Fluoxetine

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.

1 INDICATIONS AND USAGE Fluoxetine 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 and Olanzapine in Combination is indicated for the treatment of: Acute treatment of depressive episodes associated with Bipolar I Disorder. Fluoxetine monotherapy is not indicated for the treatment of depressive episodes associated with Bipolar I Disorder. When using Fluoxetine and olanzapine in combination, also refer to the Clinical Studies section of the package insert for Symbyax ® . Fluoxetine capsules are 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 ) Fluoxetine capsules and olanzapine in combination for treatment of: Acute Depressive Episodes Associated with Bipolar I Disorder ( 1 )

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) 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 (initial dose) Oral in combination with olanzapine: 2.5 mg of oral olanzapine and 20 mg of fluoxetine once daily (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 ) Fluoxetine capsules and olanzapine in combination: Dosage adjustments should be made with the individual components according to efficacy and tolerability ( 2.5 ) Fluoxetine monotherapy is not indicated for the treatment of Depressive Episodes associated with Bipolar I Disorder ( 2.5 ) Safety of the coadministration of doses above 18 mg olanzapine with 75 mg fluoxetine has not been evaluated in adults. ( 2.5 ) 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 ) 2.1 Major Depressive Disorder Initial Treatment Adult — Initiate fluoxetine 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 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 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 determin

6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling: Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults [see Boxed Warning and Warnings and Precautions (5.1) ] Serotonin Syndrome [see Warnings and Precautions (5.2) ] Allergic Reactions and Rash [see Warnings and Precautions (5.3) ] Screening Patients for Bipolar Disorder and Monitoring for Mania/Hypomania [see Warnings and Precautions (5.4) ] Seizures [see Warnings and Precautions (5.5) ] Altered Appetite and Weight [see Warnings and Precautions (5.6) ] Abnormal Bleeding [see Warnings and Precautions (5.7) ] Angle-Closure Glaucoma [see Warnings and Precautions (5.8) ] Hyponatremia [see Warnings and Precautions (5.9) ] Anxiety and Insomnia [see Warnings and Precautions (5.10) ] QT Prolongation [see Warnings and Precautions (5.11) ] Potential for Cognitive and Motor Impairment [see Warnings and Precautions (5.13) ] Discontinuation Adverse Reactions [see Warnings and Precautions (5.15) ] 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 – Also refer to the Adverse Reactions section of the package insert for Symbyax ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Vensun Pharmaceuticals, Inc. at 1-800-385-1540 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 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 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 US controlled clinical trials and Panic Disorder in US plus non-US 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 US Major Depressive Disorder, OCD, and bulimia controlled clinical trials and US plus non-US 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 1 Incidence less than 1%. 2 Includes US data for Major Depressive Disorder, OCD, Bulimia, and Panic Disorder clinical trials, plus non-US 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; N=121 placebo panic). 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 A

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 ) Olanzapine: When used in combination with fluoxetine, also refer to the Drug Interactions section of the package insert for Symbyax ( 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 , 5.11 , 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 (5.11) , 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 (5.11) , 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 admin