Cymbalta

Warnings and Precautions ( 5.4 , 5.5 ) 08/2023

1 INDICATIONS AND USAGE CYMBALTA ® 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 neuropathic pain in adults Fibromyalgia in adults and pediatric patients 13 years of age and older Chronic musculoskeletal pain in adults CYMBALTA ® 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 and pediatric patients 13 years of age and older ( 1 ) Chronic musculoskeletal pain in adults ( 1 )

2 DOSAGE AND ADMINISTRATION Take CYMBALTA once daily, with or without food. Swallow whole; do not crush, chew, or open capsule ( 2.1 ) Indication Starting Dose Target Dose Maximum Dose MDD ( 2.2 ) 40 mg/day 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 ) 30 mg/day 60 mg/day (once daily) 60 mg/day Adults and Pediatrics (13 to 17 years of age) Chronic Musculoskeletal Pain ( 2.6 ) 30 mg/day 60 mg/day (once daily) 60 mg/day Discontinuing CYMBALTA: Gradually reduce dosage to avoid discontinuation symptoms ( 2.8 , 5.7 ) 2.1 Important Administration Instructions Administer CYMBALTA 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 CYMBALTA 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 CYMBALTA 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/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 CYMBALTA 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 CYMBALTA 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 CYMBALTA 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 CYMBALTA 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 CYMBALTA 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 Adults 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 sign …

3 DOSAGE FORMS AND STRENGTHS CYMBALTA is available as delayed-release capsules: 20 mg opaque green capsules imprinted with “Lilly 3235 20mg” 30 mg opaque white and blue capsules imprinted with “Lilly 3240 30mg” 60 mg opaque green and blue capsules imprinted with “Lilly 3270 60mg” Delayed-release capsules: 20 mg, 30 mg, and 60 mg ( 3 )

4 CONTRAINDICATIONS The use of MAOIs intended to treat psychiatric disorders with CYMBALTA or within 5 days of stopping treatment with CYMBALTA is contraindicated because of an increased risk of serotonin syndrome. The use of CYMBALTA within 14 days of stopping an MAOI intended to treat psychiatric disorders is contraindicated [see Dosage and Administration ( 2.8 ) and Warnings and Precautions ( 5.4 )] . Starting CYMBALTA 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 CYMBALTA is contraindicated Use of CYMBALTA within 14 days of stopping an MAOI antidepressant is contraindicated In linezolid- or intravenous methylene blue-treated patients, initiation of CYMBALTA is contraindicated ( 4 )

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 )] 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 : decreased weight, decreased appetite, nausea, vomiting, fatigue, and diarrhea To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) 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, one treatment-emergent adverse reaction of the type listed. A reaction was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. Adverse Reactions in Adults Adult Clinical Trial Database The data described below reflect exposure to CYMBALTA in placebo-controlled adult trials for MDD (N=3779), GAD (N=1018), OA (N=503), CLBP (N=600), DPNP (N=906), and FM (N=1294). The age range in this pooled population was 17 to 89 years of age. In this pooled population, 66%, 61%, 61%, 43%, and 94% of adult patients were female; and 82%, 73%, 85%, 74%, and 86% of adult patients were Caucasian in the MDD, GAD, OA and CLBP, DPNP, and FM populations, respectively. Most patients received CYMBALTA dosages of a total of 60 to 120 mg per day [see Clinical Studies ( 14 )] . The data below do not include results of the trial that evaluated the efficacy of CYMBALTA for the treatment of GAD in patients ≥65 years old (Study GAD-5) [see Clinical Studies ( 14.3 )] ; however, the adverse reactions observed in this geriatric population were generally similar to adverse reactions in the overall adult population. Adverse Reactions Leading to Treatment Discontinuation in Adult Placebo-Controlled Trials Major Depressive Disorder Approximately 8.4% (319/3779) of CYMBALTA-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 (CYMBALTA 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 CYMBALTA-treated patients and at a rate of at least twice that of placebo-treated patients). Generalized Anxiety Disorder Approximately 13.7% (139/1018) of the CYMBALTA-treated patients in placebo-controlled adult trials for GAD discontinued treatment due to an adverse reaction, compared with 5% (38/767 …

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 CYMBALTA concentrations ( 7.2 ) CYMBALTA is a moderate inhibitor of CYP2D6 ( 7.9 ) 7.1 Inhibitors of CYP1A2 When CYMBALTA 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 CYMBALTA (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 CYMBALTA 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 CYMBALTA 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 τ,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 CYMBALTA is initiated or discontinued [see Warnings and Precautions ( 5.5 )] . 7.5 Lorazepam Under steady-state conditions for CYMBALTA (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 CYMBALTA (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 CYMBALTA has an enteric coating that resists dissolution until reaching a segment of the gastrointestinal tract where the pH exceeds 5.5. In extremely acidic conditions, CYMBALTA, unprotected by the enteric coating, may undergo hydrolysis to form naphthol. Caution is advised in using CYMBALTA 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 CYMBALTA with aluminum- and magnesium-containing antacids (51 mEq) or CYMBALTA 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 in …

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 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors the pregnancy outcomes in women exposed to antidepressants, including CYMBALTA, during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Antidepressants at 1-866-961-2388 or online at https://womensmentalhealth.org/research/pregnancyregistry/. Risk Summary Data from a postmarketing retrospective cohort study indicate that use of duloxetine in the month before delivery may be associated with an increased risk of postpartum hemorrhage. Data from published literature and from a postmarketing retrospective cohort study have not identified a clear drug-associated risk of major birth defects or other adverse developmental outcomes (see Data) . There are risks associated with untreated depression and fibromyalgia in pregnancy, and with exposure to SNRIs and SSRIs, including CYMBALTA, 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 CYMBALTA 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 CYMBALTA 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 cl …

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.

11 DESCRIPTION CYMBALTA ® (duloxetine delayed-release capsules) is a selective serotonin and norepinephrine reuptake inhibitor (SNRI) 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 FD&C Blue No. 2, gelatin, hypromellose, hydroxypropyl methylcellulose acetate succinate, sodium lauryl sulfate, sucrose, sugar spheres, talc, titanium dioxide, and triethyl citrate. The 20 and 60 mg capsules also contain iron oxide yellow. Structural Formula

10 OVERDOSAGE 10.1 Signs and Symptoms In postmarketing experience, fatal outcomes have been reported for acute CYMBALTA overdoses, primarily with mixed overdoses, but also with CYMBALTA only, including 1000 mg of CYMBALTA (approximately 8.3 times the maximum recommended dosage). Signs and symptoms of overdose (CYMBALTA 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 CYMBALTA 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 CYMBALTA, treatment should consist of those general measures employed in the management of overdose with any drug, such as assuring an adequate airway, oxygenation, and ventilation and monitoring cardiac rhythm and vital signs. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion or in symptomatic patients. Induction of emesis is not recommended. Activated charcoal may be useful in limiting absorption of duloxetine from the gastrointestinal tract. Administration of activated charcoal has been shown to decrease duloxetine AUC and C max 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 CYMBALTA 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.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied CYMBALTA (duloxetine delayed-release capsules) is available in the following strengths, colors, imprints, and presentations: a equivalent to duloxetine base Features Strengths 20 mg a 30 mg a 60 mg a Body color Opaque green Opaque white Opaque green Cap color Opaque green Opaque blue Opaque blue Cap imprint Lilly 3235 Lilly 3240 Lilly 3270 Body imprint 20mg 30mg 60mg Capsule number PU3235 PU3240 PU3270 Presentations and NDC Codes Bottles of 30 NA 0002-3240-30 0002-3270-30 Bottles of 60 0002-3235-60 NA NA Bottles of 90 NA 0002-3240-90 NA 16.2 Storage and Handling Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].

16.1 How Supplied CYMBALTA (duloxetine delayed-release capsules) is available in the following strengths, colors, imprints, and presentations: a equivalent to duloxetine base Features Strengths 20 mg a 30 mg a 60 mg a Body color Opaque green Opaque white Opaque green Cap color Opaque green Opaque blue Opaque blue Cap imprint Lilly 3235 Lilly 3240 Lilly 3270 Body imprint 20mg 30mg 60mg Capsule number PU3235 PU3240 PU3270 Presentations and NDC Codes Bottles of 30 NA 0002-3240-30 0002-3270-30 Bottles of 60 0002-3235-60 NA NA Bottles of 90 NA 0002-3240-90 NA