Duloxetine

Duloxetine Delayed-Release Capsules are indicated for the treatment of: Major depressive disorder in adults Generalized anxiety disorder in adults and pediatric patients 7 years of age and older Duloxetine Delayed-Release Capsules are a serotonin and norepinephrine reuptake inhibitor (SNRI) indicated for the treatment of: Major depressive disorder (MDD) in adults ( 1 ) Generalized anxiety disorder (GAD) in adults and pediatric patients 7 years of age and older ( 1 )

Duloxetine Delayed-Release Capsules are available as: 80 mg: Hard shell gelatin capsules, with "ALM" printed axially on the opaque pale yellow cap and "821" printed axially on the opaque white body. Each capsule contains 89.8 mg of duloxetine hydrochloride, USP equivalent to 80 mg duloxetine. 90 mg: Hard shell gelatin capsules, with "ALM" printed axially on the opaque green cap and "913" printed axially on the opaque white body. Each capsule contains 101 mg of duloxetine hydrochloride, USP equivalent to 90 mg duloxetine. 120 mg: Hard shell gelatin capsules, with "ALM" printed axially on the opaque light green cap and "791" printed axially on the opaque white body. Each capsule contains 134.7 mg of duloxetine hydrochloride, USP equivalent to 120 mg duloxetine. Delayed-release capsules: 80 mg, 90 mg, and 120 mg ( 3 )

Duloxetine Delayed-Release Capsules are contraindicated in patients who are using or within 14 days of stopping an MAOI intended to treat psychiatric disorders because of an increased risk of serotonin syndrome. Allow at least 5 days after stopping Duloxetine Delayed-Release Capsules prior to initiation of an MAOI to treat psychiatric disorders. [see Dosage and Administration ( 2.7 ), Warnings and Precautions ( 5.4 )]. who are using other MAOIs such as linezolid or intravenous methylene blue because of an increased risk of serotonin syndrome [see Dosage and Administration ( 2.8 ), Warnings and Precautions ( 5.4 )]. Concomitant use of monoamine oxidase inhibitors (MAOIs), or use within 14 days of stopping MAOIs ( 4 ) Do not start Duloxetine Delayed-Release Capsules in a patient who is being treated with linezolid or intravenous methylene blue ( 4 )

Hepatotoxicity : Hepatic failure, sometimes fatal, has been reported. Discontinue Duloxetine Delayed-Release Capsules 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 ) Serotonin Syndrome: Increased risk when co-administered with other serotonergic agents but also when taken alone. If it occurs, discontinue Duloxetine Delayed-Release Capsules and serotonergic agents. ( 5.4 ) Increased Risk of Bleeding : May increase the risk of bleeding events. Concomitant use of antiplatelet drugs and anticoagulants may increase this risk. ( 5.5 , 7 , 8.1 ) Severe Skin Reactions: Severe skin reactions, including erythema multiforme and Stevens-Johnson Syndrome (SJS), can occur. 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 ) Discontinuation 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 ) Angle-Closure Glaucoma : Has occurred in patients with untreated anatomically narrow angles treated with antidepressants. ( 5.9 ) Seizures : Prescribe with care in patients with a history of seizure disorder. ( 5.10 ) Blood Pressure Increases : Monitor blood pressure prior to initiating treatment and periodically throughout treatment. ( 5.11 ) Hyponatremia : Can occur in association with SIADH; consider discontinuation. ( 5.12 ) Glucose Control in Diabetes : Worsened glycemic control has been observed. ( 5.13 ) Conditions that Slow Gastric Emptying : Use cautiously in these patients. ( 5.13 ) Sexual Dysfunction : Duloxetine Delayed-Release Capsules may cause symptoms of sexual dysfunction. ( 5.15 )

5.1 Suicidal Thoughts and Behaviors in Pediatric and Young Adult Patients 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 patient ≥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. Monitor all antidepressant-treated patients for any indication for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy, and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing Duloxetine Delayed-Release Capsules, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.

5.2 Hepatotoxicity There have been reports of hepatic failure, sometimes fatal, in patients treated with duloxetine. These cases have presented as hepatitis with abdominal pain, hepatomegaly, and elevation of transaminase levels to more than twenty times the upper limit of normal (ULN) with or without jaundice, reflecting a mixed or hepatocellular pattern of liver injury. Duloxetine Delayed-Release Capsules should be discontinued in patients who develop jaundice or other evidence of clinically significant liver dysfunction and should not be resumed unless another cause can be established. Cases of cholestatic jaundice with minimal elevation of transaminase levels have also been reported. Other postmarketing reports indicate that elevated transaminases, bilirubin, and alkaline phosphatase have occurred in patients with chronic liver disease or cirrhosis. Duloxetine increased the risk of elevation of serum transaminase levels in development program clinical trials. Liver transaminase elevations resulted in the discontinuation of 0.3% (92/34,756) of duloxetine-treated patients. In most patients, the median time to detection of the transaminase elevation was about two months. In adult placebo-controlled trials, for patients with normal and abnormal baseline ALT values, elevation of ALT >3 times the ULN occurred in 1.25% (144/11,496) of duloxetine-treated patients compared to 0.45% (39/8,716) of placebo-treated patients. In adult placebo-controlled studies using a fixed dose design, there was evidence of a duloxetine dose response relationship for ALT and AST elevation of >3 times the ULN and >5 times the ULN, respectively. Because it is possible that Duloxetine Delayed-Release Capsules and alcohol may interact to cause liver injury or that Duloxetine Delayed-Release Capsules may aggravate pre-existing liver disease, Duloxetine Delayed-Release Capsules should not be prescribed to patients with substantial alcohol use or evidence of chronic liver disease.

5.3 Orthostatic Hypotension, Falls and Syncope Orthostatic hypotension, falls, and syncope have been reported in patients treated with recommended duloxetine dosages. Syncope and orthostatic hypotension tend to occur within the first week of therapy but can occur at any time during Duloxetine Delayed-Release Capsules treatment, particularly after dose increases. The risk of falling appears to be related to the degree of orthostatic decrease in blood pressure (BP) as well as other factors that may increase the underlying risk of falls. In an analysis of patients from all placebo-controlled trials, patients treated with duloxetine reported a higher rate of falls compared to patients treated with placebo. Risk appears to be related to the presence of orthostatic decrease in BP. The risk of BP decreases may be greater in patients taking concomitant medications that induce orthostatic hypotension (such as antihypertensives) or are potent CYP1A2 inhibitors [see Drug Interactions ( 7.1 )] and in patients taking duloxetine delayed-release capsules at doses above 60 mg daily. Consideration should be given to dose reduction or discontinuation of Duloxetine Delayed-Release Capsules in patients who experience symptomatic orthostatic hypotension, falls and/or syncope during Duloxetine Delayed-Release Capsules therapy. Risk of falling also appeared to be proportional to a patient’s underlying risk for falls and appeared to increase steadily with age. […]

The following serious adverse reactions are described below and elsewhere in the labeling: Suicidal Thoughts and Behaviors in Pediatric and Young Adult Patients [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 )] Hyponatremia [see Warnings and Precautions ( 5.12 )] Urinary Hesitation and Retention [see Warnings and Precautions ( 5.14 )] Sexual Dysfunction [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 Almatica Pharma LLC at 1-877-447-7979 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 safety of Duloxetine Delayed-Release Capsules for the treatment for major depressive disorder (MDD) in adults and for the treatment of generalized anxiety disorder (GAD) in adults and pediatric patients is based upon adequate and well-controlled studies of another duloxetine delayed-release capsule product. The results of these adequate and well-controlled studies of duloxetine delayed-release capsules are presented below. The stated frequencies of adverse reactions represent the proportion of patients who experienced, at least once, one treatment-emergent adverse reaction of the type listed. A reaction was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. Adverse Reactions in Adults Adult Clinical Trial Database The data described below reflect exposure to duloxetine delayed-release capsules in placebo-controlled trials for MDD (N=3779), GAD (N=1018), and other indications (N=3303). The population studied was 17 years to 89 years of age. 66% and 61% were female, and 82% and 73% were Caucasian in the MDD and GAD populations, respectively. Most patients received duloxetine delayed-release capsules dosages of a total of 60 mg to 120 mg per day [see Clinical Studies ( 14.1 , 14.2 )] . The data below do not include results of the trial examining the efficacy of duloxetine delayed-release capsules 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. Adverse 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-treated patients). 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% (38/767) for placebo-treated patients. Common adverse reactions reported as a reason for discontinuation and considered to be drug-related (as defined above) included nausea (duloxetine delayed-release capsules 3.3%, placebo 0.4%), and dizziness (duloxetine delayed-release capsules 1.3%, placebo 0.4%). Adverse Reactions Occurring at an Incidence of 5% or More Among Duloxetine Delayed-Release Capsules Treated Patients in Adult Placebo-Controlled Trials The most commonly observed adverse reactions in duloxetine delayed-release capsule-treated patients (incidence of at least 5% and at least twice the incidence in placebo patients) were nausea, dry mouth, somnolence, constipation, decreased appetite, and hyperhidrosis. Table 2 displays the incidence of adverse reactions in placebo-controlled trials for approved indications that occurred in 5% or more of patients treated with duloxetine delayed-release capsules and with an incidence greater than placebo-treated patients. Table 2: Adverse Reactions: Incidence of 5% or More and Greater than Placebo in Placebo-Controlled Trials of Approved Adult Populations a a Includes adults with MDD, GAD, and other indications. The inclusion of an event in the table is determined based on the percentages before rounding; however, the percentages displayed in the table are rounded to the nearest integer. b Also includes asthenia. c Events for which there was a significant dose-dependent relationship in fixed-dose studies, excluding three MDD studies which did not have a placebo lead-in period or dose titration. d Also includes initial insomnia, middle insomnia, and early morning awakening. e Also includes hypersomnia and sedation. f Also includes abdominal discomfort, abdominal pain lower, abdominal pain upper, abdominal tenderness, and gastrointestinal pain. Adverse Reaction Percentage of Patients Reporting Reaction Another Duloxetine Product (N=8100) Placebo (N=5655) Nausea c 23 8 Headache 14 12 Dry mouth 13 5 Somnolence e 10 3 Fatigue b, c 9 5 Insomnia d 9 5 Constipation c 9 4 Dizziness c 9 5 Diarrhea 9 6 Decreased appetite c 7 2 Hyperhidrosis c 6 1 Abdominal pain f 5 4 Adverse Reactions in Pooled MDD and GAD Trials in Adults Table 3 displays the incidence of adverse reactions in MDD and GAD placebo-controlled trials that occurred in 2% or more of patients treated with duloxetine delayed-release capsules and with an incidence greater than placebo-treated patients. Table 3: Adverse Reactions: Incidence of 2% or More and Greater than Placebo in MDD and GAD Placebo-Controlled Trials in Adults a,b a The inclusion of an event in the table is determined based on the percentages before rounding; however, the percentages displayed in the table are rounded to the nearest integer. b For GAD, there were no adverse reactions that were significantly different between treatments in adults ≥65 years that were also not significant in the adults <65 years. c Events for which there was a significant dose-dependent relationship in fixed-dose studies, excluding three MDD studies which did not have a placebo lead-in period or dose titration. d Includes abdominal pain upper, abdominal pain lower, abdominal tenderness, abdominal discomfort, and gastrointestinal pain. e Includes asthenia. f Includes hypersomnia and sedation. g Includes initial insomnia, middle insomnia, and early morning awakening. h Includes feeling jittery, nervousness, restlessness, tension and psychomotor hyperactivity. i Includes loss of libido. j Includes anorgasmia. […]

Strong CYP1A2 inhibitors : Avoid concomitant use. ( 7.1 ) Potent inhibitors of CYP2D6 may increase Duloxetine Delayed-Release Capsule concentrations. ( 7.1 ) Duloxetine Delayed-Release Capsule is a moderate inhibitor of CYP2D6. ( 7.1 )

7.1 Drugs Having Clinically Important Interactions with Duloxetine Delayed-Release Capsules Table 6: Clinically Significant Drug Interactions with Duloxetine Delayed-Release Capsules Monoamine Oxidase Inhibitors (MAOIs) Prevention or Management Concomitant use of Duloxetine Delayed-Release Capsules is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [see Dosage and Administration ( 2.7 , 2.8 ), Contraindications ( 4 ), Warnings and Precautions ( 5.4 )] . Mechanism and Clinical Effect(s) Concomitant use of SSRIs and SNRIs, including Duloxetine Delayed-Release Capsules, with MAOIs increases the risk of serotonin syndrome. Other Serotonergic Drugs Prevention or Management Monitor for symptoms of serotonin syndrome when Duloxetine Delayed-Release Capsules is used concomitantly with other drugs that may affect the serotonergic neurotransmitter systems. If serotonin syndrome occurs, consider discontinuation of Duloxetine Delayed-Release Capsules and/or concomitant serotonergic drugs [see Dosage and Administration ( 2.6 ), Warnings and Precautions ( 5.4 )] . Mechanism and Clinical Effect(s) Concomitant use of Duloxetine Delayed-Release Capsules with other serotonergic drugs increases the risk of serotonin syndrome. Alcohol Prevention or Management Avoid use in patients with chronic liver disease or heavy alcohol use [see Warnings and Precautions ( 5.2 )] . Mechanism and Clinical Effect(s) Concomitant use of Duloxetine Delayed-Release Capsules and alcohol may cause liver injury or aggravate pre-existing liver disease. Drugs that Interfere with Hemostasis Prevention or Management Closely monitor for bleeding for patients receiving an antiplatelet or anticoagulant drug when Duloxetine Delayed-Release Capsules are initiated or discontinued [Warnings and Precaution ( 5.5 )] . Mechanism and Clinical Effect(s) Concomitant use of Duloxetine Delayed-Release Capsules with an antiplatelet or anticoagulant drug may potentiate the risk of bleeding. Strong CYP1A2 Inhibitors Prevention or Management Avoid concomitant use of Duloxetine Delayed-Release Capsules with strong CYP1A2 inhibitors [see Clinical Pharmacology ( 12.3 )]. Mechanism and Clinical Effect(s) Concomitant use of Duloxetine Delayed-Release Capsules with CYP1A2 inhibitors increase the exposures of duloxetine. Strong CYP2D6 Inhibitors Prevention or Management Monitor for adverse events and adjust the dose of Duloxetine Delayed-Release Capsules as clinically appropriate when co-administering with strong CYP2D6 inhibitors [see Clinical Pharmacology ( 12.3 )]. Mechanism and Clinical Effect(s) Concomitant use of Duloxetine Delayed-Release Capsules with CYP2D6 inhibitors increase the exposures of duloxetine. Greater degrees of inhibition are expected with higher doses of CYP2D6 inhibitors. CYP2D6 Poor Metabolizers Using Strong Inhibitor of CYP1A2 Prevention or Management Avoid co-administration of Duloxetine Delayed-Release Capsules and strong CYP1A2 inhibitors in patients who are CYP2D6 poor metabolizers [see Clinical Pharmacology ( 12.3 )] . Mechanism and Clinical Effect(s) Concomitant administration of Duloxetine Delayed-Release Capsules with strong CYP1A2 inhibitors in patients who are CYP2D6 poor metabolizers results in increased duloxetine exposures. Drugs Metabolized by CYP2D6 Prevention or Management Monitor plasma concentrations of CYP2D6 substrate and reduce dosage of CYP2D6 substrate drug if necessary [see Clinical Pharmacology ( 12.3 )] . Mechanism and Clinical Effect(s) Concomitant use of duloxetine increases exposures of a drug primarily metabolized by CYP2D6 which may increase the risk of toxicity of the CYP2D6 substrate drug. Drugs Metabolized by CYP1A2 Prevention or Management Monitor for adverse events and adjust the dose of Duloxetine Delayed-Release Capsules as clinically appropriate [see Clinical Pharmacology ( 12.3 )]. Mechanism and Clinical Effect(s) Concomitant use of Duloxetine Delayed-Release Capsules with CYP1A2 substrates may increase the exposures of CYP1A2 substrate. CNS Drugs Prevention or Management Monitor for adverse events and adjust the dose of Duloxetine Delayed-Release Capsules as clinically appropriate [see Clinical Pharmacology ( 12.3 )] . Mechanism and Clinical Effect(s) Concomitant use of Duloxetine Delayed-Release Capsules with other centrally acting drugs may increase the CNS effects of duloxetine. Drugs that Affect Gastric Acidity Prevention or Management Monitor for adverse events and adjust the dose of Duloxetine Delayed-Release Capsules as clinically appropriate [see Clinical Pharmacology ( 12.3 )]. Mechanism and Clinical Effect(s) In patients with conditions that may slow gastric emptying (e.g., some diabetics) and drugs that raise the gastrointestinal pH may lead to earlier the release of duloxetine. Drugs Highly Bound to Plasma Protein Prevention or Management Monitor for adverse events and adjust the dose of Duloxetine Delayed-Release Capsules as clinically appropriate [see Clinical Pharmacology ( 12.3 )]. Mechanism and Clinical Effect(s) Concomitant use of Duloxetine Delayed-Release Capsules with highly protein bound drugs may cause increased free concentrations of the other drug, potentially resulting in adverse reactions.

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. ( 8.6 ) Renal Impairment : Avoid use in patients with severe renal impairment, GFR <30 mL/minute. ( 8.7 )

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors the pregnancy outcomes in women exposed to antidepressants, including Duloxetine Delayed-Release Capsules, 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/research/pregnancyregistry/antidepressants. 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 in pregnancy, and with exposure to SNRIs and SSRIs, including Duloxetine Delayed-Release Capsules, 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 times 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. Maternal Adverse Reactions Use of Duloxetine Delayed-Release Capsules 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 2,532 women exposed to duloxetine in the first trimester of pregnancy to 1,284,827 unexposed women after adjusting for several confounders. Methodologic limitations include possible residual confounding, misclassification of exposure and outcomes, lack of direct measures of disease severity, and lack of information about alcohol use, nutrition, and over-the-counter medication exposures. Animal Data In animal reproduction studies, duloxetine has been shown to have adverse effects on embryo/fetal and postnatal development. When duloxetine was administered orally to pregnant rats and rabbits during the period of organogenesis, there was no evidence of malformations or developmental variations at doses up to 45 mg/kg/day [3 times and 6 times, respectively, the MRHD of 120 mg/day given to adolescents on a mg/m 2 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 Delayed-Release Capsules and any potential adverse effects on the breastfed child from Duloxetine Delayed-Release Capsules or from the underlying maternal condition. Clinical Considerations Infants exposed to Duloxetine Delayed-Release Capsules 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 delayed-release 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 Antidepressants increased the risk of suicidal thoughts and behavior in pediatric patients. […]

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.