 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 Metabolism and Nutrition Disorders Decreased Appetite b 8 1 Musculoskeletal and Connective Tissue Musculoskeletal Pain e 3 3 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 i 10 5 Reproductive System and Breast Disorders Erectile Dysfunction b j 4 <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 a b c d e f g h i j k l 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 delayed-release capsules 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 delayed-release capsules 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 delayed-release capsules 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 Delayed-Release Capsules (n=175) Placebo (n=83) Duloxetine Delayed-Release Capsules (n=241) Placebo (n=126) ASEX Total (Items 1 to 5) 0. 07 In placebo-controlled clinical trials across approved indications for change from baseline to endpoint, duloxetine delayed-release capsules 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 delayed-release capsules 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 delayed-release capsules-treated patients, decrease of 0. 17 beats per minute in placebo- treated patients). Duloxetine delayed-release capsules 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 delayed-release capsules-treated patients when compared with placebo-treated patients [see Warnings and Precautions (5. 2) The effect of duloxetine delayed-release capsules 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 delayed-release capsules appear to be associated with concentration-dependent but not clinically meaningful QT shortening. Following is a list of treatment-emergent adverse reactions reported by patients treated with duloxetine delayed-release capsules in clinical trials. In clinical trials of all indications, 34,756 patients were treated with duloxetine delayed-release capsules. Of these, 26. 9% (9337) took duloxetine delayed-release capsules 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. Frequent: Infrequent: Frequent: Infrequent: Infrequent: Frequent: Infrequent Frequent: Infrequent Rare Frequent: Infrequent: Rare: Infrequent: Frequent: Infrequent Infrequent: Rare: Frequent: Infrequent: Frequent: Infrequent: Rare: Frequent: Infrequent: Rare: Frequent: Infrequent: Frequent: Infrequent Rare Frequent: Infrequent Frequent: Infrequent: Rare: Frequent: Infrequent: 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. 5) 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 delayed-release capsules 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 e f System Organ Class/Adverse Reaction Percentage of Pediatric Patients Reporting Reaction Duloxetine Delayed-Release Capsules (N=476) Placebo (N=362) Gastrointestinal Disorders b General Disorders and Administration Site Conditions c Investigations d Metabolism and Nutrition Disorders Nervous System Disorders e Psychiatric Disorders f Respiratory, Thoracic, and Mediastinal Disorders Other adverse reactions that occurred at an incidence of less than 2% but were reported by more duloxetine delayed-release capsules treated patients than placebo treated patients and are associated duloxetine delayed-release capsules 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 delayed-release capsules. The most commonly reported symptoms following discontinuation of duloxetine delayed-release capsules in pediatric clinical trials have included headache, dizziness, insomnia, and abdominal pain [see Warnings and Precautions (5. 7) Adverse Reactions (6. 2) The following adverse reactions have been identified during post approval use of duloxetine delayed-release capsules. 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 delayed-release capsules 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) em dash The use of MAOIs intended to treat psychiatric disorders with duloxetine delayed-release capsules or within 5 days of stopping treatment with duloxetine delayed-release capsules is contraindicated because of an increased risk of serotonin syndrome. The use of duloxetine delayed-release capsules within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated [see Dosage and Administration (2. 8) Warnings and Precautions (5. 4) Starting duloxetine delayed-release capsules 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 delayed-release capsules or within 5 days of stopping treatment with duloxetine delayed-release capsules. Do not use duloxetine delayed-release capsules within 14 days of stopping an MAOI intended to treat psychiatric disorders. In addition, do not start duloxetine delayed-release capsules in a patient who is being treated with linezolid or intravenous methylene blue ( 4.

Pregnancy: Based on animal data may cause fetal harm ( 8. 1 Nursing Mothers: Exercise caution when administered to a nursing woman ( 8. 3 Teratogenic Effects Pregnancy Category C Risk Summary Clinical Considerations Fetal/Neonatal Adverse Reaction [see Warnings and Precautions (5. 4) Data Animal Data When duloxetine was administered orally to pregnant rats and rabbits during the period of organogenesis, there was no evidence of teratogenicity at doses up to 45 mg/kg/day (4 times the maximum recommended human dose (MRHD) of 120 mg/day 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); the no-effect dose was 10 mg/kg/day. Furthermore, behaviors consistent with increased reactivity, such as increased startle response to noise and decreased habituation of locomotor activity, were observed in pups following maternal exposure to 30 mg/kg/day. Post-weaning growth and reproductive performance of the progeny were not affected adversely by maternal duloxetine treatment. Risk Summary Generalized Anxiety Disorder Clinical Studies ( 14. 2 ) Major Depressive Disorder [see Adverse Reactions (6. 11) [see Boxed Warning Warnings and Precautions (5. 1) Of the 2,418 patients in premarketing clinical studies of duloxetine delayed-release capsules 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 delayed-release capsules 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) [see Warnings and Precautions (5. 3) Adverse Reactions (6. 10) 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 delayed-release capsules, 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. 6) Warnings and Precautions (5. 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 delayed-release capsules concentrations (7. 2) Duloxetine delayed-release capsules are 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 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 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 delayed-release capsules have an enteric coating that resists dissolution until reaching a segment of the gastrointestinal tract where the pH exceeds 5. In extremely acidic conditions, duloxetine delayed-release capsules, unprotected by the enteric coating, may undergo hydrolysis to form naphthol. Caution is advised in using duloxetine delayed-release capsules 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 delayed-release capsules with aluminum- and magnesium-containing antacids (51 mEq) or duloxetine delayed-release capsules 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. 9 Contraindications (4) Warnings and Precautions (5. 4) [See Dosage and Administration (2. 4) When duloxetine delayed-release capsules and ethanol were administered several hours apart so that peak concentrations of each would coincide, duloxetine delayed-release capsules did not increase the impairment of mental and motor skills caused by alcohol. [see Warnings and Precautions (5. 12 [See Warnings and Precautions (5. 12) Because duloxetine is highly bound to plasma protein, administration of duloxetine delayed-release capsules to a patient taking another drug that is highly protein bound may cause increased free concentrations of the other drug, potentially resulting in adverse reactions. However, co-administration of duloxetine (60 or 120 mg) with warfarin (2 to 9 mg), a highly protein-bound drug, did not result in significant changes in INR and in the pharmacokinetics of either total S-or total R-warfarin (protein bound plus free drug) [see Drug Interactions (7.

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 delayed-release capsules, 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. max [see Warnings and Precautions (5. 4) Drug Interactions (7) Physicians’ Desk Reference.
NONCLINICAL TOXICOLOGY
Carcinogenesis 2 in vitro in vivo in vitro in vitro in vivo
CLINICAL STUDIES
The efficacy of duloxetine delayed-release capsules 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 delayed-release capsules 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 delayed-release capsules 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 delayed-release capsules 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 delayed-release capsules 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 delayed-release capsules 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 (95% CI) Study 1 Duloxetine delayed-release capsules b Study 2 Duloxetine delayed-release capsules b Study 3 Duloxetine delayed-release capsules b b Study 4 Duloxetine delayed-release capsules b b In another study, 533 patients meeting DSM-IV criteria for MDD received duloxetine delayed-release capsules 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 delayed-release capsules at the same dose (N=136) or to placebo (N=142) for 6 months. Patients on duloxetine delayed-release capsules 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 CGIen dashS 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 delayed-release capsules 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) Figure-1 The efficacy of duloxetine delayed-release capsules 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 delayed-release capsules 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 delayed-release capsules 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 delayed-release capsules 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 delayed-release capsules 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 delayed-release capsules 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 delayed-release capsules 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 delayed-release capsules 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 delayed-release capsules (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 delayed-release capsules 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 delayed-release capsules (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 (95% CI) Study 1 (HAM-A) Duloxetine delayed-release capsules b 25. 5) Duloxetine delayed-release capsules b 25. 3) Placebo 25. 67) -- Study 2 (HAM-A) Duloxetine delayed-release capsules b 22. 3) Placebo 23. 7) -- Study 3 (HAM-A) Duloxetine delayed-release capsules b 25. 7) Placebo 25 (5. 67) -- Study 5 Duloxetine delayed-release capsules b 24. 5) Placebo 24. 67) -- Study 6 Duloxetine delayed-release capsules b 17. 3) Placebo 17. 5) -- Duloxetine Figure 2 The efficacy of duloxetine delayed-release capsules 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 delayed-release capsules. Patients recorded their pain daily in a diary. Figure 3: Percentage of Patients Achieving Various Levels of Pain Relief as Measured by 24-Hour Average Pain Severity - DPNP-1 Figure 4: Percentage of Patients Achieving Various Levels of Pain Relief as Measured by 24-Hour Average Pain Severity - DPNP-2 Duloxetine delayed-release capsules are 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 Study CLBP-1: Study CLBP-2: Study CLBP-3: 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. 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 the value of 0% improvement. 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 7: Percentage of Patients Achieving Various Levels of Pain Relief as Measured by 24-Hour Average Pain Severity en dash CLBP-1 Figure 8: Percentage of Patients Achieving Various Levels of Pain Relief as Measured by 24-Hour Average Pain Severity en dash CLBP-3 Figure 9: Percentage of Patients Achieving Various Levels of Pain Relief as Measured by 24-Hour Average Pain Severity en dash OA-1.
Medication Guide
Duloxetine Delayed-Release Capsules USP (doo lox'' e teen) 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? 1. 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. 2. 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. 3. 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) 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) 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? Tell your healthcare provider about all the medicines that you take, Ask your healthcare provider for a list of these medicines if you are not sure. How should I take duloxetine delayed-release capsules? What should I avoid while taking duloxetine delayed-release capsules? What are the possible side effects of duloxetine delayed-release capsules? “What is the most important information I should know about duloxetine delayed-release capsules?” 1. liver damage. Symptoms may include: 2. changes in blood pressure and falls. 3. Serotonin Syndrome: This condition can be life-threatening and symptoms may include: 4. abnormal bleeding: 5. severe skin reactions: 6. discontinuation symptoms: 7. manic episodes: 8. visual problems: Only some people are at risk for these problems. You may want to undergo an eye examination to see if you are at risk and receive preventative treatment if you are. 9. seizures or convulsions 10. low salt (sodium) levels in the blood. 11. problems with urination. Symptoms may include: The most common side effects of duloxetine delayed-release capsules include: Common possible side effects in children and adolescents who take duloxetine delayed-release capsules include: 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. What are the ingredients in duloxetine delayed-release capsules? This Medication Guide has been approved by the U.S. Food and Drug Administration. Dispense with Medication Guide available at: www.prasco.com Prasco Laboratories Aurobindo Pharma Limited Repackaged By / Distributed By: RemedyRepack Inc. 625 Kolter Drive, Indiana, PA 15701 (724) 465-8762 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. 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. It is not known if duloxetine delayed-release capsules will harm your unborn baby. Talk to your healthcare provider about the benefits and risks of treating depression or other conditions with duloxetine delayed-release capsules during pregnancy. are breastfeeding or plan to breastfeed. Duloxetine delayed-release capsules can pass into your breast milk. Talk to your healthcare provider about the best way to feed your baby while taking duloxetine delayed-release capsules. 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 and fentanyl 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. 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 works. 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 hydrochloride, 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. 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 affect 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. itching right upper abdominal pain dark urine yellow skin or eyes enlarged liver increased liver enzymes 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. 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 anxiety irritability feeling tired or problems sleeping headache sweating dizziness electric shock-like sensations vomiting or nausea diarrhea greatly increased energy severe trouble sleeping racing thoughts reckless behavior unusually grand ideas excessive happiness or irritability talking more or faster than usual eye pain changes in vision swelling or redness in or around the eye headache weakness or feeling unsteady confusion, problems concentrating or thinking or memory problems decreased urine flow unable to pass any urine nausea dry mouth sleepiness fatigue constipation loss of appetite increased sweating dizziness nausea decreased weight dizziness

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