Fluoxetine

1 INDICATIONS AND USAGE Fluoxetine tablets are indicated for the treatment of: Major Depressive Disorder (MDD). The efficacy of fluoxetine in MDD was established in one 5-week trial, three 6-week trials, and one maintenance study in adults. The efficacy of fluoxetine was also established in two 8- to 9-week trials in pediatric patients 8 to 18 years of age [see Clinical Studies (14.1) ]. Obsessions and compulsions in patients with Obsessive Compulsive Disorder (OCD). The efficacy of fluoxetine in OCD was demonstrated in two 13-week trials in adults and one 13-week trial in pediatric patients 7 to 17 years of age [see Clinical Studies (14.2) ]. Binge-eating and vomiting behaviors in patients with moderate to severe Bulimia Nervosa. The efficacy of fluoxetine in Bulimia Nervosa was demonstrated in two 8-week trials and one 16-week trial in adults [see Clinical Studies (14.3) ]. Panic Disorder, with or without agoraphobia. The efficacy of fluoxetine in Panic Disorder was demonstrated in two 12-week trials in adults [see Clinical Studies (14.4) ]. Fluoxetine tablets are a selective serotonin reuptake inhibitor (SSRI) indicated for the treatment of: Major Depressive Disorder (MDD) (1) Adults: Efficacy was established in one 5-week trial, three 6- week trials, and one maintenance study ( 14.1 ) Pediatrics: Efficacy was established in two 8- to 9-week trials of patients 8 to 18 years of age ( 14.1 ) Obsessive Compulsive Disorder (OCD) ( 1 ) Adults: Efficacy was established in two 13-week trials ( 14.2 ) Pediatrics: Efficacy was established in one 13-week trial in patients 7 to 17 years of age ( 14.2 ) Bulimia Nervosa ( 1 ) Adults: Efficacy was established in two 8-week trials and one 16-week trial ( 14.3 ) Panic Disorder, with or without agoraphobia (1) Adults: Efficacy was established in two 12-week trials ( 14.4 )

2 DOSAGE AND ADMINISTRATION This product is only available in a 60 mg dosage form. A 30 mg dose may be achieved with one-half of the scored tablet. Use of this product requires initial titration with another fluoxetine product according to the dosing guidelines indicated below. Use another fluoxetine product for initial doses of 10 to 20 mg/day or for doses other than 30 mg or 60 mg: Indication Adult Pediatric MDD ( 2.1 ) 20 mg/day in morning (initial dose) 20 mg/day (target dose) 80 mg/day (maximum dose studied) 10 to 20 mg/day (initial dose)* *This product has not been studied in doses greater than 20 mg/day in pediatric MDD. OCD ( 2.2) 20 mg/day in morning (initial dose) 20 to 60 mg/day (target dose) 10 mg/day (initial dose) 10 to 60 mg/day (target dose) Bulimia Nervosa ( 2.3 ) 60 mg/day in morning — Panic Disorder ( 2.4 ) 10 mg/day (initial dose) 20 mg/day (target dose) 60 mg/day (maximum dose studied) — No additional benefits seen at higher doses above 20 mg/day in MDD ( 2.1 , 14.1 ) Use a lower or less frequent dosage in patients with hepatic impairment, the elderly, and for patients with concurrent disease or on multiple concomitant medications ( 2.5 , 8.6 ) 2.1 Major Depressive Disorder Initial Treatment Adult —Initiate fluoxetine tablets 20 mg/day orally in the morning. Consider a dose increase after several weeks if insufficient clinical improvement is observed. Administer doses above 20 mg/day once daily in the morning or twice daily (i.e., morning and noon). The maximum fluoxetine dose should not exceed 80 mg/day. In controlled trials used to support the efficacy of fluoxetine, patients were administered morning doses ranging from 20 to 80 mg/day. Studies comparing fluoxetine 20, 40, and 60 mg/day to placebo indicate that 20 mg/day is sufficient to obtain a satisfactory response in MDD in most cases [see Clinical Studies (14.1) ] . Pediatric (children and adolescents) —Treatment should be initiated with a dose of 10 or 20 mg/day. After 1 week at 10 mg/day, the dose should be increased to 20 mg/day. However, due to higher plasma levels in lower weight children, the starting and target dose in this group may be 10 mg/day. A dose increase to 20 mg/day may be considered after several weeks if insufficient clinical improvement is observed. In the short-term (8- to 9-week) controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of MDD, patients were administered fluoxetine doses of 10 to 20 mg/day [see Clinical Studies (14.1) ]. Doses greater than 20 mg/day have not been studied in pediatric patients with MDD. This product is only available in a 60 mg dosage form. Administration of doses with demonstrated efficacy of fluoxetine 10 to 20 mg/day in pediatric MDD requires the use of another formulation. All patients —As with other drugs effective in the treatment of MDD, the full effect may be delayed until 4 weeks of treatment or longer. Periodically reassess to determine the need for maintenance treatment. Switching Patients to a Tricyclic Antidepressant (TCA) —Dosage of a TCA may need to be reduced, and plasma TCA concentrations may need to be monitored temporarily when fluoxetine is co-administered or has been recently discontinued [see Warnings and Precautions (5.2) and Drug Interactions (7.6) ] . 2.2 Obsessive Compulsive Disorder Initial Treatment Adults —Initiate fluoxetine tablets 20 mg/day, orally in the morning. Consider a dose increase after several weeks if insufficient clinical improvement is observed. The full therapeutic effect may be delayed until 5 weeks of treatment or longer. Doses above 20 mg/day may be administered on a once daily (i.e., morning) or twice daily schedule (i.e., morning and noon). A dose range of 20 to 60 mg/day is recommended; however, doses of up to 80 mg/day have been well tolerated in open studies of OCD. The maximum fluoxetine dose should not exceed 80 mg/day. In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment …

5 WARNINGS AND PRECAUTIONS Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults: Monitor for clinical worsening and suicidal thinking and behavior (5.1) Serotonin Syndrome: Serotonin syndrome has been reported with SSRIs and serotonin-norepinephrine reuptake inhibitors (SNRIs), including fluoxetine, both when taken alone, but especially when co-administered with other serotonergic agents. If such symptoms occur, discontinue fluoxetine and serotonergic agents and initiate supportive treatment. If concomitant use of fluoxetine 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 (5.2) Activation of Mania/Hypomania: Screen for Bipolar Disorder and monitor for mania/hypomania (5.4) Seizures: Use cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold (5.5) Altered Appetite and Weight: Significant weight loss has occurred (5.6 ) Increased Risk of Bleeding: May increase the risk of bleeding. Use with NSAIDs, aspirin, warfarin, or drugs that affect coagulation may potentiate the risk of gastrointestinal or other bleeding ( 5.7 , 7.4 ) Angle-closure Glaucoma: Angle-closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants ( 5.8 ) Hyponatremia: Has been reported with fluoxetine in association with syndrome of inappropriate antidiuretic hormone (SIADH). Consider discontinuing if symptomatic hyponatremia occurs ( 5.9 ) QT Prolongation: QT prolongation and ventricular arrhythmia including Torsades de Pointes have been reported with fluoxetine use. Use with caution in conditions that predispose to arrhythmias or increase fluoxetine exposure. Use cautiously in patients with risk factors for QT prolongation ( 4.2 , 5.11 , 7.6 , 7.7 , 10 ) Long Half-life: Changes in dose will not be fully reflected in plasma for several weeks ( 5.14 ) Sexual Dysfunction: Fluoxetine may cause symptoms of sexual dysfunction ( 5.16 ) 5.1 Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults Patients with MDD, both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with MDD and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. The pooled analyses of placebo-controlled trials in children and adolescents with MDD, OCD, or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences…

4 CONTRAINDICATIONS Monoamine Oxidase Inhibitors (MAOIs): Do not use MAOIs intended to treat psychiatric disorders with fluoxetine tablets or within 5 weeks of stopping treatment with fluoxetine tablets. Do not use fluoxetine tablets within 14 days of stopping an MAOI intended to treat psychiatric disorders. In addition, do not start fluoxetine tablets in a patient who is being treated with linezolid or intravenous methylene blue ( 4.1 , 7.1 ) Pimozide ( 4.2 , 5.11 , 7.6 , 7.7 ) Thioridazine: Do not use concomitantly with or within 5 weeks of discontinuing fluoxetine tablets ( 4.2 , 5.11 , 7.6 , 7.7 ) Known hypersensitivity to fluoxetine products ( 4.2 , 5.3 ) 4.1 Monoamine Oxidase Inhibitors (MAOIs) The use of MAOIs intended to treat psychiatric disorders with fluoxetine tablets or within 5 weeks of stopping treatment with fluoxetine tablets are contraindicated because of an increased risk of serotonin syndrome. The use of fluoxetine tablets within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated [see Dosage and Administration (2.6) and Warnings and Precautions (5.2) ] . Starting fluoxetine tablets 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 (2.7) and Warnings and Precautions (5.2) ] . 4.2 Other Contraindications The use of fluoxetine tablets are contraindicated with the following: Pimozide [see Warnings and Precautions (5.11) and Drug Interactions (7.6 , 7.7) ] Thioridazine [see Warnings and Precautions (5.11) and Drug Interactions (7.6 , 7.7 )] Pimozide and thioridazine prolong the QT interval. Fluoxetine tablets can increase the levels of pimozide and thioridazine through inhibition of CYP2D6. Fluoxetine tablets can also prolong the QT interval. Known hypersensitivity to fluoxetine: Do not use this product in patients with known hypersensitivity to fluoxetine due to risk of anaphylactoid reactions, including bronchospasm, angioedema, laryngospasm, and urticaria [see Warnings and Precautions (5.3) ] .

7 DRUG INTERACTIONS As with all drugs, the potential for interaction by a variety of mechanisms (e.g., pharmacodynamic, pharmacokinetic drug inhibition or enhancement, etc.) is a possibility. Drugs Metabolized by CYP2D6: Fluoxetine is a potent inhibitor of CYP2D6 enzyme pathway ( 7.6 ) Tricyclic Antidepressants (TCAs): Monitor TCA levels during co-administration with fluoxetine or when fluoxetine has been recently discontinued (5.2 , 7.6 ) Benzodiazepines: Diazepam—increased t 1/2 , alprazolam—further psychomotor performance decrement due to increased levels ( 7.6 ) Antipsychotics: Potential for elevation of haloperidol and clozapine levels ( 7.6 ) Anticonvulsants: Potential for elevated phenytoin and carbamazepine levels and clinical anticonvulsant toxicity ( 7.6 ) Serotonergic Drugs: ( 2.6, 2.7 , 4.1 , 5.2 ) Drugs that Prolong the QT Interval: Do not use fluoxetine with thioridazine or pimozide. Use with caution in combination with other drugs that prolong the QT interval ( 4.2 , 5.11 , 7.6 , 7.7 ) 7.1 Monoamine Oxidase Inhibitors (MAOIs) [See Dosage and Administration (2.6 , 2.7 ), Contraindications (4.1) , and Warnings and Precautions (5.2) ] . 7.2 CNS Acting Drugs Caution is advised if the concomitant administration of fluoxetine and such drugs is required. In evaluating individual cases, consideration should be given to using lower initial doses of the concomitantly administered drugs, using conservative titration schedules, and monitoring of clinical status [see Clinical Pharmacology (12.3) ] . 7.3 Other Serotonergic Drugs The concomitant use of serotonergic drugs (including other SSRIs, SNRIs, triptans, tricyclic antidepressants, opioids, lithium, buspirone, amphetamines, tryptophan, and St. John's Wort) with fluoxetine increases the risk of serotonin syndrome. Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of fluoxetine and/or concomitant serotonergic drugs [see Warnings and Precautions (5.2) ] . 7.4 Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, Warfarin) Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SNRIs or SSRIs are co-administered with warfarin. Patients receiving warfarin therapy should be carefully monitored when fluoxetine is initiated or discontinued [see Warnings and Precautions (5.7) ]. 7.5 Potential for Other Drugs to Affect Fluoxetine Drugs tightly bound to plasma proteins —Because fluoxetine is tightly bound to plasma proteins, adverse effects may result from displacement of protein-bound fluoxetine by other tightly bound drugs [see Clinical Pharmacology (12.3) ] . 7.6 Potential for Fluoxetine to Affect Other Drugs Pimozide— Concomitant use in patients taking pimozide is contraindicated. Pimozide can prolong the QT interval. Fluoxetine can increase the level of pimozide through inhibition of CYP2D6. Fluoxetine can also prolong the QT interval. Clinical studies of pimozide with other antidepressants demonstrate an increase in drug interaction or QT prolongation. While a specific study with pimozide and fluoxetine has not been conducted, the potential for drug interactions or QT prolongation warrants restricting the concurrent use of pimozide and fluoxetine [see Contraindications (4.2) , Warnings and Precautions (5.11 ), and Drug Interactions (7.7) ] . Thioridazine —Thioridazine should not be administered with fluoxetine or within a minimum of 5 weeks after fluoxetine has been discontinued, because of the risk of QT prolongation [see Co…

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-866-961-2388 or visiting online at https://womensmentalhealth.org/research/pregnancyregistry/antidepressants/. Risk Summary Based on data from published observational studies, exposure to SSRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [see Warnings and Precautions (5.7) and Clinical Considerations] . Available data from published epidemiologic studies and postmarketing reports over several decades have not established an increased risk of major birth defects or miscarriage. Some studies have reported an increased incidence of cardiovascular malformations; however, these studies results do not establish a causal relationship [see Data] . There are risks associated with untreated depression in pregnancy and risks of persistent pulmonary hypertension of the newborn (PPHN) ( see Data) and poor neonatal adaptation with exposure to selective serotonin reuptake inhibitors (SSRIs), including fluoxetine, during pregnancy (see Clinical Considerations) . In rats and rabbits treated with fluoxetine during the period of organogenesis, there was no evidence of developmental effects at doses up to 1.6 and 3.9 times, respectively, the maximum recommended human dose (MRHD) of 60 mg on a mg/m 2 given to adolescents on a mg/m 2 basis. However, in other reproductive studies in rats, an increase in stillborn pups, a decrease in pup weight, and an increase in pup deaths early after birth occurred at doses that are 1.5 times (during gestation) and 0.97 times (during gestation and lactation) the MRHD given to adolescents on a mg/m 2 basis. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Women who discontinue antidepressants during pregnancy are more likely to experience a relapse of major depression than women who continue antidepressants. This finding is from a prospective, longitudinal study that followed 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants at the beginning of pregnancy. Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum. Maternal Adverse Reactions Use of fluoxetine in the month before delivery may be associated with an increased risk of postpartum hemorrhage [see Warnings and Precautions (5.7) ] . Fetal/Neonatal Adverse Reactions Neonates exposed to fluoxetine and other SSRIs or SNRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremors, jitteriness, irritability, and constant crying. These findings are consistent with either a direct toxic effect of SSRIs and SNRIs 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 (5.2) ] . Data Human Data It has been shown that SSRIs (including fluoxetine) can cross the placenta. Published epidemiological studies …

6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling: Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults [see Boxed Warning and Warnings and Precautions (5.1)] Serotonin Syndrome [see Warnings and Precautions (5.2) ] Allergic Reactions and Rash [see Warnings and Precautions (5.3 )] Screening Patients for Bipolar Disorder and Monitoring for Mania/Hypomania [see Warnings and Precautions (5.4 )] Seizures [see Warnings and Precautions (5.5) ] Altered Appetite and Weight [see Warnings and Precautions (5.6) ] Increased Risk of Bleeding [see Warnings and Precautions (5.7) ] Angle-closure Glaucoma [see Warnings and Precautions (5.8) ] Hyponatremia [see Warnings and Precautions (5.9 )] Anxiety and Insomnia [see Warnings and Precautions (5.10 )] QT Prolongation [see Warnings and Precautions (5.11 )] Potential for Cognitive and Motor Impairment [see Warnings and Precautions (5.13) ] Discontinuation Adverse Reactions [see Warnings and Precautions (5.15 )] Most common adverse reactions (≥ 5% and at least twice that for placebo): abnormal dreams, abnormal ejaculation, anorexia, anxiety, asthenia, diarrhea, dry mouth, dyspepsia, flu syndrome, impotence, insomnia, libido decreased, nausea, nervousness, pharyngitis, rash, sinusitis, somnolence, sweating, tremor, vasodilatation, and yawn (6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect or predict the rates observed in practice. Multiple doses of fluoxetine have been administered to 10,782 patients with various diagnoses in U.S. clinical trials. In addition, there have been 425 patients administered fluoxetine in panic clinical trials. The stated frequencies represent the proportion of individuals who experienced, at least once, an adverse reaction of the type listed. An adverse reaction was included if it occurred for the first time or worsened while receiving therapy following baseline evaluation. Incidence in MDD, OCD, Bulimia, and Panic Disorder placebo-controlled clinical trials (excluding data from extensions of trials) — Table 2 enumerates the most common adverse reactions associated with the use of fluoxetine (incidence of at least 5% for fluoxetine and at least twice that for placebo within at least 1 of the indications) for the treatment of MDD, OCD, and bulimia in U.S. controlled clinical trials and Panic Disorder in U.S. plus non-U.S. controlled trials. Table 3 provides combined data for the pool of studies that are provided separately by indication in Table 2. Table 2. Most Common Adverse Reactions: Incidence in Major Depressive Disorder, Obsessive Compulsive Disorder, Bulimia, and Panic Disorder Placebo-controlled Clinical Trials Percentage of Patients Reporting Event MDD OCD Bulimia Panic Disorder Body System/Adverse Reaction Fluoxetine (N =1728) Placebo (N = 975) Fluoxetine (N = 266) Placebo (N = 89) Fluoxetine (N = 450) Placebo (N = 267) Fluoxetine (N = 425) Placebo (N = 342) Body as a Whole Asthenia 9 5 15 11 21 9 7 7 Flu syndrome 3 4 10 7 8 3 5 5 Cardiovascular System Vasodilatation 3 2 5 — 2 1 1 — Digestive System Nausea 21 9 26 13 29 11 12 7 Diarrhea 12 8 18 13 8 6 9 4 Anorexia 11 2 17 10 8 4 4 1 Dry mouth 10 7 12 3 9 6 4 4 Dyspepsia 7 5 10 4 10 6 6 2 Nervous System Insomnia 16 9 28 22 33 13 10 7 Anxiety 12 7 14 7 15 9 6 2 Nervousness 14 9 14 15 11 5 8 6 Somnolence 13 6 17 7 13 5 5 2 Tremor 10 3 9 1 13 1 3 1 Libido decreased 3 — 11 2 5 1 1 2 Abnormal dreams 1 1 5 2 5 3 1 1 Respiratory System Pharyngitis 3 3 11 9 10 5 3 3 Sinusitis 1 4 5 2 6 4 2 3 Yawn — — 7 — 11 — 1 — Skin and Appendages Sweating 8 3 7 — 8 3 2 2 Rash 4 3 6 3 4 4 2 2 U…