FLUOXETINE- fluoxetine_capsule

Although the exact mechanism of fluoxetine is unknown, it is presumed to be linked to its inhibition of CNS neuronal uptake of serotonin. 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 alpha1-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. Systemic Bioavailability 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 Enantiomers R S Metabolism R S R Variability in Metabolism S S S R 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 see Warnings and Precautions (5. 14) The long elimination half-lives of fluoxetine and norfluoxetine assure that, even when dosing is stopped, active drug substance will persist in the body for weeks (primarily depending on individual patient characteristics, previous dosing regimen, and length of previous therapy at discontinuation). This is of potential consequence when drug discontinuation is required or when drugs are prescribed that might interact with fluoxetine and norfluoxetine following the discontinuation of fluoxetine. Liver Disease see Dosage and Administration (2. 7) Use in Specific Populations (8. 6) Renal Disease Geriatric Pharmacokinetics Pediatric Pharmacokinetics (children and adolescents) 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.

Fluoxetine Capsules are 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 and Olanzapine in Combination is indicated for the treatment of: Acute treatment of depressive episodes associated with Bipolar I Disorder. Treatment resistant depression (Major Depressive Disorder in patients, who do not respond to 2 separate trials of different antidepressants of adequate dose and duration in the current episode). Fluoxetine capsules monotherapy is not indicated for the treatment of depressive episodes associated with Bipolar I Disorder or the treatment of treatment resistant depression. When using fluoxetine and olanzapine in combination, also refer to the Clinical Studies section of the package insert for Symbyax registered Fluoxetine Capsules is a selective serotonin reuptake inhibitor indicated for: 1 1 1 1 Fluoxetine Capsules and olanzapine in combination for treatment of: 1 1.

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) Depressive Episodes Associated with Bipolar I Disorder (2. 5) Oral in combination with olanzapine: 5 mg of oral olanzapine and 20 mg of fluoxetine once daily Oral in combination with olanzapine: 2. 5 mg of oral olanzapine and 20 mg of fluoxetine once daily (initial dose) Treatment Resistant Depression (2. 6) Oral in combination with olanzapine: 5 mg of oral olanzapine and 20 mg of fluoxetine once daily 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 Fluoxetine and olanzapine in combination: Dosage adjustments should be made with the individual components according to efficacy and tolerability ( 2. 6 Fluoxetine monotherapy is not indicated for the treatment of Depressive Episodes associated with Bipolar I Disorder or treatment resistant depression ( 2. 6 Safety of the coadministration of doses above 18 mg olanzapine with 75 mg fluoxetine has not been evaluated in adults ( 2. 6 Safety of the coadministration of doses above 12 mg olanzapine with 50 mg fluoxetine has not been evaluated in children and adolescents ages 10 to 17 ( 2. 5 Initial Treatment Adult 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) see Clinical Studies (14. 1) All patients Periodically reassess to determine the need for maintenance treatment. Switching Patients to a Tricyclic Antidepressant (TCA) see Warnings and Precautions (5. 2) Drug Interactions (7. 7) Initial Treatment Adult - 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) Pediatric (children and adolescents) - 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. Initial Treatment - see Clinical Studies (14. 3) Periodically reassess to determine the need for maintenance treatment. Initial Treatment see Clinical Studies (14. 4) Periodically reassess to determine the need for continued treatment. When using fluoxetine and olanzapine in combination, also refer to the Clinical Studies section of the package insert for Symbyax. Adult Children and adolescents (10 -17 years of age) Safety and efficacy of fluoxetine in combination with olanzapine was determined in clinical trials supporting approval of Symbyax (fixed-dose combination of olanzapine and fluoxetine). Symbyax is dosed between 3 mg/25 mg (olanzapine/fluoxetine) per day and 12 mg/50 mg (olanzapine/fluoxetine) per day. The following table demonstrates the appropriate individual component doses of fluoxetine and olanzapine versus Symbyax. Adjust dosage, if indicated, with the individual components according to efficacy and tolerability. Table 1: Approximate Dose Correspondence Between Symbyax 1 1 Symbyax (olanzapine/fluoxetine HCL) is a fixed-dose combination of fluoxetine and olanzapine. For Symbyax (mg/day) Use in Combination Olanzapine (mg/day) Fluoxetine (mg/day) 3 mg olanzapine/25 mg fluoxetine 2. 5 20 6 mg olanzapine/25 mg fluoxetine 5 20 12 mg olanzapine/25 mg fluoxetine 10+2. 5 20 6 mg olanzapine/50 mg fluoxetine 5 40+10 12 mg olanzapine/50 mg fluoxetine 10+2. 5 40+10 Fluoxetine monotherapy is not indicated for the treatment of depressive episodes associated with Bipolar I Disorder. Administer fluoxetine in combination with oral olanzapine once daily in the evening, without regard to meals, generally beginning with 5 mg of oral olanzapine and 20 mg of fluoxetine. Adjust dosage, if indicated, according to efficacy and tolerability within dose ranges of fluoxetine 20 to 50 mg and oral olanzapine 5 to 20 mg. Antidepressant efficacy was demonstrated with olanzapine and fluoxetine in combination with a dose range of olanzapine 6 to 18 mg and fluoxetine 25 to 50 mg. Safety and efficacy of fluoxetine in combination with olanzapine was determined in clinical trials supporting approval of Symbyax (fixed dose combination of olanzapine and fluoxetine). Table 1 demonstrates the appropriate individual component doses of fluoxetine and olanzapine versus Symbyax. Periodically re-examine the need for continued pharmacotherapy. Safety of coadministration of doses above 18 mg olanzapine with 75 mg fluoxetine has not been evaluated in clinical studies. Fluoxetine monotherapy is not indicated for the treatment of treatment resistant depression (Major Depressive Disorder in patients who do not respond to 2 antidepressants of adequate dose and duration in the current episode). Geriatric see Use in Specific Populations (8. 5) Hepatic Impairment see Clinical Pharmacology (12. 4) Use in Specific Populations (8. 6) Concomitant Illness see Clinical Pharmacology (12. 4) Warnings and Precautions (5. 12) Fluoxetine and Olanzapine in Combination - see Warnings and Precautions (5. 16) Drug Interactions (7. 7) Symptoms associated with discontinuation of fluoxetine, SNRIs, and SSRIs, have been reported [ see Warnings and Precautions (5. 15) At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with fluoxetine. Conversely, at least 5 weeks should be allowed after stopping fluoxetine before starting an MAOI intended to treat psychiatric disorders [ see Contraindications (4. 1) Do not start fluoxetine 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 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 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 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 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.

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 5. 1 Serotonin Syndrome [ see Warnings and Precautions ( 5. 2 Allergic Reactions and Rash [ see Warnings and Precautions ( 5. 3 Screening Patients for Bipolar Disorder and Monitoring for Mania/Hypomania [ see Warnings and Precautions ( 5. 4 Seizures [ see Warnings and Precautions ( 5. 5 Altered Appetite and Weight [ see Warnings and Precautions ( 5. 6 Increased Risk of Bleeding [ see Warnings and Precautions ( 5. 7 Angle-Closure Glaucoma [ see Warnings and Precautions ( 5. 8 Hyponatremia [ see Warnings and Precautions ( 5. 9 Anxiety and Insomnia [ see Warnings and Precautions ( 5. 10 QT Prolongation [ see Warnings and Precautions ( 5. 11 Potential for Cognitive and Motor Impairment [ see Warnings and Precautions ( 5. 13 Discontinuation Adverse Reactions [ see Warnings and Precautions ( 5. 15 Sexual Dysfunction [ see Warnings and Precautions ( 5. 17 When using fluoxetine and olanzapine in combination, also refer to the Adverse Reactions section of the package insert for Symbyax. 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 Fluoxetine and olanzapine in combination en dash Also refer to the Adverse Reactions section of the package insert for Symbyax ( 6 To report SUSPECTED ADVERSE REACTIONS, contact Avet Pharmaceuticals Inc. at 1-866-901-DRUG (3784) or FDA at 1-800-FDA-1088 or www. gov/medwatch 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 US 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: Most Common Treatment-Emergent Adverse Reactions: Incidence in Major Depressive Disorder, OCD, Bulimia, and Panic Disorder Placebo-Controlled Clinical Trials 1,2 1 2 3 Percentage of Patients Reporting Event Major Depressive Disorder OCD Bulimia Panic Disorder Body System/ Adverse Reaction Fluoxetine Placebo Fluoxetine Placebo Fluoxetine Placebo Fluoxetine Placebo 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 3 -- -- 7 -- 7 -- 2 1 Table 4: Treatment-Emergent Adverse Reactions: Incidence in Major Depressive Disorder, OCD, Bulimia, and Panic Disorder Placebo-Controlled Clinical Trials 1,2 1 2 Percentage of Patients Reporting Event Major Depressive Disorder, OCD, Bulimia, and Panic Disorder Combined Body System/ Adverse Reaction Fluoxetine Placebo 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 Associated with discontinuation in Major Depressive Disorder, OCD, bulimia, and Panic Disorder placebo-controlled clinical trials (excluding data from extensions of trials) Table 5: Most Common Adverse Reactions Associated with Discontinuation in Major Depressive Disorder, OCD, Bulimia, and Panic Disorder Placebo-Controlled Clinical Trials 1 1 Major Depressive Disorder, OCD, Bulimia, and Panic Disorder Combined Major Depressive Disorder OCD Bulimia Panic Disorder Anxiety (1%) -- Anxiety (2%) -- Anxiety (2%) -- -- -- Insomnia (2%) -- -- Nervousness (1%) -- -- Nervousness (1%) -- -- Rash (1%) -- -- Other adverse reactions in pediatric patients (children and adolescents) - 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 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 1/1,000 patients; rare reactions are those occurring in fewer than 1/1,000 patients. Body as a Whole Frequent Infrequent Rare Cardiovascular System Frequent Infrequent 1 Digestive System Infrequent Rare Hemic and Lymphatic System Infrequent Rare Investigations Frequent c 3 Nervous System Frequent: 1 1 Rare: Respiratory System Rare: Skin and Appendages Infrequent: Rare: Special Senses Frequent: Infrequent: Urogenital System Frequent: Infrequent: 2 1 2 3 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: anosmia, aplastic anemia, atrial fibrillation1, cataract, cerebrovascular accident1, cholestatic jaundice, drug reaction with eosinophilia and systemic symptoms (DRESS), 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 pneumonia1, epidermal necrolysis, erythema multiforme, erythema nodosum, exfoliative dermatitis, galactorrhea, gynecomastia, heart arrest1, hepatic failure/necrosis, hyperprolactinemia, hypoglycemia, hyposmia, 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, pancreatitis1, pancytopenia, pulmonary embolism, pulmonary hypertension, QT prolongation, Stevens-Johnson syndrome, thrombocytopenia1, thrombocytopenic purpura, ventricular tachycardia (including Torsades de Pointesen dashtype arrhythmias), vaginal bleeding, and violent behaviors1. 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.

When using fluoxetine and olanzapine in combination, also refer to the Contraindications section of the package insert for Symbyax. Serotonin Syndrome and MAOIs: Do not use MAOIs intended to treat psychiatric disorders with fluoxetine or within 5 weeks of stopping treatment with fluoxetine. Do not use fluoxetine within 14 days of stopping an MAOI intended to treat psychiatric disorders. In addition, do not start fluoxetine 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. 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. 8 When using fluoxetine and olanzapine in combination, also refer to the Contraindications section of the package insert for Symbyax ( 4 The use of MAOIs intended to treat psychiatric disorders with fluoxetine or within 5 weeks of stopping treatment with fluoxetine is contraindicated because of an increased risk of serotonin syndrome. The use of fluoxetine within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated [ see Dosage and Administration (2. 9) Warnings and Precautions (5. 2) Starting fluoxetine 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) Warnings and Precautions (5. 2) The use of fluoxetine is contraindicated with the following: Pimozide [ see Warnings and Precautions (5. 8 Thioridazine [ see Warnings and Precautions (5. 8 Pimozide and thioridazine prolong the QT interval. Fluoxetine can increase the levels of pimozide and thioridazine through inhibition of CYP2D6. Fluoxetine can also prolong the QT interval.

When using fluoxetine and olanzapine in combination, also refer to the Use in Specific Populations section of the package insert for Symbyax. Pregnancy: 8. 1 Pediatric Use: 8. 4 Hepatic Impairment: 8. 6 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-research-programs/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 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 see Data 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. 9 times, respectively, the maximum recommended human dose (MRHD) of 60 mg/day given to adolescents on a mg/m 2 2 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 Women who discontinue antidepressants during pregnancy are more likely to experience a relapse of major depression than women who continue antidepressants. This finding is from a prospective, longitudinal study that followed 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants at the beginning of pregnancy. Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum. Maternal Adverse Reactions [see Warnings and Precautions ( 5. 7 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 Exposure to SSRIs, particularly later in pregnancy, may have an increased risk for PPHN. PPHN occurs in 1 to 2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. Animal Data 2 2 2 (0. 65 time the MRHD given to adolescents on a mg/m 2 Risk Summary Data from published literature report the presence of fluoxetine and norfluoxetine in human milk ( see Data see Clinical Considerations 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). Use of fluoxetine in children 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 [ see Warnings and Precautions (5. 6) Fluoxetine is approved for use in pediatric patients with MDD and OCD [ see Box Warning Warnings and Precautions (5. 1) Animal Data 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. 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. 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 Use of fluoxetine in combination with olanzapine in children and adolescents: US 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) see Clinical Pharmacology (12. 4) see Warnings and Precautions (5. 9) Clinical studies of olanzapine and fluoxetine in combination did not include sufficient numbers of patients >=65 years of age to determine whether they respond differently from younger patients. 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) Clinical Pharmacology (12.

As with all drugs, the potential for interaction by a variety of mechanisms (e. , pharmacodynamic, pharmacokinetic drug inhibition or enhancement, etc. ) is a possibility. Monoamine Oxidase Inhibitors (MAOIs): 2. 2 Drugs Metabolized by CYP2D6: 7. 7 Tricyclic Antidepressants (TCAs): 5. 7 CNS Acting Drugs: 7. 2 Benzodiazepines: 7. 7 Antipsychotics: 7. 7 Anticonvulsants: 7. 7 Serotonergic Drugs: 2. 2 Drugs that Interfere with Hemostasis (e. NSAIDs, Aspirin, Warfarin): 7. 4 Drugs Tightly Bound to Plasma Proteins: 7. 7 Olanzapine: 7. 7 Drugs that Prolong the QT Interval: 4. 8 [s ee Dosage and Administration ( 2. 2 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) The concomitant use of serotonergic drugs (including other SSRIs, SNRIs, triptans, tricyclic antidepressants, opioids, lithium, buspirone, amphetamines, tryptophan, and St. John's Wort) with fluoxetine increases the risk of serotonin syndrome. Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of fluoxetine and/or concomitant serotonergic drugs [ see Warnings and Precautions ( 5. 2 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) 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. Drugs Tightly Bound to Plasma Proteins see Clinical Pharmacology (12. 3) Pimozide see Contraindications (4. 2) Warnings and Precautions (5. 11) Drug Interactions (7. 8) Thioridazine see Contraindications (4. 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 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 see Contraindications (4. 2) Tricyclic Antidepressants (TCAs) see Warnings and Precautions (5. 2) Clinical Pharmacology (12. 3) Benzodiazepines see Clinical Pharmacology (12. 3) Antipsychotics Anticonvulsants Lithium see Warnings and Precautions (5. 2) Drugs Tightly Bound to Plasma Proteins see Clinical Pharmacology (12. 3) Drugs Metabolized by CYP3A4 in vivo Additionally, in vitro Olanzapine When using fluoxetine and olanzapine and in combination, also refer to the Drug Interactions section of the package insert for Symbyax. 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. , ziprasidone, iloperidone, chlorpromazine, mesoridazine, droperidol); specific antibiotics (e. , erythromycin, gatifloxacin, moxifloxacin, sparfloxacin); Class 1A antiarrhythmic medications (e. , quinidine, procainamide); Class III antiarrhythmics (e. , amiodarone, sotalol); and others (e. , 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. 7) Clinical Pharmacology (12.

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.
NONCLINICAL TOXICOLOGY
Carcinogenicity 2 Mutagenicity Impairment of Fertility 2 see Use in Specific Populations (8. 4) 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.
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) Efficacy for fluoxetine and olanzapine in combination was established for the: Acute treatment of depressive episodes in Bipolar I Disorder in adults, and children and adolescents (10 to 17 years) in 3 short-term, placebo-controlled trials. Acute and maintenance treatment of treatment resistant depression in adults (18 to 85 years) in 3 short-term, placebo-controlled trials and 1 randomized withdrawal study with an active control. When using fluoxetine and olanzapine in combination, also refer to the Clinical Studies section of the package insert for Symbyax. Daily Dosing Adult 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) 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. An additional maintenance study was conducted involving adult outpatients meeting DSM-IV criteria for Major Depressive Disorder who had responded (defined as having a modified HAMD-17 score of <=9, a CGI-Severity rating of <=2, and no longer meeting criteria for Major Depressive Disorder) for 3 consecutive weeks at the end of 13 weeks of open-label treatment with fluoxetine 20 mg once daily. These patients were randomized to double-blind, once-weekly continuation treatment with fluoxetine delayed-release capsules 90 mg once weekly, fluoxetine 20 mg once daily, or placebo. Fluoxetine 20 mg once daily demonstrated superior efficacy (having a significantly longer time to relapse of depressive symptoms) compared with placebo for a period of 25 weeks. Adult 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) Subgroup analyses on outcome did not suggest any differential responsiveness on the basis of age or gender. 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. 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.

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