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 )] .

Duloxetine delayed-release capsules are indicated for the treatment of: Major Depressive Disorder [see Clinical Studies ( 14.1 )] . Generalized Anxiety Disorder [see Clinical Studies ( 14.2 )] . Diabetic Peripheral Neuropathy [see Clinical Studies ( 14.3 )] . Chronic Musculoskeletal Pain [see Clinical Studies ( 14.5 )] .

         Swallow duloxetine delayed-release capsules whole. Do not chew or crush. Do not open the capsule and sprinkle its contents on food or mix with liquids. All of these might affect the enteric coating. Duloxetine delayed-release capsules can be given without regard to meals. If a dose of duloxetine delayed-release capsules is missed, take the missed dose as soon as it is remembered. If it is almost time for the next dose, skip the missed dose and take the next dose at the regular time. Do not take two doses of duloxetine delayed-release capsules at the same time.

         Monoamine Oxidase Inhibitors (MAOIs) - The use of MAOIs intended to treat psychiatric disorders with duloxetine or within 5 days of stopping treatment with duloxetine is contraindicated because of an increased risk of serotonin syndrome. The use of duloxetine 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 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 )].

         Duloxetine hydrochloride USP is 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 molecular formula is C 18 H 19 NOS•HCl, which corresponds to a molecular weight of 333.88. The structural formula is:          Duloxetine hydrochloride USP is a white to brownish-white solid, which is slightly soluble in water.          Each capsule contains enteric-coated pellets of 22.4, 33.7, or 67.3 mg of duloxetine hydrochloride USP equivalent to 20, 30, or 60 mg of duloxetine, 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, hypromellose, sucrose, talc, methacrylic acid copolymer dispersion, and triethyl citrate.          The capsule shell contains gelatin, FD & C Blue No. 2, titanium dioxide, and sodium lauryl sulfate.           For 20 mg, 30 mg  (body & cap) and 60 mg (body only) strengths, imprinting black ink contains shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, strong ammonia solution, black iron oxide, potassium hydroxide and purified water.          For 60 mg (cap only) strength, imprinting white ink contains shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, strong ammonia solution, purified water, potassium hydroxide, and titanium dioxide.          USP Assay & Organic Impurities test pending.

         Both CYP1A2 and CYP2D6 are responsible for duloxetine metabolism.

            See FDA-approved patient labeling (Medication Guide). Information on Medication Guide - Inform patients, their families, and their caregivers about the benefits and risks associated with treatment with duloxetine delayed-release capsules and counsel them in its appropriate use. A patient Medication Guide is available for duloxetine delayed-release capsules. Instruct patients, their families, and their caregivers to read the Medication Guide before starting duloxetine delayed-release capsules and each time their prescription is renewed, and assist them in understanding its contents. Give patients the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Advise patients of the following issues and ask them to alert their prescriber if these occur while taking duloxetine delayed-release capsules. Suicidal Thoughts and Behaviors - Encourage patients, their families, and their caregivers to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Advise families and caregivers of patients to observe for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication [see Boxed Warning, and Warnings and Precautions ( 5.1 )] . Duloxetine delayed-release capsules should be swallowed whole and should not be chewed or crushed, nor should the capsule be opened and its contents be sprinkled on food or mixed with liquids. All of these might affect the enteric coating. Continuing the Therapy Prescribed - While patients may notice improvement with duloxetine delayed-release capsules therapy in 1 to 4 weeks, advise patients to continue therapy as directed. 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 with heavy alcohol intake may be associated with severe liver injury [see Warnings and Precautions ( 5.2 )]. Alcohol - Although duloxetine does not increase the impairment of mental and motor skills caused by alcohol, use of duloxetine 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 [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. Abnormal Bleeding - Caution patients about the concomitant use of duloxetine 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 )]. Severe Skin Reactions - Caution patients that duloxetine 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 physician [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 physician 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 physicians 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 )]. Duloxetine is 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 and Nursing Mothers Advise patients to notify their physician if they: become pregnant during therapy intend to become pregnant during therapy are nursing [see Use in Specific Populations ( 8.1 , 8.3 )] . Pediatric Use – Safety and efficacy of duloxetine in patients 7 to 17 years of age have been established for the treatment of GAD. The types of adverse reactions observed with duloxetine in children and adolescents were generally similar to those observed in adults. The safety and effectiveness of duloxetine have not been established in pediatric patients less than 18 years of age with other indications. [See Use in Specific Populations ( 8.4 )]. Interference with Psychomotor Performance - Any psychoactive drug may impair judgment, thinking, or motor skills. Although in controlled studies duloxetine has not been shown to impair psychomotor performance, cognitive function, or memory, it may be associated with sedation and dizziness. Therefore, caution patients about operating hazardous machinery including automobiles, until they are reasonably certain that duloxetine therapy does not affect their ability to engage in such activities. Literature revised 01/2018 Marketed by: Ajanta Pharma USA Inc. Bridgewater, NJ 08807. Made in INDIA.

         Risk Summary          Duloxetine is present in human milk. In a published study, lactating women who were weaning their infants were given duloxetine. At steady state, the concentration of duloxetine in breast milk was approximately 25% that of maternal plasma. The estimated daily infant dose was approximately 0.14% of the maternal dose. The developmental and health benefits of human milk feeding should be considered along with the mother’s clinical need for duloxetine and any potential adverse effects on the milk-fed child from the drug or from the underlying maternal condition. Exercise caution when duloxetine is administered to a nursing woman.          Data          The 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. The presence of duloxetine metabolites in breast milk was not examined.

Generalized Anxiety Disorder — In pediatric patients aged 7 to 17 years, efficacy was demonstrated in one 10 week, placebo-controlled trial. The study included 272 pediatric patients with GAD of which 47% were 7 to 11 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 ( 14.2 )]. The safety and effectiveness in pediatric patients less than 7 years of age have not been established. Major Depressive Disorder — Efficacy was not demonstrated in two 10-week, placebo-controlled trials with 800 pediatric patients with MDD, age 7-17. Neither duloxetine nor an active control (indicated for treatment of pediatric depression) was superior to placebo. The safety and effectiveness in pediatric patients less than 7 years of age have not been established. The most frequently observed adverse reactions in the 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. Perform regular monitoring of weight and growth in children and adolescents treated with an SNRI such as duloxetine [see Adverse Reactions ( 6.11 )]. Use of duloxetine in a child or adolescent must balance the potential risks with the clinical need [see Boxed Warning and Warnings and Precautions ( 5.1 )]. Animal 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).

Of the 2,418 patients in premarketing clinical studies of duloxetine for MDD, 5.9% (143) were 65 years of age or over. Of the 1041 patients in CLBP premarketing studies, 21.2% (221) were 65 years of age or over. Of the 487 patients in OA premarketing studies, 40.5% (197) were 65 years of age or over. Of the 1,074 patients in the DPNP premarketing studies, 33% (357) were 65 years of age or over. In the MDD, GAD, DPNP, OA, CLBP, and other studies, no overall differences in safety or effectiveness were generally observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. SSRIs and SNRIs, including duloxetine have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event [see Warnings and Precautions ( 5.13 )] . In an analysis of data from all placebo-controlled-trials, patients treated with duloxetine reported a higher rate of falls compared to patients treated with placebo. The increased risk appears to be proportional to a patient’s underlying risk for falls. Underlying risk appears to increase steadily with age. As elderly 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 treatment with duloxetine is unclear. Falls with serious consequences including bone fractures and hospitalizations have been reported [see Warnings and Precautions ( 5.3 ) and Adverse Reactions ( 6.10 )] . 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 patient is not necessary.

Carcinogenesis — Duloxetine was administered in the diet to mice and rats for 2 years.          In female mice receiving duloxetine at 140 mg/kg/day (6 times the maximum recommended human dose (MRHD) of 120 mg/day 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 (2 times the MRHD). Tumor incidence was not increased in male mice receiving duloxetine at doses up to 100 mg/kg/day (4 times the MRHD).          In rats, dietary doses of duloxetine up to 27 mg/kg/day in females (2 times the MRHD) and up to 36 mg/kg/day in males (3 times the MRHD) 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 (4 times the MRHD) did not alter mating or fertility.

The following serious adverse reactions are described below and elsewhere in the labeling: Suicidal Thoughts and Behaviors in Children, Adolescents and Young Adults [see Boxed Warning and Warnings and Precautions ( 5.1 )] Hepatotoxicity [see Warnings and Precautions ( 5.2 )] Orthostatic Hypotension, Falls and Syncope [see Warnings and Precautions ( 5.3 )] Serotonin Syndrome [see Warnings and Precautions ( 5.4 )] Abnormal Bleeding [see Warnings and Precautions ( 5.5 )] Severe Skin Reactions [see Warnings and Precautions ( 5.6 )] Discontinuation of Treatment with Duloxetine Delayed-Release Capsules [see Warnings and Precautions ( 5.7 )] Activation of Mania/Hypomania [see Warnings and Precautions ( 5.8 )] Angle-Closure Glaucoma [see Warnings and Precautions ( 5.9 )] Seizures [see Warnings and Precautions ( 5.10 )] Effect on Blood Pressure [see Warnings and Precautions ( 5.11 )] Clinically Important Drug Interactions [see Warnings and Precautions ( 5.12 )] Hyponatremia [see Warnings and Precautions ( 5.13 )] Urinary Hesitation and Retention [see Warnings and Precautions ( 5.15 )]

         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).

         In drug dependence studies, duloxetine did not demonstrate dependence-producing potential in rats.

The efficacy of duloxetine has been established in the following adequate and well-controlled trials: Major Depressive Disorder (MDD): 4 short-term and 1 maintenance trial in adults [see Clinical Studies ( 14.1 )] . Generalized Anxiety Disorder (GAD): 3 short-term trials in adults, 1 maintenance trial in adults, and 1 short-term trial in children and adolescents [see Clinical Studies ( 14.2 )] . Diabetic Peripheral Neuropathic Pain (DPNP): Two 12-week trials in adults, and 1 short-term trial in children and adolescents [see Clinical Studies ( 14.3 )] . Chronic Musculoskeletal Pain: Two 12- to 13-week trials in adult patients with chronic low back pain (CLBP) and one 13-week trial in adult patients with chronic pain due to osteoarthritis [see Clinical Studies ( 14.5 )] .

Pregnancy Category C          Risk Summary — There are no adequate and well-controlled studies of duloxetine administration in pregnant women. In animal studies with duloxetine, fetal weights were decreased but there was no evidence of teratogenicity in pregnant rats and rabbits at oral doses administered during the period of organogenesis up to 4 and 7 times the maximum recommended human dose (MRHD) of 120 mg/day, respectively. 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. 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. Duloxetine should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus. Clinical Considerations          Fetal/Neonatal Adverse Reaction — Neonates exposed during pregnancy to serotonin - norepinephrine reuptake inhibitors (SNRIs) or selective serotonin reuptake inhibitors (SSRIs) have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding which 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 features 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          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 teratogenicity at doses up to 45 mg/kg/day (4 times the maximum recommended human dose (MRHD) of 120 mg/day on a mg/m 2 basis, in rat; 7 times the MRHD in rabbit). 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; 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); 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.

         Administer duloxetine delayed-release capsules at a total dose of 40 mg/day (given as 20 mg twice daily) to 60 mg/day (given either once daily or as 30 mg twice daily). For some patients, it may be desirable to start at 30 mg once daily for 1 week, to allow patients to adjust to the medication before increasing to 60 mg once daily. While a 120 mg/day dose was shown to be effective, there is no evidence that doses greater than 60 mg/day confer any additional benefits. The safety of doses above 120 mg/day has not been adequately evaluated. Periodically reassess to determine the need for maintenance treatment and the appropriate dose for such treatment [see Clinical Studies ( 14.1 )] .

Duloxetine Delayed-Release Capsules (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? Duloxetine 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. 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). 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 belongs 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) 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?”). What should I tell my healthcare provider before taking duloxetine? Before starting duloxetine, tell your healthcare provider if you: have heart problems or high blood pressure have diabetes (duloxetine treatment makes it harder for some people with diabetes to control their blood sugar) have liver problems have kidney problems have glaucoma have or had seizures or convulsions have bipolar disorder or mania have low sodium levels in your blood have delayed stomach emptying have or had bleeding problems are pregnant or plan to become pregnant. It is not known if duloxetine will harm your unborn baby. Talk to your healthcare provider about the benefits and risks of treating depression or other conditions with duloxetine during pregnancy. are breastfeeding or plan to breastfeed. Duloxetine can pass into your breast milk. Talk to your healthcare provider about the best way to feed your baby while taking duloxetine. Tell your healthcare provider about all the medicines that you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Duloxetine 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 amphetamines    cimetidine the antibiotics ciprofloxacin, enoxacin medicine to treat irregular heart rate (like propafenone, flecainide, quinidine) theophylline the blood thinner warfarin (Coumadin, Jantoven) non-steroidal anti-inflammatory drug (NSAID) (like ibuprofen, naproxen or aspirin). over-the-counter supplements such as tryptophan or St. John's Wort thioridazine (Mellaril). Mellaril together with duloxetine 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 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 works. Duloxetine delayed-release capsules may be taken with or without food. If you miss a dose of duloxetine delayed-release capsules, take the missed dose as soon as you remember. If it is almost time for the next dose, skip the missed dose and take your next dose at the regular time. Do not take two doses of duloxetine delayed-release capsules at the same time. If you take too much duloxetine delayed-release capsules, call your healthcare provider or poison control center at 1800-222-1222 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 affects 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 may: increase your blood pressure. decrease your blood pressure when standing and cause dizziness or fainting, mostly when first starting duloxetine 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 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 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 without first talking to your healthcare provider. Stopping duloxetine 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 .   v isual 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 include: nausea dry mouth sleepiness fatigue constipation loss of appetite increased sweating dizziness Common possible side effects in children and adolescents who take duloxetine include: nausea decreased weight dizziness Side effects in adults may also occur in children and adolescents who take duloxetine. 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. 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 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [ see USP Controlled Room Temperature]. 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, call 1-855-664-7744. What are the ingredients in duloxetine delayed-release capsules? Active ingredient: duloxetine hydrochloride, USP Inactive ingredients: sugar spheres, hypromellose,  sucrose, talc, methacrylic acid copolymer dispersion, and triethyl citrate. The capsule shell contains gelatin, FD & C Blue No. 2, titanium dioxide, and sodium lauryl sulfate. For 20 mg, 30 mg  (body & cap) and 60 mg (body only) strengths, imprinting black ink contains shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, strong ammonia solution, black iron oxide, potassium hydroxide, and purified water. For 60 mg (cap only) strength, imprinting white ink contains shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, strong ammonia solution, purified water, potassium hydroxide, and titanium dioxide. This Medication Guide has been approved by the U.S. Food and Drug Administration All trademarks are the properties of their respective owners. Medication Guide revised: 01/2018 Marketed by: Ajanta Pharma USA Inc. Bridgewater, NJ 08807. Made un INDIA.

         Duloxetine delayed-release capsules are available as:          20 mg white and blue capsules imprinted with “ap DLX20”          30 mg blue and blue capsules imprinted with “ap DLX30”          60 mg white and blue capsules imprinted with “ap DLX60”

         Although the exact mechanisms of the antidepressant, central pain inhibitory and anxiolytic actions of duloxetine in humans are unknown, these actions are believed to be related to its potentiation of serotonergic and noradrenergic activity in the CNS.

         Preclinical studies have shown that duloxetine is a potent inhibitor of neuronal serotonin and norepinephrine reuptake and a less potent inhibitor of dopamine reuptake. Duloxetine has no significant affinity for dopaminergic, adrenergic, cholinergic, histaminergic, opioid, glutamate, and GABA receptors in vitro . Duloxetine does not inhibit monoamine oxidase (MAO).          Duloxetine is in a class of drugs known to affect urethral resistance. If symptoms of urinary hesitation develop during treatment with duloxetine, consideration should be given to the possibility that they might be drug-related.

         Duloxetine has an elimination half-life of about 12 hours (range 8 to 17 hours) and its pharmacokinetics are dose proportional over the therapeutic range. Steady-state plasma concentrations are typically achieved after 3 days of dosing. Elimination of duloxetine is mainly through hepatic metabolism involving two P450 isozymes, CYP1A2 and CYP2D6. Absorption and Distribution — Orally administered 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. Food does not affect the C max 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%. There is a 3 hour lag in absorption and a one-third increase in apparent clearance of duloxetine after an evening dose as compared to a morning dose.          The apparent volume of distribution averages about 1640 L. Duloxetine is highly bound ( > 90%) to proteins in human plasma, binding primarily to albumin and α 1 -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. Metabolism and Elimination — 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. 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.  Children and Adolescents (ages 7 to 17 years) - Duloxetine steady-state plasma concentration was comparable in children (7 to 12 years of age), adolescents (13 to 17 years of age) and adults. The average steady-state duloxetine concentration was approximately 30% lower in the pediatric population (children and adolescents) relative to the adults. The model-predicted duloxetine steady state plasma concentrations in children and adolescents were mostly within the concentration range observed in adult patients and did not exceed the concentration range in adults.

None.

Pregnancy: Based on animal data may cause fetal harm ( 8.1 ) Nursing Mothers: Exercise caution when administered to a nursing woman ( 8.3 )

Hepatotoxicity: Hepatic failure, sometimes fatal, has been reported in patients treated with duloxetine. Duloxetine 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. Duloxetine should not be prescribed to patients with substantial alcohol use or evidence of chronic liver disease ( 5.2 ) Orthostatic Hypotension, Falls and Syncope: Cases have been reported with duloxetine therapy ( 5.3 ) Serotonin Syndrome: Serotonin syndrome has been reported with SSRIs and SNRIs, including with duloxetine, both when taken alone, but especially when co-administered with other serotonergic agents (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. John’s Wort). If such symptoms occur, discontinue duloxetine and initiate supportive treatment. If concomitant use of duloxetine with other serotonergic drugs is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases ( 5.4 ) Abnormal Bleeding: Duloxetine may increase the risk of bleeding events. Patients should be cautioned about the risk of bleeding associated with the concomitant use of duloxetine and NSAIDs, aspirin, or other drugs that affect coagulation ( 5.5 , 7.4 ) Severe Skin Reactions: Severe skin reactions, including erythema multiforme and Stevens-Johnson Syndrome (SJS), can occur with duloxetine. Duloxetine should be discontinued 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: May result in symptoms, including dizziness, headache, nausea, diarrhea, paresthesia, irritability, vomiting, insomnia, anxiety, hyperhidrosis, and fatigue ( 5.7 ) Activation of mania or hypomania has occurred ( 5.8 ) Angle-Closure Glaucoma: 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: Monitor blood pressure prior to initiating treatment and periodically throughout treatment ( 5.11 ) Inhibitors of CYP1A2 or Thioridazine: Should not administer with duloxetine ( 5.12 ) Hyponatremia: Cases of hyponatremia have been reported ( 5.13 ) Glucose Control in Diabetes: In diabetic peripheral neuropathic pain patients, small increases in fasting blood glucose, and HbA 1c have been observed ( 5.14 ) Conditions that Slow Gastric Emptying: Use cautiously in these patients ( 5.14 ) Urinary Hesitation and Retention ( 5.15 )

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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 )] .

Duloxetine delayed-release capsules are indicated for the treatment of: Major Depressive Disorder [see Clinical Studies ( 14.1 )] . Generalized Anxiety Disorder [see Clinical Studies ( 14.2 )] . Diabetic Peripheral Neuropathy [see Clinical Studies ( 14.3 )] . Chronic Musculoskeletal Pain [see Clinical Studies ( 14.5 )] .

         Swallow duloxetine delayed-release capsules whole. Do not chew or crush. Do not open the capsule and sprinkle its contents on food or mix with liquids. All of these might affect the enteric coating. Duloxetine delayed-release capsules can be given without regard to meals. If a dose of duloxetine delayed-release capsules is missed, take the missed dose as soon as it is remembered. If it is almost time for the next dose, skip the missed dose and take the next dose at the regular time. Do not take two doses of duloxetine delayed-release capsules at the same time.

         Monoamine Oxidase Inhibitors (MAOIs) - The use of MAOIs intended to treat psychiatric disorders with duloxetine or within 5 days of stopping treatment with duloxetine is contraindicated because of an increased risk of serotonin syndrome. The use of duloxetine 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 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 )].

         Both CYP1A2 and CYP2D6 are responsible for duloxetine metabolism.

            See FDA-approved patient labeling (Medication Guide). Information on Medication Guide - Inform patients, their families, and their caregivers about the benefits and risks associated with treatment with duloxetine delayed-release capsules and counsel them in its appropriate use. A patient Medication Guide is available for duloxetine delayed-release capsules. Instruct patients, their families, and their caregivers to read the Medication Guide before starting duloxetine delayed-release capsules and each time their prescription is renewed, and assist them in understanding its contents. Give patients the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Advise patients of the following issues and ask them to alert their prescriber if these occur while taking duloxetine delayed-release capsules. Suicidal Thoughts and Behaviors - Encourage patients, their families, and their caregivers to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Advise families and caregivers of patients to observe for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication [see Boxed Warning, and Warnings and Precautions ( 5.1 )] . Duloxetine delayed-release capsules should be swallowed whole and should not be chewed or crushed, nor should the capsule be opened and its contents be sprinkled on food or mixed with liquids. All of these might affect the enteric coating. Continuing the Therapy Prescribed - While patients may notice improvement with duloxetine delayed-release capsules therapy in 1 to 4 weeks, advise patients to continue therapy as directed. 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 with heavy alcohol intake may be associated with severe liver injury [see Warnings and Precautions ( 5.2 )]. Alcohol - Although duloxetine does not increase the impairment of mental and motor skills caused by alcohol, use of duloxetine 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 [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. Abnormal Bleeding - Caution patients about the concomitant use of duloxetine 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 )]. Severe Skin Reactions - Caution patients that duloxetine 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 physician [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 physician 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 physicians 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 )]. Duloxetine is 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 and Nursing Mothers Advise patients to notify their physician if they: become pregnant during therapy intend to become pregnant during therapy are nursing [see Use in Specific Populations ( 8.1 , 8.3 )] . Pediatric Use – Safety and efficacy of duloxetine in patients 7 to 17 years of age have been established for the treatment of GAD. The types of adverse reactions observed with duloxetine in children and adolescents were generally similar to those observed in adults. The safety and effectiveness of duloxetine have not been established in pediatric patients less than 18 years of age with other indications. [See Use in Specific Populations ( 8.4 )]. Interference with Psychomotor Performance - Any psychoactive drug may impair judgment, thinking, or motor skills. Although in controlled studies duloxetine has not been shown to impair psychomotor performance, cognitive function, or memory, it may be associated with sedation and dizziness. Therefore, caution patients about operating hazardous machinery including automobiles, until they are reasonably certain that duloxetine therapy does not affect their ability to engage in such activities. Literature revised 01/2018 Marketed by: Ajanta Pharma USA Inc. Bridgewater, NJ 08807. Made in INDIA.

         Risk Summary          Duloxetine is present in human milk. In a published study, lactating women who were weaning their infants were given duloxetine. At steady state, the concentration of duloxetine in breast milk was approximately 25% that of maternal plasma. The estimated daily infant dose was approximately 0.14% of the maternal dose. The developmental and health benefits of human milk feeding should be considered along with the mother’s clinical need for duloxetine and any potential adverse effects on the milk-fed child from the drug or from the underlying maternal condition. Exercise caution when duloxetine is administered to a nursing woman.          Data          The 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. The presence of duloxetine metabolites in breast milk was not examined.

Generalized Anxiety Disorder — In pediatric patients aged 7 to 17 years, efficacy was demonstrated in one 10 week, placebo-controlled trial. The study included 272 pediatric patients with GAD of which 47% were 7 to 11 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 ( 14.2 )]. The safety and effectiveness in pediatric patients less than 7 years of age have not been established. Major Depressive Disorder — Efficacy was not demonstrated in two 10-week, placebo-controlled trials with 800 pediatric patients with MDD, age 7-17. Neither duloxetine nor an active control (indicated for treatment of pediatric depression) was superior to placebo. The safety and effectiveness in pediatric patients less than 7 years of age have not been established. The most frequently observed adverse reactions in the 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. Perform regular monitoring of weight and growth in children and adolescents treated with an SNRI such as duloxetine [see Adverse Reactions ( 6.11 )]. Use of duloxetine in a child or adolescent must balance the potential risks with the clinical need [see Boxed Warning and Warnings and Precautions ( 5.1 )]. Animal 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).

Of the 2,418 patients in premarketing clinical studies of duloxetine for MDD, 5.9% (143) were 65 years of age or over. Of the 1041 patients in CLBP premarketing studies, 21.2% (221) were 65 years of age or over. Of the 487 patients in OA premarketing studies, 40.5% (197) were 65 years of age or over. Of the 1,074 patients in the DPNP premarketing studies, 33% (357) were 65 years of age or over. In the MDD, GAD, DPNP, OA, CLBP, and other studies, no overall differences in safety or effectiveness were generally observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. SSRIs and SNRIs, including duloxetine have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event [see Warnings and Precautions ( 5.13 )] . In an analysis of data from all placebo-controlled-trials, patients treated with duloxetine reported a higher rate of falls compared to patients treated with placebo. The increased risk appears to be proportional to a patient’s underlying risk for falls. Underlying risk appears to increase steadily with age. As elderly 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 treatment with duloxetine is unclear. Falls with serious consequences including bone fractures and hospitalizations have been reported [see Warnings and Precautions ( 5.3 ) and Adverse Reactions ( 6.10 )] . 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 patient is not necessary.

Carcinogenesis — Duloxetine was administered in the diet to mice and rats for 2 years.          In female mice receiving duloxetine at 140 mg/kg/day (6 times the maximum recommended human dose (MRHD) of 120 mg/day 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 (2 times the MRHD). Tumor incidence was not increased in male mice receiving duloxetine at doses up to 100 mg/kg/day (4 times the MRHD).          In rats, dietary doses of duloxetine up to 27 mg/kg/day in females (2 times the MRHD) and up to 36 mg/kg/day in males (3 times the MRHD) 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 (4 times the MRHD) did not alter mating or fertility.

The following serious adverse reactions are described below and elsewhere in the labeling: Suicidal Thoughts and Behaviors in Children, Adolescents and Young Adults [see Boxed Warning and Warnings and Precautions ( 5.1 )] Hepatotoxicity [see Warnings and Precautions ( 5.2 )] Orthostatic Hypotension, Falls and Syncope [see Warnings and Precautions ( 5.3 )] Serotonin Syndrome [see Warnings and Precautions ( 5.4 )] Abnormal Bleeding [see Warnings and Precautions ( 5.5 )] Severe Skin Reactions [see Warnings and Precautions ( 5.6 )] Discontinuation of Treatment with Duloxetine Delayed-Release Capsules [see Warnings and Precautions ( 5.7 )] Activation of Mania/Hypomania [see Warnings and Precautions ( 5.8 )] Angle-Closure Glaucoma [see Warnings and Precautions ( 5.9 )] Seizures [see Warnings and Precautions ( 5.10 )] Effect on Blood Pressure [see Warnings and Precautions ( 5.11 )] Clinically Important Drug Interactions [see Warnings and Precautions ( 5.12 )] Hyponatremia [see Warnings and Precautions ( 5.13 )] Urinary Hesitation and Retention [see Warnings and Precautions ( 5.15 )]

         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).

         In drug dependence studies, duloxetine did not demonstrate dependence-producing potential in rats.

         Duloxetine hydrochloride USP is 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 molecular formula is C 18 H 19 NOS•HCl, which corresponds to a molecular weight of 333.88. The structural formula is:          Duloxetine hydrochloride USP is a white to brownish-white solid, which is slightly soluble in water.          Each capsule contains enteric-coated pellets of 22.4, 33.7, or 67.3 mg of duloxetine hydrochloride USP equivalent to 20, 30, or 60 mg of duloxetine, 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, hypromellose, sucrose, talc, methacrylic acid copolymer dispersion, and triethyl citrate.          The capsule shell contains gelatin, FD & C Blue No. 2, titanium dioxide, and sodium lauryl sulfate.           For 20 mg, 30 mg  (body & cap) and 60 mg (body only) strengths, imprinting black ink contains shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, strong ammonia solution, black iron oxide, potassium hydroxide and purified water.          For 60 mg (cap only) strength, imprinting white ink contains shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, strong ammonia solution, purified water, potassium hydroxide, and titanium dioxide.          USP Assay & Organic Impurities test pending.

The efficacy of duloxetine has been established in the following adequate and well-controlled trials: Major Depressive Disorder (MDD): 4 short-term and 1 maintenance trial in adults [see Clinical Studies ( 14.1 )] . Generalized Anxiety Disorder (GAD): 3 short-term trials in adults, 1 maintenance trial in adults, and 1 short-term trial in children and adolescents [see Clinical Studies ( 14.2 )] . Diabetic Peripheral Neuropathic Pain (DPNP): Two 12-week trials in adults, and 1 short-term trial in children and adolescents [see Clinical Studies ( 14.3 )] . Chronic Musculoskeletal Pain: Two 12- to 13-week trials in adult patients with chronic low back pain (CLBP) and one 13-week trial in adult patients with chronic pain due to osteoarthritis [see Clinical Studies ( 14.5 )] .

Pregnancy Category C          Risk Summary — There are no adequate and well-controlled studies of duloxetine administration in pregnant women. In animal studies with duloxetine, fetal weights were decreased but there was no evidence of teratogenicity in pregnant rats and rabbits at oral doses administered during the period of organogenesis up to 4 and 7 times the maximum recommended human dose (MRHD) of 120 mg/day, respectively. 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. 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. Duloxetine should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus. Clinical Considerations          Fetal/Neonatal Adverse Reaction — Neonates exposed during pregnancy to serotonin - norepinephrine reuptake inhibitors (SNRIs) or selective serotonin reuptake inhibitors (SSRIs) have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding which 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 features 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          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 teratogenicity at doses up to 45 mg/kg/day (4 times the maximum recommended human dose (MRHD) of 120 mg/day on a mg/m 2 basis, in rat; 7 times the MRHD in rabbit). 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; 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); 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.

         Administer duloxetine delayed-release capsules at a total dose of 40 mg/day (given as 20 mg twice daily) to 60 mg/day (given either once daily or as 30 mg twice daily). For some patients, it may be desirable to start at 30 mg once daily for 1 week, to allow patients to adjust to the medication before increasing to 60 mg once daily. While a 120 mg/day dose was shown to be effective, there is no evidence that doses greater than 60 mg/day confer any additional benefits. The safety of doses above 120 mg/day has not been adequately evaluated. Periodically reassess to determine the need for maintenance treatment and the appropriate dose for such treatment [see Clinical Studies ( 14.1 )] .

Duloxetine Delayed-Release Capsules (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? Duloxetine 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. 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). 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 belongs 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) 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?”). What should I tell my healthcare provider before taking duloxetine? Before starting duloxetine, tell your healthcare provider if you: have heart problems or high blood pressure have diabetes (duloxetine treatment makes it harder for some people with diabetes to control their blood sugar) have liver problems have kidney problems have glaucoma have or had seizures or convulsions have bipolar disorder or mania have low sodium levels in your blood have delayed stomach emptying have or had bleeding problems are pregnant or plan to become pregnant. It is not known if duloxetine will harm your unborn baby. Talk to your healthcare provider about the benefits and risks of treating depression or other conditions with duloxetine during pregnancy. are breastfeeding or plan to breastfeed. Duloxetine can pass into your breast milk. Talk to your healthcare provider about the best way to feed your baby while taking duloxetine. Tell your healthcare provider about all the medicines that you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Duloxetine 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 amphetamines    cimetidine the antibiotics ciprofloxacin, enoxacin medicine to treat irregular heart rate (like propafenone, flecainide, quinidine) theophylline the blood thinner warfarin (Coumadin, Jantoven) non-steroidal anti-inflammatory drug (NSAID) (like ibuprofen, naproxen or aspirin). over-the-counter supplements such as tryptophan or St. John's Wort thioridazine (Mellaril). Mellaril together with duloxetine 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 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 works. Duloxetine delayed-release capsules may be taken with or without food. If you miss a dose of duloxetine delayed-release capsules, take the missed dose as soon as you remember. If it is almost time for the next dose, skip the missed dose and take your next dose at the regular time. Do not take two doses of duloxetine delayed-release capsules at the same time. If you take too much duloxetine delayed-release capsules, call your healthcare provider or poison control center at 1800-222-1222 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 affects 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 may: increase your blood pressure. decrease your blood pressure when standing and cause dizziness or fainting, mostly when first starting duloxetine 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 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 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 without first talking to your healthcare provider. Stopping duloxetine 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 .   v isual 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 include: nausea dry mouth sleepiness fatigue constipation loss of appetite increased sweating dizziness Common possible side effects in children and adolescents who take duloxetine include: nausea decreased weight dizziness Side effects in adults may also occur in children and adolescents who take duloxetine. 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. 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 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [ see USP Controlled Room Temperature]. 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, call 1-855-664-7744. What are the ingredients in duloxetine delayed-release capsules? Active ingredient: duloxetine hydrochloride, USP Inactive ingredients: sugar spheres, hypromellose,  sucrose, talc, methacrylic acid copolymer dispersion, and triethyl citrate. The capsule shell contains gelatin, FD & C Blue No. 2, titanium dioxide, and sodium lauryl sulfate. For 20 mg, 30 mg  (body & cap) and 60 mg (body only) strengths, imprinting black ink contains shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, strong ammonia solution, black iron oxide, potassium hydroxide, and purified water. For 60 mg (cap only) strength, imprinting white ink contains shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, strong ammonia solution, purified water, potassium hydroxide, and titanium dioxide. This Medication Guide has been approved by the U.S. Food and Drug Administration All trademarks are the properties of their respective owners. Medication Guide revised: 01/2018 Marketed by: Ajanta Pharma USA Inc. Bridgewater, NJ 08807. Made un INDIA.

         Duloxetine delayed-release capsules are available as:          20 mg white and blue capsules imprinted with “ap DLX20”          30 mg blue and blue capsules imprinted with “ap DLX30”          60 mg white and blue capsules imprinted with “ap DLX60”

         Although the exact mechanisms of the antidepressant, central pain inhibitory and anxiolytic actions of duloxetine in humans are unknown, these actions are believed to be related to its potentiation of serotonergic and noradrenergic activity in the CNS.

         Preclinical studies have shown that duloxetine is a potent inhibitor of neuronal serotonin and norepinephrine reuptake and a less potent inhibitor of dopamine reuptake. Duloxetine has no significant affinity for dopaminergic, adrenergic, cholinergic, histaminergic, opioid, glutamate, and GABA receptors in vitro . Duloxetine does not inhibit monoamine oxidase (MAO).          Duloxetine is in a class of drugs known to affect urethral resistance. If symptoms of urinary hesitation develop during treatment with duloxetine, consideration should be given to the possibility that they might be drug-related.

         Duloxetine has an elimination half-life of about 12 hours (range 8 to 17 hours) and its pharmacokinetics are dose proportional over the therapeutic range. Steady-state plasma concentrations are typically achieved after 3 days of dosing. Elimination of duloxetine is mainly through hepatic metabolism involving two P450 isozymes, CYP1A2 and CYP2D6. Absorption and Distribution — Orally administered 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. Food does not affect the C max 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%. There is a 3 hour lag in absorption and a one-third increase in apparent clearance of duloxetine after an evening dose as compared to a morning dose.          The apparent volume of distribution averages about 1640 L. Duloxetine is highly bound ( > 90%) to proteins in human plasma, binding primarily to albumin and α 1 -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. Metabolism and Elimination — 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. 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.  Children and Adolescents (ages 7 to 17 years) - Duloxetine steady-state plasma concentration was comparable in children (7 to 12 years of age), adolescents (13 to 17 years of age) and adults. The average steady-state duloxetine concentration was approximately 30% lower in the pediatric population (children and adolescents) relative to the adults. The model-predicted duloxetine steady state plasma concentrations in children and adolescents were mostly within the concentration range observed in adult patients and did not exceed the concentration range in adults.

None.

Pregnancy: Based on animal data may cause fetal harm ( 8.1 ) Nursing Mothers: Exercise caution when administered to a nursing woman ( 8.3 )

Hepatotoxicity: Hepatic failure, sometimes fatal, has been reported in patients treated with duloxetine. Duloxetine 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. Duloxetine should not be prescribed to patients with substantial alcohol use or evidence of chronic liver disease ( 5.2 ) Orthostatic Hypotension, Falls and Syncope: Cases have been reported with duloxetine therapy ( 5.3 ) Serotonin Syndrome: Serotonin syndrome has been reported with SSRIs and SNRIs, including with duloxetine, both when taken alone, but especially when co-administered with other serotonergic agents (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. John’s Wort). If such symptoms occur, discontinue duloxetine and initiate supportive treatment. If concomitant use of duloxetine with other serotonergic drugs is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases ( 5.4 ) Abnormal Bleeding: Duloxetine may increase the risk of bleeding events. Patients should be cautioned about the risk of bleeding associated with the concomitant use of duloxetine and NSAIDs, aspirin, or other drugs that affect coagulation ( 5.5 , 7.4 ) Severe Skin Reactions: Severe skin reactions, including erythema multiforme and Stevens-Johnson Syndrome (SJS), can occur with duloxetine. Duloxetine should be discontinued 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: May result in symptoms, including dizziness, headache, nausea, diarrhea, paresthesia, irritability, vomiting, insomnia, anxiety, hyperhidrosis, and fatigue ( 5.7 ) Activation of mania or hypomania has occurred ( 5.8 ) Angle-Closure Glaucoma: 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: Monitor blood pressure prior to initiating treatment and periodically throughout treatment ( 5.11 ) Inhibitors of CYP1A2 or Thioridazine: Should not administer with duloxetine ( 5.12 ) Hyponatremia: Cases of hyponatremia have been reported ( 5.13 ) Glucose Control in Diabetes: In diabetic peripheral neuropathic pain patients, small increases in fasting blood glucose, and HbA 1c have been observed ( 5.14 ) Conditions that Slow Gastric Emptying: Use cautiously in these patients ( 5.14 ) Urinary Hesitation and Retention ( 5.15 )

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