DRIZALMA SPRINKLE

1 INDICATIONS AND USAGE DRIZALMA SPRINKLE is 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 Neuropathy 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. DRIZALMA SPRINKLE is a serotonin and norepinephrine reuptake inhibitor (SNRI) indicated for the treatment of following conditions: • Major Depressive Disorder (MDD) in adults (1) • Generalized Anxiety Disorder (GAD) in adults and pediatric patients ages 7 years of age and older (1) • Diabetic Peripheral Neuropathic Pain (DPNP) in adults (1) • Fibromyalgia (FM) in adults (1) • Chronic Musculoskeletal Pain in adults (1)

2 DOSAGE AND ADMINISTRATION • Take DRIZALMA SPRINKLE with or without food (2.1) • DRIZALMA SPRINKLE may be: swallowed whole (do not crush or chew capsule); opened and sprinkled over applesauce; or administered via nasogastric tube (2.1) • Take a missed dose as soon as it is remembered. Do not take two doses of DRIZALMA SPRINKLE at the same time (2.1) Indication Starting Dose Target Dose Maximum Dose MDD (2.2) Adults 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 60 mg/day 60 mg/day (once daily) 120 mg/day Geriatric 30 mg/day 60 mg/day (once daily) 120 mg/day Pediatrics (7 to 17 years of age) 30 mg/day 30 to 60 mg/day (once daily) 120 mg/day DPNP (2.4) 60 mg/day 60 mg/day (once daily) 60 mg/day FM (2.5) Adults 30 mg/day 60 mg/day (once daily) 60 mg/day Chronic Musculoskeletal Pain (2.6) Adults 30 mg/day 60 mg/day (once daily) 60 mg/day • There is no evidence that doses greater than 60 mg/day confers additional benefit, while some adverse reactions were observed to be dose-dependent (2) • Discontinuing DRIZALMA SPRINKLE: Gradually reduce dosage to avoid discontinuation symptoms (2.8, 5.7) 2.1 Important Administration Instructions Administer DRIZALMA SPRINKLE with or without food. Swallow DRIZALMA SPRINKLE whole (do not chew or crush the capsule). For patients unable to swallow an intact capsule, refer to the alternative administration instructions below. Directions for use with applesauce For patients with swallowing difficulty, DRIZALMA SPRINKLE can be opened and the contents sprinkled over applesauce. The contents of the capsules should be swallowed along with a small amount (tablespoonful) of applesauce. The drug/food mixture should be swallowed immediately and not stored for future use. Nasogastric tube administration Open and add contents of capsule to an all plastic catheter tip syringe and add 50 mL of water. Gently shake the syringe for approximately 10 seconds. Promptly deliver through a 12 French or larger nasogastric tube. Ensure no pellets are left in the syringe. Rinse with additional water (about 15 mL) if needed. If a dose of DRIZALMA SPRINKLE 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 DRIZALMA SPRINKLE at the same time. 2.2 Dosage for Treatment of Major Depressive Disorder in Adults The recommended starting dosage in adults with MDD is 40 mg per day (given as 20 mg twice daily) to 60 mg per 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 DRIZALMA SPRINKLE before increasing to 60 mg once daily. While a 120 mg per day dose was shown to be effective, there is no evidence that doses greater than 60 mg per day confer any additional benefits. Periodically reassess to determine the need for maintenance treatment and the appropriate dosage for such treatment [see Clinical Studies (14.1)] . 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 DRIZALMA SPRINKLE 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 DRIZALMA SPRINKLE 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 per 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. The safety of doses above 120 mg once daily has not been adequately evaluated. Periodically reassess to determine the continued need for maintenance treatment and the appropriate dosage for such t…

5 WARNINGS AND PRECAUTIONS Hepatotoxicity : Hepatic failure, sometimes fatal, has been reported. Discontinue DRIZALMA SPRINKLE in patients who develop jaundice or other evidence of clinically significant liver dysfunction and should not be resumed unless another cause can be established. Avoid use in patients with substantial alcohol use or evidence of chronic liver disease (5.2) Orthostatic Hypotension, Falls and Syncope : Consider dosage reduction or discontinuation if these events occur (5.3) S ero t on in Syndrome : Increased risk when co-administered with other serotonergic agents, but also when taken alone. If it occurs, discontinue DRIZALMA SPRINKLE and serotonergic agents and initiate supportive treatment (5.4) Increased Risk of B leeding : May increase the risk of bleeding events. Concomitant use of antiplatelet drugs and anticoagulants may increase this risk (5.5, 7, 8.1) S ever e Skin Reactions : Severe skin reactions, including erythema multiforme and Stevens-Johnson Syndrome (SJS), can occur with duloxetine. Discontinue at the first appearance of blisters, peeling rash, mucosal erosions, or any other sign of hypersensitivity if no other etiology can be identified (5.6) D iscontinuation Syndrome : Taper dose when possible and monitor for discontinuation symptoms (5.7) Activation of Mania or Hypomania : Prior to initiating, screen patients for personal or family history of bipolar disorder, mania, or hypomania (5.8) A ng le-Closure Glaucoma : Has occurred in patients with untreated anatomically narrow angles treated with antidepressants (5.9) S e izures : Prescribe with care in patients with a history of seizure disorder (5.10) B lood Pressure Increases : Monitor blood pressure prior to initiating treatment and periodically throughout treatment (5.11) Inhibitors of CYP1A2 or Thioridazine : Avoid co-administration with DRIZALMA SPRINKLE (5.12) Hypona t r emia : Can occur in association with SIADH; consider discontinuation (5.13) Glucose Control in Diabetes : In DPNP patients, increase in fasting blood glucose, and HbA1c have been observed (5.14) Conditions that Slow Gastric Emptying : Use cautiously in these patients (5.14) Sexual Dysfunction : DRIZALMA SPRINKLE may cause symptoms of sexual dysfunction (5.16) 5.1 Suicidal Thoughts and Behaviors in Adolescents and Young Adults In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and 4,500 pediatric patients, the incidence of suicidal thoughts and behaviors in the antidepressant-treated patients age 24 years and younger was greater than in placebo-treated patients. There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied. There were differences in absolute risk of suicidal thoughts and behaviors across the different indications, with the highest incidence in MDD. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1000 patients treated are provided in Table 1. Table 1: Risk Differences of the Number of Patients of Suicidal Thoughts and Behavior in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Patients Age Range Drug-Placebo Difference in Number of Patients of Suicidal Thoughts or Behaviors per 1000 Patients Treated Increases Compared to Placebo <18 14 additional patients 18 to 24 5 additional patients Decreases Compared to Placebo 25 to 64 1 fewer patients ≥65 6 fewer patients It is unknown whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with MDD that antidepressants delay the recurrence of depression and that depression itself is a risk factor for suicidal thoughts and behaviors. Monito…

4 CONTRAINDICATIONS The use of MAOIs intended to treat psychiatric disorders with DRIZALMA SPRINKLE, or within 5 days of stopping treatment with DRIZALMA SPRINKLE, are contraindicated because of an increased risk of serotonin syndrome. The use of DRIZALMA SPRINKLE within 14 days of stopping an MAOI intended to treat psychiatric disorders is contraindicated [see Dosage and Administration (2.10), Warnings and Precautions (5.4), Drug Interactions (7)] . Starting DRIZALMA SPRINKLE in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is contraindicated because of an increased risk of serotonin syndrome [see Warnings and Precautions (5.4)] . Serotonin Syndrome and MAOIs : Do not use MAOIs intended to treat psychiatric disorders with DRIZALMA SPRINKLE or within 5 days of stopping treatment with DRIZALMA SPRINKLE. Do not use DRIZALMA SPRINKLE within 14 days of stopping an MAOI intended to treat psychiatric disorders. In addition, do not start DRIZALMA SPRINKLE in a patient who is being treated with linezolid or intravenous methylene blue (4)

7 DRUG INTERACTIONS • Potent CYP1A2 Inhibitors: Avoid concomitant use (2.6, 7) • CYP2D6 Substrates: Consider dose reduction with concomitant use (7) 7.1 Drugs Having Clinically Important Interactions with DRIZALMA SPRINKLE Table 7: Clinically Important Drug Interactions Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact Concomitant use of SSRIs and SNRIs including duloxetine with MAOIs increases the risk of serotonin syndrome. Intervention •The use of MAOIs intended to treat psychiatric disorders with duloxetine or within 5 days of stopping treatment with duloxetine is contraindicated [see Contraindications (4) and Warnings and Precautions (5.4)] .•The use of duloxetine delayed-release capsules within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated [see Contraindications (4) and Warnings and Precautions (5.4)] .•Starting duloxetine in a patient who is being treated with MAOIs is also contraindicated [see Dosage and Administration (2.10), Contraindications (4), Warnings and Precautions (5.4)] . Examples Selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, intravenous methylene blue Other Serotonergic Drugs Clinical Impact Concomitant use of duloxetine with other serotonergic drugs increases the risk of serotonin syndrome. Intervention •Patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.•Monitor for symptoms of serotonin syndrome when duloxetine is used concomitantly with other drugs that may affect the serotonergic neurotransmitter systems.•Treatment with duloxetine delayed-release capsules and any concomitant serotonergic agents, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated [see Warnings and Precautions (5.4)] . Examples Other SNRIs, SSRIs, triptans, tricyclic antidepressants, opioids, lithium, tryptophan, buspirone, amphetamines, and St. John’s Wort Inhibitors of CYP1A2 Clinical Impact Concomitant use of duloxetine with CYP1A2 inhibitors increases AUC, C max , t 1/2 of duloxetine. Intervention Avoid concomitant use of duloxetine delayed-release capsules with potent CYP1A2 inhibitors [see Warnings and Precautions (5.12), Clinical Pharmacology (12.3)]. Examples Fluvoxamine, cimetidine, ciprofloxacin, enoxacin Dual Inhibition of CYP1A2 and CYP2D6 Clinical Impact Concomitant administration of duloxetine with potent CYP1A2 inhibitors to CYP2D6 poor metabolizers results in increased AUC and C max of duloxetine. Intervention Avoid co-administration of duloxetine delayed-release capsules and potent CYP1A2 inhibitors to CYP2D6 poor metabolizers [see Clinical Pharmacology (12.3)] . Examples Fluvoxamine, cimetidine, ciprofloxacin, enoxacin Drugs that Interfere with Hemostasis Clinical Impact Concomitant use of duloxetine with an antiplatelet or anticoagulant drug may potentiate the risk of bleeding. Intervention Closely monitor for bleeding for patients receiving an antiplatelet or anticoagulant drug when duloxetine is initiated or discontinued [Warnings and Precaution (5.5)] . Examples NSAIDs, aspirin, warfarin Inhibitors of CYP2D6 Clinical Impact Concomitant use of duloxetine with CYP2D6 inhibitors increase AUC of duloxetine. Greater degrees of inhibition are expected with higher doses of CYP2D6 inhibitors. Intervention Exercise caution when co-administering duloxetine delayed-release capsules and potent CYP2D6 inhibitors [see Warnings and Precautions (5.12), Clinical Pharmacology (12.3)]. Examples Paroxetine, fluoxetine, quinidine Drugs Metabolized by CYP2D6 Clinical Impact Concomitant use of duloxetine increases AUC of a drug primarily metabolized by CYP2D6 which may increase the risk of toxicity of the CYP2D6 substrate drug. Intervention Monitor plasma concentrations of CYP2D6 substrate and reduce dosage of CYP2D6 substrate drug if necessary [see Warnings and Precautions (5.12), Clinical Pharmacology (12.3)] .…

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/antidepressants/ Risk Summary Based on data from published observational studies, exposure to SNRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [see Warnings and Precautions (5.5) and Clinical Considerations] . 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 in pregnancy and with exposure to SNRIs and SSRIs, including DRIZALMA SPRINKLE, 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 of 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 discontinued antidepressants during pregnancy are more likely to experience a relapse of major depression than women who continued 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 the 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 DRIZALMA SPRINKLE 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, vo…

6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling: Suicidal Thoughts and Behaviors in Adolescents and Young Adults [see Boxed Warning and Warnings and Precautions (5.1)] Hepatotoxicity [see Warnings and Precautions (5.2)] Orthostatic Hypotension, Falls and Syncope [see Warnings and Precautions (5.3)] Serotonin Syndrome [see Warnings and Precautions (5.4)] Increased Risk of Bleeding [see Warnings and Precautions (5.5)] Severe Skin Reactions [see Warnings and Precautions (5.6)] Discontinuation Syndrome [see Warnings and Precautions (5.7)] Activation of Mania/Hypomania [see Warnings and Precautions (5.8)] Angle-Closure Glaucoma [see Warnings and Precautions (5.9)] Seizures [see Warnings and Precautions (5.10)] Increases in Blood Pressure [see Warnings and Precautions (5.11)] Clinically Important Drug Interactions [see Warnings and Precautions (5.12)] Hyponatremia [see Warnings and Precautions (5.13)] Urinary Hesitation and Retention [see Warnings and Precautions (5.15)] Sexual Dysfunction [see Warnings and Precautions (5.16)] Most common adverse reactions (≥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 : nausea, diarrhea, decreased weight To report SUSPECTED ADVERSE REACTIONS, contact Sun Pharmaceutical Industries, Inc. at 1-800-818-4555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The stated frequencies of adverse reactions represent the proportion of patients who experienced, at least once, a treatment-emergent adverse reaction of the type listed. Adverse Reactions in Adults The data described below reflect exposure to duloxetine delayed-release capsules in placebo-controlled trials for MDD (N = 3779), GAD (N = 1018), OA (N = 503), CLBP (N = 600), and DPNP (N = 906), and FM (N = 1294). The population studied was 17 to 89 years of age; 65.7%, 60.8%, 60.6%, 42.9%, and 94.4% female; and 81.8%, 72.6%, 85.3%, 74.0%, and 85.7% Caucasian for MDD, GAD, OA and CLBP, DPNP, and FM, respectively. Most patients received doses of a total of 60 to 120 mg per day [see Clinical Studies (14)] . The data below do not include results of the trial examining the efficacy of duloxetine delayed-release in patients ≥ 65 years old for the treatment of generalized anxiety disorder; however, the adverse reactions observed in this geriatric sample were generally similar to adverse reactions in the overall adult population. A dverse Reactions Reported as Reasons for Discontinuation of Treatment in Adult Placebo-Controlled Trials Major Depressive Disorder: Approximately 8.4% (319/3779) of the duloxetine delayed-release capsules-treated patients in placebo-controlled adult trials for MDD discontinued treatment due to an adverse reaction, compared with 4.6% (117/2536) of placebo-treated patients. Nausea (duloxetine delayed-release capsules 1.1%, placebo 0.4%) was the only adverse reaction reported as a reason for discontinuation and considered to be drug-related (i.e., discontinuation occurring in at least 1% of the duloxetine delayed-release capsules-treated patients and at a rate of at least twice that of placebo). Generalized Anxiety Disorder: Approximately 13.7% (139/1018) of the duloxetine delayed-release capsules-treated patients in placebo-controlled adult trials for GAD discontinued treatment due to an adverse reaction, compared with 5.0% (38/767) of placebo-treated patients. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine delayed-release capsules 3.3%, placebo 0.…