Fluoxetine

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)] Abnormal 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 Par Pharmaceutical at 1-800-828-9393 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 Urogenital System Impotence a 2 — — — 7 — 1 — Abnormal ejaculation a — — 7 — 7 — 2 1 Note: Includes U.S. data for MDD, OCD, Bulimia, and Panic Disorder clinical trials, plus non-U.S. data for Panic Disorder clinical trials. a = Denominator used was for males only (N = 690 fluoxetine MDD; N = 410 placebo MDD; N = 116 fluoxetine OCD; N = 43 placebo OCD; N = 14 fluoxetine Bulimia; N = 1 placebo Bulimia; N = 162 fluoxetine Panic Disorder; N = 121 placebo Panic Disorder). — =Incidence less than 1%. Table 3. 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, and Panic Disorder Combined Body System/Adverse Reaction Fluoxetine (N = 2869) Placebo (N = 1673) Body as a Whole Headache 21 19 Asthenia 11 6 Flu syndrome 5 4 Fever 2 1 Cardiovascular System Vasodilatation 2 1 Digestive System Nausea 22 9 Diarrhea 11 7 Anorexia 10 3 Dry mouth 9 6 Dyspepsia 8 4 Constipation 5 4 Flatulence 3 2 Vomiting 3 2 Metabolic and Nutritional Disorders Weight loss 2 1 Nervous System Insomnia 19 10 Nervousness 13 8 Anxiety 12 6 Somnolence 12 5 Dizziness 9 6 Tremor 9 2 Libido decreased 4 1 Thinking abnormal 2 1 Respiratory System Yawn 3 — Skin and Appendages Sweating 7 3 Rash 4 3 Pruritus 3 2 Special Senses Abnormal vision 2 1 Note: Includes U.S. data for MDD, OCD, Bulimia, and Panic Disorder clinical trials, plus non-U.S. data for Panic Disorder clinical trials. — =Incidence less than 1%. Associated with discontinuation in MDD, OCD, Bulimia, and Panic Disorder placebo-controlled clinical trials (excluding data from extensions of trials)—Table 4 lists the adverse reactions associated with discontinuation of fluoxetine treatment (incidence at least twice that for placebo and at least 1% for fluoxetine in clinical trials collecting only a primary reaction associated with discontinuation) in MDD, OCD, Bulimia, and Panic Disorder clinical trials, plus non-U.S. Panic Disorder clinical trials. Table 4. Most Common Adverse Reactions Associated with Discontinuation in Major Depressive Disorder, Obsessive Compulsive Disorder, Bulimia, and Panic Disorder Placebo-controlled Clinical Trials MDD, OCD, Bulimia, and Panic Disorder Combined (N = 1533) MDD (N = 392) OCD (N = 266) Bulimia (N = 450) Panic Disorder (N = 425) Anxiety (1%) — Anxiety (2%) — Anxiety (2%) — — — Insomnia (2%) — — Nervousness (1%) — — Nervousness (1%) — — Rash (1%) — — Note: Includes U.S. data for MDD, OCD, Bulimia, and Panic Disorder clinical trials, plus non-U.S. data for Panic Disorder clinical trials. —= Incidence less than 1%. Other adverse reactions in pediatric patients (children and adolescents) —Adverse reactions were collected in 322 pediatric patients (180 fluoxetine-treated, 142 placebo-treated). The overall profile of adverse reactions was generally similar to that seen in adult studies, as shown in Table 2 and Table 3 . However, the following adverse reactions (excluding those which appear in the body or footnotes of Table 2 and Table 3 and those for which the COSTART terms were uninformative or misleading) were reported at an incidence of at least 2% for fluoxetine and greater than placebo: thirst, hyperkinesia, agitation, personality disorder, epistaxis, urinary frequency, and menorrhagia. The most common adverse reaction (incidence at least 1% for fluoxetine and greater than placebo) associated with discontinuation in 3 pediatric placebo-controlled trials (N = 418 randomized; 228 fluoxetine-treated; 190 placebo-treated) was mania/hypomania (1.8% for fluoxetine-treated, 0% for placebo-treated). In these clinical trials, only a primary reaction associated with discontinuation was collected. Male and female sexual dysfunction with SSRIs —Although changes in sexual desire, sexual performance, and sexual satisfaction often occur as manifestations of a psychiatric disorder, they may also be a consequence of pharmacologic treatment. In particular, some evidence suggests that SSRIs can cause such untoward sexual experiences. Reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance, and satisfaction are difficult to obtain, however, in part because patients and physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance, cited in product labeling, are likely to underestimate their actual incidence. In patients enrolled in U.S. MDD, OCD, and bulimia placebo-controlled clinical trials, decreased libido was the only sexual adverse reaction reported by at least 2% of patients taking fluoxetine (4% fluoxetine, < 1% placebo). There have been spontaneous reports in women taking fluoxetine of orgasmic dysfunction, including anorgasmia. There are no adequate and well-controlled studies examining sexual dysfunction with fluoxetine treatment. Symptoms of sexual dysfunction occasionally persist after discontinuation of fluoxetine treatment. Priapism has been reported with all SSRIs. While it is difficult to know the precise risk of sexual dysfunction associated with the use of SSRIs, physicians should routinely inquire about such possible adverse reactions. Other adverse reactions observed during the premarketing evaluation of fluoxetine —Following is a list of adverse reactions reported by patients treated with fluoxetine in clinical trials. This listing is not intended to include reactions (1) already listed in previous tables or elsewhere in labeling, (2) for which a drug cause was remote, (3) which were so general as to be uninformative, (4) which were not considered to have significant clinical implications, or (5) which occurred at a rate equal to or less than placebo. Reactions are classified by body system using the following definitions: frequent adverse reactions are those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in fewer than 1/1000 patients. Body as a Whole — Frequent : chills; Infrequent : suicide attempt; Rare : acute abdominal syndrome, photosensitivity reaction. Cardiovascular System — Frequent : palpitation; Infrequent : arrhythmia, hypotension 1 . Digestive System — Infrequent : dysphagia, gastritis, gastroenteritis, melena, stomach ulcer; Rare : bloody diarrhea, duodenal ulcer, esophageal ulcer, gastrointestinal hemorrhage, hematemesis, hepatitis, peptic ulcer, stomach ulcer hemorrhage. Hemic and Lymphatic System — Infrequent : ecchymosis; Rare : petechia, purpura. Nervous System — Frequent : emotional lability; Infrequent : akathisia, ataxia, balance disorder 1 , bruxism 1 , buccoglossal syndrome, depersonalization, euphoria, hypertonia, libido increased, myoclonus, paranoid reaction; Rare : delusions. Respiratory System — Rare : larynx edema. Skin and Appendages — Infrequent : alopecia; Rare : purpuric rash. Special Senses — Frequent : taste perversion; Infrequent : mydriasis. Urogenital System — Frequent : micturition disorder; Infrequent : dysuria, gynecological bleeding 2 . 1 MedDRA dictionary term from integrated database of placebo-controlled trials of 15,870 patients, of which 9673 received fluoxetine. 2 Group term that includes individual MedDRA terms: cervix hemorrhage uterine, dysfunctional uterine bleeding, genital hemorrhage, menometrorrhagia, menorrhagia, metrorrhagia, polymenorrhea, postmenopausal hemorrhage, uterine hemorrhage, vaginal hemorrhage. Adjusted for gender. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of fluoxetine. Because these reactions are reported voluntarily from a population of uncertain size, it is difficult to reliably estimate their frequency or evaluate a causal relationship to drug exposure. Voluntary reports of adverse reactions temporally associated with fluoxetine that have been received since market introduction and that may have no causal relationship with the drug include the following: aplastic anemia, atrial fibrillation 1 , cataract, cerebrovascular accident 1 , cholestatic jaundice, dyskinesia (including, for example, a case of buccal-lingual-masticatory syndrome with involuntary tongue protrusion reported to develop in a 77-year-old female after 5 weeks of fluoxetine therapy and which completely resolved over the next few months following drug discontinuation), eosinophilic pneumonia 1 , epidermal necrolysis, erythema multiforme, erythema nodosum, exfoliative dermatitis, galactorrhea, gynecomastia, heart arrest 1 , hepatic failure/necrosis, hyperprolactinemia, hypoglycemia, immune-related hemolytic anemia, kidney failure, memory impairment, movement disorders developing in patients with risk factors including drugs associated with such reactions and worsening of preexisting movement disorders, optic neuritis, pancreatitis 1 , pancytopenia, pulmonary embolism, pulmonary hypertension, QT prolongation, Stevens-Johnson syndrome, thrombocytopenia 1 , thrombocytopenic purpura, ventricular tachycardia (including Torsades de Pointes-type arrhythmias), vaginal bleeding, and violent behaviors 1 . 1 These terms represent serious adverse events, but do not meet the definition for adverse drug reactions. They are included here because of their seriousness.

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 is 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 is 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 tablets: Do not use this product in patients with known hypersensitivity to fluoxetine tablets due to risk of anaphylactoid reactions, including bronchospasm, angioedema, laryngospasm, and urticaria [see Warnings and Precautions (5.3)].

11 DESCRIPTION Fluoxetine hydrochloride is a selective serotonin reuptake inhibitor for oral administration. It is designated (±)- N -methyl-3-phenyl-3-[(α,α,α-trifluoro- p -tolyl)oxy]propylamine hydrochloride and has the molecular formula of C 17 H 18 F 3 NO•HCl. Its molecular weight is 345.79. The structural formula is: Fluoxetine hydrochloride, USP is a white or almost white powder, very soluble in ethanol and in chloroform, slightly soluble in acetone and practically insoluble in toluene. Each scored tablet contains fluoxetine hydrochloride, USP equivalent to 60 mg (194 µmol) of fluoxetine. In addition, each scored tablet also contains the following inactive ingredients: colloidal silicon dioxide, corn starch, crospovidone, magnesium stearate, mannitol, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, talc and titanium dioxide. FLUOXETINE

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 tablets dose should not exceed 80 mg/day. In controlled trials used to support the efficacy of fluoxetine tablets, patients were administered morning doses ranging from 20 to 80 mg/day. Studies comparing fluoxetine tablets 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 tablets supporting its effectiveness in the treatment of MDD, patients were administered fluoxetine tablets 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 tablets 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 tablets are 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 tablets dose should not exceed 80 mg/day. In the controlled clinical trials of fluoxetine tablets supporting its effectiveness in the treatment of OCD, patients were administered fixed daily doses of 20, 40, or 60 mg of fluoxetine tablets or placebo [see Clinical Studies (14.2)]. In one of these studies, no dose-response relationship for effectiveness was demonstrated. Pediatric (children and adolescents) —In adolescents and higher weight children, treatment should be initiated with a dose of 10 mg/day. After 2 weeks, the dose should be increased to 20 mg/day. Additional dose increases may be considered after several more weeks if insufficient clinical improvement is observed. A dose range of 20 to 60 mg/day is recommended. In lower weight children, treatment should be initiated with a dose of 10 mg/day. Additional dose increases may be considered after several more weeks if insufficient clinical improvement is observed. A dose range of 20 to 30 mg/day is recommended. Experience with daily doses greater than 20 mg is very minimal, and there is no experience with doses greater than 60 mg. In the controlled clinical trial of fluoxetine tablets supporting its effectiveness in the treatment of OCD, patients were administered fluoxetine tablets doses in the range of 10 to 60 mg/day [see Clinical Studies (14.2)]. Periodically reassess to determine the need for treatment. 2.3 Bulimia Nervosa Initial Treatment —Administer fluoxetine tablets 60 mg/day in the morning. For some patients it may be advisable to titrate up to this target dose over several days. Fluoxetine tablets doses above 60 mg/day have not been systematically studied in patients with Bulimia Nervosa. In the controlled clinical trials of fluoxetine tablets supporting its effectiveness in the treatment of Bulimia Nervosa, patients were administered fixed daily fluoxetine tablets doses of 20 or 60 mg, or placebo [see Clinical Studies (14.3)]. Only the 60 mg dose was statistically significantly superior to placebo in reducing the frequency of binge-eating and vomiting. Periodically reassess to determine the need for maintenance treatment. 2.4 Panic Disorder Initial Treatment —Treatment should be initiated with a dose of 10 mg/day. After 1 week, the dose should be increased to 20 mg/day. A dose increase may be considered after several weeks if no clinical improvement is observed. Fluoxetine tablets doses above 60 mg/day have not been systematically evaluated in patients with Panic Disorder. In the controlled clinical trials of fluoxetine tablets supporting its effectiveness in the treatment of Panic Disorder, patients were administered fluoxetine tablets doses in the range of 10 to 60 mg/day [see Clinical Studies (14.4)]. The most frequently administered dose in the 2 flexible-dose clinical trials was 20 mg/day. Periodically reassess to determine the need for continued treatment. 2.5 Dosing in Specific Populations Treatment of Pregnant Women —When treating pregnant women with fluoxetine tablets, the physician should carefully consider the potential risks and potential benefits of treatment. Neonates exposed to serotonin-norepinephrine reuptake inhibitors (SNRIs) or selective serotonin reuptake inhibitors (SSRIs) late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding [see Use in Specific Populations (8.1)]. Geriatrics —A lower or less frequent dosage should be considered for the elderly [see Use in Specific Populations (8.5)]. Hepatic Impairment —As with many other medications, a lower or less frequent dosage should be used in patients with hepatic impairment [see Clinical Pharmacology (12.3) and Use in Specific Populations (8.6)]. 2.6 Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with fluoxetine tablets. Conversely, at least 5 weeks should be allowed after stopping fluoxetine tablets before starting an MAOI intended to treat psychiatric disorders [see Contraindications (4.1)]. 2.7 Use of Fluoxetine Tablets with Other MAOIs Such as Linezolid or Methylene Blue Do not start fluoxetine tablets in a patient who is being treated with linezolid or intravenous methylene blue because there is an increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered [see Contraindications (4.1)]. In some cases, a patient already receiving fluoxetine tablets therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, fluoxetine tablets should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for 5 weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with fluoxetine tablets may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue [see Warnings and Precautions (5.2)]. The risk of administering methylene blue by nonintravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with fluoxetine tablets is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use [see Warnings and Precautions (5.2)].

1. INDICATIONS AND USAGE Fluoxetine tablets are indicated for the treatment of: Major Depressive Disorder (MDD). The efficacy of fluoxetine tablets in MDD was established in one 5-week trial, three 6-week trials, and one maintenance study in adults. The efficacy of fluoxetine tablets 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 tablets 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 tablets 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 tablets in Panic Disorder was demonstrated in two 12-week trials in adults [see Clinical Studies (14.4)]. Fluoxetine is 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)

9 DRUG ABUSE AND DEPENDENCE 9.3 Dependence Fluoxetine has not been systematically studied, in animals or humans, for its potential for abuse, tolerance, or physical dependence. While the premarketing clinical experience with fluoxetine did not reveal any tendency for a withdrawal syndrome or any drug-seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited 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 history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of fluoxetine (e.g., development of tolerance, incrementation of dose, drug-seeking behavior).

10 OVERDOSAGE 10.1 Human Experience Worldwide exposure to fluoxetine hydrochloride is estimated to be over 38 million patients (circa 1999). Of the 1578 cases of overdose involving fluoxetine hydrochloride, alone or with other drugs, reported from this population, there were 195 deaths. Among 633 adult patients who overdosed on fluoxetine hydrochloride alone, 34 resulted in a fatal outcome, 378 completely recovered, and 15 patients experienced sequelae after overdosage, including abnormal accommodation, abnormal gait, confusion, unresponsiveness, nervousness, pulmonary dysfunction, vertigo, tremor, elevated blood pressure, impotence, movement disorder, and hypomania. The remaining 206 patients had an unknown outcome. The most common signs and symptoms associated with nonfatal overdosage were seizures, somnolence, nausea, tachycardia, and vomiting. The largest known ingestion of fluoxetine hydrochloride in adult patients was 8 g in a patient who took fluoxetine alone and who subsequently recovered. However, in an adult patient who took fluoxetine alone, an ingestion as low as 520 mg has been associated with lethal outcome, but causality has not been established. Among pediatric patients (ages 3 months to 17 years), there were 156 cases of overdose involving fluoxetine alone or in combination with other drugs. Six patients died, 127 patients completely recovered, 1 patient experienced renal failure, and 22 patients had an unknown outcome. One of the six fatalities was a 9-year-old boy who had a history of OCD, Tourette’s syndrome with tics, attention deficit disorder, and fetal alcohol syndrome. He had been receiving 100 mg of fluoxetine daily for 6 months in addition to clonidine, methylphenidate, and promethazine. Mixed-drug ingestion or other methods of suicide complicated all 6 overdoses in children that resulted in fatalities. The largest ingestion in pediatric patients was 3 grams which was nonlethal. Other important adverse reactions reported with fluoxetine overdose (single or multiple drugs) include coma, delirium, ECG abnormalities (such as nodal rhythm, QT interval prolongation, and ventricular arrhythmias, including Torsades de Pointes-type arrhythmias), hypotension, mania, neuroleptic malignant syndrome-like reactions, pyrexia, stupor, and syncope. 10.2 Animal Experience Studies in animals do not provide precise or necessarily valid information about the treatment of human overdose. However, animal experiments can provide useful insights into possible treatment strategies. The oral median lethal dose in rats and mice was found to be 452 and 248 mg/kg, respectively. Acute high oral doses produced hyperirritability and convulsions in several animal species. Among 6 dogs purposely overdosed with oral fluoxetine, 5 experienced grand mal seizures. Seizures stopped immediately upon the bolus intravenous administration of a standard veterinary dose of diazepam. In this short-term study, the lowest plasma concentration at which a seizure occurred was only twice the maximum plasma concentration seen in humans taking 80 mg/day, chronically. In a separate single-dose study, the ECG of dogs given high doses did not reveal prolongation of the PR, QRS, or QT intervals. Tachycardia and an increase in blood pressure were observed. Consequently, the value of the ECG in predicting cardiac toxicity is unknown. Nonetheless, the ECG should ordinarily be monitored in cases of human overdose [see Overdosage (10.3)]. 10.3 Management of Overdose For current information on the management of fluoxetine overdose, contact a certified poison control center (1.800.222.1222 or www.poison.org). Treatment should consist of those general measures employed in the management of overdosage with any drug. Consider the possibility of multi-drug overdose. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. Use general supportive and symptomatic measures. Induction of emesis is not recommended. Activated charcoal should be administered. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit. No specific antidotes for fluoxetine are known. A specific caution involves patients who are taking or have recently taken fluoxetine and might ingest excessive quantities of a TCA. In such a case, accumulation of the parent tricyclic and/or an active metabolite may increase the possibility of clinically significant sequelae and extend the time needed for close medical observation [see Drug Interactions (7.6)].

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 t½, 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 Serotonergic Drugs [See Dosage and Administration (2.6, 2.7), Contraindications (4.1), and Warnings and Precautions (5.2)]. 7.4 Drugs that Interfere with Hemostasis (eg, 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 Contraindications (4.2), Warnings and Precautions (5.11), and Drug Interactions (7.7)]. In a study of 19 healthy male subjects, which included 6 slow and 13 rapid hydroxylators of debrisoquin, a single 25 mg oral dose of thioridazine produced a 2.4-fold higher C max and a 4.5-fold higher area under the curve (AUC) for thioridazine in the slow hydroxylators compared with the rapid hydroxylators. The rate of debrisoquin hydroxylation is felt to depend on the level of CYP2D6 isozyme activity. Thus, this study suggests that drugs which inhibit CYP2D6, such as certain SSRIs, including fluoxetine, will produce elevated plasma levels of thioridazine. Thioridazine administration produces a dose-related prolongation of the QT interval, which is associated with serious ventricular arrhythmias, such as Torsades de Pointes-type arrhythmias, and sudden death. This risk is expected to increase with fluoxetine-induced inhibition of thioridazine metabolism. Drugs metabolized by CYP2D6 —Fluoxetine inhibits the activity of CYP2D6, and may make individuals with normal CYP2D6 metabolic activity resemble a poor metabolizer. Co-administration of fluoxetine with other drugs that are metabolized by CYP2D6, including certain antidepressants (e.g., TCAs), antipsychotics (e.g., phenothiazines and most atypicals), and antiarrhythmics (e.g., propafenone, flecainide, and others) should be approached with caution. Therapy with medications that are predominantly metabolized by the CYP2D6 system and that have a relatively narrow therapeutic index (see list below) should be initiated at the low end of the dose range if a patient is receiving fluoxetine concurrently or has taken it in the previous 5 weeks. Thus, his/her dosing requirements resemble those of poor metabolizers. If fluoxetine is added to the treatment regimen of a patient already receiving a drug metabolized by CYP2D6, the need for decreased dose of the original medication should be considered. Drugs with a narrow therapeutic index represent the greatest concern (e.g., flecainide, propafenone, vinblastine, and TCAs). Due to the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, thioridazine should not be administered with fluoxetine or within a minimum of 5 weeks after fluoxetine has been discontinued [see Contraindications (4.2)]. Tricyclic antidepressants (TCAs) —In 2 studies, previously stable plasma levels of imipramine and desipramine have increased greater than 2- to 10-fold when fluoxetine has been administered in combination. This influence may persist for 3 weeks or longer after fluoxetine is discontinued. Thus, the dose of TCAs 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 Clinical Pharmacology (12.3)]. Benzodiazepines —The half-life of concurrently administered diazepam may be prolonged in some patients [see Clinical Pharmacology (12.3)]. Co-administration of alprazolam and fluoxetine has resulted in increased alprazolam plasma concentrations and in further psychomotor performance decrement due to increased alprazolam levels. Antipsychotics —Some clinical data suggests a possible pharmacodynamic and/or pharmacokinetic interaction between SSRIs and antipsychotics. Elevation of blood levels of haloperidol and clozapine has been observed in patients receiving concomitant fluoxetine. Anticonvulsants —Patients on stable doses of phenytoin and carbamazepine have developed elevated plasma anticonvulsant concentrations and clinical anticonvulsant toxicity following initiation of concomitant fluoxetine treatment. Lithium —There have been reports of both increased and decreased lithium levels when lithium was used concomitantly with fluoxetine. Cases of lithium toxicity and increased serotonergic effects have been reported. Lithium levels should be monitored when these drugs are administered concomitantly [see Warnings and Precautions (5.2)]. Drugs tightly bound to plasma proteins —Because fluoxetine is tightly bound to plasma proteins, the administration of fluoxetine to a patient taking another drug that is tightly bound to protein (e.g., Coumadin, digitoxin) may cause a shift in plasma concentrations potentially resulting in an adverse effect [see Clinical Pharmacology (12.3)]. Drugs metabolized by CYP3A4 —In an in vivo interaction study involving co-administration of fluoxetine with single doses of terfenadine (a CYP3A4 substrate), no increase in plasma terfenadine concentrations occurred with concomitant fluoxetine. Additionally, in vitro studies have shown ketoconazole, a potent inhibitor of CYP3A4 activity, to be at least 100 times more potent than fluoxetine or norfluoxetine as an inhibitor of the metabolism of several substrates for this enzyme, including astemizole, cisapride, and midazolam. These data indicate that fluoxetine’s extent of inhibition of CYP3A4 activity is not likely to be of clinical significance. Olanzapine —Fluoxetine (60 mg single dose or 60 mg daily dose for 8 days) causes a small (mean 16%) increase in the maximum concentration of olanzapine and a small (mean 16%) decrease in olanzapine clearance. The magnitude of the impact of this factor is small in comparison to the overall variability between individuals, and therefore dose modification is not routinely recommended. 7.7 Drugs That Prolong the QT Interval Do not use fluoxetine in combination with thioridazine or pimozide. Use fluoxetine with caution in combination with other drugs that cause QT prolongation. These include: specific antipsychotics (e.g., ziprasidone, iloperidone, chlorpromazine, mesoridazine, droperidol); specific antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin, sparfloxacin); Class IA antiarrhythmic medications (e.g., quinidine, procainamide); Class III antiarrhythmics (e.g., amiodarone, sotalol); and others (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus). Fluoxetine is primarily metabolized by CYP2D6. Concomitant treatment with CYP2D6 inhibitors can increase the concentration of fluoxetine. Concomitant use of other highly protein-bound drugs can increase the concentration of fluoxetine [see Contraindications (4.2), Warnings and Precautions (5.11), Drug Interactions (7.6), and Clinical Pharmacology (12.3)].

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Although the exact mechanism of fluoxetine is unknown, it is presumed to be linked to its inhibition of CNS neuronal uptake of serotonin. 12.2 Pharmacodynamics Studies at clinically relevant doses in man have demonstrated that fluoxetine blocks the uptake of serotonin into human platelets. Studies in animals also suggest that fluoxetine is a much more potent uptake inhibitor of serotonin than of norepinephrine. Antagonism of muscarinic, histaminergic, and α 1 -adrenergic receptors has been hypothesized to be associated with various anticholinergic, sedative, and cardiovascular effects of classical TCA drugs. Fluoxetine binds to these and other membrane receptors from brain tissue much less potently in vitro than do the tricyclic drugs. 12.3 Pharmacokinetics Systemic bioavailability —In man, following a single, oral dose of fluoxetine 60 mg tablet, USP, the peak plasma concentration of fluoxetine and time to achieve peak plasma concentration were 49.6 ± 10.0 ng/mL, and 7.20 ± 1.41 hours, respectively (both values are mean ± SD). The capsule, tablet, and oral solution dosage forms of fluoxetine are bioequivalent. The exposure (C max , AUC) to fluoxetine was similar after administration of either 1 × 60 mg fluoxetine tablet USP or 3 × 20 mg fluoxetine tablets. Food does not appear to affect the systemic bioavailability of fluoxetine, although it may delay its absorption by 1 to 2 hours, which is probably not clinically significant. Thus, fluoxetine may be administered with or without food. Protein binding —Over the concentration range from 200 to 1000 ng/mL, approximately 94.5% of fluoxetine is bound in vitro to human serum proteins, including albumin and α 1 -glycoprotein. The interaction between fluoxetine and other highly protein-bound drugs has not been fully evaluated, but may be important. Enantiomers —Fluoxetine is a racemic mixture (50/50) of R -fluoxetine and S -fluoxetine enantiomers. In animal models, both enantiomers are specific and potent serotonin uptake inhibitors with essentially equivalent pharmacologic activity. The S -fluoxetine enantiomer is eliminated more slowly and is the predominant enantiomer present in plasma at steady state. Metabolism —Fluoxetine is extensively metabolized in the liver to norfluoxetine and a number of other unidentified metabolites. The only identified active metabolite, norfluoxetine, is formed by demethylation of fluoxetine. In animal models, S -norfluoxetine is a potent and selective inhibitor of serotonin uptake and has activity essentially equivalent to R - or S -fluoxetine. R -norfluoxetine is significantly less potent than the parent drug in the inhibition of serotonin uptake. The primary route of elimination appears to be hepatic metabolism to inactive metabolites excreted by the kidney. Variability in metabolism —A subset (about 7%) of the population has reduced activity of the drug metabolizing enzyme cytochrome P450 2D6 (CYP2D6). Such individuals are referred to as “poor metabolizers” of drugs such as debrisoquin, dextromethorphan, and the TCAs. In a study involving labeled and unlabeled enantiomers administered as a racemate, these individuals metabolized S -fluoxetine at a slower rate and thus achieved higher concentrations of S -fluoxetine. Consequently, concentrations of S -norfluoxetine at steady state were lower. The metabolism of R -fluoxetine in these poor metabolizers appears normal. When compared with normal metabolizers, the total sum at steady state of the plasma concentrations of the 4 active enantiomers was not significantly greater among poor metabolizers. Thus, the net pharmacodynamic activities were essentially the same. Alternative, nonsaturable pathways (non-2D6) also contribute to the metabolism of fluoxetine. This explains how fluoxetine achieves a steady-state concentration rather than increasing without limit. Because fluoxetine’s metabolism, like that of a number of other compounds including TCAs and other SSRIs, involves the CYP2D6 system, concomitant therapy with drugs also metabolized by this enzyme system (such as the TCAs) may lead to drug interactions [see Drug Interactions (7.6)]. Accumulation and slow elimination —The relatively slow elimination of fluoxetine (elimination half-life of 1 to 3 days after acute administration and 4 to 6 days after chronic administration) and its active metabolite, norfluoxetine (elimination half-life of 4 to 16 days after acute and chronic administration), leads to significant accumulation of these active species in chronic use and delayed attainment of steady state, even when a fixed dose is used [see Warnings and Precautions (5.14)] . After 30 days of dosing at 40 mg/day, plasma concentrations of fluoxetine in the range of 91 to 302 ng/mL and norfluoxetine in the range of 72 to 258 ng/mL have been observed. Plasma concentrations of fluoxetine were higher than those predicted by single-dose studies, because fluoxetine’s metabolism is not proportional to dose. Norfluoxetine, however, appears to have linear pharmacokinetics. Its mean terminal half-life after a single dose was 8.6 days and after multiple dosing was 9.3 days. Steady-state levels after prolonged dosing are similar to levels seen at 4 to 5 weeks. The long elimination half-lives of fluoxetine and norfluoxetine assure that, even when dosing is stopped, active drug substance will persist in the body for weeks (primarily depending on individual patient characteristics, previous dosing regimen, and length of previous therapy at discontinuation). This is of potential consequence when drug discontinuation is required or when drugs are prescribed that might interact with fluoxetine and norfluoxetine following the discontinuation of fluoxetine. Liver disease —As might be predicted from its primary site of metabolism, liver impairment can affect the elimination of fluoxetine. The elimination half-life of fluoxetine was prolonged in a study of cirrhotic patients, with a mean of 7.6 days compared with the range of 2 to 3 days seen in subjects without liver disease; norfluoxetine elimination was also delayed, with a mean duration of 12 days for cirrhotic patients compared with the range of 7 to 9 days in normal subjects. This suggests that the use of fluoxetine in patients with liver disease must be approached with caution. If fluoxetine is administered to patients with liver disease, a lower or less frequent dose should be used [see Dosage and Administration (2.5) and Use in Specific Populations (8.6)] . Renal disease —In depressed patients on dialysis (N = 12), fluoxetine administered as 20 mg once daily for 2 months produced steady-state fluoxetine and norfluoxetine plasma concentrations comparable with those seen in patients with normal renal function. While the possibility exists that renally excreted metabolites of fluoxetine may accumulate to higher levels in patients with severe renal dysfunction, use of a lower or less frequent dose is not routinely necessary in renally impaired patients. Geriatric pharmacokinetics —The disposition of single doses of fluoxetine in healthy elderly subjects (> 65 years of age) did not differ significantly from that in younger normal subjects. However, given the long half-life and nonlinear disposition of the drug, a single-dose study is not adequate to rule out the possibility of altered pharmacokinetics in the elderly, particularly if they have systemic illness or are receiving multiple drugs for concomitant diseases. The effects of age upon the metabolism of fluoxetine have been investigated in 260 elderly but otherwise healthy depressed patients (≥60 years of age) who received 20 mg fluoxetine for 6 weeks. Combined fluoxetine plus norfluoxetine plasma concentrations were 209.3 ± 85.7 ng/mL at the end of 6 weeks. No unusual age-associated pattern of adverse reactions was observed in those elderly patients. Pediatric pharmacokinetics (children and adolescents)— Fluoxetine pharmacokinetics were evaluated in 21 pediatric patients (10 children ages 6 to < 13, 11 adolescents ages 13 to < 18) diagnosed with MDD or OCD. Fluoxetine 20 mg/day was administered for up to 62 days. The average steady-state concentrations of fluoxetine in these children were 2-fold higher than in adolescents (171 and 86 ng/mL, respectively). The average norfluoxetine steady-state concentrations in these children were 1.5-fold higher than in adolescents (195 and 113 ng/mL, respectively). These differences can be almost entirely explained by differences in weight. No gender-associated difference in fluoxetine pharmacokinetics was observed. Similar ranges of fluoxetine and norfluoxetine plasma concentrations were observed in another study in 94 pediatric patients (ages 8 to < 18) diagnosed with MDD. Higher average steady-state fluoxetine and norfluoxetine concentrations were observed in children relative to adults; however, these concentrations were within the range of concentrations observed in the adult population. As in adults, fluoxetine and norfluoxetine accumulated extensively following multiple oral dosing; steady-state concentrations were achieved within 3 to 4 weeks of daily dosing.

12.1 Mechanism of Action Although the exact mechanism of fluoxetine is unknown, it is presumed to be linked to its inhibition of CNS neuronal uptake of serotonin.

12.2 Pharmacodynamics Studies at clinically relevant doses in man have demonstrated that fluoxetine blocks the uptake of serotonin into human platelets. Studies in animals also suggest that fluoxetine is a much more potent uptake inhibitor of serotonin than of norepinephrine. Antagonism of muscarinic, histaminergic, and α 1 -adrenergic receptors has been hypothesized to be associated with various anticholinergic, sedative, and cardiovascular effects of classical TCA drugs. Fluoxetine binds to these and other membrane receptors from brain tissue much less potently in vitro than do the tricyclic drugs.

12.3 Pharmacokinetics Systemic bioavailability —In man, following a single, oral dose of fluoxetine 60 mg tablet, USP, the peak plasma concentration of fluoxetine and time to achieve peak plasma concentration were 49.6 ± 10.0 ng/mL, and 7.20 ± 1.41 hours, respectively (both values are mean ± SD). The capsule, tablet, and oral solution dosage forms of fluoxetine are bioequivalent. The exposure (C max , AUC) to fluoxetine was similar after administration of either 1 × 60 mg fluoxetine tablet USP or 3 × 20 mg fluoxetine tablets. Food does not appear to affect the systemic bioavailability of fluoxetine, although it may delay its absorption by 1 to 2 hours, which is probably not clinically significant. Thus, fluoxetine may be administered with or without food. Protein binding —Over the concentration range from 200 to 1000 ng/mL, approximately 94.5% of fluoxetine is bound in vitro to human serum proteins, including albumin and α 1 -glycoprotein. The interaction between fluoxetine and other highly protein-bound drugs has not been fully evaluated, but may be important. Enantiomers —Fluoxetine is a racemic mixture (50/50) of R -fluoxetine and S -fluoxetine enantiomers. In animal models, both enantiomers are specific and potent serotonin uptake inhibitors with essentially equivalent pharmacologic activity. The S -fluoxetine enantiomer is eliminated more slowly and is the predominant enantiomer present in plasma at steady state. Metabolism —Fluoxetine is extensively metabolized in the liver to norfluoxetine and a number of other unidentified metabolites. The only identified active metabolite, norfluoxetine, is formed by demethylation of fluoxetine. In animal models, S -norfluoxetine is a potent and selective inhibitor of serotonin uptake and has activity essentially equivalent to R - or S -fluoxetine. R -norfluoxetine is significantly less potent than the parent drug in the inhibition of serotonin uptake. The primary route of elimination appears to be hepatic metabolism to inactive metabolites excreted by the kidney. Variability in metabolism —A subset (about 7%) of the population has reduced activity of the drug metabolizing enzyme cytochrome P450 2D6 (CYP2D6). Such individuals are referred to as “poor metabolizers” of drugs such as debrisoquin, dextromethorphan, and the TCAs. In a study involving labeled and unlabeled enantiomers administered as a racemate, these individuals metabolized S -fluoxetine at a slower rate and thus achieved higher concentrations of S -fluoxetine. Consequently, concentrations of S -norfluoxetine at steady state were lower. The metabolism of R -fluoxetine in these poor metabolizers appears normal. When compared with normal metabolizers, the total sum at steady state of the plasma concentrations of the 4 active enantiomers was not significantly greater among poor metabolizers. Thus, the net pharmacodynamic activities were essentially the same. Alternative, nonsaturable pathways (non-2D6) also contribute to the metabolism of fluoxetine. This explains how fluoxetine achieves a steady-state concentration rather than increasing without limit. Because fluoxetine’s metabolism, like that of a number of other compounds including TCAs and other SSRIs, involves the CYP2D6 system, concomitant therapy with drugs also metabolized by this enzyme system (such as the TCAs) may lead to drug interactions [see Drug Interactions (7.6)]. Accumulation and slow elimination —The relatively slow elimination of fluoxetine (elimination half-life of 1 to 3 days after acute administration and 4 to 6 days after chronic administration) and its active metabolite, norfluoxetine (elimination half-life of 4 to 16 days after acute and chronic administration), leads to significant accumulation of these active species in chronic use and delayed attainment of steady state, even when a fixed dose is used [see Warnings and Precautions (5.14)] . After 30 days of dosing at 40 mg/day, plasma concentrations of fluoxetine in the range of 91 to 302 ng/mL and norfluoxetine in the range of 72 to 258 ng/mL have been observed. Plasma concentrations of fluoxetine were higher than those predicted by single-dose studies, because fluoxetine’s metabolism is not proportional to dose. Norfluoxetine, however, appears to have linear pharmacokinetics. Its mean terminal half-life after a single dose was 8.6 days and after multiple dosing was 9.3 days. Steady-state levels after prolonged dosing are similar to levels seen at 4 to 5 weeks. The long elimination half-lives of fluoxetine and norfluoxetine assure that, even when dosing is stopped, active drug substance will persist in the body for weeks (primarily depending on individual patient characteristics, previous dosing regimen, and length of previous therapy at discontinuation). This is of potential consequence when drug discontinuation is required or when drugs are prescribed that might interact with fluoxetine and norfluoxetine following the discontinuation of fluoxetine. Liver disease —As might be predicted from its primary site of metabolism, liver impairment can affect the elimination of fluoxetine. The elimination half-life of fluoxetine was prolonged in a study of cirrhotic patients, with a mean of 7.6 days compared with the range of 2 to 3 days seen in subjects without liver disease; norfluoxetine elimination was also delayed, with a mean duration of 12 days for cirrhotic patients compared with the range of 7 to 9 days in normal subjects. This suggests that the use of fluoxetine in patients with liver disease must be approached with caution. If fluoxetine is administered to patients with liver disease, a lower or less frequent dose should be used [see Dosage and Administration (2.5) and Use in Specific Populations (8.6)] . Renal disease —In depressed patients on dialysis (N = 12), fluoxetine administered as 20 mg once daily for 2 months produced steady-state fluoxetine and norfluoxetine plasma concentrations comparable with those seen in patients with normal renal function. While the possibility exists that renally excreted metabolites of fluoxetine may accumulate to higher levels in patients with severe renal dysfunction, use of a lower or less frequent dose is not routinely necessary in renally impaired patients. Geriatric pharmacokinetics —The disposition of single doses of fluoxetine in healthy elderly subjects (> 65 years of age) did not differ significantly from that in younger normal subjects. However, given the long half-life and nonlinear disposition of the drug, a single-dose study is not adequate to rule out the possibility of altered pharmacokinetics in the elderly, particularly if they have systemic illness or are receiving multiple drugs for concomitant diseases. The effects of age upon the metabolism of fluoxetine have been investigated in 260 elderly but otherwise healthy depressed patients (≥60 years of age) who received 20 mg fluoxetine for 6 weeks. Combined fluoxetine plus norfluoxetine plasma concentrations were 209.3 ± 85.7 ng/mL at the end of 6 weeks. No unusual age-associated pattern of adverse reactions was observed in those elderly patients. Pediatric pharmacokinetics (children and adolescents)— Fluoxetine pharmacokinetics were evaluated in 21 pediatric patients (10 children ages 6 to < 13, 11 adolescents ages 13 to < 18) diagnosed with MDD or OCD. Fluoxetine 20 mg/day was administered for up to 62 days. The average steady-state concentrations of fluoxetine in these children were 2-fold higher than in adolescents (171 and 86 ng/mL, respectively). The average norfluoxetine steady-state concentrations in these children were 1.5-fold higher than in adolescents (195 and 113 ng/mL, respectively). These differences can be almost entirely explained by differences in weight. No gender-associated difference in fluoxetine pharmacokinetics was observed. Similar ranges of fluoxetine and norfluoxetine plasma concentrations were observed in another study in 94 pediatric patients (ages 8 to < 18) diagnosed with MDD. Higher average steady-state fluoxetine and norfluoxetine concentrations were observed in children relative to adults; however, these concentrations were within the range of concentrations observed in the adult population. As in adults, fluoxetine and norfluoxetine accumulated extensively following multiple oral dosing; steady-state concentrations were achieved within 3 to 4 weeks of daily dosing.

20230811

103

3 DOSAGE FORMS AND STRENGTHS Fluoxetine tablets, USP are available as 60 mg (fluoxetine base equivalent), white to off-white, film-coated, capsule-shaped tablets, functionally scored and debossed with “P” and “4” on one side with score and plain on the other side. Tablets : 60 mg, functionally scored (3)

Fluoxetine Fluoxetine SILICON DIOXIDE STARCH, CORN CROSPOVIDONE MAGNESIUM STEARATE MANNITOL MICROCRYSTALLINE CELLULOSE POLYETHYLENE GLYCOL 3350 POLYVINYL ALCOHOL, UNSPECIFIED TALC TITANIUM DIOXIDE FLUOXETINE HYDROCHLORIDE FLUOXETINE white to off-white P;4

13.2 Animal Toxicology and/or Pharmacology Phospholipids are increased in some tissues of mice, rats, and dogs given fluoxetine chronically. This effect is reversible after cessation of fluoxetine treatment. Phospholipid accumulation in animals has been observed with many cationic amphiphilic drugs, including fenfluramine, imipramine, and ranitidine. The significance of this effect in humans is unknown.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity —The dietary administration of fluoxetine to rats and mice for 2 years at doses of up to 10 and 12 mg/kg/day, respectively (approximately 1.2 and 0.7 times, respectively, the MRHD of 80 mg on a mg/m 2 basis), produced no evidence of carcinogenicity. Mutagenicity —Fluoxetine and norfluoxetine have been shown to have no genotoxic effects based on the following assays: bacterial mutation assay, DNA repair assay in cultured rat hepatocytes, mouse lymphoma assay, and in vivo sister chromatid exchange assay in Chinese hamster bone marrow cells. Impairment of fertility —Two fertility studies conducted in adult rats at doses of up to 7.5 and 12.5 mg/kg/day (approximately 0.9 and 1.5 times the MRHD on a mg/m 2 basis) indicated that fluoxetine had no adverse effects on fertility. However, adverse effects on fertility were seen when juvenile rats were treated with fluoxetine [see Use in Specific Populations (8.4)].

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity —The dietary administration of fluoxetine to rats and mice for 2 years at doses of up to 10 and 12 mg/kg/day, respectively (approximately 1.2 and 0.7 times, respectively, the MRHD of 80 mg on a mg/m 2 basis), produced no evidence of carcinogenicity. Mutagenicity —Fluoxetine and norfluoxetine have been shown to have no genotoxic effects based on the following assays: bacterial mutation assay, DNA repair assay in cultured rat hepatocytes, mouse lymphoma assay, and in vivo sister chromatid exchange assay in Chinese hamster bone marrow cells. Impairment of fertility —Two fertility studies conducted in adult rats at doses of up to 7.5 and 12.5 mg/kg/day (approximately 0.9 and 1.5 times the MRHD on a mg/m 2 basis) indicated that fluoxetine had no adverse effects on fertility. However, adverse effects on fertility were seen when juvenile rats were treated with fluoxetine [see Use in Specific Populations (8.4)]. 13.2 Animal Toxicology and/or Pharmacology Phospholipids are increased in some tissues of mice, rats, and dogs given fluoxetine chronically. This effect is reversible after cessation of fluoxetine treatment. Phospholipid accumulation in animals has been observed with many cationic amphiphilic drugs, including fenfluramine, imipramine, and ranitidine. The significance of this effect in humans is unknown.

ANDA209419

Fluoxetine

Fluoxetine

63629-2201

HUMAN PRESCRIPTION DRUG

ORAL

Fluoxetine Hcl 60 mg Tablet, #30 Label

RECENT MAJOR CHANGES Boxed Warning 02/2016 Dosage and Administration, Use with Other MAOIs (2.7) 02/2016 Contraindications, MAOIs (4.1) 02/2016 Warnings and Precautions, Serotonin Syndrome (5.2) 01/2017 Warnings and Precautions, QT Prolongation (5.11) 02/2016

17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide). Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking fluoxetine. 17.1 Information on Medication Guide and Benefits/Risks of Fluoxetine Tablets Healthcare providers should instruct their patients to read the Medication Guide before starting therapy with fluoxetine tablets and to reread it each time the prescription is renewed. Healthcare providers should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with fluoxetine tablets and should counsel them in its appropriate use. Healthcare providers should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. Patients should be advised of the following issues and asked to alert their healthcare provider if these occur while taking fluoxetine tablets. 17.2 Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults Patients, their families, and their caregivers should be encouraged 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. Families and caregivers of patients should be advised to look 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)]. 17.3 Serotonin Syndrome Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of fluoxetine tablets and other serotonergic agents including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, amphetamines, and St. John’s Wort [see Contraindications (4.1), Warnings and Precautions (5.2), and Drug Interactions (7.3)]. Patients should be advised 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). Patients should be cautioned to seek medical care immediately if they experience these symptoms. 17.4 Allergic Reactions and Rash Patients should be advised to notify their physician if they develop a rash or hives [see Warnings and Precautions (5.3)]. Patients should also be advised of the signs and symptoms associated with a severe allergic reaction, including swelling of the face, eyes, or mouth, or have trouble breathing. Patients should be cautioned to seek medical care immediately if they experience these symptoms. 17.5 Abnormal Bleeding Patients should be cautioned about the concomitant use of fluoxetine tablets and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents have been associated with an increased risk of bleeding [see Warnings and Precautions (5.7) and Drug Interactions (7.4)]. Patients should be advised to call their doctor if they experience any increased or unusual bruising or bleeding while taking fluoxetine. 17.6 Angle-closure Glaucoma Patients should be advised that taking fluoxetine tablets 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 Warning and Precautions (5.8)]. 17.7 Hyponatremia Patients should be advised that hyponatremia has been reported as a result of treatment with SNRIs and SSRIs, including fluoxetine. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. More severe and/or acute cases have been associated with hallucination, syncope, seizure, coma, respiratory arrest, and death [see Warnings and Precautions (5.9)]. 17.8 QT Prolongation Patients should be advised that QT interval prolongation and ventricular arrhythmia including Torsades de Pointes have been reported in patients treated with fluoxetine. Signs and symptoms of ventricular arrhythmia include fast, slow, or irregular heart rate, dyspnea, syncope, or dizziness, which may indicate serious cardiac arrhythmia [see Warnings and Precautions (5.11)]. 17.9 Potential for Cognitive and Motor Impairment Fluoxetine tablets may impair judgment, thinking, or motor skills. Patients should be advised to avoid driving a car or operating hazardous machinery until they are reasonably certain that their performance is not affected [see Warnings and Precautions (5.13)]. 17.10 Use of Concomitant Medications Patients should be advised to inform their physician if they are taking, or plan to take, any prescription medication, including Prozac ® (fluoxetine hydrochloride), Symbyax ® (olanzapine and fluoxetine hydrochloride capsules), Sarafem ® (fluoxetine tablets), or over-the-counter drugs, including herbal supplements or alcohol. Patients should also be advised to inform their physicians if they plan to discontinue any medications they are taking while on fluoxetine. 17.11 Discontinuation of Treatment Patients should be advised to take fluoxetine tablets exactly as prescribed, and to continue taking fluoxetine tablets as prescribed even after their symptoms improve. Patients should be advised that they should not alter their dosing regimen, or stop taking fluoxetine tablets without consulting their physician [see Warnings and Precautions (5.15)]. Patients should be advised to consult with their healthcare provider if their symptoms do not improve with fluoxetine. 17.12 Use in Specific Populations Pregnancy —Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy. Fluoxetine tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus [see Use in Specific Populations (8.1)]. Nursing mothers —Patients should be advised to notify their physician if they intend to breast-­feed an infant during therapy. Because fluoxetine is excreted in human milk, nursing while taking fluoxetine tablets is not recommended [see Use in Specific Populations (8.3)]. Pediatric use —Fluoxetine tablets are approved for use in pediatric patients with MDD and OCD [see Boxed Warning and Warnings and Precautions (5.1)]. Limited evidence is available concerning the longer-term effects of fluoxetine tablets on the development and maturation of children and adolescent patients. Height and weight should be monitored periodically in pediatric patients receiving fluoxetine tablets [see Warnings and Precautions (5.6) and Use in Specific Populations (8.4)]. The brands listed are trademarks of their respective owners and are not trademarks of the Par Pharmaceutical. The makers of these brands are not affiliated with and do not endorse the Par Pharmaceutical or its products.

MEDICATION GUIDE Fluoxetine Tablets, USP (floo ox' e teen) Read the Medication Guide that comes with fluoxetine tablets before you start taking them and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or treatment. Talk with your healthcare provider if there is something you do not understand or want to learn more about. What is the most important information I should know about fluoxetine tablets? Fluoxetine tablets and other antidepressant medicines may cause serious side effects, including: 1. Suicidal thoughts or actions: Fluoxetine tablets 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 or other serious mental illnesses are the most important causes of suicidal thoughts or actions. Watch for these changes and call your healthcare provider right away if you notice: New or sudden changes in mood, behavior, actions, thoughts, or feelings, especially if severe. Pay particular attention to such changes when fluoxetine tablets are started or when the dose is changed. Keep all follow-up visits with your healthcare provider and call between visits if you are worried about symptoms. Call your healthcare provider right away if you have any of the following symptoms, or call 911 if an emergency, especially if they are new, worse, or worry you: attempts to commit suicide acting on dangerous impulses acting aggressive or violent thoughts about suicide or dying new or worse depression new or worse anxiety or panic attacks feeling agitated, restless, angry, or irritable trouble sleeping an increase in activity or talking more than what is normal for you other unusual changes in behavior or mood Call your healthcare provider right away if you have any of the following symptoms, or call 911 if an emergency. Fluoxetine tablets may be associated with these serious side effects: 2. Serotonin Syndrome. This condition can be life-threatening and 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 3. Severe allergic reactions: trouble breathing swelling of the face, tongue, eyes, or mouth rash, itchy welts (hives) or blisters, alone or with fever or joint pain 4. Abnormal bleeding: Fluoxetine tablets and other antidepressant medicines may increase your risk of bleeding or bruising, especially if you take the blood thinner warfarin (Coumadin ® , Jantoven ® ), a nonsteroidal anti-inflammatory drug (NSAIDs, like ibuprofen or naproxen), or aspirin. 5. Visual 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. 6. Seizures or convulsions 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. Changes in appetite or weight. Children and adolescents should have height and weight monitored during treatment. 9. 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 10. Changes in the electrical activity of your heart (QT prolongation and ventricular arrhythmia including Torsades de Pointes). This condition can be life threatening. The symptoms may include: fast, slow, or irregular heartbeat shortness of breath dizziness or fainting Do not stop fluoxetine tablets without first talking to your healthcare provider . Stopping fluoxetine tablets too quickly may cause serious symptoms including: anxiety, irritability, high or low mood, feeling restless, or changes in sleep habits headache, sweating, nausea, dizziness electric shock-like sensations, shaking, confusion What are fluoxetine tablets? Fluoxetine tablets are a prescription medicine used to treat depression. It is important to talk with your healthcare provider about the risks of treating depression and also the risks of not treating it. You should discuss all treatment choices with your healthcare provider. Fluoxetine tablets are used to treat: Major Depressive Disorder (MDD) Obsessive Compulsive Disorder (OCD) Bulimia Nervosa* Panic Disorder* Depressive episodes associated with Bipolar I Disorder, taken with olanzapine (Zyprexa)* Treatment Resistant Depression (depression that has not gotten better with at least 2 other treatments), taken with olanzapine (Zyprexa)* *Not approved for use in children. Talk to your healthcare provider if you do not think that your condition is getting better with fluoxetine tablets treatment. Who should not take fluoxetine tablets? Do not take fluoxetine tablets if you: are allergic to fluoxetine hydrochloride or any of the ingredients in fluoxetine tablets. See the end of this Medication Guide for a complete list of ingredients in fluoxetine tablets. 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. Do not take an MAOI within 5 weeks of stopping fluoxetine tablets unless directed to do so by your physician. Do not start fluoxetine tablets if you stopped taking an MAOI in the last 2 weeks unless directed to do so by your physician. People who take fluoxetine tablets close in time to an MAOI may have serious or even life-threatening side effects. Get medical help right away if you have any of these symptoms: high fever uncontrolled muscle spasms stiff muscles rapid changes in heart rate or blood pressure confusion loss of consciousness (pass out) take Mellaril ® (thioridazine). Do not take Mellaril ® within 5 weeks of stopping fluoxetine tablets because this can cause serious heart rhythm problems or sudden death . take the antipsychotic medicine pimozide (Orap ® ) because this can cause serious heart problems . What should I tell my healthcare provider before taking fluoxetine tablets? Ask if you are not sure. Before starting fluoxetine tablets, tell your healthcare provider if you: are taking certain drugs or treatments such as: Triptans used to treat migraine headache Medicines used to treat mood, anxiety, psychotic, or thought disorders, including tricyclics, lithium, SSRIs, SNRIs, MAOIs, or antipsychotics Tramadol and fentanyl Amphetamines Over-the-counter supplements such as tryptophan or St. John’s Wort Electroconvulsive therapy (ECT) have liver problems have kidney problems have heart problems have or had seizures or convulsions have bipolar disorder or mania have low sodium levels in your blood have a history of a stroke have high blood pressure have or had bleeding problems are pregnant or plan to become pregnant. It is not known if fluoxetine tablets will harm your unborn baby. Talk to your healthcare provider about the benefits and risks of treating depression during pregnancy. are breast-feeding or plan to breast-feed. Some fluoxetine may pass into your breast milk. Talk to your healthcare provider about the best way to feed your baby while taking fluoxetine tablets. Tell your healthcare provider about all the medicines that you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. Fluoxetine tablets and some medicines may interact with each other, may not work as well, or may cause serious side effects. Your healthcare provider or pharmacist can tell you if it is safe to take fluoxetine tablets with your other medicines. Do not start or stop any medicine while taking fluoxetine tablets without talking to your healthcare provider first. If you take fluoxetine tablets, you should not take any other medicines that contain fluoxetine hydrochloride including: Symbyax ® (olanzapine and fluoxetine hydrochloride) Sarafem ® (fluoxetine) Prozac ® Prozac ® Weekly™ How should I take fluoxetine tablets? Take fluoxetine tablets exactly as prescribed. Your healthcare provider may need to change the dose of fluoxetine tablets until it is the right dose for you. Each tablet can be broken in half (along the functional score). Fluoxetine tablets may be taken with or without food. If you miss a dose of fluoxetine tablets, 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 fluoxetine tablets at the same time. If you take too much fluoxetine, call your healthcare provider or poison control center right away, or get emergency treatment. What should I avoid while taking fluoxetine tablets? Fluoxetine tablets 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 fluoxetine tablets affect you. Do not drink alcohol while using fluoxetine tablets. What are the possible side effects of fluoxetine tablets? Fluoxetine tablets may cause serious side effects, including: See “ What is the most important information I should know about fluoxetine tablets?” Problems with blood sugar control . People who have diabetes and take fluoxetine tablets may have problems with low blood sugar while taking fluoxetine tablets. High blood sugar can happen when fluoxetine tablets are stopped. Your healthcare provider may need to change the dose of your diabetes medicines when you start or stop taking fluoxetine tablets. Feeling anxious or trouble sleeping Common possible side effects in people who take fluoxetine tablets include: unusual dreams sexual problems loss of appetite, diarrhea, indigestion, nausea or vomiting, weakness, or dry mouth flu symptoms feeling tired or fatigued change in sleep habits yawning sinus infection or sore throat tremor or shaking sweating feeling anxious or nervous hot flashes rash Other side effects in children and adolescents include: increased thirst abnormal increase in muscle movement or agitation nose bleed urinating more often heavy menstrual periods possible slowed growth rate and weight change. Your child’s height and weight should be monitored during treatment with fluoxetine tablets. 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 fluoxetine tablets. For more information, ask your healthcare provider or pharmacist. CALL YOUR DOCTOR FOR MEDICAL ADVICE ABOUT SIDE EFFECTS. YOU MAY REPORT SIDE EFFECTS TO THE FDA AT 1-800-FDA-1088. How should I store fluoxetine tablets? Store fluoxetine tablets at room temperature between 68° and 77°F (20° to 25°C). Keep fluoxetine tablets away from light. Keep fluoxetine tablets bottle closed tightly. Keep fluoxetine tablets and all medicines out of the reach of children. General information about fluoxetine tablets Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use fluoxetine tablets for a condition for which it was not prescribed. Do not give fluoxetine tablets to other people, even if they have the same condition. They may harm them. This Medication Guide summarizes the most important information about fluoxetine tablets. If you would like more information, talk with your healthcare provider. You may ask your healthcare provider or pharmacist for information about fluoxetine tablets that is written for healthcare professionals. For more information about fluoxetine tablets, call Par Pharmaceutical at 1-800-828-9393. What are the ingredients in fluoxetine tablets, 60 mg? Active ingredient: fluoxetine hydrochloride Inactive ingredients: colloidal silicon dioxide, corn starch, crospovidone, magnesium stearate, mannitol, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, talc and titanium dioxide. This Medication Guide has been approved by the U.S. Food and Drug Administration. The brands listed are trademarks of their respective owners and are not trademarks of the Par Pharmaceutical. The makers of these brands are not affiliated with and do not endorse the Par Pharmaceutical or its products. Dist. by: Par Pharmaceutical Chestnut Ridge, NY 10977 U.S.A. Mfg. by: Par Formulations Private Limited, 9/215, Pudupakkam, Kelambakkam-603 103. Made in India Mfg. Lic. No.: TN00002121 OS468-01-74-01 Issued: 09/2017

14 CLINICAL STUDIES Efficacy for fluoxetine was established for the: Acute and maintenance treatment of MDD in adults, and children and adolescents (8 to 18 years) in 7 short-term and 2 long-term, placebo-controlled trials [see Clinical Studies 14.1)]. Acute treatment of obsessions and compulsions in adults, and children and adolescents (7 to 17 years) with OCD in 3 short-term, placebo-controlled trials [see Clinical Studies (14.2)]. Acute and maintenance treatment of binge-eating and vomiting behaviors in adult patients with moderate to severe Bulimia Nervosa in 3 short-term and 1 long-term, placebo-controlled trials [see Clinical Studies (14.3)]. Acute treatment of Panic Disorder, with or without agoraphobia, in adult patients in 2 short-term, placebo-controlled trials [see Clinical Studies (14.4)]. 14.1 Major Depressive Disorder Daily Dosing Adult —The efficacy of fluoxetine was studied in 5- and 6-week placebo-controlled trials with depressed adult and geriatric outpatients (≥18 years of age) whose diagnoses corresponded most closely to the DSM-III (currently DSM-IV) category of MDD. Fluoxetine was shown to be significantly more effective than placebo as measured by the Hamilton Depression Rating Scale (HAM-D). Fluoxetine was also significantly more effective than placebo on the HAM-D subscores for depressed mood, sleep disturbance, and the anxiety subfactor. Two 6-week controlled studies (N = 671, randomized) comparing fluoxetine 20 mg and placebo have shown fluoxetine 20 mg daily to be effective in the treatment of elderly patients (≥60 years of age) with MDD. In these studies, fluoxetine produced a significantly higher rate of response and remission as defined, respectively, by a 50% decrease in the HAM-D score and a total endpoint HAM-D score of ≤8. Fluoxetine was well tolerated and the rate of treatment discontinuations due to adverse reactions did not differ between fluoxetine (12%) and placebo (9%). A study was conducted involving depressed outpatients who had responded (modified HAMD-17 score of ≤7 during each of the last 3 weeks of open-label treatment and absence of MDD by DSM-III-R criteria) by the end of an initial 12-week, open-treatment phase on fluoxetine 20 mg/day. These patients (N = 298) were randomized to continuation on double- blind fluoxetine 20 mg/day or placebo. At 38 weeks (50 weeks total), a statistically significantly lower relapse rate (defined as symptoms sufficient to meet a diagnosis of MDD for 2 weeks or a modified HAMD-17 score of ≥14 for 3 weeks) was observed for patients taking fluoxetine compared with those on placebo. Pediatric (children and adolescents) —The efficacy of fluoxetine 20 mg/day in children and adolescents (N = 315 randomized; 170 children ages 8 to < 13, 145 adolescents ages 13 to ≤18) was studied in two 8- to 9-week placebo-controlled clinical trials in depressed outpatients whose diagnoses corresponded most closely to the DSM-III-R or DSM-IV category of MDD. In both studies independently, fluoxetine produced a statistically significantly greater mean change on the Childhood Depression Rating Scale-Revised (CDRS-R) total score from baseline to endpoint than did placebo. Subgroup analyses on the CDRS-R total score did not suggest any differential responsiveness on the basis of age or gender. 14.2 Obsessive Compulsive Disorder Adult —The effectiveness of fluoxetine for the treatment of OCD was demonstrated in two 13-week, multicenter, parallel-group studies (studies 1 and 2) of adult outpatients who received fixed fluoxetine doses of 20, 40, or 60 mg/day (on a once-a-day schedule, in the morning) or placebo. Patients in both studies had moderate to severe OCD (DSM-III-R), with mean baseline ratings on the Yale-Brown Obsessive Compulsive Scale (YBOCS, total score) ranging from 22 to 26. In study 1, patients receiving fluoxetine experienced mean reductions of approximately 4 to 6 units on the YBOCS total score, compared with a 1-unit reduction for placebo patients. In study 2, patients receiving fluoxetine experienced mean reductions of approximately 4 to 9 units on the YBOCS total score, compared with a 1-unit reduction for placebo patients. While there was no indication of a dose-response relationship for effectiveness in study 1, a dose-response relationship was observed in study 2, with numerically better responses in the 2 higher dose groups. Table 5 provides the outcome classification by treatment group on the Clinical Global Impression (CGI) improvement scale for studies 1 and 2 combined: Table 5. Outcome Classification (%) on CGI Improvement Scale for Completers in Pool of Two OCD Studies Fluoxetine Outcome Classification Placebo 20 mg 40 mg 60 mg Worse 8% 0% 0% 0% No change 64% 41% 33% 29% Minimally improved 17% 23% 28% 24% Much improved 8% 28% 27% 28% Very much improved 3% 8% 12% 19% Exploratory analyses for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or sex. Pediatric (children and adolescents)— In one 13-week clinical trial in pediatric patients (N = 103 randomized; 75 children ages 7 to < 13, 28 adolescents ages 13 to < 18) with OCD (DSM-IV), patients received fluoxetine 10 mg/day for 2 weeks, followed by 20 mg/day for 2 weeks. The dose was then adjusted in the range of 20 to 60 mg/day on the basis of clinical response and tolerability. Fluoxetine produced a statistically significantly greater mean change from baseline to endpoint than did placebo as measured by the Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS). Subgroup analyses on outcome did not suggest any differential responsiveness on the basis of age or gender. 14.3 Bulimia Nervosa The effectiveness of fluoxetine for the treatment of bulimia was demonstrated in two 8-week and one 16-week, multicenter, parallel-group studies of adult outpatients meeting DSM-III-R criteria for bulimia. Patients in the 8-week studies received either 20 or 60 mg/day of fluoxetine or placebo in the morning. Patients in the 16-week study received a fixed fluoxetine dose of 60 mg/day (once a day) or placebo. Patients in these 3 studies had moderate to severe bulimia with median binge-eating and vomiting frequencies ranging from 7 to 10 per week and 5 to 9 per week, respectively. In these 3 studies, fluoxetine 60 mg, but not 20 mg, was statistically significantly superior to placebo in reducing the number of binge-eating and vomiting episodes per week. The statistically significantly superior effect of 60 mg versus placebo was present as early as week 1 and persisted throughout each study. The fluoxetine-related reduction in bulimic episodes appeared to be independent of baseline depression as assessed by the HAM-D. In each of these 3 studies, the treatment effect, as measured by differences between fluoxetine 60 mg and placebo on median reduction from baseline in frequency of bulimic behaviors at endpoint, ranged from 1 to 2 episodes per week for binge-eating and 2 to 4 episodes per week for vomiting. The size of the effect was related to baseline frequency, with greater reductions seen in patients with higher baseline frequencies. Although some patients achieved freedom from binge-eating and purging as a result of treatment, for the majority, the benefit was a partial reduction in the frequency of binge-eating and purging. In a longer-term trial, 150 patients meeting DSM-IV criteria for Bulimia Nervosa, purging subtype, who had responded during a single-blind, 8-week, acute-treatment phase with fluoxetine 60 mg/day, were randomized to continuation of fluoxetine 60 mg/day or placebo, for up to 52 weeks of observation for relapse. Response during the single-blind phase was defined by having achieved at least a 50% decrease in vomiting frequency compared with baseline. Relapse during the double-blind phase was defined as a persistent return to baseline vomiting frequency or physician judgment that the patient had relapsed. Patients receiving continued fluoxetine 60 mg/day experienced a significantly longer time to relapse over the subsequent 52 weeks compared with those receiving placebo. 14.4 Panic Disorder The effectiveness of fluoxetine in the treatment of Panic Disorder was demonstrated in 2 double-blind, randomized, placebo-controlled, multicenter studies of adult outpatients who had a primary diagnosis of Panic Disorder (DSM-IV), with or without agoraphobia. Study 1 (N = 180 randomized) was a 12-week, flexible-dose study. Fluoxetine was initiated at 10 mg/day for the first week, after which patients were dosed in the range of 20 to 60 mg/day on the basis of clinical response and tolerability. A statistically significantly greater percentage of fluoxetine-treated patients were free from panic attacks at endpoint than placebo-treated patients, 42% versus 28%, respectively. Study 2 (N = 214 randomized) was a 12-week, flexible-dose study. Fluoxetine was initiated at 10 mg/day for the first week, after which patients were dosed in a range of 20 to 60 mg/day on the basis of clinical response and tolerability. A statistically significantly greater percentage of fluoxetine-treated patients were free from panic attacks at endpoint than placebo-treated patients, 62% versus 44%, respectively.

8.5 Geriatric Use U.S. fluoxetine clinical trials included 687 patients ≥65 years of age and 93 patients ≥75 years of age. The efficacy in geriatric patients has been established [see Clinical Studies (14.1)]. For pharmacokinetic information in geriatric patients, [see Clinical Pharmacology (12.3)]. No overall differences in safety or effectiveness were 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. SNRIs and SSRIs, including fluoxetine, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse reaction [see Warnings and Precautions (5.9)].

8.2 Labor and Delivery The effect of fluoxetine on labor and delivery in humans is unknown. However, because fluoxetine crosses the placenta and because of the possibility that fluoxetine may have adverse effects on the newborn, fluoxetine should be used during labor and delivery only if the potential benefit justifies the potential risk to the fetus.

8.3 Nursing Mothers Because fluoxetine is excreted in human milk, nursing while on fluoxetine is not recommended. In one breast-milk sample, the concentration of fluoxetine plus norfluoxetine was 70.4 ng/mL. The concentration in the mother’s plasma was 295.0 ng/mL. No adverse effects on the infant were reported. In another case, an infant nursed by a mother on fluoxetine developed crying, sleep disturbance, vomiting, and watery stools. The infant’s plasma drug levels were 340 ng/mL of fluoxetine and 208 ng/mL of norfluoxetine on the second day of feeding.

8.4 Pediatric Use Use of fluoxetine in children —The efficacy of fluoxetine for the treatment of MDD was demonstrated in two 8- to 9-week placebo-controlled clinical trials with 315 pediatric outpatients ages 8 to ≤18 [see Clinical Studies (14.1)]. The efficacy of fluoxetine for the treatment of OCD was demonstrated in one 13-week placebo-controlled clinical trial with 103 pediatric outpatients ages 7 to < 18 [see Clinical Studies (14.2)]. The safety and effectiveness in pediatric patients < 8 years of age in MDD and < 7 years of age in OCD have not been established. Fluoxetine pharmacokinetics were evaluated in 21 pediatric patients (ages 6 to ≤18) with MDD or OCD [see Clinical Pharmacology (12.3)]. The acute adverse reaction profiles observed in the 3 studies (N = 418 randomized; 228 fluoxetine-treated, 190 placebo-treated) were generally similar to that observed in adult studies with fluoxetine. The longer-term adverse reaction profile observed in the 19-week MDD study (N = 219 randomized; 109 fluoxetine-treated, 110 placebo-treated) was also similar to that observed in adult trials with fluoxetine [see Adverse Reactions (6.1)]. Manic reaction, including mania and hypomania, was reported in 6 (1 mania, 5 hypomania) out of 228 (2.6%) fluoxetine-treated patients and in 0 out of 190 (0%) placebo-treated patients. Mania/hypomania led to the discontinuation of 4 (1.8%) fluoxetine-treated patients from the acute phases of the 3 studies combined. Consequently, regular monitoring for the occurrence of mania/hypomania is recommended. As with other SSRIs, decreased weight gain has been observed in association with the use of fluoxetine in children and adolescent patients. After 19 weeks of treatment in a clinical trial, pediatric subjects treated with fluoxetine gained an average of 1.1 cm less in height and 1.1 kg less in weight than subjects treated with placebo. In addition, fluoxetine treatment was associated with a decrease in alkaline phosphatase levels. The safety of fluoxetine treatment for pediatric patients has not been systematically assessed for chronic treatment longer than several months in duration. In particular, there are no studies that directly evaluate the longer-term effects of fluoxetine on the growth, development, and maturation of children and adolescent patients. Therefore, height and weight should be monitored periodically in pediatric patients receiving fluoxetine [see Warnings and Precautions (5.6)]. Fluoxetine is approved for use in pediatric patients with MDD and OCD [see Boxed Warning and Warnings and Precautions (5.1)]. Anyone considering the use of fluoxetine in a child or adolescent must balance the potential risks with the clinical need. Animal data —Significant toxicity on muscle tissue, neurobehavior, reproductive organs, and bone development has been observed following exposure of juvenile rats to fluoxetine from weaning through maturity. Oral administration of fluoxetine to rats from weaning postnatal day 21 through adulthood day 90 at 3, 10, or 30 mg/kg/day was associated with testicular degeneration and necrosis, epididymal vacuolation, and hypospermia (at 30 mg/kg/day corresponding to plasma exposures [AUC] approximately 5 to 10 times the average AUC in pediatric patients at the MRHD of 20 mg/day); increased serum levels of creatine kinase (at AUC as low as 1 to 2 times the average AUC in pediatric patients at the MRHD of 20 mg/day); skeletal muscle degeneration and necrosis; decreased femur length/growth; and body weight gain (at AUC 5 to 10 times the average AUC in pediatric patients at the MRHD of 20 mg/day). The high dose of 30 mg/kg/day exceeded a maximum tolerated dose. When animals were evaluated after a drug-free period (up to 11 weeks after cessation of dosing), fluoxetine was associated with neurobehavioral abnormalities (decreased reactivity at AUC as low as approximately 0.1 to 0.2 times the average AUC in pediatric patients at the MRHD and learning deficit at the high dose) and reproductive functional impairment (decreased mating at all doses and impaired fertility at the high dose). In addition, the testicular and epididymal microscopic lesions and decreased sperm concentrations found in the high dose group were also observed, indicating that the drug effects on reproductive organs are irreversible. The reversibility of fluoxetine-induced muscle damage was not assessed. These fluoxetine toxicities in juvenile rats have not been observed in adult animals. Plasma exposures (AUC) to fluoxetine in juvenile rats receiving 3, 10, or 30 mg/kg/day doses in this study are approximately 0.1 to 0.2, 1 to 2, and 5 to 10 times, respectively, the average exposure in pediatric patients receiving the MRHD of 20 mg/day. Rat exposures to the major metabolite, norfluoxetine, were approximately 0.3 to 0.8, 1 to 8, and 3 to 20 times, respectively, the pediatric exposure at the MRHD. A specific effect on bone development was reported in juvenile mice administered fluoxetine by the intraperitoneal route to 4-week-old mice for 4 weeks at doses 0.5 and 2 times the oral MRHD of 20 mg/day on a mg/m 2 basis. There was a decrease in bone mineralization and density at both doses, but the overall growth (body weight gain or femur length) was not affected.

8.1 Pregnancy Pregnancy Category C —Fluoxetine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. All pregnancies have a background risk of birth defects, loss, or other adverse outcome regardless of drug exposure. Treatment of pregnant women during the first trimester —There are no adequate and well-controlled clinical studies on the use of fluoxetine in pregnant women. Results of a number of published epidemiological studies assessing the risk of fluoxetine exposure during the first trimester of pregnancy have demonstrated inconsistent results. More than 10 cohort studies and case-control studies failed to demonstrate an increased risk for congenital malformations overall. However, one prospective cohort study conducted by the European Network of Teratology Information Services reported an increased risk of cardiovascular malformations in infants born to women (N = 253) exposed to fluoxetine during the first trimester of pregnancy compared to infants of women (N = 1359) who were not exposed to fluoxetine. There was no specific pattern of cardiovascular malformations. Overall, however, a causal relationship has not been established. Nonteratogenic effects —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, tremor, jitteriness, irritability, and constant crying. These features 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)]. Infants exposed to SSRIs in pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 to 2 per 1000 live births in the general population and is associated with substantial neonatal morbidity and mortality. Several recent epidemiological studies suggest a positive statistical association between SSRI use (including fluoxetine) in pregnancy and PPHN. Other studies do not show a significant statistical association. Physicians should also note the results of a prospective longitudinal study of 201 pregnant women with a history of major depression, who were either on antidepressants or had received antidepressants less than 12 weeks prior to their last menstrual period, and were in remission. Women who discontinued antidepressant medication during pregnancy showed a significant increase in relapse of their major depression compared to those women who remained on antidepressant medication throughout pregnancy. When treating a pregnant woman with fluoxetine, the physician should carefully consider both the potential risks of taking an SSRI, along with the established benefits of treating depression with an antidepressant. The decision can only be made on a case by case basis [see Dosage and Administration (2.5)]. Animal data —In embryo-fetal development studies in rats and rabbits, there was no evidence of teratogenicity following administration of fluoxetine at doses up to 12.5 and 15 mg/kg/day, respectively (1.5 and 3.6 times, respectively, the maximum recommended human dose [MRHD] of 80 mg on a mg/m 2 basis) throughout organogenesis. However, in rat reproduction studies, an increase in stillborn pups, a decrease in pup weight, and an increase in pup deaths during the first 7 days postpartum occurred following maternal exposure to 12 mg/kg/day (1.5 times the MRHD on a mg/m 2 basis) during gestation or 7.5 mg/kg/day (0.9 times the MRHD on a mg/m 2 basis) during gestation and lactation. There was no evidence of developmental neurotoxicity in the surviving offspring of rats treated with 12 mg/kg/day during gestation. The no-effect dose for rat pup mortality was 5 mg/kg/day (0.6 times the MRHD on a mg/m 2 basis).

8 USE IN SPECIFIC POPULATIONS Pregnancy: Fluoxetine should be used during pregnancy only if the potential benefit justifies the potential risks to the fetus (8.1) Nursing Mothers: Breast feeding is not recommended (8.3) Pediatric Use: Safety and effectiveness of fluoxetine in patients < 8 years of age with MDD and < 7 years of age with OCD have not been established (8.4) 8.1 Pregnancy Pregnancy Category C —Fluoxetine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. All pregnancies have a background risk of birth defects, loss, or other adverse outcome regardless of drug exposure. Treatment of pregnant women during the first trimester —There are no adequate and well-controlled clinical studies on the use of fluoxetine in pregnant women. Results of a number of published epidemiological studies assessing the risk of fluoxetine exposure during the first trimester of pregnancy have demonstrated inconsistent results. More than 10 cohort studies and case-control studies failed to demonstrate an increased risk for congenital malformations overall. However, one prospective cohort study conducted by the European Network of Teratology Information Services reported an increased risk of cardiovascular malformations in infants born to women (N = 253) exposed to fluoxetine during the first trimester of pregnancy compared to infants of women (N = 1359) who were not exposed to fluoxetine. There was no specific pattern of cardiovascular malformations. Overall, however, a causal relationship has not been established. Nonteratogenic effects —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, tremor, jitteriness, irritability, and constant crying. These features 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)]. Infants exposed to SSRIs in pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 to 2 per 1000 live births in the general population and is associated with substantial neonatal morbidity and mortality. Several recent epidemiological studies suggest a positive statistical association between SSRI use (including fluoxetine) in pregnancy and PPHN. Other studies do not show a significant statistical association. Physicians should also note the results of a prospective longitudinal study of 201 pregnant women with a history of major depression, who were either on antidepressants or had received antidepressants less than 12 weeks prior to their last menstrual period, and were in remission. Women who discontinued antidepressant medication during pregnancy showed a significant increase in relapse of their major depression compared to those women who remained on antidepressant medication throughout pregnancy. When treating a pregnant woman with fluoxetine, the physician should carefully consider both the potential risks of taking an SSRI, along with the established benefits of treating depression with an antidepressant. The decision can only be made on a case by case basis [see Dosage and Administration (2.5)]. Animal data —In embryo-fetal development studies in rats and rabbits, there was no evidence of teratogenicity following administration of fluoxetine at doses up to 12.5 and 15 mg/kg/day, respectively (1.5 and 3.6 times, respectively, the maximum recommended human dose [MRHD] of 80 mg on a mg/m 2 basis) throughout organogenesis. However, in rat reproduction studies, an increase in stillborn pups, a decrease in pup weight, and an increase in pup deaths during the first 7 days postpartum occurred following maternal exposure to 12 mg/kg/day (1.5 times the MRHD on a mg/m 2 basis) during gestation or 7.5 mg/kg/day (0.9 times the MRHD on a mg/m 2 basis) during gestation and lactation. There was no evidence of developmental neurotoxicity in the surviving offspring of rats treated with 12 mg/kg/day during gestation. The no-effect dose for rat pup mortality was 5 mg/kg/day (0.6 times the MRHD on a mg/m 2 basis). 8.2 Labor and Delivery The effect of fluoxetine on labor and delivery in humans is unknown. However, because fluoxetine crosses the placenta and because of the possibility that fluoxetine may have adverse effects on the newborn, fluoxetine should be used during labor and delivery only if the potential benefit justifies the potential risk to the fetus. 8.3 Nursing Mothers Because fluoxetine is excreted in human milk, nursing while on fluoxetine is not recommended. In one breast-milk sample, the concentration of fluoxetine plus norfluoxetine was 70.4 ng/mL. The concentration in the mother’s plasma was 295.0 ng/mL. No adverse effects on the infant were reported. In another case, an infant nursed by a mother on fluoxetine developed crying, sleep disturbance, vomiting, and watery stools. The infant’s plasma drug levels were 340 ng/mL of fluoxetine and 208 ng/mL of norfluoxetine on the second day of feeding. 8.4 Pediatric Use Use of fluoxetine in children —The efficacy of fluoxetine for the treatment of MDD was demonstrated in two 8- to 9-week placebo-controlled clinical trials with 315 pediatric outpatients ages 8 to ≤18 [see Clinical Studies (14.1)]. The efficacy of fluoxetine for the treatment of OCD was demonstrated in one 13-week placebo-controlled clinical trial with 103 pediatric outpatients ages 7 to < 18 [see Clinical Studies (14.2)]. The safety and effectiveness in pediatric patients < 8 years of age in MDD and < 7 years of age in OCD have not been established. Fluoxetine pharmacokinetics were evaluated in 21 pediatric patients (ages 6 to ≤18) with MDD or OCD [see Clinical Pharmacology (12.3)]. The acute adverse reaction profiles observed in the 3 studies (N = 418 randomized; 228 fluoxetine-treated, 190 placebo-treated) were generally similar to that observed in adult studies with fluoxetine. The longer-term adverse reaction profile observed in the 19-week MDD study (N = 219 randomized; 109 fluoxetine-treated, 110 placebo-treated) was also similar to that observed in adult trials with fluoxetine [see Adverse Reactions (6.1)]. Manic reaction, including mania and hypomania, was reported in 6 (1 mania, 5 hypomania) out of 228 (2.6%) fluoxetine-treated patients and in 0 out of 190 (0%) placebo-treated patients. Mania/hypomania led to the discontinuation of 4 (1.8%) fluoxetine-treated patients from the acute phases of the 3 studies combined. Consequently, regular monitoring for the occurrence of mania/hypomania is recommended. As with other SSRIs, decreased weight gain has been observed in association with the use of fluoxetine in children and adolescent patients. After 19 weeks of treatment in a clinical trial, pediatric subjects treated with fluoxetine gained an average of 1.1 cm less in height and 1.1 kg less in weight than subjects treated with placebo. In addition, fluoxetine treatment was associated with a decrease in alkaline phosphatase levels. The safety of fluoxetine treatment for pediatric patients has not been systematically assessed for chronic treatment longer than several months in duration. In particular, there are no studies that directly evaluate the longer-term effects of fluoxetine on the growth, development, and maturation of children and adolescent patients. Therefore, height and weight should be monitored periodically in pediatric patients receiving fluoxetine [see Warnings and Precautions (5.6)]. Fluoxetine is approved for use in pediatric patients with MDD and OCD [see Boxed Warning and Warnings and Precautions (5.1)]. Anyone considering the use of fluoxetine in a child or adolescent must balance the potential risks with the clinical need. Animal data —Significant toxicity on muscle tissue, neurobehavior, reproductive organs, and bone development has been observed following exposure of juvenile rats to fluoxetine from weaning through maturity. Oral administration of fluoxetine to rats from weaning postnatal day 21 through adulthood day 90 at 3, 10, or 30 mg/kg/day was associated with testicular degeneration and necrosis, epididymal vacuolation, and hypospermia (at 30 mg/kg/day corresponding to plasma exposures [AUC] approximately 5 to 10 times the average AUC in pediatric patients at the MRHD of 20 mg/day); increased serum levels of creatine kinase (at AUC as low as 1 to 2 times the average AUC in pediatric patients at the MRHD of 20 mg/day); skeletal muscle degeneration and necrosis; decreased femur length/growth; and body weight gain (at AUC 5 to 10 times the average AUC in pediatric patients at the MRHD of 20 mg/day). The high dose of 30 mg/kg/day exceeded a maximum tolerated dose. When animals were evaluated after a drug-free period (up to 11 weeks after cessation of dosing), fluoxetine was associated with neurobehavioral abnormalities (decreased reactivity at AUC as low as approximately 0.1 to 0.2 times the average AUC in pediatric patients at the MRHD and learning deficit at the high dose) and reproductive functional impairment (decreased mating at all doses and impaired fertility at the high dose). In addition, the testicular and epididymal microscopic lesions and decreased sperm concentrations found in the high dose group were also observed, indicating that the drug effects on reproductive organs are irreversible. The reversibility of fluoxetine-induced muscle damage was not assessed. These fluoxetine toxicities in juvenile rats have not been observed in adult animals. Plasma exposures (AUC) to fluoxetine in juvenile rats receiving 3, 10, or 30 mg/kg/day doses in this study are approximately 0.1 to 0.2, 1 to 2, and 5 to 10 times, respectively, the average exposure in pediatric patients receiving the MRHD of 20 mg/day. Rat exposures to the major metabolite, norfluoxetine, were approximately 0.3 to 0.8, 1 to 8, and 3 to 20 times, respectively, the pediatric exposure at the MRHD. A specific effect on bone development was reported in juvenile mice administered fluoxetine by the intraperitoneal route to 4-week-old mice for 4 weeks at doses 0.5 and 2 times the oral MRHD of 20 mg/day on a mg/m 2 basis. There was a decrease in bone mineralization and density at both doses, but the overall growth (body weight gain or femur length) was not affected. 8.5 Geriatric Use U.S. fluoxetine clinical trials included 687 patients ≥65 years of age and 93 patients ≥75 years of age. The efficacy in geriatric patients has been established [see Clinical Studies (14.1)]. For pharmacokinetic information in geriatric patients, [see Clinical Pharmacology (12.3)]. No overall differences in safety or effectiveness were 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. SNRIs and SSRIs, including fluoxetine, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse reaction [see Warnings and Precautions (5.9)]. 8.6 Hepatic Impairment In subjects with cirrhosis of the liver, the clearances of fluoxetine and its active metabolite, norfluoxetine, were decreased, thus increasing the elimination half-lives of these substances. A lower or less frequent dose of fluoxetine should be used in patients with cirrhosis. Caution is advised when using fluoxetine in patients with diseases or conditions that could affect its metabolism [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)].

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Fluoxetine tablets, USP are available as 60 mg (fluoxetine base equivalent), white to off-white, film-coated, capsule-shaped tablets, functionally scored and debossed with “P” and “4” on one side with score and plain on the other side with score in bottles of 30 tablets (NDC 63629-2201-1). 16.2 Storage and Handling Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Protect from light.

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS 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 behavior. Advise families and caregivers of the need for close observation and communication with the prescriber [see Warnings and Precautions (5.1)]. Fluoxetine is not approved for use in children less than 7 years of age [see Warnings and Precautions (5.1) and Use in Specific Populations (8.4)]. WARNING: SUICIDAL THOUGHTS AND BEHAVIORS See full prescribing information for complete boxed warning. Increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants (5.1). Monitor for worsening and emergence of suicidal thoughts and behaviors (5.1).