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) ] Hyponatremia [see Warnings and Precautions (5.8) ] Anxiety and Insomnia [see Warnings and Precautions (5.9) ] QT Prolongation [see Warnings and Precautions (5.10) ] Potential for Cognitive and Motor Impairment [see Warnings and Precautions (5.12) ] Angle-Closure Glaucoma [see Warnings and Precautions (5.13) ] Discontinuation Adverse Reactions [see Warnings and Precautions (5.15) ] Sexual Dysfunction [see Warnings and Precautions (5.17) ] Most common adverse reactions (≥5% and at least twice that for placebo) associated with: Major Depressive Disorder, Obsessive Compulsive Disorder, Bulimia, and Panic Disorder: abnormal dreams, abnormal ejaculation, anorexia, anxiety, asthenia, diarrhea, dry mouth, dyspepsia, flu syndrome, impotence, insomnia, libido decreased, nausea, nervousness, pharyngitis, rash, sinusitis, somnolence, sweating, tremor, vasodilatation, and yawn (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect or predict the rates observed in practice. Multiple doses of fluoxetine have been administered to 10,782 patients with various diagnoses in U.S. clinical trials. In addition, there have been 425 patients administered fluoxetine in panic clinical trials. The stated frequencies represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse reaction of the type listed. A reaction was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. Incidence in Major Depressive Disorder, OCD, bulimia, and Panic Disorder placebo-controlled clinical trials (excluding data from extensions of trials) — Table 3 enumerates the most common treatment-emergent 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 Major Depressive Disorder, OCD, and bulimia in U.S. controlled clinical trials and Panic Disorder in U.S. plus non-U.S. controlled trials. Table 5 enumerates treatment-emergent adverse reactions that occurred in 2% or more patients treated with fluoxetine and with incidence greater than placebo who participated in U.S. Major Depressive Disorder, OCD, and bulimia controlled clinical trials and U.S. plus non-U.S. Panic Disorder controlled clinical trials. Table 4 provides combined data for the pool of studies that are provided separately by indication in Table 3. Table 3: Most Common Treatment-Emergent Adverse Reactions: Incidence in Major Depressive Disorder, OCD, Bulimia, and Panic Disorder Placebo-Controlled Clinical Trials 1,2 Percentage of Patients Reporting Event Major Depressive Disorder 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 3 2 -- -- -- 7 -- 1 -- Abnormal ejaculation 3 -- -- 7 -- 7 -- 2 1 1 Incidence less than 1%. 2 Includes U.S. data for Major Depressive Disorder, OCD, Bulimia, and Panic Disorder clinical trials, plus non-U.S. data for Panic Disorder clinical trials. 3 Denominator used was for males only (N=690 fluoxetine Major Depressive Disorder; N=410 placebo Major Depressive Disorder; 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). Table 4: Treatment-Emergent Adverse Reactions: Incidence in Major Depressive Disorder, OCD, Bulimia, and Panic Disorder Placebo-Controlled Clinical Trials 1,2 Percentage of Patients Reporting Event Major Depressive Disorder, 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 1 Incidence less than 1%. 2 Includes U.S. data for Major Depressive Disorder, OCD, Bulimia, and Panic Disorder clinical trials, plus non-U.S. data for Panic Disorder clinical trials. Associated with discontinuation in Major Depressive Disorder, OCD, bulimia, and Panic Disorder placebo-controlled clinical trials (excluding data from extensions of trials) — Table 5 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 Major Depressive Disorder, OCD, bulimia, and Panic Disorder clinical trials, plus non-U.S. Panic Disorder clinical trials. Table 5: Most Common Adverse Reactions Associated with Discontinuation in Major Depressive Disorder, OCD, Bulimia, and Panic Disorder Placebo-Controlled Clinical Trials 1 Major Depressive Disorder, OCD, Bulimia, and Panic Disorder Combined (N=1533) Major Depressive Disorder (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%) -- -- 1 Includes U.S. Major Depressive Disorder, OCD, Bulimia, and Panic Disorder clinical trials, plus non-U.S. Panic Disorder clinical trials. Other adverse reactions in pediatric patients (children and adolescents) — Treatment-emergent 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 Tables 4 and 5. However, the following adverse reactions (excluding those which appear in the body or footnotes of Tables 4 and 5 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 healthcare providers 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. Major Depressive Disorder, OCD, and bulimia placebo-controlled clinical trials, decreased libido was the only sexual side effect 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, healthcare providers should routinely inquire about such possible side effects. Other Reactions Following is a list of treatment-emergent 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. Investigations — Frequent: QT interval prolongation (QT C F ≥450 msec) 3 . 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 9,673 patients 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. 3 QT prolongation data are based on routine ECG measurements in clinical trials. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of fluoxetine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible 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 pre-existing 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 , drug reaction with eosinophilia and systemic symptoms (DRESS), and anosmia, hyposmia. 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 Serotonin Syndrome and MAOIs: Do not use MAOIs intended to treat psychiatric disorders with fluoxetine oral solution or within 5 weeks of stopping treatment with fluoxetine oral solution. Do not use fluoxetine oral solution within 14 days of stopping an MAOI intended to treat psychiatric disorders. In addition, do not start fluoxetine oral solution in a patient who is being treated with linezolid or intravenous methylene blue (4.1) Pimozide: Do not use. Risk of QT prolongation and drug interaction (4.2, 5.10, 7.7, 7.8) Thioridazine: Do not use. Risk of QT interval prolongation and elevated thioridazine plasma levels. Do not use thioridazine within 5 weeks of discontinuing fluoxetine oral solution (4.2, 5.10, 7.7, 7.8) 4.1 Monoamine Oxidase Inhibitors (MAOIs) The use of MAOIs intended to treat psychiatric disorders with fluoxetine oral solution or within 5 weeks of stopping treatment with fluoxetine oral solution is contraindicated because of an increased risk of serotonin syndrome. The use of fluoxetine oral solution within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated [see Dosage and Administration (2.9) and Warnings and Precautions (5.2)] . Starting fluoxetine oral solution 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 (2.10) and Warnings and Precautions (5.2)] . 4.2 Other Contraindications The use of fluoxetine oral solution is contraindicated with the following: Pimozide [see Warnings and Precautions (5.10) and Drug Interactions (7.7, 7.8) ] Thioridazine [see Warnings and Precautions (5.10) and Drug Interactions (7.7, 7.8) ] Pimozide and thioridazine prolong the QT interval. Fluoxetine oral solution can increase the levels of pimozide and thioridazine through inhibition of CYP2D6. Fluoxetine oral solution can also prolong the QT interval.

11 DESCRIPTION Fluoxetine oral solution, USP 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 to off-white crystalline solid with a solubility of 14 mg/mL in water. The oral solution contains fluoxetine hydrochloride equivalent to 20 mg/5 mL (64.7 μmol) of fluoxetine. It also contains alcohol 0.23%, sucrose, glycerin, benzoic acid, natural peppermint flavor, and purified water. Fluoxetine Structure

2 DOSAGE AND ADMINISTRATION Indication Adult Pediatric MDD (2.1) 20 mg/day in am (initial dose) 10 to 20 mg/day (initial dose) OCD (2.2) 20 mg/day in am (initial dose) 10 mg/day (initial dose) Bulimia Nervosa (2.3) 60 mg/day in am Panic Disorder (2.4) 10 mg/day (initial dose) A lower or less frequent dosage should be used in patients with hepatic impairment, the elderly, and for patients with concurrent disease or on multiple concomitant medications (2.7) 2.1 Major Depressive Disorder Initial Treatment Adult — Initiate fluoxetine oral solution 20 mg/day orally in the morning. Consider a dose increase after several weeks if insufficient clinical improvement is observed. Administer doses above 20 mg/day once daily in the morning or twice daily (i.e., morning and noon). The maximum fluoxetine dose should not exceed 80 mg/day. In controlled trials used to support the efficacy of fluoxetine, patients were administered morning doses ranging from 20 to 80 mg/day. Studies comparing fluoxetine 20, 40, and 60 mg/day to placebo indicate that 20 mg/day is sufficient to obtain a satisfactory response in Major Depressive Disorder in most cases [see Clinical Studies (14.1) ]. Pediatric (children and adolescents) — Initiate fluoxetine oral solution 10 or 20 mg/day. After 1 week at 10 mg/day, increase the dose 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. Consider a dose increase to 20 mg/day after several weeks if insufficient clinical improvement is observed. In the short-term (8 to 9 week) controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of Major Depressive Disorder, patients were administered fluoxetine doses of 10 to 20 mg/day [see Clinical Studies (14.1) ] . All patients — As with other drugs effective in the treatment of Major Depressive Disorder, the full effect may be delayed until 4 weeks of treatment or longer. Periodically reassess to determine the need for maintenance treatment. Switching Patients to a Tricyclic Antidepressant (TCA) — Dosage of a TCA may need to be reduced, and plasma TCA concentrations may need to be monitored temporarily when fluoxetine is coadministered or has been recently discontinued [see Warnings and Precautions (5.2) and Drug Interactions (7.7) ] . 2.2 Obsessive Compulsive Disorder Initial Treatment Adult — Initiate fluoxetine oral solution 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. Administer doses above 20 mg/day once daily in the morning or twice daily (i.e., morning and noon). A dose range of 20 to 60 mg/day is recommended; however, doses of up to 80 mg/day have been well tolerated in open studies of OCD. The maximum fluoxetine dose should not exceed 80 mg/day. In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of OCD, patients were administered fixed daily doses of 20, 40, or 60 mg of fluoxetine 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, initiate treatment with a dose of 10 mg/day. After 2 weeks, increase the dose to 20 mg/day. Consider additional dose increases 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, initiate treatment with a dose of 10 mg/day. Consider additional dose increases 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 supporting its effectiveness in the treatment of OCD, patients were administered fluoxetine 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 oral solution 60 mg/day in the morning. For some patients it may be advisable to titrate up to this target dose over several days. Fluoxetine doses above 60 mg/day have not been systematically studied in patients with bulimia. In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of Bulimia Nervosa, patients were administered fixed daily fluoxetine 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 — Initiate treatment with fluoxetine oral solution 10 mg/day. After one week, increase the dose to 20 mg/day. Consider a dose increase after several weeks if no clinical improvement is observed. Fluoxetine doses above 60 mg/day have not been systematically evaluated in patients with Panic Disorder. In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of Panic Disorder, patients were administered fluoxetine 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. 2.7 Dosing in Specific Populations Geriatric — Consider a lower or less frequent dosage for the elderly [see Use in Specific Populations (8.5) ] . Hepatic Impairment — As with many other medications, use a lower or less frequent dosage in patients with hepatic impairment [see Clinical Pharmacology (12.4) and Use in Specific Populations (8.6) ] . Concomitant Illness — Patients with concurrent disease or on multiple concomitant medications may require dosage adjustments [see Clinical Pharmacology (12.4) and Warnings and Precautions (5.11) ] . 2.8 Discontinuation of Treatment Symptoms associated with discontinuation of fluoxetine, SNRIs, and SSRIs, have been reported [see Warnings and Precautions (5.15) ]. 2.9 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 oral solution. Conversely, at least 5 weeks should be allowed after stopping fluoxetine oral solution before starting an MAOI intended to treat psychiatric disorders [see Contraindications (4.1) ] . 2.10 Use of Fluoxetine Oral Solution with Other MAOIs such as Linezolid or Methylene Blue Do not start fluoxetine oral solution 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 oral solution 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 oral solution should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for five weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with fluoxetine oral solution 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 non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with fluoxetine oral solution is unclear. The healthcare provider 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 oral solution is indicated for the treatment of: Acute and maintenance treatment of Major Depressive Disorder [see Clinical Studies (14.1) ] . Acute and maintenance treatment of obsessions and compulsions in patients with Obsessive Compulsive Disorder (OCD) [see Clinical Studies (14.2) ]. Acute and maintenance treatment of binge-eating and vomiting behaviors in patients with moderate to severe Bulimia Nervosa [see Clinical Studies (14.3) ] . Acute treatment of Panic Disorder, with or without agoraphobia [see Clinical Studies (14.4) ]. Fluoxetine oral solution is a selective serotonin reuptake inhibitor indicated for: Acute and maintenance treatment of Major Depressive Disorder (MDD) (1) Acute and maintenance treatment of Obsessive Compulsive Disorder (OCD) (1) Acute and maintenance treatment of Bulimia Nervosa (1) Acute treatment of Panic Disorder, with or without agoraphobia (1)

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, healthcare providers 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).

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, healthcare providers 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 The following have been reported with fluoxetine overdosage: Seizures, which may be delayed, and altered mental status including coma. Cardiovascular toxicity, which may be delayed, including QRS and QTc interval prolongation, wide complex tachyarrhythmias, torsade de pointes, and cardiac arrest. Hypertension most commonly seen, but rarely can see hypotension alone or with co-ingestants including alcohol. Serotonin syndrome (patients with a multiple drug overdosage with other pro-serotonergic drugs may have a higher risk). Gastrointestinal decontamination with activated charcoal should be considered in patients who present early after a fluoxetine overdose. Consider contacting a Poison Center (1-800-221-2222) or a medical toxicologist for additional overdosage management recommendations.

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. Monoamine Oxidase Inhibitors (MAOIs): (2.9 , 2.10 , 4.1 , 5.2) Drugs Metabolized by CYP2D6: Fluoxetine is a potent inhibitor of CYP2D6 enzyme pathway (7.7) Tricyclic Antidepressants (TCAs): Monitor TCA levels during coadministration with fluoxetine or when fluoxetine has been recently discontinued (5.2 , 7.7) CNS Acting Drugs: Caution should be used when taken in combination with other centrally acting drugs (7.2) Benzodiazepines: Diazepam – increased t½, alprazolam – further psychomotor performance decrement due to increased levels (7.7) Antipsychotics: Potential for elevation of haloperidol and clozapine levels (7.7) Anticonvulsants: Potential for elevated phenytoin and carbamazepine levels and clinical anticonvulsant toxicity (7.7) Serotonergic Drugs: (2.9 , 2.10 , 4.1 , 5.2) Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, Warfarin): May potentiate the risk of bleeding (7.4) Drugs Tightly Bound to Plasma Proteins : May cause a shift in plasma concentrations (7.6 , 7.7) 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 , 5.10 , 7.7 , 7.8) 7.1 Monoamine Oxidase Inhibitors (MAOI) [See Dosage and Administration (2.9, 2.10 ), 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 (2.9 , 2.10 ), Contraindications (4.1) , and Warnings and Precautions (5.2) ] . 7.4 Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, Warfarin) Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SNRIs or SSRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when fluoxetine is initiated or discontinued [see Warnings and Precautions (5.7) ] . 7.5 Electroconvulsive Therapy (ECT) There are no clinical studies establishing the benefit of the combined use of ECT and fluoxetine. There have been rare reports of prolonged seizures in patients on fluoxetine receiving ECT treatment. 7.6 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) ] . 7.7 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 (5.10) , and Drug Interactions (7.8) ] . 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 (5.10) , and Drug Interactions (7.8) ] . 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 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. Coadministration 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 coadministered or has been recently discontinued [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3) ] . Benzodiazapines — The half-life of concurrently administered diazepam may be prolonged in some patients [see Clinical Pharmacology (12.3) ] . Coadministration 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 coadministration 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. 7.8 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 1A 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 (5.10) , Drug Interactions (7.7) , 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 tricyclic antidepressant (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 40 mg dose, peak plasma concentrations of fluoxetine from 15 to 55 ng/mL are observed after 6 to 8 hours. 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 selective serotonin reuptake inhibitors (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 (7.7) ] . 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. 12.4 Specific Populations 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 (2.7) 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 Major Depressive Disorder or Obsessive Compulsive Disorder (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 Major Depressive Disorder. 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 tricyclic antidepressant (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 40 mg dose, peak plasma concentrations of fluoxetine from 15 to 55 ng/mL are observed after 6 to 8 hours. 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 selective serotonin reuptake inhibitors (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 (7.7) ] . 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.

20230802

22

3 DOSAGE FORMS AND STRENGTHS Fluoxetine Oral Solution USP, 20 mg/5 mL is a clear, colorless peppermint flavored liquid in round amber colored glass bottle with child-resistant closure. Oral Solution: 20 mg/5 mL (3)

Fluoxetine Fluoxetine FLUOXETINE HYDROCHLORIDE FLUOXETINE ALCOHOL SUCROSE GLYCERIN BENZOIC ACID WATER Natural Peppermint

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 2.4 and 1.44 times, respectively, the maximum recommended human dose (MRHD) of 20 mg given to children 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 0.97 and 1.6 times, respectively, the MRHD of 60 mg given to adolescents 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 2.4 and 1.44 times, respectively, the maximum recommended human dose (MRHD) of 20 mg given to children 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 0.97 and 1.6 times, respectively, the MRHD of 60 mg given to adolescents 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.

ANDA079209

Fluoxetine

Fluoxetine

65862-306

HUMAN PRESCRIPTION DRUG

ORAL

PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 20 mg/5 mL (120 mL Bottle) NDC 65862-306-12 Rx only Fluoxetine Oral Solution, USP 20 mg/5 mL PHARMACIST: Dispense the Medication Guide provided separately to each patient. AUROBINDO 120 mL PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 20 mg/5 mL (120 mL Bottle)

Warnings and Precautions, Serotonin Syndrome ( 5.2 ) 06/2023 Warnings and Precautions ( 5.7 ) 06/2023

17 PATIENT COUNSELING INFORMATION Advise the patient to read the 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. General Information Healthcare providers should instruct their patients to read the Medication Guide before starting therapy with fluoxetine 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 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. 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 Box Warning and Warnings and Precautions (5.1) ]. Serotonin Syndrome Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of fluoxetine and other serotonergic agents including triptans, tricyclic antidepressants, opioids, lithium, tryptophan, buspirone, 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. Allergic Reactions and Rash Patients should be advised to notify their healthcare provider 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. Abnormal Bleeding Patients should be cautioned about the concomitant use of fluoxetine 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 healthcare provider if they experience any increased or unusual bruising or bleeding while taking fluoxetine. 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 (5.8) ]. 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 (5.10) ]. Potential for Cognitive and Motor Impairment Fluoxetine 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 (5.12) ]. Angle-Closure Glaucoma Patients should be advised that taking fluoxetine oral solution can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle-closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle-closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle-closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle-closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible. [see Warnings and Precautions (5.13) ] Use of Concomitant Medications Patients should be advised to inform their healthcare provider if they are taking, or plan to take, any prescription medication, including Symbyax, Sarafem, or over-the-counter drugs, including herbal supplements or alcohol. Patients should also be advised to inform their healthcare providers if they plan to discontinue any medications they are taking while on fluoxetine. Discontinuation of Treatment Patients should be advised to take fluoxetine exactly as prescribed, and to continue taking fluoxetine as prescribed even after their symptoms improve. Patients should be advised that they should not alter their dosing regimen, or stop taking fluoxetine without consulting their healthcare provider [see Warnings and Precautions (5.15) ] . Patients should be advised to consult with their healthcare provider if their symptoms do not improve with fluoxetine. Sexual Dysfunction Advise patients that use of fluoxetine may cause symptoms of sexual dysfunction in both male and female patients. Inform patients that they should discuss any changes in sexual function and potential management strategies with their healthcare provider [see Warnings and Precautions (5.17) ]. Use in Specific Populations Pregnancy — Advise pregnant women to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with fluoxetine. Advise patients that fluoxetine use later in pregnancy may lead to increased risk for neonatal complications requiring prolonged hospitalization, respiratory support, tube feeding, and/or persistent pulmonary hypertension of the newborn (PPHN) [see Use in Specific Populations (8.1) ] . Advise women that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to fluoxetine during pregnancy [see Use in Specific Populations (8.1 )] . Lactation —Advise breastfeeding women using fluoxetine to monitor infants for agitation, irritability, poor feeding and poor weight gain and to seek medical care if they notice these signs [see Use in Specific Populations (8.2) ] . Pediatric Use of Fluoxetine — Fluoxetine is approved for use in pediatric patients with MDD and OCD [see Box Warning and Warnings and Precautions (5.1) ] . Limited evidence is available concerning the longer-term effects of fluoxetine on the development and maturation of children and adolescent patients. Height and weight should be monitored periodically in pediatric patients receiving fluoxetine [see Warnings and Precautions (5.6) and Use in Specific Populations (8.4) ] . Symbyax ® and Sarafem ® are registered trademarks of Eli Lilly. Dispense with Medication Guide available at: www.aurobindousa.com/medication-guides Distributed by: Aurobindo Pharma USA, Inc. 279 Princeton-Hightstown Road East Windsor, NJ 08520 Manufactured by: Aurobindo Pharma Limited Hyderabad-500 032, India Revised: 08/2023

Medication Guide Fluoxetine Oral Solution, USP (floo ox' e teen) Read the Medication Guide that comes with fluoxetine oral solution before you start taking it 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 oral solution? Fluoxetine oral solution and other antidepressant medicines may cause serious side effects, including: 1. Suicidal thoughts or actions: Fluoxetine oral solution 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 oral solution is 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 oral solution 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 oral solution and other antidepressant medicines may increase your risk of bleeding or bruising, especially if you take the blood thinner warfarin (Coumadin ® , Jantoven ® ), a non-steroidal anti-inflammatory drug (NSAIDs, like ibuprofen or naproxen), or aspirin. 5. Seizures or convulsions 6. 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 7. Changes in appetite or weight. Children and adolescents should have height and weight monitored during treatment. 8. 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 9. 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 10 . 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. 11. Sexual problems (dysfunction). Taking selective serotonin reuptake inhibitors (SSRIs), including fluoxetine oral solution, may cause sexual problems. Symptoms in males may include: Delayed ejaculation or inability to have an ejaculation Decreased sex drive Problems getting or keeping an erection Symptoms in females may include: Decreased sex drive Delayed orgasm or inability to have an orgasm Talk to your healthcare provider if you develop any changes in your sexual function or if you have any questions or concerns about sexual problems during treatment with fluoxetine oral solution. There may be treatments your healthcare provider can suggest. Do not stop fluoxetine oral solution without first talking to your healthcare provider. Stopping fluoxetine oral solution 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 is fluoxetine oral solution? Fluoxetine oral solution is 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 oral solution is used to treat: Major Depressive Disorder (MDD) Obsessive Compulsive Disorder (OCD) Bulimia Nervosa* Panic Disorder* *Not approved for use in children Talk to your healthcare provider if you do not think that your condition is getting better with fluoxetine oral solution treatment. Who should not take fluoxetine oral solution? Do not take fluoxetine oral solution if you: are allergic to fluoxetine hydrochloride or any of the ingredients in fluoxetine oral solution. See the end of this Medication Guide for a complete list of ingredients in fluoxetine oral solution. 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 oral solution unless directed to do so by your physician. Do not start fluoxetine oral solution if you stopped taking an MAOI in the last 2 weeks unless directed to do so by your physician. People who take fluoxetine oral solution 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 oral solution 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 oral solution? Ask if you are not sure. Before starting fluoxetine oral solution, 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, buspirone, SSRIs, SNRIs, MAOIs or antipsychotics Amphetamines Tramadol and fentanyl Meperidine and methadone or other opioids 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. Taking fluoxetine oral solution late in pregnancy may lead to an increased risk of certain problems in your newborn. Talk to your healthcare provider about the benefits and risks of treating depression during pregnancy. If you become pregnant while taking fluoxetine oral solution, talk to your healthcare provider about registering with the National Pregnancy Registry for Antidepressants. You can register by calling 1-844-405-6185 or go to https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/antidepressants/. are breast-feeding or plan to breast-feed. Fluoxetine may pass into your breast milk. Talk to your healthcare provider about the best way to feed your baby if taking fluoxetine oral solution. Tell your healthcare provider about all the medicines that you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Fluoxetine oral solution 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 oral solution with your other medicines. Do not start or stop any medicine while taking fluoxetine oral solution without talking to your healthcare provider first. If you take fluoxetine oral solution, you should not take any other medicines that contain fluoxetine hydrochloride including: Symbyax Sarafem How should I take fluoxetine oral solution? Take fluoxetine oral solution exactly as prescribed. Your healthcare provider may need to change the dose of fluoxetine oral solution until it is the right dose for you. Fluoxetine oral solution may be taken with or without food. If you miss a dose of fluoxetine oral solution, 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 oral solution at the same time. If you take too much fluoxetine oral solution, call your healthcare provider or poison control center right away, or get emergency treatment. What should I avoid while taking fluoxetine oral solution? Fluoxetine oral solution 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 oral solution affects you. Do not drink alcohol while using fluoxetine oral solution. What are the possible side effects of fluoxetine oral solution? Fluoxetine oral solution may cause serious side effects, including: See “What is the most important information I should know about fluoxetine oral solution?” Problems with blood sugar control. People who have diabetes and take fluoxetine oral solution may have problems with low blood sugar while taking fluoxetine oral solution. High blood sugar can happen when fluoxetine oral solution is stopped. Your healthcare provider may need to change the dose of your diabetes medicines when you start or stop taking fluoxetine oral solution. Feeling anxious or trouble sleeping Common possible side effects in people who take fluoxetine oral solution 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 oral solution. 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 oral solution. 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 oral solution? Store fluoxetine oral solution at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Keep fluoxetine oral solution away from light. Keep fluoxetine oral solution bottle closed tightly. Keep fluoxetine oral solution and all medicines out of the reach of children. General information about fluoxetine oral solution Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use fluoxetine oral solution for a condition for which it was not prescribed. Do not give fluoxetine oral solution to other people, even if they have the same condition. It may harm them. This Medication Guide summarizes the most important information about fluoxetine oral solution. If you would like more information, talk with your healthcare provider. You may ask your healthcare provider or pharmacist for information about fluoxetine oral solution that is written for healthcare professionals. For more information about fluoxetine oral solution, call Aurobindo Pharma USA, Inc. at 1-866-850-2876. What are the ingredients in fluoxetine oral solution? Active ingredient: fluoxetine hydrochloride Inactive ingredients in oral solution: alcohol 0.23%, sucrose, glycerin, benzoic acid, natural peppermint flavor, and purified water This Medication Guide has been approved by the U.S. Food and Drug Administration. Symbyax ® and Sarafem ® are registered trademarks of Eli Lilly and Company. Mellaril ® is a registered trademark of Novartis AG Corporation. Orap ® is a registered trademark of Teva Pharmaceuticals USA. Coumadin ® is a registered trademark of Bristol Myers Squibb. Jantoven ® is a registered trademark of Upsher-Smith Laboratories Inc. Dispense with Medication Guide available at: www.aurobindousa.com/medication-guides Distributed by: Aurobindo Pharma USA, Inc. 279 Princeton-Hightstown Road East Windsor, NJ 08520 Manufactured by: Aurobindo Pharma Limited Hyderabad-500 032, India Revised: 08/2023

14 CLINICAL STUDIES Efficacy for fluoxetine was established for the: Acute and maintenance treatment of Major Depressive Disorder 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 Obsessive Compulsive Disorder (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 Major Depressive Disorder . 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 Major Depressive Disorder. 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%). 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 Major Depressive Disorder. 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. Maintenance Treatment 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 Major Depressive Disorder 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 Major Depressive Disorder 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. 14.2 Obsessive Compulsive Disorder Adult — The effectiveness of fluoxetine for the treatment of Obsessive Compulsive Disorder (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. The following table provides the outcome classification by treatment group on the Clinical Global Impression (CGI) improvement scale for Studies 1 and 2 combined: Table 6: 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 Hamilton Depression Rating Scale. 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 healthcare provider 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 (12.4) ] . 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 (5.8) ] .

8.2 Lactation Risk Summary Data from published literature report the presence of fluoxetine and norfluoxetine in human milk (see Data). There are reports of agitation, irritability, poor feeding, and poor weight gain in infants exposed to fluoxetine through breast milk (see Clinical Considerations). There are no data on the effect of fluoxetine or its metabolites on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for fluoxetine and any potential adverse effects on the breastfed child from fluoxetine or the underlying maternal condition. Clinical Considerations Infants exposed to fluoxetine should be monitored for agitation, irritability, poor feeding, and poor weight gain. Data A study of 19 nursing mothers on fluoxetine with daily doses of 10 to 60 mg showed that fluoxetine was detectable in 30% of nursing infant sera (range: 1 to 84 ng/mL) whereas norfluoxetine was found in 85% (range: <1 to 265 ng/mL).

8.4 Pediatric Use Use of fluoxetine in children - The efficacy of fluoxetine for the treatment of Major Depressive Disorder 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 Major Depressive Disorder and <7 years of age in OCD have not been established. Fluoxetine pharmacokinetics were evaluated in 21 pediatric patients (ages 6 to ≤18) with Major Depressive Disorder 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 Major Depressive Disorder 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 [s ee Warnings and Precautions (5.6) ] . Fluoxetine is approved for use in pediatric patients with MDD and OCD [see Box 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 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, are 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 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 Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting online at https://womensmentalhealth.org/clinical-and-research­programs/pregnancyregistry/antidepressants/. Risk Summary Based on data from published observational studies, exposure to SSRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [see Warnings and Precautions (5.7) and Clinical Considerations] . Available data from published epidemiologic studies and postmarketing reports over several decades have not established an increased risk of major birth defects or miscarriage. Some studies have reported an increased incidence of cardiovascular malformations; however, these studies results do not establish a causal relationship (see Data) . There are risks associated with untreated depression in pregnancy and risks of persistent pulmonary hypertension of the newborn (PPHN) (see Data) and poor neonatal adaptation with exposure to selective serotonin reuptake inhibitors (SSRIs), including fluoxetine, during pregnancy (see Clinical Considerations). In rats and rabbits treated with fluoxetine during the period of organogenesis, there was no evidence of developmental effects at doses up to 1.6 and 3.9 times, respectively, the maximum recommended human dose (MRHD) of 60 mg/day given to adolescents on a mg/m 2 basis. However, in other reproductive studies in rats, an increase in stillborn pups, a decrease in pup weight, and an increase in pup deaths early after birth occurred at doses that are 1.5 times (during gestation) and 0.97 time (during gestation and lactation) the MRHD given to adolescents on a mg/m 2 basis. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Maternal Adverse Reactions Use of fluoxetine in the month before delivery may be associated with an increased risk of postpartum hemorrhage [see Warnings and Precautions (5.7) ]. Women who discontinue antidepressants during pregnancy are more likely to experience a relapse of major depression than women who continue antidepressants. This finding is from a prospective, longitudinal study that followed 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants at the beginning of pregnancy. Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum. Fetal/Neonatal adverse reactions Neonates exposed to fluoxetine and other SSRI or SNRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremors, jitteriness, irritability, and constant crying. These findings are consistent with either a direct toxic effect of SSRIs and SNRIs or possibly a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome [see Warnings and Precautions (5.2) ] . Data Human Data — It has been shown that SSRIs (including fluoxetine) can cross the placenta. Published epidemiological studies of pregnant women exposed to fluoxetine have not established an increased risk of major birth defects, miscarriage, and other adverse developmental outcomes. Several publications reported an increased incidence of cardiovascular malformations in children with in utero exposure to fluoxetine. However, these studies results do not establish a causal relationship. Methodologic limitations of these observational studies include possible exposure and outcome misclassification, lack of adequate controls, adjustment for confounders and confirmatory studies. However, these studies cannot definitely establish or exclude any drug-associated risk during pregnancy. Exposure to SSRIs, particularly later in pregnancy, may have an increased risk for PPHN. PPHN occurs in 1 to 2 per 1000 live births in the general population and is associated with substantial neonatal morbidity and mortality. Animal Data — In embryofetal development studies in rats and rabbits, there was no evidence of malformations or developmental variations following administration of fluoxetine at doses up to 12.5 and 15 mg/kg/day, respectively (1.6 and 3.9 times, respectively, the MRHD of 60 mg given to adolescents 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 given to adolescents on a mg/m 2 basis) during gestation or 7.5 mg/kg/day (0.97 time the MRHD given to adolescents 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 (0.65 time the MRHD given to adolescents on a mg/m 2 basis).

8 USE IN SPECIFIC POPULATIONS Pregnancy: SSRI use, particularly later in pregnancy, may increase risk for persistent pulmonary hypertension and symptoms of poor adaptation (respiratory distress, temperature instability, feeding difficulty, hypotonia, tremor, irritability) in the neonate ( 8.1 ) Pediatric Use : Safety and effectiveness of fluoxetine in patients <8 years of age with Major Depressive Disorder and <7 years of age with OCD have not been established. ( 8.4 ) Hepatic Impairment: Lower or less frequent dosing may be appropriate in patients with cirrhosis ( 8.6 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting online at https://womensmentalhealth.org/clinical-and-research­programs/pregnancyregistry/antidepressants/. Risk Summary Based on data from published observational studies, exposure to SSRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [see Warnings and Precautions (5.7) and Clinical Considerations] . Available data from published epidemiologic studies and postmarketing reports over several decades have not established an increased risk of major birth defects or miscarriage. Some studies have reported an increased incidence of cardiovascular malformations; however, these studies results do not establish a causal relationship (see Data) . There are risks associated with untreated depression in pregnancy and risks of persistent pulmonary hypertension of the newborn (PPHN) (see Data) and poor neonatal adaptation with exposure to selective serotonin reuptake inhibitors (SSRIs), including fluoxetine, during pregnancy (see Clinical Considerations). In rats and rabbits treated with fluoxetine during the period of organogenesis, there was no evidence of developmental effects at doses up to 1.6 and 3.9 times, respectively, the maximum recommended human dose (MRHD) of 60 mg/day given to adolescents on a mg/m 2 basis. However, in other reproductive studies in rats, an increase in stillborn pups, a decrease in pup weight, and an increase in pup deaths early after birth occurred at doses that are 1.5 times (during gestation) and 0.97 time (during gestation and lactation) the MRHD given to adolescents on a mg/m 2 basis. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Maternal Adverse Reactions Use of fluoxetine in the month before delivery may be associated with an increased risk of postpartum hemorrhage [see Warnings and Precautions (5.7) ]. Women who discontinue antidepressants during pregnancy are more likely to experience a relapse of major depression than women who continue antidepressants. This finding is from a prospective, longitudinal study that followed 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants at the beginning of pregnancy. Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum. Fetal/Neonatal adverse reactions Neonates exposed to fluoxetine and other SSRI or SNRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremors, jitteriness, irritability, and constant crying. These findings are consistent with either a direct toxic effect of SSRIs and SNRIs or possibly a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome [see Warnings and Precautions (5.2) ] . Data Human Data — It has been shown that SSRIs (including fluoxetine) can cross the placenta. Published epidemiological studies of pregnant women exposed to fluoxetine have not established an increased risk of major birth defects, miscarriage, and other adverse developmental outcomes. Several publications reported an increased incidence of cardiovascular malformations in children with in utero exposure to fluoxetine. However, these studies results do not establish a causal relationship. Methodologic limitations of these observational studies include possible exposure and outcome misclassification, lack of adequate controls, adjustment for confounders and confirmatory studies. However, these studies cannot definitely establish or exclude any drug-associated risk during pregnancy. Exposure to SSRIs, particularly later in pregnancy, may have an increased risk for PPHN. PPHN occurs in 1 to 2 per 1000 live births in the general population and is associated with substantial neonatal morbidity and mortality. Animal Data — In embryofetal development studies in rats and rabbits, there was no evidence of malformations or developmental variations following administration of fluoxetine at doses up to 12.5 and 15 mg/kg/day, respectively (1.6 and 3.9 times, respectively, the MRHD of 60 mg given to adolescents 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 given to adolescents on a mg/m 2 basis) during gestation or 7.5 mg/kg/day (0.97 time the MRHD given to adolescents 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 (0.65 time the MRHD given to adolescents on a mg/m 2 basis). 8.2 Lactation Risk Summary Data from published literature report the presence of fluoxetine and norfluoxetine in human milk (see Data). There are reports of agitation, irritability, poor feeding, and poor weight gain in infants exposed to fluoxetine through breast milk (see Clinical Considerations). There are no data on the effect of fluoxetine or its metabolites on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for fluoxetine and any potential adverse effects on the breastfed child from fluoxetine or the underlying maternal condition. Clinical Considerations Infants exposed to fluoxetine should be monitored for agitation, irritability, poor feeding, and poor weight gain. Data A study of 19 nursing mothers on fluoxetine with daily doses of 10 to 60 mg showed that fluoxetine was detectable in 30% of nursing infant sera (range: 1 to 84 ng/mL) whereas norfluoxetine was found in 85% (range: <1 to 265 ng/mL). 8.4 Pediatric Use Use of fluoxetine in children - The efficacy of fluoxetine for the treatment of Major Depressive Disorder 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 Major Depressive Disorder and <7 years of age in OCD have not been established. Fluoxetine pharmacokinetics were evaluated in 21 pediatric patients (ages 6 to ≤18) with Major Depressive Disorder 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 Major Depressive Disorder 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 [s ee Warnings and Precautions (5.6) ] . Fluoxetine is approved for use in pediatric patients with MDD and OCD [see Box 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 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, are 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 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 (12.4) ] . 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 (5.8) ] . 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 (2.7) and Clinical Pharmacology (12.4) ].

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Fluoxetine Oral Solution USP, 20 mg * /5 mL is a clear, colorless peppermint flavored liquid in round amber colored glass bottle with child-resistant closure. Bottle of 120 mL NDC 65862-306-12 *Fluoxetine base equivalent. 16.2 Storage and Handling Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Dispense in a tight, light-resistant container.

16.2 Storage and Handling Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Dispense in a tight, light-resistant container.

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 behaviors. 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 ).