DULOXETINE

6 ADVERSE REACTIONS 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 )] Most common adverse reactions (≥5% and at least twice the incidence of placebo-treated patients): ( 6. 1). Adults : nausea, dry mouth, somnolence, constipation, decreased appetite, and hyperhidrosis Pediatric Patients : decreased weight, decreased appetite, nausea, vomiting, fatigue, and diarrhea To report SUSPECTED ADVERSE REACTIONS, contact Solco Healthcare US LLC . at 1-866-257-2597 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 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 therapy and not mentioned elsewhere in labeling include: anaphylactic reaction, aggression and anger (particularly early in treatment or after treatment discontinuation), angioneurotic edema, angle-closure glaucoma, 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.

4 CONTRAINDICATIONS 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 ) and 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 ) and Warnings and Precautions ( 5.4 )] . Concomitant use of an MAOI antidepressant with duloxetine delayed-release capsules is contraindicated Use of duloxetine delayed-release capsules within 14 days of stopping an MAOI antidepressant is contraindicated In linezolid-or intravenous methylene blue-treated patients, initiation of duloxetine delayed-release capsules is contraindicated ( 4 )

11 DESCRIPTION Duloxetine delayed-release capsules, USP are a selective serotonin and norepinephrine reuptake inhibitor (SSNRI) for oral administration. Its chemical designation is (+)-( S )- N -methyl-γ-(1-naphthyloxy)-2-thiophenepropylamine hydrochloride. The empirical formula is C 18 H 19 NOS•HCl, which corresponds to a molecular weight of 333.88. The structural formula is: Duloxetine hydrochloride is a white to slightly brownish white solid, which is slightly soluble in water. Each capsule contains enteric-coated pellets of 20, 30, or 60 mg of duloxetine (equivalent to 22.4, 33.7, or 67.3 mg of duloxetine hydrochloride, respectively). These enteric-coated pellets are designed to prevent degradation of the drug in the acidic environment of the stomach. Inactive ingredients include sugar spheres (sucrose and maize starch), hypromellose, sucrose, talc, hydroxypropyl methylcellulose acetate succinate, triethyl citrate, polyvinyl alcohol-part hydrolyzed, titanium dioxide, macrogol/peg and gelatin. The 30 mg capsules also contain FD&C Blue 1 and D&C Yellow 10. The 60 mg capsules also contain FD&C Blue 1 and FD&C Red 3. Chemical Structure

2 DOSAGE AND ADMINISTRATION Take duloxetine delayed-release capsules once daily, with or without food. Swallow duloxetine delayed-release capsules whole; do not crush, chew, or open capsule. ( 2 .1) Indication Starting Dose Target Dose Maximum Dose MDD ( 2. 2) 40 mg/day to 60 mg/day Acute Treatment: 40 mg/day (20 mg twice daily) to 60 mg/day (once daily or as 30 mg twice daily); Maintenance Treatment: 60 mg/day 120 mg/day GAD ( 2. 3) Adults Geriatric Pediatrics (7 to 17 years of age) 60 mg/day 30 mg/day 30 mg/day 60 mg/day (once daily) 60 mg/day (once daily) 30 to 60 mg/day (once daily) 120 mg/day 120 mg/day 120 mg/day DPNP ( 2. 4) 60 mg/day 60 mg/day (once daily) 60 mg/day FM ( 2.5 ) Adults 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. 8, 5.7 ) 2.1 Important Administration Instructions 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. 2.2 Dosage for Treatment of Major Depressive Disorder in Adult 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. 2.3 Dosage for Treatment of Generalized Anxiety Disorder 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. 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 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 to 17 Years of Age Initiate duloxetine delayed-release capsules in pediatric patients 7 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 dosage range is 30 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. The maximum dose studied was 120 mg per day. 2.4 Dosage for Treatment of Diabetic Peripheral Neuropathic Pain in Adult 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. For patients for whom tolerability is a concern, a lower starting dose may be considered. 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. 7) and Clinical Pharmacology ( 12.3 )] . 2.5 Dosage for Treatment of Fibromyalgia Recommended Dosage in Adults The recommended duloxetine delayed-release capsules 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. Additional pediatric use information is approved for Eli Lilly and Company, Inc.’s CYMBALTA (duloxetine) delayed-release capsules. However, due to Eli Lilly and Company Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 2.6 Dosage for Treatment of Chronic Musculoskeletal Pain in Adults 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 )] . 2.7 Dosage in Patients with Hepatic Impairment or Severe Renal Impairment Avoid use in patients with chronic liver disease or cirrhosis [see Warnings and Precautions ( 5.14 ) and Use in Specific Populations ( 8.9 )] . Avoid use in patients with severe renal impairment, GFR <30 mL/minute [see Warnings and Precautions ( 5.14 ) and Use in Specific Populations ( 8.10 )] . 2.8 Discontinuing Duloxetine Delayed-Release Capsules 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 )] . 2.9 Switching a Patient to or from a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with duloxetine delayed-release capsules. Conversely, at least 5 days should be allowed after stopping duloxetine delayed-release capsules before starting an MAOI intended to treat psychiatric disorders [see Contraindications ( 4 )]. 2.10 Use of Duloxetine Delayed-Release Capsules with Other MAOIs such as Linezolid or Methylene Blue Do not start duloxetine delayed-release capsules in a patient who is being treated with linezolid or intravenous methylene blue because there is an increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered [see Contraindications ( 4 )] . In some cases, a patient already receiving duloxetine therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, duloxetine 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 may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue [see Warnings and Precautions ( 5.4 )] . The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with duloxetine is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use [see Warnings and Precautions ( 5.4 )] .

1 INDICATIONS AND USAGE Duloxetine delayed-release capsules, USP 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 Chronic musculoskeletal pain in adults Additional pediatric use information is approved for Eli Lilly and Company, Inc.’s CYMBALTA (duloxetine) delayed-release capsules. However, due to Eli Lilly and Company Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. Duloxetine is 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 ( 1 ) Chronic musculoskeletal pain in adult ( 1 )

9 DRUG ABUSE AND DEPENDENCE 9.2 Abuse In animal studies, duloxetine did not demonstrate barbiturate-like (depressant) abuse potential. While duloxetine has not been systematically studied in humans for its potential for abuse, there was no indication of drug-seeking behavior in the clinical trials. However, it is not possible to predict on the basis of premarketing experience the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for a history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of duloxetine (e.g., development of tolerance, incrementation of dose, drug-seeking behavior). 9.3 Dependence In drug dependence studies, duloxetine did not demonstrate dependence-producing potential in rats.

10 OVERDOSAGE 10.1 Signs and Symptoms In postmarketing experience, fatal outcomes have been reported for acute 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. 10.2 Management of Overdose 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 Cmax by an average of one-third, although some patients had a limited effect of activated charcoal. Due to the large volume of distribution of duloxetine, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be beneficial. In managing overdose, the possibility of multiple drug involvement should be considered. A specific caution involves patients who 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 ) and Drug Interactions ( 7 )] . Consider contacting a poison control center (1-800-222-1222 or www.poison.org) for additional information on the treatment of overdosage.

7 DRUG INTERACTIONS Both CYP1A2 and CYP2D6 are responsible for duloxetine metabolism. Potent inhibitors of CYP1A2 should be avoided ( 7.1 ). Potent inhibitors of CYP2D6 may increase duloxetine concentrations ( 7.2 ). Duloxetine is a moderate inhibitor of CYP2D6 ( 7.9 ). 7.1 Inhibitors of CYP1A2 When duloxetine 60 mg was co-administered with fluvoxamine 100 mg, a potent CYP1A2 inhibitor, to male subjects (n=14) duloxetine AUC was increased approximately 6-fold, the C max was increased about 2.5-fold, and duloxetine t 1/2 was increased approximately 3-fold. Other drugs that inhibit CYP1A2 metabolism include cimetidine and quinolone antimicrobials such as ciprofloxacin and enoxacin [see Warnings and Precautions ( 5.12 )] . 7.2 Inhibitors of CYP2D6 Concomitant use of duloxetine (40 mg once daily) with paroxetine (20 mg once daily) increased the concentration of duloxetine AUC by about 60%, and greater degrees of inhibition are expected with higher doses of paroxetine. Similar effects would be expected with other potent CYP2D6 inhibitors (e.g., fluoxetine, quinidine) [see Warnings and Precautions ( 5.12 )] . 7.3 Dual Inhibition of CYP1A2 and CYP2D6 Concomitant administration of duloxetine 40 mg twice daily with fluvoxamine 100 mg, a potent CYP1A2 inhibitor, to CYP2D6 poor metabolizer subjects (n=14) resulted in a 6-fold increase in duloxetine AUC and C max . 7.4 Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin) Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs or SNRIs are co-administered with warfarin. Concomitant administration of warfarin (2-9 mg once daily) under steady state conditions with duloxetine 60 or 120 mg once daily for up to 14 days in healthy subjects (n=15) did not significantly change INR from baseline (mean INR changes ranged from 0.05 to +0.07). The total warfarin (protein bound plus free drug) pharmacokinetics (AUC ԏ,ss , C max,ss or t max,ss ) for both R- and S-warfarin were not altered by duloxetine. Because of the potential effect of duloxetine on platelets, patients receiving warfarin therapy should be carefully monitored when duloxetine is initiated or discontinued [see Warnings and Precautions ( 5.5 )] . 7.5 Lorazepam Under steady-state conditions for duloxetine (60 mg Q 12 hours) and lorazepam (2 mg Q 12 hours), the pharmacokinetics of duloxetine were not affected by co-administration. 7.6 Temazepam Under steady-state conditions for duloxetine (20 mg qhs) and temazepam (30 mg qhs), the pharmacokinetics of duloxetine were not affected by co-administration. 7.7 Drugs that Affect Gastric Acidity Duloxetine delayed-release capsules have an enteric coating that resists dissolution until reaching a segment of the gastrointestinal tract where the pH exceeds 5.5. In extremely acidic conditions, duloxetine, 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.g., 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 )] . 7.8 Drugs Metabolized by CYP1A2 In vitro drug interaction studies demonstrate that duloxetine does not induce CYP1A2 activity. Therefore, an increase in the metabolism of CYP1A2 substrates (e.g., theophylline, caffeine) resulting from induction is not anticipated, although clinical studies of induction have not been performed. Duloxetine is an inhibitor of the CYP1A2 isoform in in vitro studies, and in two clinical studies the average (90% confidence interval) increase in theophylline AUC was 7% (1%-15%) and 20% (13%-27%) when co-administered with duloxetine (60 mg twice daily). 7.9 Drugs Metabolized by CYP2D6 Duloxetine is a moderate inhibitor of CYP2D6. When duloxetine was administered (at a dose of 60 mg twice daily) in conjunction with a single 50 mg dose of desipramine, a CYP2D6 substrate, the AUC of desipramine increased 3-fold [see Warnings and Precautions ( 5.12 )] . 7.10 Drugs Metabolized by CYP2C9 Results of in vitro studies demonstrate that duloxetine does not inhibit activity. In a clinical study, the pharmacokinetics of S-warfarin, a CYP2C9 substrate, were not significantly affected by duloxetine [see Drug Interactions ( 7.4 )] . 7.11 Drugs Metabolized by CYP3A Results of in vitro studies demonstrate that duloxetine does not inhibit or induce CYP3A activity. Therefore, an increase or decrease in the metabolism of CYP3A substrates (e.g., oral contraceptives and other steroidal agents) resulting from induction or inhibition is not anticipated, although clinical studies have not been performed. 7.12 Drugs Metabolized by CYP2C19 Results of in vitro studies demonstrate that duloxetine does not inhibit CYP2C19 activity at therapeutic concentrations. Inhibition of the metabolism of CYP2C19 substrates is therefore not anticipated, although clinical studies have not been performed. 7.13 Monoamine Oxidase Inhibitors (MAOIs) [See Dosage and Administration ( 2. 9, 2.10 ), Contraindications ( 4 ), and Warnings and Precautions ( 5.4 )] . 7.14 Serotonergic Drugs [See Dosage and Administration ( 2.9 , 2.10 ), Contraindications ( 4 ), and Warnings and Precautions ( 5.4 )] . 7.15 Alcohol When duloxetine and ethanol were administered several hours apart so that peak concentrations of each would coincide, duloxetine did not increase the impairment of mental and motor skills caused by alcohol. In the duloxetine clinical trials database, three duloxetine-treated patients had liver injury as manifested by ALT and total bilirubin elevations, with evidence of obstruction. Substantial intercurrent ethanol use was present in each of these cases, and this may have contributed to the abnormalities seen [see Warnings and Precautions ( 5.2 , 5.12 )] . 7.16 CNS Drugs [See Warnings and Precautions ( 5.12 )] . 7.17 Drugs Highly Bound to Plasma Protein 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 (2-9 mg), a highly protein-bound drug, did not result in significant changes in INR and in the pharmacokinetics of either total S-or total R-warfarin (protein bound plus free drug) [see Drug Interactions ( 7.4 )] .

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 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. 12.2 Pharmacodynamics 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 does not inhibit monoamine oxidase (MAO). 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 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. 12.3 Pharmacokinetics 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 After oral duloxetine administration, duloxetine hydrochloride is well absorbed. There is a median 2 hour lag until absorption begins (T lag ), with maximal plasma concentrations (C max ) of duloxetine occurring 6 hours post dose. There is a 3 hour delay in absorption and a one-third increase in apparent clearance of duloxetine after an evening dose as compared to a morning dose. Effect of Food: Food does not affect the Cmax of duloxetine, but delays the time to reach peak concentration from 6 to 10 hours and it marginally decreases the extent of absorption (AUC) by about 10%. Distribution The apparent volume of distribution averages about 1640 L. Duloxetine is highly bound (>90%) to proteins in human plasma, binding primarily to albumin and α1-acid glycoprotein. The interaction between duloxetine and other highly protein bound drugs has not been fully evaluated. Plasma protein binding of duloxetine is not affected by renal or hepatic impairment. Elimination Metabolism Biotransformation and disposition of duloxetine in humans have been determined following oral administration of 14 C-labeled duloxetine. Duloxetine comprises about 3% of the total radiolabeled material in the plasma, indicating that it undergoes extensive metabolism to numerous metabolites. The major biotransformation pathways for duloxetine involve oxidation of the naphthyl ring followed by conjugation and further oxidation. Both CYP1A2 and CYP2D6 catalyze the oxidation of the naphthyl ring in vitro . Metabolites found in plasma include 4-hydroxy duloxetine glucuronide and 5-hydroxy, 6-methoxy duloxetine sulfate. Excretion Many additional metabolites have been identified in urine, some representing only minor pathways of elimination. Only trace (<1% of the dose) amounts of unchanged duloxetine are present in the urine. Most (about 70%) of the duloxetine dose appears in the urine as metabolites of duloxetine; about 20% is excreted in the feces. Duloxetine undergoes extensive metabolism, but the major circulating metabolites have not been shown to contribute significantly to the pharmacologic activity of duloxetine. Specific Populations Pediatric Patients Duloxetine steady-state plasma concentration was comparable in pediatric patients 7 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 to 17 years of age were mostly within the concentration range observed in adult patients and did not exceed the concentration range in adults.

20230320

2

3 DOSAGE FORMS AND STRENGTHS Duloxetine is available as delayed-release capsules: 20 mg opaque white capsules imprinted with “557” on the cap and “20mg” on the body. 30 mg opaque white cap/opaque light green body imprinted “558” on the cap and “30mg” on the body. 60 mg opaque white cap/opaque dark blue body imprinted “559” on the cap and “60mg” on the body. Delayed-release capsules: 20 mg, 30 mg, and 60 mg ( 3 )

DULOXETINE Duloxetine STARCH, CORN HYPROMELLOSE 2910 (5 MPA.S) SUCROSE TALC HYPROMELLOSE ACETATE SUCCINATE 06081224 (3 MM2/S) TRIETHYL CITRATE POLYVINYL ALCOHOL, UNSPECIFIED TITANIUM DIOXIDE POLYETHYLENE GLYCOL 3350 GELATIN, UNSPECIFIED FD&C BLUE NO. 1 D&C YELLOW NO. 10 DULOXETINE HYDROCHLORIDE DULOXETINE cap: opaque white body: opaque light green 558;30mg

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 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 basis), there was an increased incidence of hepatocellular adenomas and carcinomas. The no- effect dose was 50 mg/kg/day (1 time the MRHD given to children). Tumor incidence was not increased in male mice receiving duloxetine at doses up to 100 mg/kg/day (2 times the MRHD given to children). In rats, dietary doses of duloxetine up to 27 mg/kg/day in females (1 time the MRHD given to children) and up to 36 mg/kg/day in males (1.4 times the MRHD given to children) did not increase the incidence of tumors. Mutagenesis Duloxetine was not mutagenic in the in vitro bacterial reverse mutation assay (Ames test) and was not clastogenic in an in vivo chromosomal aberration test in mouse bone marrow cells. Additionally, duloxetine was not genotoxic in an in vitro mammalian forward gene mutation assay in mouse lymphoma cells or in an in vitro unscheduled DNA synthesis (UDS) assay in primary rat hepatocytes, and did not induce sister chromatid exchange in Chinese hamster bone marrow 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 basis) did not alter mating or fertility.

ANDA206653

DULOXETINE

Duloxetine

70518-3177

HUMAN PRESCRIPTION DRUG

ORAL

DRUG: DULOXETINE GENERIC: Duloxetine DOSAGE: CAPSULE, DELAYED RELEASE ADMINSTRATION: ORAL NDC: 70518-3177-0 NDC: 70518-3177-1 COLOR: white SHAPE: CAPSULE SCORE: No score SIZE: 16 mm IMPRINT: 558;30mg PACKAGING: 90 in 1 BOTTLE, PLASTIC PACKAGING: 30 in 1 BLISTER PACK ACTIVE INGREDIENT(S): DULOXETINE HYDROCHLORIDE 30mg in 1 INACTIVE INGREDIENT(S): STARCH, CORN HYPROMELLOSE 2910 (5 MPA.S) SUCROSE TALC HYPROMELLOSE ACETATE SUCCINATE 06081224 (3 MM2/S) TRIETHYL CITRATE POLYVINYL ALCOHOL, UNSPECIFIED TITANIUM DIOXIDE POLYETHYLENE GLYCOL 3350 GELATIN, UNSPECIFIED FD&C BLUE NO. 1 D&C YELLOW NO. 10 Remedy_Label MM2

Dosage and Administration (2.5) 04/2020 Warnings and Precautions (5.5) 10/2019

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Suicidal Thoughts and Behaviors — Advise patients, their families, and their caregivers to look for the emergence of suicidal ideation and behavior, especially during treatment and when the dose is adjusted up or down and instruct them to report such symptoms to their healthcare provider [see Boxed Warning and Warnings and Precautions (5.1)] . Administration — Advise patients to swallow duloxetine delayed-release capsules whole and to not chew, crush, or open the capsule (do not sprinkle contents on food or mixed with liquids) because these actions might affect the enteric coating. Hepatotoxicity — Inform patients that severe liver problems, sometimes fatal, have been reported in patients treated with duloxetine delayed-release capsules. Instruct patients to talk to their healthcare provider if they develop itching, right upper belly pain, dark urine, or yellow skin/eyes while taking duloxetine delayed-release capsules, which may be signs of liver problems. Instruct patients to talk to their healthcare provider about their alcohol consumption. Use of duloxetine delayed-release capsules with heavy alcohol intake may be associated with severe liver injury [ see Warnings and Precautions (5.2) ]. Alcohol — Although duloxetine delayed-release capsules do not increase the impairment of mental and motor skills caused by alcohol, use of duloxetine delayed-release capsules concomitantly with heavy alcohol intake may be associated with severe liver injury. For this reason, duloxetine delayed-release capsules should not be prescribed for patients with substantial alcohol use [ see Warnings and Precautions (5.2) and Drug Interactions (7.15) ]. Orthostatic Hypotension, Falls and Syncope — Advise patients of the risk of orthostatic hypotension, falls and syncope, especially during the period of initial use and subsequent dose escalation, and in association with the use of concomitant drugs that might potentiate the orthostatic effect of duloxetine delayed-release capsules [ see Warnings and Precautions (5.3) ]. Serotonin Syndrome — Caution patients about the risk of serotonin syndrome with the concomitant use of duloxetine delayed-release capsules and other serotonergic agents including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, amphetamines, and St. John’s Wort [ see Contraindications (4), Warnings and Precautions (5.4), and Drug Interactions (7.14) ]. Advise patients of the signs and symptoms associated with serotonin syndrome that may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular changes (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Caution patients to seek medical care immediately if they experience these symptoms. Increased Risk of Bleeding — Caution patients about the concomitant use of duloxetine delayed-release capsules and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding [ see Warnings and Precautions (5.5) and Use in Specific Populations (8.1)]. Severe Skin Reactions — Caution patients that duloxetine delayed-release capsules may cause serious skin reactions. This may need to be treated in a hospital and may be life-threatening. Counsel patients to call their doctor right away or get emergency help if they have skin blisters, peeling rash, sores in their mouth, hives, or any other allergic reactions [ see Warnings and Precautions (5.6) ]. Discontinuation of Treatment — Instruct patients that discontinuation of duloxetine delayed-release capsules may be associated with symptoms such as dizziness, headache, nausea, diarrhea, paresthesia, irritability, vomiting, insomnia, anxiety, hyperhidrosis, and fatigue, and should be advised not to alter their dosing regimen, or stop taking duloxetine delayed-release capsules without consulting their health provider [ see Warnings and Precautions (5.7) ]. Activation of Mania or Hypomania — Adequately screen patients with depressive symptoms for risk of bipolar disorder (e.g. family history of suicide, bipolar disorder, and depression) prior to initiating treatment with duloxetine delayed-release capsules. Advise patients to report any signs or symptoms of a manic reaction such as greatly increased energy, severe trouble sleeping, racing thoughts, reckless behavior, talking more or faster than usual, unusually grand ideas, and excessive happiness or irritability [ see Warnings and Precautions (5.8) ]. Angle-Closure Glaucoma — Advise patients that taking duloxetine delayed-release capsules can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle-closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle-closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle-closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle-closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible. [ see Warnings and Precautions (5.9) ]. Seizures — Advise patients to inform their health provider if they have a history of seizure disorder [ see Warnings and Precautions (5.10) ] Effects on Blood Pressure — Caution patients that duloxetine delayed-release capsules may cause an increase in blood pressure [ see Warnings and Precautions (5.11) ]. Concomitant Medications — Advise patients to inform their health provider if they are taking, or plan to take, any prescription or over-the-counter medications, since there is a potential for interactions [ see Dosage and Administration (2.8, 2.9), Contraindications (4), Warnings and Precautions (5.4, 5.12), and Drug Interactions (7) ]. Hyponatremia — Advise patients that hyponatremia has been reported as a result of treatment with SNRIs and SSRIs, including duloxetine delayed-release capsules. Advise patients of the signs and symptoms of hyponatremia [ see Warnings and Precautions (5.13) ]. Concomitant Illnesses — Advise patients to inform their physicians about all of their medical conditions [ see Warnings and Precautions (5.14) ]. Urinary Hesitation and Retention — Duloxetine delayed-release capsules are in a class of medicines that may affect urination. Instruct patients to consult with their healthcare provider if they develop any problems with urine flow [see Warnings and Precautions (5.15)] . Pregnancy Advise women to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with duloxetine delayed-release capsules. Advise pregnant women or patients who intend to become pregnant that duloxetine delayed-release capsules use during the month before delivery may lead to an increased risk for postpartum hemorrhage and may increase the risk of neonatal complications requiring prolonged hospitalization, respiratory support, and tube feeding. Advise pregnant women that there is a risk of relapse with discontinuation of antidepressants. Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to duloxetine during pregnancy [see Use in Specific Populations (8.1)] . Lactation ― Advise breastfeeding women using duloxetine delayed-release capsules to monitor infants for sedation, poor feeding and poor weight gain and to seek medical care if they notice these signs [see Use in Specific Populations (8.2)] . Interference with Psychomotor Performance — Duloxetine delayed-release capsules may be associated with sedation and dizziness. Therefore, caution patients about operating hazardous machinery including automobiles, until they are reasonably certain that duloxetine delayed-release capsules therapy does not affect their ability to engage in such activities. Repackaged By / Distributed By: RemedyRepack Inc. 625 Kolter Drive, Indiana, PA 15701 (724) 465-8762

MEDICATION GUIDE Duloxetine delayed-release capsules, USP (Doo-Lox-e-teen) 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? 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. These include people who have (or have a family history of) bipolar illness (also called manic-depressive illness). 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? Duloxetine delayed-release capsules are a prescription medicine used to treat a certain type of depression called Major Depressive Disorder (MDD). Duloxetine delayed-release capsules belong to a class of medicines known as SNRIs (or serotonin-norepinephrine reuptake inhibitors). Duloxetine delayed-release capsules are also used to treat or manage: 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). Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI, including the antibiotic linezolid or intravenous methylene blue. 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? Before starting duloxetine delayed-release capsules, tell your healthcare provider if you: 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. If you become pregnant while taking duloxetine delayed-release capsules, talk to your healthcare provider. 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, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Duloxetine delayed-release capsules and some medicines may interact with each other, may not work as well, or may cause serious side effects. 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 and fentanyl 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. Do not take duloxetine delayed-release capsules with any other medicine that contain duloxetine. 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 many 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 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. What are the possible side effects of duloxetine delayed-release capsules? Duloxetine delayed-release capsules may cause serious side effects, including: See “What is the most important information I should know about 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. 3. 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: Duloxetine delayed-release capsules and other antidepressant medicines may increase your risk of bleeding or bruising, especially if you take the blood thinner warfarin (Coumadin, Jantoven), a non-steroidal anti-inflammatory drug (NSAIDs, like ibuprofen or naproxen), or aspirin. 5. severe skin reactions: Duloxetine delayed-release capsules may cause serious skin reactions that may require stopping its use. This may need to be treated in a hospital and may be life-threatening. Call your healthcare provider right away or get emergency help if you have skin blisters, peeling rash, sores in the mouth, hives or any other allergic reactions. 6. discontinuation symptoms: Do not stop duloxetine delayed-release capsules without first talking to your healthcare provider. Stopping duloxetine delayed-release capsules too quickly or changing from another antidepressant too quickly may result in serious symptoms including: 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 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. Elderly people may be at greater risk for this. Symptoms may include: 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 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. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of duloxetine delayed-release capsules. For more information, ask your healthcare provider or pharmacist. 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? Store duloxetine delayed-release capsules at room temperature between 68°F to 77°F (20°C to 25°C). 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. For more information about duloxetine delayed-release capsules call Solcon Healthcare US LLC. at 1-866-257-2597. What are the ingredients in duloxetine delayed-release capsules? Active ingredient: duloxetine hydrochloride Inactive ingredients: sugar spheres (maize starch), hypromellose, sucrose, talc, hydroxypropyl methylcellulose acetate succinate, triethyl citrate, polyvinyl alcohol-part hydrolyzed, titanium dioxide, macrogol/peg and gelatin. The 30 mg capsules also contain FD&C Blue 1 and D&C Yellow 10. The 60 mg capsules also contain FD&C Blue 1 and FD&C Red 3. This Medication Guide has been approved by the U.S. Food and Drug Administration. Coumadin, Jantoven, and Mellaril are trademarks of their respective owners and not trademarks of Prinston Pharmaceutical Inc. Repackaged By / Distributed By: RemedyRepack Inc. 625 Kolter Drive, Indiana, PA 15701 (724) 465-8762

14 CLINICAL STUDIES 14.1 Overview of the Clinical Trials The efficacy of duloxetine has been established in the following populations in adequate and well-controlled trials: Major Depressive Disorder (MDD): 4 short-term (Studies MDD-1, MDD-2, MDD-3, and MDD-4) and 1 maintenance trial (Study MDD-5) in adults [see Clinical Studies ( 14.1 )] . Generalized Anxiety Disorder (GAD): 3 short-term trials in adults (Studies GAD-1, GAD-2, and GAD-3), 1 maintenance trial in adults (Study GAD-4), 1 short-term trial in geriatric patients (Study GAD-5) , and 1 short-term trial in pediatric patients 7 to 17 years of age (Study GAD-6) [see Clinical Studies ( 14.2 )] . Diabetic Peripheral Neuropathic Pain (DPNP): Two 12-week trials in adults (Studies DPNP-1 and DPNP-2) [see Clinical Studies ( 14.3 )]. Fibromyalgia (FM): Two trials in adults (one of 3 months duration and one of 6 months duration) (Studies FM-1 and FM-2) [see Clinical Studies ( 14.5 )]. Chronic Musculoskeletal Pain: Two 12-to 13-week trials in adult patients with chronic low back pain (CLBP) (Studies CLBP-1 and CLBP-3) and one 13-week trial in adult patients with chronic pain due to osteoarthritis (OA) (Study OA-1) [see Clinical Studies ( 14.6 )] . Additionally, a summary of the following trials that did not demonstrate efficacy are presented below: Study FM-3 (a 16week 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). Additional pediatric use information is approved for Eli Lilly and Company, Inc.’s CYMBALTA (duloxetine) delayed-release capsules. However, due to Eli Lilly and Company Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 14.2 Major Depressive Disorder in Adults 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 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 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 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 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 8: Summary of the Primary Efficacy Results for Adult Trials in MDD 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 Difference (drug minus placebo) in least-squares mean change from baseline. b Doses statistically significantly superior to placebo. 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 MDD-1 Duloxetine (60 mg/day) b 21.5 (4.10) -10.9 (0.70) -4.9 (-6.8, -2.9) Placebo 21.1 (3.71) -6.1 (0.69) -- Study MDD-2 Duloxetine (60 mg/day) b 20.3 (3.32) -10.5 (0.71) -2.2 (-4.0, -0.3) Placebo 20.5 (3.42) -8.3 (0.67) -- Study MDD-3 Duloxetine (20 mg BID) b 18.6 (5.85) -7.4 (0.80) -2.4 (-4.7, -0.2) Duloxetine (40 mg BID) b 18.1 (4.52) -8.6 (0.81) -3.6 (-5.9, -1.4) Placebo 17.2 (5.11) -5.0 (0.81) -- Study MDD-4 Duloxetine (40 mg BID) b 19.9 (3.54) -11.0 (0.49) -2.2 (-3.6, -0.9) Duloxetine (60 mg BID) b 20.2 (3.41) -12.1 (0.49) -3.3 (-4.7, -1.9) Placebo 19.9 (3.58) -8.8 (0.50) -- In Study MDD-5, 533 patients meeting DSM-IV criteria for MDD received duloxetine 60 mg once daily during an initial 12-week open-label treatment phase. Two hundred and seventy-eight patients who responded to open label treatment [defined as meeting the following criteria at weeks 10 and 12: a HAMD-17 total score ≤9, Clinical Global Impressions of Severity (CGI-S) ≤2, and not meeting the DSM-IV criteria for MDD] were randomly assigned to continuation of duloxetine at the same 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 ≥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 of Adult Patients with MDD Relapse (MDD Study 5) a Kaplan-Meier estimator method. Image 1 14.3 Generalized Anxiety Disorder 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 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 104.8 mg/day. 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 ≥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 ≥65 years of age with GAD 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 (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 to 17 Years Old The efficacy of duloxetine in the treatment of pediatric patients 7 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 57.6 mg/day. 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 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 Difference (drug minus placebo) in least squares mean change from baseline. b Dose statistically significantly superior to placebo. 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 GAD-1 (Adult) (HAM-A) Duloxetine (60 mg/day) b 25.1 (7.18) -12.8 (0.68) -4.4 (-6.2, -2.5) Duloxetine (120 mg/day) b 25.1 (7.24) -12.5 (0.67) -4.1 (-5.9, -2.3) Placebo 25.8 (7.66) -8.4 (0.67) -- Study GAD-2 (Adult) (HAM-A) Duloxetine (60-120 mg/day) b 22.5 (7.44) -8.1 (0.70) -2.2 (-4.2, -0.3) Placebo 23.5 (7.91) -5.9 (0.70) -- Study GAD-3 (Adult) (HAM-A) Duloxetine (60-120 mg/day) b 25.8 (5.66) -11.8 (0.69) -2.6 (-4.5, -0.7) Placebo 25.0 (5.82) -9.2 (0.67) -- Study GAD-5 (Geriatric) (HAM-A) Duloxetine (60-120 mg/day) b 24.6 (6.21) -15.9 (0.63) -4.2 (-5.9, -2.5) Placebo 24.5 (7.05) -11.7 (0.67) -- Study GAD-6 (Pediatric) (PARS for GAD) Duloxetine (30-120 mg/day) b 17.5 (1.98) -9.7 (0.50) -2.7 (-4.0, -1.3) Placebo 17.4 (2.24) -7.1 (0.50) -- Figure 2: Cumulative Proportiona of Adult Patients with GAD Relapse (Study GAD-4) a Kaplan-Meier estimator method. Image 2 14.4 Diabetic Peripheral Neuropathic Pain in Adult 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 ≥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-HourAverage Pain Severity (Study DPNP-2) Image 3 Image 4 14.5 Fibromyalgia 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%. 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. 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 at 60 mg/day was evaluated in a separate trial (Study FM-3). Adult patients were initially treated with duloxetine 60 mg once daily for eight weeks in open-label fashion. Subsequently, completers of this phase were randomized to double-blind treatment with duloxetine 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 120 mg as compared to those who were blindly continued on duloxetine 60 mg. Additional pediatric use information is approved for Eli Lilly and Company, Inc.’s CYMBALTA (duloxetine) delayed-release capsules. However, due to Eli Lilly and Company Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. Image 5 Image 6 14.6 Chronic Musculoskeletal Pain in Adults Duloxetine is 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 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 in the treatment of CLBP. Patients in all trials had no signs of radiculopathy or spinal stenosis. Study CLBP-1: Two hundred thirty-six adult patients (N=115 on duloxetine, N=121 on placebo) enrolled and 182 (77%) completed 13-week treatment phase. After 7 weeks of treatment, duloxetine-treated patients with less than 30% reduction in average daily pain and who were able to tolerate 60 mg once daily had their duloxetine dosage, in a double-blinded fashion, increased to 120 mg once daily for the remainder of the trial. Patients had a mean baseline pain rating of 6 on a numerical rating scale ranging from 0 (no pain) to 10 (worst possible pain). After 13 weeks of treatment, patients taking duloxetine 60-120 mg daily had a significantly greater pain reduction compared to patients taking placebo. Randomization was stratified by the patients’ baseline NSAIDs use status. Subgroup analyses did not indicate that there were differences in treatment outcomes as a function of NSAIDs use. Study CLBP-2: Four hundred and four patients were randomized to receive fixed dosages of duloxetine daily or a matching placebo (N=59 on duloxetine 20 mg, N=116 on duloxetine 60 mg, N=112 on duloxetine 120 mg, N=117 on placebo) and 267 (66%) completed the entire 13-week trial. After 13 weeks of treatment, none of the three duloxetine dosages showed a statistically significant difference in pain reduction compared to placebo. Study CLBP-3: Four hundred and one patients were randomized to receive fixed doses of duloxetine 60 mg daily or placebo (N=198 on duloxetine, N=203 on placebo), and 303 (76%) completed the trial. Patients had a mean baseline pain rating of 6 on a numerical rating scale ranging from 0 (no pain) to 10 (worst possible pain). After 12 weeks of treatment, patients taking duloxetine 60 mg daily had significantly greater pain reduction compared to patients taking placebo. 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. 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 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 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 started treatment in both trials at a dose of 30 mg once daily for one week. After the first week, the dose of duloxetine was increased to 60 mg once daily. After 7 weeks of treatment with duloxetine 60 mg once daily, in Study OA-1 patients with sub-optimal response to treatment (<30% pain reduction) and tolerated duloxetine 60 mg once daily had their dose increased to 120 mg. However, in Study OA-2, all patients, regardless of their response to treatment after 7 weeks, were re-randomized to either continue receiving duloxetine 60 mg once daily or have their 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 60 mg and 120 mg once daily treatment groups compared to the placebo group. Study OA-1: Two hundred fifty-six patients (N=128 on duloxetine, N=128 on placebo) enrolled and 204 (80%) completed the trial. Patients had a mean baseline pain rating of 6 on a numerical rating scale ranging from 0 (no pain) to 10 (worst possible pain). After 13 weeks of treatment, patients taking duloxetine had significantly greater pain reduction than patients taking placebo. Subgroup analyses did not indicate that there were differences in treatment outcomes as a function of NSAIDs use. Study OA-2: Two hundred thirty-one patients (N=111 on duloxetine, N=120 on placebo) enrolled and 173 (75%) completed the trial. Patients had a mean baseline pain of 6 on a numerical rating scale ranging from 0 (no pain) to 10 (worst possible pain). After 13 weeks of treatment, patients taking duloxetine did not show a significantly greater pain reduction than patients taking placebo. 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%. Patients who did not complete the trial were assigned the value of 0% improvement. 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) Image 7 Image 8 Image 9

8 USE IN SPECIFIC POPULATIONS Pregnancy : Third trimester use may increase risk for symptoms of poor adaptation (respiratory distress, temperature instability, feeding difficulty, hypotonia, tremor, irritability) in the neonate ( 8.1 ) 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/minute ( 5.14 ) Additional pediatric use information is approved for Eli Lilly and Company, Inc.’s CYMBALTA (duloxetine) delayed-release capsules. However, due to Eli Lilly and Company Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 8.1 Pregnancy 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). There are risks associated with untreated depression and fibromyalgia in pregnancy, and with exposure to SNRIs and SSRIs, including duloxetine, during pregnancy (see Clinical Considerations) . In rats and rabbits treated with duloxetine during the period of organogenesis, fetal weights were decreased but there was no evidence of developmental effects at doses up to 3 and 6 times, respectively, the maximum recommended human dose (MRHD) of 120 mg/day given to adolescents on a mg/m 2 basis. When duloxetine was administered orally to pregnant rats throughout gestation and lactation, pup weights at birth and pup survival to 1 day postpartum were decreased at a dose 2 times the MRHD given to adolescents on a mg/m 2 basis. At this dose, pup behaviors consistent with increased reactivity, such as increased startle response to noise and decreased habituation of locomotor activity were observed. Post-weaning growth was not adversely affected. 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. In the U.S. 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 possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome [see Warnings and Precautions ( 5.4 )]. Data Human Data Data from a postmarketing retrospective claims-based cohort study found an increased risk for postpartum hemorrhage among 955 pregnant women exposed to duloxetine in the last month of pregnancy compared to 4,128,460 unexposed pregnant women (adjusted relative risk: 1.53; 95% CI: 1.08-2.18). 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 and 6 times, respectively, the MRHD of 120 mg/day given to adolescents on a mg/m 2 basis]. However, fetal weights were decreased at this dose, with a no-effect dose of 10 mg/kg/day (approximately equal to the MRHD in rats and 2 times the MRHD in rabbits). When duloxetine was administered orally to pregnant rats throughout gestation and lactation, the survival of pups to 1 day postpartum and pup body weights at birth and during the lactation period were decreased at a dose of 30 mg/kg/day (2 times the MRHD given to adolescents on a mg/m 2 basis); the no-effect dose was 10 mg/kg/day. Furthermore, behaviors consistent with increased reactivity, such as increased startle response to noise and decreased habituation of locomotor activity, were observed in pups following maternal exposure to 30 mg/kg/day. Post-weaning growth and reproductive performance of the progeny were not affected adversely by maternal duloxetine treatment. 8.2 Lactation Risk Summary Data from published literature report the presence of duloxetine in human milk (see Data) . There are reports of sedation, poor feeding, and poor weight gain in infants exposed to duloxetine through breast milk (see Clinical Considerations) . There are no data on the effect of duloxetine on milk production. 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 3.5 days. 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. 8.4 Pediatric Use The safety and effectiveness of duloxetine have been established for treatment of generalized anxiety disorder (GAD) in patients 7 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)] . Perform regular monitoring of weight and growth in pediatric patients treated with duloxetine [see Adverse Reactions (6.1)] . Generalized Anxiety Disorder Use of duloxetine for the treatment of GAD in patients 7 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 to 11 years of age (53% were 12 to 17 years of age). duloxetine demonstrated superiority over placebo as measured by greater improvement in the Pediatric Anxiety Rating Scale (PARS) for GAD severity score [see Clinical Studies (14.3)] . 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 The safety and effectiveness of duloxetine for the treatment of fibromyalgia in patients less than 13 years of age have not been established. 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 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 (≈1 times the MRHD, for a child). Additional pediatric use information is approved for Eli Lilly and Company, Inc.’s CYMBALTA (duloxetine) delayed-release capsules. However, due to Eli Lilly and Company Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 8.5 Geriatric Use 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 1041 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 ( 5.3 ) and Adverse Reactions ( 6.1 )] . The pharmacokinetics of duloxetine after a single dose of 40 mg were compared in healthy elderly females (65 to 77 years) and healthy middle-age females (32 to 50 years). There was no difference in the Cmax, but the AUC of duloxetine was somewhat (about 25%) higher and the half-life about 4 hours longer in the elderly females. Population pharmacokinetic analyses suggest that the typical values for clearance decrease by approximately 1% for each year of age between 25 to 75 years of age; but age as a predictive factor only accounts for a small percentage of between-patient variability. Dosage adjustment based on the age of the adult patient is not necessary. 8.6 Gender Duloxetine’s half-life is similar in men and women. Dosage adjustment based on gender is not necessary. 8.7 Smoking Status Duloxetine bioavailability (AUC) appears to be reduced by about one-third in smokers. Dosage modifications are not recommended for smokers. 8.8 Race No specific pharmacokinetic study was conducted to investigate the effects of race. 8.9 Hepatic Impairment 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 was similar to normals in the cirrhotic patients, the half-life was about 3 times longer [see Dosage and Administration ( 2.7 ) and Warnings and Precautions ( 5.14 )] . 8.10 Severe Renal Impairment Limited data are available on the effects of duloxetine in patients with end-stage renal disease (ESRD). After a single 60 mg dose of duloxetine, C max and AUC values were approximately 100% greater in patients with ESRD receiving chronic intermittent hemodialysis than in subjects with normal renal function. The elimination half-life, however, was similar in both groups. The AUCs of the major circulating metabolites, 4-hydroxy duloxetine glucuronide and 5-hydroxy, 6-methoxy duloxetine sulfate, largely excreted in urine, were approximately 7- to 9-fold higher and would be expected to increase further with multiple dosing. Population PK analyses suggest that mild to moderate degrees of renal impairment (estimated CrCl 30-80 mL/min) have no significant effect on duloxetine apparent clearance [see Dosage and Administration ( 2.7 ) and Warnings and Precautions ( 5.14 )] .

16 HOW SUPPLIED/STORAGE AND HANDLING Duloxetine delayed-release capsules, USP are available as delayed release capsules in the following strengths, colors, imprints, and presentations: 30 mg Body color: Opaque light green Cap color: Opaque white Cap imprint: 558 Body imprint: 30mg NDC: 70518-3177-00 NDC: 70518-3177-01 PACKAGING: 90 in 1 BOTTLE PLASTIC PACKAGING: 30 in 1 BLISTER PACK Store at 20o to 25oC (68o to 77oF); excursions permitted between 15o to 30oC (59o to 86oF) [See USP Controlled Room Temperature]. Repackaged and Distributed By: Remedy Repack, Inc. 625 Kolter Dr. Suite #4 Indiana, PA 1-724-465-8762

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24; there was a reduction in risk with antidepressant use in patients aged 65 and older [see Warnings and Precautions ( 5.1 )] . In patients of all ages who are started on antidepressant therapy, monitor closely for worsening, and for emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication with the prescriber [see Warnings and Precautions ( 5.1 )] . WARNING: SUICIDAL THOUGHTS AND BEHAVIORS See full prescribing information for complete boxed warning. Increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants ( 5.1 ) Monitor for worsening and emergence of suicidal thoughts and behaviors ( 5.1 )