ADVERSE REACTIONS SECTION.

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)]. Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults [see Boxed Warning and Warnings and Precautions (5.1)]. Serotonin Syndrome [see Warnings and Precautions (5.2)]. Allergic Reactions and Rash [see Warnings and Precautions (5.3)]. Screening Patients for Bipolar Disorder and Monitoring for Mania/Hypomania [see Warnings and Precautions (5.4)]. Seizures [see Warnings and Precautions (5.5)]. Altered Appetite and Weight [see Warnings and Precautions (5.6)]. Abnormal Bleeding [see Warnings and Precautions (5.7)]. Angle-closure Glaucoma [see Warnings and Precautions (5.8)]. Hyponatremia [see Warnings and Precautions (5.9)]. Anxiety and Insomnia [see Warnings and Precautions (5.10)]. QT Prolongation [see Warnings and Precautions (5.11)]. Potential for Cognitive and Motor Impairment [see Warnings and Precautions (5.13)]. Discontinuation Adverse Reactions [see Warnings and Precautions (5.15)]. Most common adverse reactions (>= 5% and at least twice that for placebo): abnormal dreams, abnormal ejaculation, anorexia, anxiety, asthenia, diarrhea, dry mouth, dyspepsia, flu syndrome, impotence, insomnia, libido decreased, nausea, nervousness, pharyngitis, rash, sinusitis, somnolence, sweating, tremor, vasodilatation, and yawn (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Teva Pharmaceuticals USA, Inc. at 1-888-838-2872 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 drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect or predict the rates observed in practice.Multiple doses of fluoxetine have been administered to 10,782 patients with various diagnoses in U.S. clinical trials. In addition, there have been 425 patients administered fluoxetine in panic clinical trials. The stated frequencies represent the proportion of individuals who experienced, at least once, an adverse reaction of the type listed. An adverse reaction was included if it occurred for the first time or worsened while receiving therapy following baseline evaluation.Incidence in MDD, OCD, Bulimia, and Panic Disorder placebo-controlled clinical trials (excluding data from extensions of trials)--Table enumerates the most common adverse reactions associated with the use of fluoxetine (incidence of at least 5% for fluoxetine and at least twice that for placebo within at least of the indications) for the treatment of MDD, OCD, and bulimia in U.S. controlled clinical trials and Panic Disorder in U.S. plus non-U.S. controlled trials. Table provides combined data for the pool of studies that are provided separately by indication in Table 2.Table 2. Most Common Adverse Reactions: Incidence in Major Depressive Disorder, Obsessive Compulsive Disorder, Bulimia, and Panic Disorder Placebo-controlled Clinical TrialsPercentage of Patients Reporting EventMDDOCDBulimiaPanic DisorderBody System/Adverse ReactionFluoxetine(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 Whole Asthenia95151121977 Flu syndrome341078355Cardiovascular System Vasodilatation325--211--Digestive System Nausea21926132911127 Diarrhea12818138694 Anorexia11217108441 Dry mouth1071239644 Dyspepsia7510410662Nervous System Insomnia16928223313107 Anxiety12714715962 Nervousness149141511586 Somnolence13617713552 Tremor1039113131 Libido decreased3--1125112 Abnormal dreams11525311Respiratory System Pharyngitis3311910533 Sinusitis14526423 Yawn----7--11--1--Skin and Appendages Sweating837--8322 Rash43634422Urogenital System Impotencea 2------7--1-- Abnormal ejaculationa ----7--7--21Note: Includes U.S. data for MDD, OCD, Bulimia, and Panic Disorder clinical trials, plus non-U.S. data for Panic Disorder clinical trials.a Denominator used was for males only (N 690 fluoxetine MDD; = 410 placebo MDD; = 116 fluoxetine OCD; = 43 placebo OCD; = 14 fluoxetine Bulimia; = placebo Bulimia; = 162 fluoxetine Panic Disorder; = 121 placebo Panic Disorder).-- Incidence less than 1%.Table 3. Adverse Reactions: Incidence in Major Depressive Disorder, Obsessive Compulsive Disorder, Bulimia, and Panic Disorder Placebo-controlled Clinical TrialsPercentage of Patients Reporting EventMDD, OCD, Bulimia, and Panic Disorder CombinedBody System/Adverse ReactionFluoxetine (N 2869)Placebo (N 1673)Body as Whole Headache2119 Asthenia116 Flu syndrome54 Fever21Cardiovascular System Vasodilatation21Digestive System Nausea229 Diarrhea117 Anorexia103 Dry mouth96 Dyspepsia84 Constipation54 Flatulence32 Vomiting32Metabolic and Nutritional Disorders Weight loss21Nervous System Insomnia1910 Nervousness138 Anxiety126 Somnolence125 Dizziness96 Tremor92 Libido decreased41 Thinking abnormal21Respiratory System Yawn3--Skin and Appendages Sweating73 Rash43 Pruritus32Special Senses Abnormal vision21Note: Includes U.S. data for MDD, OCD, Bulimia, and Panic Disorder clinical trials, plus non-U.S. data for Panic Disorder clinical trials.-- Incidence less than 1%.Associated with discontinuation in MDD, OCD, Bulimia, and Panic Disorder placebo-controlled clinical trials (excluding data from extensions of trials)--Table 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 primary reaction associated with discontinuation) in MDD, OCD, Bulimia, and Panic Disorder clinical trials, plus non-U.S. Panic Disorder clinical trials.Table 4. Most Common Adverse Reactions Associated with Discontinuation in Major Depressive Disorder, Obsessive Compulsive Disorders, Bulimia, and Panic Disorder Placebo-controlled Clinical TrialsMDD, OCD, Bulimia, and Panic Disorder Combined(N 1533)MDD(N 392)OCD(N 266)Bulimia(N 450)Panic Disorder(N 425)Anxiety (1%)--Anxiety (2%)--Anxiety (2%)------Insomnia (2%)----Nervousness (1%)----Nervousness (1%)----Rash (1%)----Note: Includes U.S. data for MDD, OCD, Bulimia, and Panic Disorder clinical trials, plus non-U.S. data for Panic Disorder clinical trials.-- Incidence less than 1%.Other adverse reactions in pediatric patients (children and adolescents)--Adverse reactions were collected in 322 pediatric patients (180 fluoxetine-treated, 142 placebo-treated). The overall profile of adverse reactions was generally similar to that seen in adult studies, as shown in Table and Table 3. However, the following adverse reactions (excluding those which appear in the body or footnotes of Table and Table 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 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 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 psychiatric disorder, they may also be consequence of pharmacologic treatment. In particular, some evidence suggests that SSRIs can cause such untoward sexual experiences. Reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance, and satisfaction are difficult to obtain, however, in part because patients and physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance, cited in product labeling, are likely to underestimate their actual incidence. In patients enrolled in U.S. MDD, OCD, and bulimia placebo-controlled clinical trials, decreased libido was the only sexual adverse reaction reported by at least 2% of patients taking fluoxetine (4% fluoxetine, 1% placebo). There have been spontaneous reports in women taking fluoxetine of orgasmic dysfunction, including anorgasmia.There are no adequate and well-controlled studies examining sexual dysfunction with fluoxetine treatment.Symptoms of sexual dysfunction occasionally persist after discontinuation of fluoxetine treatment.Priapism has been reported with all SSRIs.While it is difficult to know the precise risk of sexual dysfunction associated with the use of SSRIs, physicians should routinely inquire about such possible adverse reactions.Other adverse reactions observed during the premarketing evaluation of fluoxetine--Following is list of adverse reactions reported by patients treated with fluoxetine in clinical trials. This listing is not intended to include reactions (1) already listed in previous tables or elsewhere in labeling, (2) for which 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 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 Whole--Frequent: chills; Infrequent: suicide attempt; Rare: acute abdominal syndrome, photosensitivity reaction.Cardiovascular System--Frequent: palpitation; Infrequent: arrhythmia, hypotension1.Digestive System--Infrequent: dysphagia, gastritis, gastroenteritis, melena, stomach ulcer; Rare: bloody diarrhea, duodenal ulcer, esophageal ulcer, gastrointestinal hemorrhage, hematemesis, hepatitis, peptic ulcer, stomach ulcer hemorrhage.Hemic and Lymphatic System--Infrequent: ecchymosis; Rare: petechia, purpura.Nervous System--Frequent: emotional lability; Infrequent: akathisia, ataxia, balance disorder1, bruxism1, 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 bleeding2.1MedDRA dictionary term from integrated database of placebo-controlled trials of 15,870 patients, of which 9673 received fluoxetine.2Group term that includes individual MedDRA terms: cervix hemorrhage uterine, dysfunctional uterine bleeding, genital hemorrhage, menometrorrhagia, menorrhagia, metrorrhagia, polymenorrhea, postmenopausal hemorrhage, uterine hemorrhage, vaginal hemorrhage. Adjusted for gender.. 6.2 Postmarketing Experience. The following adverse reactions have been identified during postapproval use of fluoxetine. Because these reactions are reported voluntarily from population of uncertain size, it is difficult to reliably estimate their frequency or evaluate 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 fibrillation1, cataract, cerebrovascular accident1, cholestatic jaundice, dyskinesia (including, for example, case of buccal-lingual-masticatory syndrome with involuntary tongue protrusion reported to develop in 77-year-old female after 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, immune-related hemolytic anemia, kidney failure, memory impairment, movement disorders developing in patients with risk factors including drugs associated with such reactions and worsening of preexisting movement disorders, optic neuritis, pancreatitis1, pancytopenia, pulmonary embolism, pulmonary hypertension, QT prolongation, Stevens-Johnson syndrome, thrombocytopenia1, thrombocytopenic purpura, ventricular tachycardia (including Torsades de Pointes-type arrhythmias), vaginal bleeding, and violent behaviors1.1These terms represent serious adverse events, but do not meet the definition for adverse drug reactions. They are included here because of their seriousness.

CLINICAL PHARMACOLOGY SECTION.

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 much more potent uptake inhibitor of serotonin than of norepinephrine. Antagonism of muscarinic, histaminergic, and 1-adrenergic receptors has been hypothesized to be associated with various anticholinergic, sedative, and cardiovascular effects of classical TCA drugs. Fluoxetine binds to these and other membrane receptors from brain tissue much less potently in vitro than do the tricyclic drugs.. 12.3 Pharmacokinetics. Systemic bioavailability--In man, following single, oral dose of fluoxetine 60 mg tablet, the peak plasma concentration of fluoxetine and time to achieve peak plasma concentration were 49.6 +- 10.0 ng/mL, and 7.20 +- 1.41 hours, respectively (both values are mean +- SD).The capsule, tablet, and oral solution dosage forms of fluoxetine are bioequivalent. The exposure (Cmax, AUC) to fluoxetine was similar after administration of either x 60 mg fluoxetine tablet or x 20 mg fluoxetine tablets. Food does not appear to affect the systemic bioavailability of fluoxetine, although it may delay its absorption by to 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 1-glycoprotein. The interaction between fluoxetine and other highly protein-bound drugs has not been fully evaluated, but may be important.Enantiomers--Fluoxetine is 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 number of other unidentified metabolites. The only identified active metabolite, norfluoxetine, is formed by demethylation of fluoxetine. In animal models, S-norfluoxetine is 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 study involving labeled and unlabeled enantiomers administered as racemate, these individuals metabolized S-fluoxetine at 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 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 steady-state concentration rather than increasing without limit.Because fluoxetines metabolism, like that of number of other compounds including TCAs and other SSRIs, involves the CYP2D6 system, concomitant therapy with drugs also metabolized by this enzyme system (such as the TCAs) may lead to drug interactions [see Drug Interactions (7.6)].Accumulation and slow elimination--The relatively slow elimination of fluoxetine (elimination half-life of to days after acute administration and to days after chronic administration) and its active metabolite, norfluoxetine (elimination half-life of 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 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 fluoxetines metabolism is not proportional to dose. Norfluoxetine, however, appears to have linear pharmacokinetics. Its mean terminal half-life after 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 to weeks.The long elimination half-lives of fluoxetine and norfluoxetine assure that, even when dosing is stopped, active drug substance will persist in the body for weeks (primarily depending on individual patient characteristics, previous dosing regimen, and length of previous therapy at discontinuation). This is of potential consequence when drug discontinuation is required or when drugs are prescribed that might interact with fluoxetine and norfluoxetine following the discontinuation of fluoxetine.Liver disease--As might be predicted from its primary site of metabolism, liver impairment can affect the elimination of fluoxetine. The elimination half-life of fluoxetine was prolonged in study of cirrhotic patients, with mean of 7.6 days compared with the range of to days seen in subjects without liver disease; norfluoxetine elimination was also delayed, with mean duration of 12 days for cirrhotic patients compared with the range of to 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, lower or less frequent dose should be used [see Dosage and Administration (2.5) and Use in Specific Populations (8.6)].Renal disease--In depressed patients on dialysis (N 12), fluoxetine administered as 20 mg once daily for 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 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, 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 weeks. Combined fluoxetine plus norfluoxetine plasma concentrations were 209.3 +- 85.7 ng/mL at the end of 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 to 13, 11 adolescents ages 13 to 18) diagnosed with MDD or OCD. Fluoxetine 20 mg/day was administered for up to 62 days. The average steady-state concentrations of fluoxetine in these children were 2-fold higher than in adolescents (171 and 86 ng/mL, respectively). The average norfluoxetine steady-state concentrations in these children were 1.5-fold higher than in adolescents (195 and 113 ng/mL, respectively). These differences can be almost entirely explained by differences in weight. No gender-associated difference in fluoxetine pharmacokinetics was observed. Similar ranges of fluoxetine and norfluoxetine plasma concentrations were observed in another study in 94 pediatric patients (ages to 18) diagnosed with MDD.Higher average steady-state fluoxetine and norfluoxetine concentrations were observed in children relative to adults; however, these concentrations were within the range of concentrations observed in the adult population. As in adults, fluoxetine and norfluoxetine accumulated extensively following multiple oral dosing; steady-state concentrations were achieved within to weeks of daily dosing.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. Efficacy for fluoxetine was established for the:Acute and maintenance treatment of MDD in adults, and children and adolescents (8 to 18 years) in short-term and long-term, placebo-controlled trials [see Clinical Studies (14.1)].Acute treatment of obsessions and compulsions in adults, and children and adolescents (7 to 17 years) with OCD in 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 short-term and long-term, placebo-controlled trials [see Clinical Studies (14.3)].Acute treatment of Panic Disorder, with or without agoraphobia, in adult patients in short-term, placebo-controlled trials [see Clinical Studies (14.4)].. Acute and maintenance treatment of MDD in adults, and children and adolescents (8 to 18 years) in short-term and long-term, placebo-controlled trials [see Clinical Studies (14.1)].. Acute treatment of obsessions and compulsions in adults, and children and adolescents (7 to 17 years) with OCD in 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 short-term and long-term, placebo-controlled trials [see Clinical Studies (14.3)].. Acute treatment of Panic Disorder, with or without agoraphobia, in adult patients in short-term, placebo-controlled trials [see Clinical Studies (14.4)].. 14.1 Major Depressive Disorder. Daily DosingAdult--The efficacy of fluoxetine was studied in 5- and 6-week placebo-controlled trials with depressed adult and geriatric outpatients (>= 18 years of age) whose diagnoses corresponded most closely to the DSM-III (currently DSM-IV) category of MDD. Fluoxetine was shown to be significantly more effective than placebo as measured by the Hamilton Depression Rating Scale (HAM-D). Fluoxetine was also significantly more effective than placebo on the HAM-D subscores for depressed mood, sleep disturbance, and the anxiety subfactor.Two 6-week controlled studies (N 671, randomized) comparing fluoxetine 20 mg and placebo have shown fluoxetine 20 mg daily to be effective in the treatment of elderly patients (>= 60 years of age) with MDD. In these studies, fluoxetine produced significantly higher rate of response and remission as defined, respectively, by 50% decrease in the HAM-D score and total endpoint HAM-D score of <= 8. Fluoxetine was well tolerated and the rate of treatment discontinuations due to adverse reactions did not differ between fluoxetine (12%) and placebo (9%).A study was conducted involving depressed outpatients who had responded (modified HAMD-17 score of <= during each of the last weeks of open-label treatment and absence of MDD by DSM-III-R criteria) by the end of an initial 12-week, open-treatment phase on fluoxetine 20 mg/day. These patients (N 298) were randomized to continuation on double-blind fluoxetine 20 mg/day or placebo. At 38 weeks (50 weeks total), statistically significantly lower relapse rate (defined as symptoms sufficient to meet diagnosis of MDD for weeks or modified HAMD-17 score of >= 14 for weeks) was observed for patients taking fluoxetine compared with those on placebo.Pediatric (children and adolescents)--The efficacy of fluoxetine 20 mg/day in children and adolescents (N 315 randomized; 170 children ages to 13, 145 adolescents ages 13 to <= 18) was studied in two 8- to 9-week placebo-controlled clinical trials in depressed outpatients whose diagnoses corresponded most closely to the DSM-III-R or DSM-IV category of MDD.In both studies independently, fluoxetine produced statistically significantly greater mean change on the Childhood Depression Rating Scale-Revised (CDRS-R) total score from baseline to endpoint than did placebo.Subgroup analyses on the CDRS-R total score did not suggest any differential responsiveness on the basis of age or gender.. 14.2 Obsessive Compulsive Disorder. Adult--The effectiveness of fluoxetine for the treatment of OCD was demonstrated in two 13-week, multicenter, parallel-group studies (studies and 2) of adult outpatients who received fixed fluoxetine doses of 20, 40, or 60 mg/day (on 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 to units on the YBOCS total score, compared with 1-unit reduction for placebo patients. In study 2, patients receiving fluoxetine experienced mean reductions of approximately to units on the YBOCS total score, compared with 1-unit reduction for placebo patients. While there was no indication of dose-response relationship for effectiveness in study 1, dose-response relationship was observed in study 2, with numerically better responses in the higher dose groups. Table provides the outcome classification by treatment group on the Clinical Global Impression (CGI) improvement scale for studies and combined:Table 5. Outcome Classification (%) on CGI Improvement Scale for Completers in Pool of Two OCD StudiesFluoxetineOutcome ClassificationPlacebo20 mg40 mg60 mgWorse8%0%0%0%No change64%41%33%29%Minimally improved17%23%28%24%Much improved8%28%27%28%Very much improved3%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 to 13, 28 adolescents ages 13 to 18) with OCD (DSM-IV), patients received fluoxetine 10 mg/day for weeks, followed by 20 mg/day for 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 statistically significantly greater mean change from baseline to endpoint than did placebo as measured by the Childrens 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 fixed fluoxetine dose of 60 mg/day (once day) or placebo. Patients in these studies had moderate to severe bulimia with median binge-eating and vomiting frequencies ranging from to 10 per week and to per week, respectively. In these 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 and persisted throughout each study.The fluoxetine-related reduction in bulimic episodes appeared to be independent of baseline depression as assessed by the HAM-D. In each of these 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 to episodes per week for binge-eating and to 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 result of treatment, for the majority, the benefit was partial reduction in the frequency of binge-eating and purging.In longer-term trial, 150 patients meeting DSM-IV criteria for Bulimia Nervosa, purging subtype, who had responded during 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 50% decrease in vomiting frequency compared with baseline. Relapse during the double-blind phase was defined as persistent return to baseline vomiting frequency or physician judgment that the patient had relapsed. Patients receiving continued fluoxetine 60 mg/day experienced 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 double-blind, randomized, placebo-controlled, multicenter studies of adult outpatients who had primary diagnosis of Panic Disorder (DSM-IV), with or without agoraphobia.Study (N 180 randomized) was 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. statistically significantly greater percentage of fluoxetine-treated patients were free from panic attacks at endpoint than placebo-treated patients, 42% versus 28%, respectively.Study (N 214 randomized) was 12-week, flexible-dose study. Fluoxetine was initiated at 10 mg/day for the first week, after which patients were dosed in range of 20 to 60 mg/day on the basis of clinical response and tolerability. statistically significantly greater percentage of fluoxetine-treated patients were free from panic attacks at endpoint than placebo-treated patients, 62% versus 44%, respectively.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. This product is only available in 60-mg dosage form. 30-mg dose may be achieved with one-half of the scored tablet. Use of this product requires initial titration with another fluoxetine product according to the dosing guidelines indicated below.. Use another fluoxetine product for initial doses of 10 to 20 mg/day or for doses other than 30 mg or 60 mg:IndicationAdultPediatricMDD (2.1)20 mg/day in morning (initial dose)20 mg/day (target dose)80 mg/day (maximum dose studied)10 to 20 mg/day (initial dose) This product has not been studied in doses greater than 20 mg/day in pediatric MDD.OCD (2.2)20 mg/day in morning (initial dose)20 to 60 mg/day (target dose)10 mg/day (initial dose)10 to 60 mg/day (target dose)Bulimia Nervosa (2.3)60 mg/day in morning--Panic Disorder (2.4)10 mg/day (initial dose)20 mg/day (target dose)60 mg/day (maximum dose studied)--No additional benefits seen at higher doses above 20 mg/day in MDD (2.1, 14.1)Use lower or less frequent dosage in patients with hepatic impairment, the elderly, and for patients with concurrent disease or on multiple concomitant medications (2.5, 8.6). Use another fluoxetine product for initial doses of 10 to 20 mg/day or for doses other than 30 mg or 60 mg:. No additional benefits seen at higher doses above 20 mg/day in MDD (2.1, 14.1). Use lower or less frequent dosage in patients with hepatic impairment, the elderly, and for patients with concurrent disease or on multiple concomitant medications (2.5, 8.6). 2.1 Major Depressive Disorder. Initial TreatmentAdult--Initiate fluoxetine 20 mg/day orally in the morning. Consider 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 satisfactory response in MDD in most cases [see Clinical Studies (14.1)].Pediatric (children and adolescents)--Treatment should be initiated with dose of 10 or 20 mg/day. After week at 10 mg/day, the dose should be increased to 20 mg/day. However, due to higher plasma levels in lower weight children, the starting and target dose in this group may be 10 mg/day. dose increase to 20 mg/day may be considered after several weeks if insufficient clinical improvement is observed. In the short-term (8- to 9-week) controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of MDD, patients were administered fluoxetine doses of 10 to 20 mg/day [see Clinical Studies (14.1)]. Doses greater than 20 mg/day have not been studied in pediatric patients with MDD. This product is only available in 60-mg dosage form. Administration of doses with demonstrated efficacy of fluoxetine 10 to 20 mg/day in pediatric MDD requires the use of another formulation.All patients--As with other drugs effective in the treatment of MDD, the full effect may be delayed until weeks of treatment or longer.Periodically reassess to determine the need for maintenance treatment.Switching Patients to Tricyclic Antidepressant (TCA)--Dosage of 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 (7.6)].. 2.2 Obsessive Compulsive Disorder. Initial TreatmentAdults--Initiate fluoxetine 20 mg/day, orally in the morning. Consider dose increase after several weeks if insufficient clinical improvement is observed. The full therapeutic effect may be delayed until weeks of treatment or longer. Doses above 20 mg/day may be administered on once daily (i.e., morning) or twice daily schedule (i.e., morning and noon). 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, treatment should be initiated with dose of 10 mg/day. After weeks, the dose should be increased to 20 mg/day. Additional dose increases may be considered after several more weeks if insufficient clinical improvement is observed. dose range of 20 to 60 mg/day is recommended.In lower weight children, treatment should be initiated with dose of 10 mg/day. Additional dose increases may be considered after several more weeks if insufficient clinical improvement is observed. 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 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 Nervosa. 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--Treatment should be initiated with dose of 10 mg/day. After week, the dose should be increased to 20 mg/day. dose increase may be considered 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 flexible-dose clinical trials was 20 mg/day.Periodically reassess to determine the need for continued treatment.. 2.5 Dosing in Specific Populations. Treatment of Pregnant Women--When treating pregnant women with fluoxetine, the physician should carefully consider the potential risks and potential benefits of treatment. Neonates exposed to serotonin-norepinephrine reuptake inhibitors (SNRIs) or selective serotonin reuptake inhibitors (SSRIs) late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding [see Use in Specific Populations (8.1)].Geriatrics--A lower or less frequent dosage should be considered for the elderly [see Use in Specific Populations (8.5)].Hepatic Impairment--As with many other medications, lower or less frequent dosage should be used in patients with hepatic impairment [see Clinical Pharmacology (12.3) and Use in Specific Populations (8.6)].. 2.6 Switching Patient To or From 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. Conversely, at least weeks should be allowed after stopping fluoxetine before starting an MAOI intended to treat psychiatric disorders [see Contraindications (4.1)].. 2.7 Use of Fluoxetine with Other MAOIs Such as Linezolid or Methylene Blue. Do not start fluoxetine in patient who is being treated with linezolid or intravenous methylene blue because there is an increased risk of serotonin syndrome. In patient who requires more urgent treatment of psychiatric condition, other interventions, including hospitalization, should be considered [see Contraindications (4.1)].In some cases, 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 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 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 nonintravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than mg/kg with fluoxetine is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use [see Warnings and Precautions (5.2)].

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. As with all drugs, the potential for interaction by variety of mechanisms (e.g., pharmacodynamic, pharmacokinetic drug inhibition or enhancement, etc.) is possibility.. Drugs Metabolized by CYP2D6: Fluoxetine is potent inhibitor of CYP2D6 enzyme pathway (7.6)Tricyclic Antidepressants (TCAs): Monitor TCA levels during coadministration with fluoxetine or when fluoxetine has been recently discontinued (5.2, 7.6)Benzodiazepines: Diazepam--increased t1/2, alprazolam--further psychomotor performance decrement due to increased levels (7.6)Antipsychotics: Potential for elevation of haloperidol and clozapine levels (7.6)Anticonvulsants: Potential for elevated phenytoin and carbamazepine levels and clinical anticonvulsant toxicity (7.6)Serotonergic Drugs: (2.6, 2.7, 4.1, 5.2)Drugs that Prolong the QT Interval: Do not use fluoxetine with thioridazine or pimozide. Use with caution in combination with other drugs that prolong the QT interval (4.2, 5.11, 7.6, 7.7). Drugs Metabolized by CYP2D6: Fluoxetine is potent inhibitor of CYP2D6 enzyme pathway (7.6). Tricyclic Antidepressants (TCAs): Monitor TCA levels during coadministration with fluoxetine or when fluoxetine has been recently discontinued (5.2, 7.6). Benzodiazepines: Diazepam--increased t1/2, alprazolam--further psychomotor performance decrement due to increased levels (7.6). Antipsychotics: Potential for elevation of haloperidol and clozapine levels (7.6). Anticonvulsants: Potential for elevated phenytoin and carbamazepine levels and clinical anticonvulsant toxicity (7.6). Serotonergic Drugs: (2.6, 2.7, 4.1, 5.2). Drugs that Prolong the QT Interval: Do not use fluoxetine with thioridazine or pimozide. Use with caution in combination with other drugs that prolong the QT interval (4.2, 5.11, 7.6, 7.7). 7.1 Monoamine Oxidase Inhibitors (MAOIs). [See Dosage and Administration (2.6, 2.7), Contraindications (4.1), and Warnings and Precautions (5.2)].. 7.2 CNS Acting Drugs. Caution is advised if the concomitant administration of fluoxetine and such drugs is required. In evaluating individual cases, consideration should be given to using lower initial doses of the concomitantly administered drugs, using conservative titration schedules, and monitoring of clinical status [see Clinical Pharmacology (12.3)].. 7.3 Serotonergic Drugs. [See Dosage and Administration (2.6, 2.7), Contraindications (4.1), and Warnings and Precautions (5.2)].. 7.4 Drugs that Interfere with Hemostasis (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 Potential for Other Drugs to Affect Fluoxetine. Drugs tightly bound to plasma proteins--Because fluoxetine is tightly bound to plasma proteins, adverse effects may result from displacement of protein-bound fluoxetine by other tightly bound drugs [see Clinical Pharmacology (12.3)].. 7.6 Potential for Fluoxetine to Affect Other Drugs. Pimozide--Concomitant use in patients taking pimozide is contraindicated. Pimozide can prolong the QT interval. Fluoxetine can increase the level of pimozide through inhibition of CYP2D6. Fluoxetine can also prolong the QT interval. Clinical studies of pimozide with other antidepressants demonstrate an increase in drug interaction or QT prolongation. While specific study with pimozide and fluoxetine has not been conducted, the potential for drug interactions or QT prolongation warrants restricting the concurrent use of pimozide and fluoxetine [see Contraindications (4.2), Warnings and Precautions (5.11), and Drug Interactions (7.7)].Thioridazine--Thioridazine should not be administered with fluoxetine or within minimum of weeks after fluoxetine has been discontinued, because of the risk of QT prolongation [see Contraindications (4.2), Warnings and Precautions (5.11), and Drug Interactions (7.7)].In study of 19 healthy male subjects, which included slow and 13 rapid hydroxylators of debrisoquin, single 25-mg oral dose of thioridazine produced 2.4-fold higher Cmax and 4.5-fold higher area under the curve (AUC) for thioridazine in the slow hydroxylators compared with the rapid hydroxylators. The rate of debrisoquin hydroxylation is felt to depend on the level of CYP2D6 isozyme activity. Thus, this study suggests that drugs which inhibit CYP2D6, such as certain SSRIs, including fluoxetine, will produce elevated plasma levels of thioridazine.Thioridazine administration produces 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 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 relatively narrow therapeutic index (see list below) should be initiated at the low end of the dose range if patient is receiving fluoxetine concurrently or has taken it in the previous weeks. Thus, his/her dosing requirements resemble those of poor metabolizers. If fluoxetine is added to the treatment regimen of patient already receiving drug metabolized by CYP2D6, the need for decreased dose of the original medication should be considered. Drugs with 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 minimum of weeks after fluoxetine has been discontinued [see Contraindications (4.2)].Tricyclic antidepressants (TCAs)--In 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 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)].Benzodiazepines--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 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 patient taking another drug that is tightly bound to protein (e.g., Coumadin, digitoxin) may cause 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, 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 fluoxetines extent of inhibition of CYP3A4 activity is not likely to be of clinical significance.Olanzapine--Fluoxetine (60-mg single dose or 60-mg daily dose for days) causes small (mean 16%) increase in the maximum concentration of olanzapine and small (mean 16%) decrease in olanzapine clearance. The magnitude of the impact of this factor is small in comparison to the overall variability between individuals, and therefore dose modification is not routinely recommended.. 7.7 Drugs that Prolong the QT Interval. Do not use fluoxetine in combination with thioridazine or pimozide. Use fluoxetine with caution in combination with other drugs that cause QT prolongation. These include: specific antipsychotics (e.g., ziprasidone, iloperidone, chlorpromazine, mesoridazine, droperidol); specific antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin, sparfloxacin); Class IA antiarrhythmic medications (e.g., quinidine, procainamide); Class III antiarrhythmics (e.g., amiodarone, sotalol); and others (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus). Fluoxetine is primarily metabolized by CYP2D6. Concomitant treatment with CYP2D6 inhibitors can increase the concentration of fluoxetine. Concomitant use of other highly protein-bound drugs can increase the concentration of fluoxetine [see Contraindications (4.2), Warnings and Precautions (5.11), Drug Interactions (7.6), and Clinical Pharmacology (12.3)].

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. See FDA-approved patient labeling (Medication Guide).Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking fluoxetine.. 17.1 Information on Medication Guide and Benefits/Risks of Fluoxetine. Healthcare providers should instruct their patients to read the Medication Guide before starting therapy with fluoxetine tablets and to reread it each time the prescription is renewed.Healthcare providers should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with fluoxetine tablets and should counsel them in its appropriate use. Healthcare providers should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have.Patients should be advised of the following issues and asked to alert their healthcare provider if these occur while taking fluoxetine tablets.. 17.2 Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults. Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patients prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patients presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate need for very close monitoring and possibly changes in the medication [see Boxed Warning and Warnings and Precautions (5.1)].. 17.3 Serotonin Syndrome. Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of fluoxetine and other serotonergic agents including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, amphetamines, and St. Johns Wort [see Contraindications (4.1), Warnings and Precautions (5.2), and Drug Interactions (7.3)].Patients should be advised of the signs and symptoms associated with serotonin syndrome that may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular changes (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be cautioned to seek medical care immediately if they experience these symptoms.. 17.4 Allergic Reactions and Rash. Patients should be advised to notify their physician if they develop rash or hives [see Warnings and Precautions (5.3)]. Patients should also be advised of the signs and symptoms associated with severe allergic reaction, including swelling of the face, eyes, or mouth, or have trouble breathing. Patients should be cautioned to seek medical care immediately if they experience these symptoms.. 17.5 Abnormal Bleeding. Patients should be cautioned about the concomitant use of fluoxetine and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents have been associated with an increased risk of bleeding [see Warnings and Precautions (5.7) and Drug Interactions (7.4)]. Patients should be advised to call their doctor if they experience any increased or unusual bruising or bleeding while taking fluoxetine.. 17.6 Angle-closure Glaucoma. Patients should be advised that taking fluoxetine can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle-closure glaucoma. Preexisting glaucoma is almost always open-angle glaucoma because angle-closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not risk factor for angle-closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have prophylactic procedure (e.g., iridectomy), if they are susceptible [see Warning and Precautions (5.8)].. 17.7 Hyponatremia. Patients should be advised that hyponatremia has been reported as result of treatment with SNRIs and SSRIs, including fluoxetine. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. More severe and/or acute cases have been associated with hallucination, syncope, seizure, coma, respiratory arrest, and death [see Warnings and Precautions (5.9)].. 17.8 QT Prolongation. Patients should be advised that QT interval prolongation and ventricular arrhythmia including Torsades de Pointes have been reported in patients treated with fluoxetine. Signs and symptoms of ventricular arrhythmia include fast, slow, or irregular heart rate, dyspnea, syncope, or dizziness, which may indicate serious cardiac arrhythmia [see Warnings and Precautions (5.11)].. 17.9 Potential for Cognitive and Motor Impairment. Fluoxetine may impair judgment, thinking, or motor skills. Patients should be advised to avoid driving car or operating hazardous machinery until they are reasonably certain that their performance is not affected [see Warnings and Precautions (5.13)].. 17.10 Use of Concomitant Medications. Patients should be advised to inform their physician if they are taking, or plan to take, any prescription medication, including Prozac(R) (fluoxetine hydrochloride), Symbyax(R) (olanzapine and fluoxetine hydrochloride capsules), Sarafem(R) (fluoxetine tablets), or over-the-counter drugs, including herbal supplements or alcohol. Patients should also be advised to inform their physicians if they plan to discontinue any medications they are taking while on fluoxetine.. 17.11 Discontinuation of Treatment. Patients should be advised to take fluoxetine 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 physician [see Warnings and Precautions (5.15)]. Patients should be advised to consult with their healthcare provider if their symptoms do not improve with fluoxetine.. 17.12 Use in Specific Populations. Pregnancy--Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy. Fluoxetine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus [see Use in Specific Populations (8.1)].Nursing mothers--Patients should be advised to notify their physician if they intend to breastfeed an infant during therapy. Because fluoxetine is excreted in human milk, nursing while taking fluoxetine is not recommended [see Use in Specific Populations (8.3)].Pediatric use--Fluoxetine is approved for use in pediatric patients with MDD and OCD [see Boxed Warning and Warnings and Precautions (5.1)]. Limited evidence is available concerning the longer-term effects of fluoxetine 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)].All brand names listed are the registered trademarks of their respective owners and are not trademarks of Teva Pharmaceuticals USA, Inc.Manufactured In Israel By: Teva Pharmaceutical Ind. Ltd. Kfar Saba, 4410202, IsraelManufactured For: Teva Pharmaceuticals USA, Inc. Parsippany, NJ 07054Rev. 4/2020.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Systemic bioavailability--In man, following single, oral dose of fluoxetine 60 mg tablet, the peak plasma concentration of fluoxetine and time to achieve peak plasma concentration were 49.6 +- 10.0 ng/mL, and 7.20 +- 1.41 hours, respectively (both values are mean +- SD).The capsule, tablet, and oral solution dosage forms of fluoxetine are bioequivalent. The exposure (Cmax, AUC) to fluoxetine was similar after administration of either x 60 mg fluoxetine tablet or x 20 mg fluoxetine tablets. Food does not appear to affect the systemic bioavailability of fluoxetine, although it may delay its absorption by to 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 1-glycoprotein. The interaction between fluoxetine and other highly protein-bound drugs has not been fully evaluated, but may be important.Enantiomers--Fluoxetine is 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 number of other unidentified metabolites. The only identified active metabolite, norfluoxetine, is formed by demethylation of fluoxetine. In animal models, S-norfluoxetine is 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 study involving labeled and unlabeled enantiomers administered as racemate, these individuals metabolized S-fluoxetine at 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 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 steady-state concentration rather than increasing without limit.Because fluoxetines metabolism, like that of number of other compounds including TCAs and other SSRIs, involves the CYP2D6 system, concomitant therapy with drugs also metabolized by this enzyme system (such as the TCAs) may lead to drug interactions [see Drug Interactions (7.6)].Accumulation and slow elimination--The relatively slow elimination of fluoxetine (elimination half-life of to days after acute administration and to days after chronic administration) and its active metabolite, norfluoxetine (elimination half-life of 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 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 fluoxetines metabolism is not proportional to dose. Norfluoxetine, however, appears to have linear pharmacokinetics. Its mean terminal half-life after 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 to weeks.The long elimination half-lives of fluoxetine and norfluoxetine assure that, even when dosing is stopped, active drug substance will persist in the body for weeks (primarily depending on individual patient characteristics, previous dosing regimen, and length of previous therapy at discontinuation). This is of potential consequence when drug discontinuation is required or when drugs are prescribed that might interact with fluoxetine and norfluoxetine following the discontinuation of fluoxetine.Liver disease--As might be predicted from its primary site of metabolism, liver impairment can affect the elimination of fluoxetine. The elimination half-life of fluoxetine was prolonged in study of cirrhotic patients, with mean of 7.6 days compared with the range of to days seen in subjects without liver disease; norfluoxetine elimination was also delayed, with mean duration of 12 days for cirrhotic patients compared with the range of to 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, lower or less frequent dose should be used [see Dosage and Administration (2.5) and Use in Specific Populations (8.6)].Renal disease--In depressed patients on dialysis (N 12), fluoxetine administered as 20 mg once daily for 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 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, 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 weeks. Combined fluoxetine plus norfluoxetine plasma concentrations were 209.3 +- 85.7 ng/mL at the end of 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 to 13, 11 adolescents ages 13 to 18) diagnosed with MDD or OCD. Fluoxetine 20 mg/day was administered for up to 62 days. The average steady-state concentrations of fluoxetine in these children were 2-fold higher than in adolescents (171 and 86 ng/mL, respectively). The average norfluoxetine steady-state concentrations in these children were 1.5-fold higher than in adolescents (195 and 113 ng/mL, respectively). These differences can be almost entirely explained by differences in weight. No gender-associated difference in fluoxetine pharmacokinetics was observed. Similar ranges of fluoxetine and norfluoxetine plasma concentrations were observed in another study in 94 pediatric patients (ages to 18) diagnosed with MDD.Higher average steady-state fluoxetine and norfluoxetine concentrations were observed in children relative to adults; however, these concentrations were within the range of concentrations observed in the adult population. As in adults, fluoxetine and norfluoxetine accumulated extensively following multiple oral dosing; steady-state concentrations were achieved within to weeks of daily dosing.

SPL MEDGUIDE SECTION.

MEDICATION GUIDE. FLUOXETINE (floo ox teen) TABLETSRead the Medication Guide that comes with fluoxetine tablets before you start taking them and each time you get 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 should know about fluoxetine tabletsFluoxetine tablets and other antidepressant medicines may cause serious side effects, including:1. Suicidal thoughts or actions:Fluoxetine tablets and other antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, or young adults within the first few months of treatment or when the dose is changed.Depression or other serious mental illnesses are the most important causes of suicidal thoughts or actions.Watch for these changes and call your healthcare provider right away if you notice:New or sudden changes in mood, behavior, actions, thoughts, or feelings, especially if severe.Pay particular attention to such changes when fluoxetine tablets are started or when the dose is changed. Keep all follow-up visits with your healthcare provider and call between visits if you are worried about symptoms.Call your healthcare provider right away if you have any of the following symptoms, or call 911 if an emergency, especially if they are new, worse, or worry you:attempts to commit suicideacting on dangerous impulsesacting aggressive or violentthoughts about suicide or dyingnew or worse depressionnew or worse anxiety or panic attacksfeeling agitated, restless, angry, or irritabletrouble sleepingan increase in activity or talking more than what is normal for youother unusual changes in behavior or moodCall your healthcare provider right away if you have any of the following symptoms, or call 911 if an emergency. Fluoxetine tablets may be associated with these serious side effects:2. Serotonin Syndrome. This condition can be life-threatening and may include:agitation, hallucinations, coma, or other changes in mental statuscoordination problems or muscle twitching (overactive reflexes)racing heartbeat, high or low blood pressuresweating or fevernausea, vomiting, or diarrheamuscle rigiditydizzinessflushingtremorseizures3. Severe allergic reactions:trouble breathingswelling of the face, tongue, eyes, or mouthrash, itchy welts (hives) or blisters, alone or with fever or joint pain4. Abnormal bleeding: Fluoxetine tablets and other antidepressant medicines may increase your risk of bleeding or bruising, especially if you take the blood thinner warfarin (Coumadin(R), Jantoven(R)), non-steroidal anti-inflammatory drug (NSAIDs, like ibuprofen or naproxen), or aspirin.5. Visual problems:eye painchanges in visionswelling or redness in or around the eyeOnly some people are at risk for these problems. You may want to undergo an eye examination to see if you are at risk and receive preventative treatment if you are.6. Seizures or convulsions7. Manic episodes:greatly increased energysevere trouble sleepingracing thoughtsreckless behaviorunusually grand ideasexcessive happiness or irritabilitytalking more or faster than usual8. Changes in appetite or weight. Children and adolescents should have height and weight monitored during treatment.9. Low salt (sodium) levels in the blood. Elderly people may be at greater risk for this. Symptoms may include:headacheweakness or feeling unsteadyconfusion, problems concentrating, or thinking or memory problems10. 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 heartbeatshortness of breathdizziness or faintingDo not stop fluoxetine tablets without first talking to your healthcare provider. Stopping fluoxetine tablets too quickly may cause serious symptoms including:anxiety, irritability, high or low mood, feeling restless, or changes in sleep habitsheadache, sweating, nausea, dizzinesselectric shock-like sensations, shaking, confusionWhat are fluoxetine tabletsFluoxetine tablets are prescription medicine used to treat depression. It is important to talk with your healthcare provider about the risks of treating depression and also the risks of not treating it. You should discuss all treatment choices with your healthcare provider.Fluoxetine tablets are used to treat:Major Depressive Disorder (MDD)Obsessive Compulsive Disorder (OCD)Bulimia Nervosa Panic Disorder Depressive episodes associated with Bipolar Disorder, taken with olanzapine (Zyprexa) Treatment Resistant Depression (depression that has not gotten better with at least other treatments), taken with olanzapine (Zyprexa) Not approved for use in children.Talk to your healthcare provider if you do not think that your condition is getting better with fluoxetine tablet treatment.Who should not take fluoxetine tabletsDo not take fluoxetine tablets if you:are allergic to fluoxetine hydrochloride or any of the ingredients in fluoxetine tablets. See the end of this Medication Guide for complete list of ingredients in fluoxetine tablets.take 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 weeks of stopping fluoxetine tablets unless directed to do so by your physician.Do not start fluoxetine tablets if you stopped taking an MAOI in the last weeks unless directed to do so by your physician. People who take fluoxetine tablets close in time to an MAOI may have serious or even life-threatening side effects. Get medical help right away if you have any of these symptoms:high feveruncontrolled muscle spasmsstiff musclesrapid changes in heart rate or blood pressureconfusionloss of consciousness (pass out)take Mellaril(R) (thioridazine). Do not take Mellaril(R) within weeks of stopping fluoxetine tablets because this can cause serious heart rhythm problems or sudden death. take the antipsychotic medicine pimozide (Orap(R)) because this can cause serious heart problems. What should tell my healthcare provider before taking fluoxetine tablets Ask if you are not sure.Before starting fluoxetine tablets, tell your healthcare provider if you:are taking certain drugs or treatments such as:Triptans used to treat migraine headache Medicines used to treat mood, anxiety, psychotic, or thought disorders, including tricyclics, lithium, SSRIs, SNRIs, MAOIs, or antipsychoticsTramadol and fentanylAmphetaminesOver-the-counter supplements such as tryptophan or St. Johns WortElectroconvulsive therapy (ECT) have liver problemshave kidney problemshave heart problemshave or had seizures or convulsionshave bipolar disorder or maniahave low sodium levels in your bloodhave history of strokehave high blood pressurehave or had bleeding problemsare pregnant or plan to become pregnant. It is not known if fluoxetine tablets will harm your unborn baby. Talk to your healthcare provider about the benefits and risks of treating depression during pregnancy.are breast-feeding or plan to breast-feed. Some fluoxetine may pass into your breast milk. Talk to your healthcare provider about the best way to feed your baby while taking fluoxetine tablets.Tell your healthcare provider about all the medicines that you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. Fluoxetine tablets and some medicines may interact with each other, may not work as well, or may cause serious side effects.Your healthcare provider or pharmacist can tell you if it is safe to take fluoxetine tablets with your other medicines. Do not start or stop any medicine while taking fluoxetine tablets without talking to your healthcare provider first.If you take fluoxetine tablets, you should not take any other medicines that contain fluoxetine hydrochloride including:Symbyax(R) (olanzapine and fluoxetine hydrochloride)Sarafem(R) (fluoxetine)Prozac(R) Prozac(R) Weekly(TM) How should take fluoxetine tabletsTake fluoxetine tablets exactly as prescribed. Your healthcare provider may need to change the dose of fluoxetine tablets until it is the right dose for you. Each tablet can be broken in half (along the functional score).Fluoxetine tablets may be taken with or without food.If you miss dose of fluoxetine tablets, take the missed dose as soon as you remember. If it is almost time for the next dose, skip the missed dose and take your next dose at the regular time. Do not take two doses of fluoxetine tablets at the same time.If you take too many fluoxetine tablets, call your healthcare provider or poison control center right away, or get emergency treatment.What should avoid while taking fluoxetine tabletsFluoxetine tablets can cause sleepiness or may affect your ability to make decisions, think clearly, or react quickly. You should not drive, operate heavy machinery, or do other dangerous activities until you know how fluoxetine tablets affect you. Do not drink alcohol while using fluoxetine tablets.What are the possible side effects of fluoxetine tabletsFluoxetine tablets may cause serious side effects, including:See What is the most important information should know about fluoxetine tabletsProblems with blood sugar control. People who have diabetes and take fluoxetine tablets may have problems with low blood sugar while taking fluoxetine tablets. High blood sugar can happen when fluoxetine tablets are stopped. Your healthcare provider may need to change the dose of your diabetes medicines when you start or stop taking fluoxetine tablets.Feeling anxious or trouble sleepingCommon possible side effects in people who take fluoxetine tablets include:unusual dreamssexual problemsloss of appetite, diarrhea, indigestion, nausea or vomiting, weakness, or dry mouthflu symptomsfeeling tired or fatiguedchange in sleep habitsyawningsinus infection or sore throattremor or shakingsweatingfeeling anxious or nervoushot flashesrashOther side effects in children and adolescents include:increased thirstabnormal increase in muscle movement or agitationnose bleedurinating more oftenheavy menstrual periodspossible slowed growth rate and weight change. Your childs height and weight should be monitored during treatment with fluoxetine tablets.Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of fluoxetine tablets. For more information, ask your healthcare provider or pharmacist.CALL YOUR DOCTOR FOR MEDICAL ADVICE ABOUT SIDE EFFECTS. YOU MAY REPORT SIDE EFFECTS TO THE FDA AT 1-800-FDA-1088.How should store fluoxetine tabletsStore fluoxetine tablets at room temperature between 68F and 77F (20C to 25C).Keep fluoxetine tablets away from light.Keep fluoxetine tablets bottle closed tightly.Keep fluoxetine tablets and all medicines out of the reach of children.General information about fluoxetine tabletsMedicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use fluoxetine tablets for condition for which they were not prescribed. Do not give fluoxetine tablets to other people, even if they have the same condition. They may harm them.This Medication Guide summarizes the most important information about fluoxetine tablets. If you would like more information, talk with your healthcare provider. You may ask your healthcare provider or pharmacist for information about fluoxetine tablets that is written for healthcare professionals.For more information about fluoxetine tablets, call 1-888-838-2872.What are the ingredients in fluoxetine tablets, 60 mgActive ingredient: fluoxetine hydrochlorideInactive ingredients: magnesium stearate, mannitol, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol part. hydrolyzed, povidone, pregelatinized maize starch, talc, and titanium dioxide.This Medication Guide has been approved by the U.S. Food and Drug Administration.All brand names listed are the registered trademarks of their respective owners and are not trademarks of Teva Pharmaceuticals USA, Inc.Orap(R) is registered trademark of Teva Pharmaceuticals USA, Inc.Manufactured In Israel By: Teva Pharmaceutical Ind. Ltd. Kfar Saba, 4410202, IsraelManufactured For: Teva Pharmaceuticals USA, Inc. Parsippany, NJ 07054Rev. 4/2020. Fluoxetine tablets and other antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, or young adults within the first few months of treatment or when the dose is changed.. Depression or other serious mental illnesses are the most important causes of suicidal thoughts or actions.. Watch for these changes and call your healthcare provider right away if you notice:New or sudden changes in mood, behavior, actions, thoughts, or feelings, especially if severe.Pay particular attention to such changes when fluoxetine tablets are started or when the dose is changed. New or sudden changes in mood, behavior, actions, thoughts, or feelings, especially if severe.. Pay particular attention to such changes when fluoxetine tablets are started or when the dose is changed.. 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. 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. trouble breathing. swelling of the face, tongue, eyes, or mouth. rash, itchy welts (hives) or blisters, alone or with fever or joint pain. 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.. greatly increased energy. severe trouble sleeping. racing thoughts. reckless behavior. unusually grand ideas. excessive happiness or irritability. talking more or faster than usual. headache. weakness or feeling unsteady. confusion, problems concentrating, or thinking or memory problems. fast, slow, or irregular heartbeat. shortness of breath. dizziness or fainting. anxiety, irritability, high or low mood, feeling restless, or changes in sleep habits. headache, sweating, nausea, dizziness. electric shock-like sensations, shaking, confusion. Major Depressive Disorder (MDD). Obsessive Compulsive Disorder (OCD). Bulimia Nervosa Panic Disorder Depressive episodes associated with Bipolar Disorder, taken with olanzapine (Zyprexa) Treatment Resistant Depression (depression that has not gotten better with at least other treatments), taken with olanzapine (Zyprexa) are allergic to fluoxetine hydrochloride or any of the ingredients in fluoxetine tablets. See the end of this Medication Guide for complete list of ingredients in fluoxetine tablets.. take 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 weeks of stopping fluoxetine tablets unless directed to do so by your physician.Do not start fluoxetine tablets if you stopped taking an MAOI in the last weeks unless directed to do so by your physician. Do not take an MAOI within weeks of stopping fluoxetine tablets unless directed to do so by your physician.. Do not start fluoxetine tablets if you stopped taking an MAOI in the last weeks unless directed to do so by your physician.. People who take fluoxetine tablets close in time to an MAOI may have serious or even life-threatening side effects. Get medical help right away if you have any of these symptoms:high feveruncontrolled muscle spasmsstiff musclesrapid changes in heart rate or blood pressureconfusionloss of consciousness (pass out). high fever. uncontrolled muscle spasms. stiff muscles. rapid changes in heart rate or blood pressure. confusion. loss of consciousness (pass out). take Mellaril(R) (thioridazine). Do not take Mellaril(R) within weeks of stopping fluoxetine tablets because this can cause serious heart rhythm problems or sudden death. take the antipsychotic medicine pimozide (Orap(R)) because this can cause serious heart problems. are taking certain drugs or treatments such as:Triptans used to treat migraine headache Medicines used to treat mood, anxiety, psychotic, or thought disorders, including tricyclics, lithium, SSRIs, SNRIs, MAOIs, or antipsychoticsTramadol and fentanylAmphetaminesOver-the-counter supplements such as tryptophan or St. Johns WortElectroconvulsive therapy (ECT) Triptans used to treat migraine headache Medicines used to treat mood, anxiety, psychotic, or thought disorders, including tricyclics, lithium, SSRIs, SNRIs, MAOIs, or antipsychotics. Tramadol and fentanyl. Amphetamines. Over-the-counter supplements such as tryptophan or St. Johns 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 history of stroke. have high blood pressure. have or had bleeding problems. are pregnant or plan to become pregnant. It is not known if fluoxetine tablets will harm your unborn baby. Talk to your healthcare provider about the benefits and risks of treating depression during pregnancy.. are breast-feeding or plan to breast-feed. Some fluoxetine may pass into your breast milk. Talk to your healthcare provider about the best way to feed your baby while taking fluoxetine tablets.. Symbyax(R) (olanzapine and fluoxetine hydrochloride). Sarafem(R) (fluoxetine). Prozac(R) Prozac(R) Weekly(TM) Take fluoxetine tablets exactly as prescribed. Your healthcare provider may need to change the dose of fluoxetine tablets until it is the right dose for you. Each tablet can be broken in half (along the functional score).. Fluoxetine tablets may be taken with or without food.. If you miss dose of fluoxetine tablets, take the missed dose as soon as you remember. If it is almost time for the next dose, skip the missed dose and take your next dose at the regular time. Do not take two doses of fluoxetine tablets at the same time.. If you take too many fluoxetine tablets, call your healthcare provider or poison control center right away, or get emergency treatment.. See What is the most important information should know about fluoxetine tablets. Problems with blood sugar control. People who have diabetes and take fluoxetine tablets may have problems with low blood sugar while taking fluoxetine tablets. High blood sugar can happen when fluoxetine tablets are stopped. Your healthcare provider may need to change the dose of your diabetes medicines when you start or stop taking fluoxetine tablets.. Feeling anxious or trouble sleeping. 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. 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 childs height and weight should be monitored during treatment with fluoxetine tablets.. Store fluoxetine tablets at room temperature between 68F and 77F (20C to 25C).. Keep fluoxetine tablets away from light.. Keep fluoxetine tablets bottle closed tightly.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Pregnancy: Fluoxetine should be used during pregnancy only if the potential benefit justifies the potential risks to the fetus (8.1)Nursing Mothers: Breast feeding is not recommended (8.3)Pediatric Use: Safety and effectiveness of fluoxetine in patients 8 years of age with MDD and 7 years of age with OCD have not been established (8.4). Pregnancy: Fluoxetine should be used during pregnancy only if the potential benefit justifies the potential risks to the fetus (8.1). Nursing Mothers: Breast feeding is not recommended (8.3). Pediatric Use: Safety and effectiveness of fluoxetine in patients 8 years of age with MDD and 7 years of age with OCD have not been established (8.4). 8.1 Pregnancy. Pregnancy Category C--Fluoxetine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. All pregnancies have background risk of birth defects, loss, or other adverse outcome regardless of drug exposure.Treatment of pregnant women during the first trimester--There are no adequate and well-controlled clinical studies on the use of fluoxetine in pregnant women. Results of number of published epidemiological studies assessing the risk of fluoxetine exposure during the first trimester of pregnancy have demonstrated inconsistent results. More than 10 cohort studies and case-control studies failed to demonstrate an increased risk for congenital malformations overall. However, one prospective cohort study conducted by the European Network of Teratology Information Services reported an increased risk of cardiovascular malformations in infants born to women (N 253) exposed to fluoxetine during the first trimester of pregnancy compared to infants of women (N 1359) who were not exposed to fluoxetine. There was no specific pattern of cardiovascular malformations. Overall, however, causal relationship has not been established.Nonteratogenic effects--Neonates exposed to fluoxetine and other SSRIs or SNRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either direct toxic effect of SSRIs and SNRIs or, possibly, drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome [see Warnings and Precautions (5.2)].Infants exposed to SSRIs in pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in to per 1000 live births in the general population and is associated with substantial neonatal morbidity and mortality. Several recent epidemiological studies suggest positive statistical association between SSRI use (including fluoxetine) in pregnancy and PPHN. Other studies do not show significant statistical association.Physicians should also note the results of prospective longitudinal study of 201 pregnant women with history of major depression, who were either on antidepressants or had received antidepressants less than 12 weeks prior to their last menstrual period, and were in remission. Women who discontinued antidepressant medication during pregnancy showed significant increase in relapse of their major depression compared to those women who remained on antidepressant medication throughout pregnancy.When treating pregnant woman with fluoxetine, the physician should carefully consider both the potential risks of taking an SSRI, along with the established benefits of treating depression with an antidepressant. The decision can only be made on case by case basis [see Dosage and Administration (2.5)].Animal data--In embryo-fetal development studies in rats and rabbits, there was no evidence of teratogenicity following administration of fluoxetine at doses up to 12.5 and 15 mg/kg/day, respectively (1.5 and 3.6 times, respectively, the maximum recommended human dose [MRHD] of 80 mg on mg/m2 basis) throughout organogenesis. However, in rat reproduction studies, an increase in stillborn pups, decrease in pup weight, and an increase in pup deaths during the first days postpartum occurred following maternal exposure to 12 mg/kg/day (1.5 times the MRHD on mg/m2 basis) during gestation or 7.5 mg/kg/day (0.9 times the MRHD on mg/m2 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 mg/kg/day (0.6 times the MRHD on mg/m2 basis).. 8.2 Labor and Delivery. The effect of fluoxetine on labor and delivery in humans is unknown. However, because fluoxetine crosses the placenta and because of the possibility that fluoxetine may have adverse effects on the newborn, fluoxetine should be used during labor and delivery only if the potential benefit justifies the potential risk to the fetus.. 8.3 Nursing Mothers. Because fluoxetine is excreted in human milk, nursing while on fluoxetine is not recommended. In one breast-milk sample, the concentration of fluoxetine plus norfluoxetine was 70.4 ng/mL. The concentration in the mothers plasma was 295.0 ng/mL. No adverse effects on the infant were reported. In another case, an infant nursed by mother on fluoxetine developed crying, sleep disturbance, vomiting, and watery stools. The infants plasma drug levels were 340 ng/mL of fluoxetine and 208 ng/mL of norfluoxetine on the second day of feeding.. 8.4 Pediatric Use. Use of fluoxetine in children--The efficacy of fluoxetine for the treatment of MDD was demonstrated in two 8- to 9-week placebo-controlled clinical trials with 315 pediatric outpatients ages 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 to 18 [see Clinical Studies (14.2)].The safety and effectiveness in pediatric patients 8 years of age in MDD and 7 years of age in OCD have not been established.Fluoxetine pharmacokinetics were evaluated in 21 pediatric patients (ages to <= 18) with MDD or OCD [see Clinical Pharmacology (12.3)].The acute adverse reaction profiles observed in the studies (N 418 randomized; 228 fluoxetine-treated, 190 placebo-treated) were generally similar to that observed in adult studies with fluoxetine. The longer-term adverse reaction profile observed in the 19-week MDD study (N 219 randomized; 109 fluoxetine-treated, 110 placebo-treated) was also similar to that observed in adult trials with fluoxetine [see Adverse Reactions (6.1)].Manic reaction, including mania and hypomania, was reported in (1 mania, hypomania) out of 228 (2.6%) fluoxetine-treated patients and in out of 190 (0%) placebo-treated patients. Mania/hypomania led to the discontinuation of (1.8%) fluoxetine-treated patients from the acute phases of the 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 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 decrease in alkaline phosphatase levels. The safety of fluoxetine treatment for pediatric patients has not been systematically assessed for chronic treatment longer than several months in duration. In particular, there are no studies that directly evaluate the longer-term effects of fluoxetine on the growth, development, and maturation of children and adolescent patients. Therefore, height and weight should be monitored periodically in pediatric patients receiving fluoxetine [see Warnings and Precautions (5.6)].Fluoxetine is approved for use in pediatric patients with MDD and OCD [see Boxed Warning and Warnings and Precautions (5.1)]. Anyone considering the use of fluoxetine in 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 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 to 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 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 maximum tolerated dose. When animals were evaluated after drug-free period (up to 11 weeks after cessation of dosing), fluoxetine was associated with neurobehavioral abnormalities (decreased reactivity at AUC as low as approximately 0.1 to 0.2 times the average AUC in pediatric patients at the MRHD and learning deficit at the high dose) and reproductive functional impairment (decreased mating at all doses and impaired fertility at the high dose). In addition, the testicular and epididymal microscopic lesions and decreased sperm concentrations found in the high dose group were also observed, indicating that the drug effects on reproductive organs are irreversible. The reversibility of fluoxetine-induced muscle damage was not assessed.These fluoxetine toxicities in juvenile rats have not been observed in adult animals. Plasma exposures (AUC) to fluoxetine in juvenile rats receiving 3, 10, or 30 mg/kg/day doses in this study are approximately 0.1 to 0.2, to 2, and to 10 times, respectively, the average exposure in pediatric patients receiving the MRHD of 20 mg/day. Rat exposures to the major metabolite, norfluoxetine, were approximately 0.3 to 0.8, to 8, and 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 weeks at doses 0.5 and times the oral MRHD of 20 mg/day on mg/m2 basis. There was decrease in bone mineralization and density at both doses, but the overall growth (body weight gain or femur length) was not affected.. 8.5 Geriatric Use. U.S. fluoxetine clinical trials included 687 patients >= 65 years of age and 93 patients >= 75 years of age. The efficacy in geriatric patients has been established [see Clinical Studies (14.1)]. For pharmacokinetic information in geriatric patients, [see Clinical Pharmacology (12.3)]. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. SNRIs and SSRIs, including fluoxetine, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse reaction [see Warnings and Precautions (5.9)].. 8.6 Hepatic Impairment. In subjects with cirrhosis of the liver, the clearances of fluoxetine and its active metabolite, norfluoxetine, were decreased, thus increasing the elimination half-lives of these substances. lower or less frequent dose of fluoxetine should be used in patients with cirrhosis. Caution is advised when using fluoxetine in patients with diseases or conditions that could affect its metabolism [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults: Monitor for clinical worsening and suicidal thinking and behavior (5.1)Serotonin Syndrome: Serotonin syndrome has been reported with SSRIs and serotonin-norepinephrine reuptake inhibitors (SNRIs), including fluoxetine, both when taken alone, but especially when coadministered with other serotonergic agents (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. Johns Wort). If such symptoms occur, discontinue fluoxetine and initiate supportive treatment. If concomitant use of fluoxetine with other serotonergic drugs is clinically warranted, patients should be made aware of potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases (5.2)Activation of Mania/Hypomania: Screen for Bipolar Disorder and monitor for mania/hypomania (5.4)Seizures: Use cautiously in patients with history of seizures or with conditions that potentially lower the seizure threshold (5.5)Altered Appetite and Weight: Significant weight loss has occurred (5.6)Abnormal Bleeding: May increase the risk of bleeding. Use with NSAIDs, aspirin, warfarin, or drugs that affect coagulation may potentiate the risk of gastrointestinal or other bleeding (5.7, 7.4)Angle-closure Glaucoma: Angle-closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants (5.8)Hyponatremia: Has been reported with fluoxetine in association with syndrome of inappropriate antidiuretic hormone (SIADH). Consider discontinuing if symptomatic hyponatremia occurs (5.9)QT Prolongation: QT prolongation and ventricular arrhythmia including Torsades de Pointes have been reported with fluoxetine use. Use with caution in conditions that predispose to arrhythmias or increase fluoxetine exposure. Use cautiously in patients with risk factors for QT prolongation (4.2, 5.11, 7.6, 7.7, 10.1)Long Half-life: Changes in dose will not be fully reflected in plasma for several weeks (5.14). Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults: Monitor for clinical worsening and suicidal thinking and behavior (5.1). Serotonin Syndrome: Serotonin syndrome has been reported with SSRIs and serotonin-norepinephrine reuptake inhibitors (SNRIs), including fluoxetine, both when taken alone, but especially when coadministered with other serotonergic agents (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. Johns Wort). If such symptoms occur, discontinue fluoxetine and initiate supportive treatment. If concomitant use of fluoxetine with other serotonergic drugs is clinically warranted, patients should be made aware of potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases (5.2). Activation of Mania/Hypomania: Screen for Bipolar Disorder and monitor for mania/hypomania (5.4). Seizures: Use cautiously in patients with history of seizures or with conditions that potentially lower the seizure threshold (5.5). Altered Appetite and Weight: Significant weight loss has occurred (5.6). Abnormal Bleeding: May increase the risk of bleeding. Use with NSAIDs, aspirin, warfarin, or drugs that affect coagulation may potentiate the risk of gastrointestinal or other bleeding (5.7, 7.4). Angle-closure Glaucoma: Angle-closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants (5.8). Hyponatremia: Has been reported with fluoxetine in association with syndrome of inappropriate antidiuretic hormone (SIADH). Consider discontinuing if symptomatic hyponatremia occurs (5.9). QT Prolongation: QT prolongation and ventricular arrhythmia including Torsades de Pointes have been reported with fluoxetine use. Use with caution in conditions that predispose to arrhythmias or increase fluoxetine exposure. Use cautiously in patients with risk factors for QT prolongation (4.2, 5.11, 7.6, 7.7, 10.1). Long Half-life: Changes in dose will not be fully reflected in plasma for several weeks (5.14). 5.1 Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults. Patients with MDD, both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been long-standing concern, however, that antidepressants may have role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with MDD and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was reduction with antidepressants compared to placebo in adults aged 65 and older.The pooled analyses of placebo-controlled trials in children and adolescents with MDD, OCD, or other psychiatric disorders included total of 24 short-term trials of antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included total of 295 short-term trials (median duration of months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug versus placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1.Table 1. Risk Differences in the Number of Suicidality Cases by Age Group in the Pooled Placebo-controlled Trials of Antidepressants in Pediatric and Adult PatientsAge Range (years)Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients TreatedIncreases Compared to Placebo< 1814 additional cases18 to 245 additional casesDecreases Compared to Placebo25 to 641 fewer case>= 656 fewer casesNo suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of course of drug therapy, or at times of dose changes, either increases or decreases.The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for MDD as well as for other indications, both psychiatric and nonpsychiatric. Although causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patients presenting symptoms.If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms [see Warnings and Precautions (5.15)].Families and caregivers of patients being treated with antidepressants for MDD or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for fluoxetine should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.It should be noted that fluoxetine is approved in the pediatric population only for MDD and OCD.. 5.2 Serotonin Syndrome. The development of potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including fluoxetine, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. Johns Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome.The concomitant use of fluoxetine with MAOIs intended to treat psychiatric disorders is contraindicated. Fluoxetine should also not be started in patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of to mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in patient taking fluoxetine. Fluoxetine should be discontinued before initiating treatment with the MAOI [see Contraindications 4.1) and Dosage and Administration (2.6, 2.7)].If concomitant use of fluoxetine with other serotonergic drugs, i.e., triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, amphetamines, and St. Johns Wort, is clinically warranted, patients should be made aware of potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.Treatment with fluoxetine and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.. 5.3 Allergic Reactions and Rash. In U.S. fluoxetine clinical trials, 7% of 10,782 patients developed various types of rashes and/or urticaria. Among the cases of rash and/or urticaria reported in premarketing clinical trials, almost third were withdrawn from treatment because of the rash and/or systemic signs or symptoms associated with the rash. Clinical findings reported in association with rash include fever, leukocytosis, arthralgias, edema, carpal tunnel syndrome, respiratory distress, lymphadenopathy, proteinuria, and mild transaminase elevation. Most patients improved promptly with discontinuation of fluoxetine and/or adjunctive treatment with antihistamines or steroids, and all patients experiencing these reactions were reported to recover completely.In premarketing clinical trials, patients are known to have developed serious cutaneous systemic illness. In neither patient was there an unequivocal diagnosis, but one was considered to have leukocytoclastic vasculitis, and the other, severe desquamating syndrome that was considered variously to be vasculitis or erythema multiforme. Other patients have had systemic syndromes suggestive of serum sickness.Since the introduction of fluoxetine, systemic reactions, possibly related to vasculitis and including lupus-like syndrome, have developed in patients with rash. Although these reactions are rare, they may be serious, involving the lung, kidney, or liver. Death has been reported to occur in association with these systemic reactions.Anaphylactoid reactions, including bronchospasm, angioedema, laryngospasm, and urticaria alone and in combination, have been reported.Pulmonary reactions, including inflammatory processes of varying histopathology and/or fibrosis, have been reported rarely. These reactions have occurred with dyspnea as the only preceding symptom.Whether these systemic reactions and rash have common underlying cause or are due to different etiologies or pathogenic processes is not known. Furthermore, specific underlying immunologic basis for these reactions has not been identified. Upon the appearance of rash or of other possibly allergic phenomena for which an alternative etiology cannot be identified, fluoxetine should be discontinued.. 5.4 Screening Patients for Bipolar Disorder and Monitoring for Mania/Hypomania. major depressive episode may be the initial presentation of Bipolar Disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of mixed/manic episode in patients at risk for Bipolar Disorder. Whether any of the symptoms described for clinical worsening and suicide risk represent such conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for Bipolar Disorder; such screening should include detailed psychiatric history, including family history of suicide, Bipolar Disorder, and depression. Fluoxetine monotherapy is not indicated for the treatment of depressive episodes associated with Bipolar Disorder.In U.S. placebo-controlled clinical trials for MDD, mania/hypomania was reported in 0.1% of patients treated with fluoxetine and 0.1% of patients treated with placebo. Activation of mania/hypomania has also been reported in small proportion of patients with Major Affective Disorder treated with other marketed drugs effective in the treatment of MDD [see Use in Specific Populations (8.4)].In U.S. placebo-controlled clinical trials for OCD, mania/hypomania was reported in 0.8% of patients treated with fluoxetine and no patients treated with placebo. No patients reported mania/hypomania in U.S. placebo-controlled clinical trials for bulimia. In U.S. fluoxetine clinical trials, 0.7% of 10,782 patients reported mania/hypomania [see Use in Specific Populations (8.4)].. 5.5 Seizures. In U.S. placebo-controlled clinical trials for MDD, convulsions (or reactions described as possibly having been seizures) were reported in 0.1% of patients treated with fluoxetine and 0.2% of patients treated with placebo. No patients reported convulsions in U.S. placebo-controlled clinical trials for either OCD or bulimia. In U.S. fluoxetine clinical trials, 0.2% of 10,782 patients reported convulsions. The percentage appears to be similar to that associated with other marketed drugs effective in the treatment of MDD. Fluoxetine should be introduced with care in patients with history of seizures. There have been rare reports of prolonged seizures in patients taking fluoxetine who are also receiving electroconvulsive therapy (ECT) treatment.. 5.6 Altered Appetite and Weight. Significant weight loss, especially in underweight depressed or bulimic patients, may be an undesirable result of treatment with fluoxetine.In U.S. placebo-controlled clinical trials for MDD, 11% of patients treated with fluoxetine and 2% of patients treated with placebo reported anorexia (decreased appetite). Weight loss was reported in 1.4% of patients treated with fluoxetine and in 0.5% of patients treated with placebo. However, only rarely have patients discontinued treatment with fluoxetine because of anorexia or weight loss [see Use in Specific Populations (8.4)].In U.S. placebo-controlled clinical trials for OCD, 17% of patients treated with fluoxetine and 10% of patients treated with placebo reported anorexia (decreased appetite). One patient discontinued treatment with fluoxetine because of anorexia [see Use in Specific Populations (8.4)].In U.S. placebo-controlled clinical trials for Bulimia Nervosa, 8% of patients treated with fluoxetine 60 mg and 4% of patients treated with placebo reported anorexia (decreased appetite). Patients treated with fluoxetine 60 mg on average lost 0.45 kg compared with gain of 0.16 kg by patients treated with placebo in the 16-week double-blind trial. Weight change should be monitored during therapy.. 5.7 Abnormal Bleeding. SNRIs and SSRIs, including fluoxetine, may increase the risk of bleeding reactions. Concomitant use of aspirin, non-steroidal anti-inflammatory drugs, warfarin, and other anti-coagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding reactions related to SNRIs and SSRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages. Patients should be cautioned about the risk of bleeding associated with the concomitant use of fluoxetine and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation [see Drug Interactions (7.4)].. 5.8 Angle-closure Glaucoma. The pupillary dilation that occurs following use of many antidepressant drugs including fluoxetine may trigger an angle closure attack in patient with anatomically narrow angles who does not have patent iridectomy.. 5.9 Hyponatremia. Hyponatremia has been reported during treatment with SNRIs and SSRIs, including fluoxetine. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported and appeared to be reversible when fluoxetine was discontinued. Elderly patients may be at greater risk of developing hyponatremia with SNRIs and SSRIs. Also, patients taking diuretics or who are otherwise volume-depleted may be at greater risk [see Use in Specific Populations (8.5)]. Discontinuation of fluoxetine should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.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.. 5.10 Anxiety and Insomnia. In U.S. placebo-controlled clinical trials for MDD, 12% to 16% of patients treated with fluoxetine and 7% to 9% of patients treated with placebo reported anxiety, nervousness, or insomnia.In U.S. placebo-controlled clinical trials for OCD, insomnia was reported in 28% of patients treated with fluoxetine and in 22% of patients treated with placebo. Anxiety was reported in 14% of patients treated with fluoxetine and in 7% of patients treated with placebo.In U.S. placebo-controlled clinical trials for Bulimia Nervosa, insomnia was reported in 33% of patients treated with fluoxetine 60 mg, and 13% of patients treated with placebo. Anxiety and nervousness were reported, respectively, in 15% and 11% of patients treated with fluoxetine 60 mg and in 9% and 5% of patients treated with placebo.Among the most common adverse reactions associated with discontinuation (incidence at least twice that for placebo and at least 1% for fluoxetine in clinical trials collecting only primary reaction associated with discontinuation) in U.S. placebo-controlled fluoxetine clinical trials were anxiety (2% in OCD), insomnia (1% in combined indications and 2% in bulimia), and nervousness (1% in MDD) [Table 4].. 5.11 QT Prolongation. Postmarketing cases of QT interval prolongation and ventricular arrhythmia including Torsades de Pointes have been reported in patients treated with fluoxetine. Fluoxetine should be used with caution in patients with congenital long QT syndrome; previous history of QT prolongation; family history of long QT syndrome or sudden cardiac death; and other conditions that predispose to QT prolongation and ventricular arrhythmia. Such conditions include concomitant use of drugs that prolong the QT interval; hypokalemia or hypomagnesemia; recent myocardial infarction, uncompensated heart failure, bradyarrhythmias, and other significant arrhythmias; and conditions that predispose to increased fluoxetine exposure (overdose, hepatic impairment, use of CYP2D6 inhibitors, CYP2D6 poor metabolizer status, or use of other highly protein-bound drugs). Fluoxetine is primarily metabolized by CYP2D6 [see Contraindications (4.2), Drug Interactions (7.6, 7.7), Overdose (10.1), and Clinical Pharmacology (12.3)].Pimozide and thioridazine are contraindicated for use with fluoxetine. Avoid the concomitant use of drugs known to prolong the QT interval. These include specific antipsychotics (e.g., ziprasidone, iloperidone, chlorpromazine, mesoridazine, droperidol); specific antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin, sparfloxacin); Class IA antiarrhythmic medications (e.g., quinidine, procainamide); Class III antiarrhythmics (e.g., amiodarone, sotalol); and others (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus) [see Drug Interactions (7.6, 7.7) and Clinical Pharmacology (12.3)].Consider ECG assessment and periodic ECG monitoring if initiating treatment with fluoxetine in patients with risk factors for QT prolongation and ventricular arrhythmia. Consider discontinuing fluoxetine and obtaining cardiac evaluation if patients develop signs or symptoms consistent with ventricular arrhythmia.. 5.12 Use in Patients with Concomitant Illness. Clinical experience with fluoxetine in patients with concomitant systemic illness is limited. Caution is advisable in using fluoxetine in patients with diseases or conditions that could affect metabolism or hemodynamic responses.Cardiovascular--Fluoxetine has not been evaluated or used to any appreciable extent in patients with recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were systematically excluded from clinical studies during the products premarket testing. However, the ECGs of 312 patients who received fluoxetine in double-blind trials were retrospectively evaluated; no conduction abnormalities that resulted in heart block were observed. The mean heart rate was reduced by approximately beats/min.Glycemic Control--In patients with diabetes, fluoxetine may alter glycemic control. Hypoglycemia has occurred during therapy with fluoxetine, and hyperglycemia has developed following discontinuation of the drug. As is true with many other types of medication when taken concurrently by patients with diabetes, insulin and/or oral hypoglycemic, dosage may need to be adjusted when therapy with fluoxetine is instituted or discontinued.. 5.13 Potential for Cognitive and Motor Impairment. As with any CNS-active drug, fluoxetine has the potential to impair judgment, thinking, or motor skills. Patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that the drug treatment does not affect them adversely.. 5.14 Long Elimination Half-Life. Because of the long elimination half-lives of the parent drug and its major active metabolite, changes in dose will not be fully reflected in plasma for several weeks, affecting both strategies for titration to final dose and withdrawal from treatment. 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 [see Clinical Pharmacology (12.3)].. 5.15 Discontinuation Adverse Reactions. During marketing of fluoxetine, SNRIs, and SSRIs, there have been spontaneous reports of adverse reactions occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these reactions are generally self-limiting, there have been reports of serious discontinuation symptoms. Patients should be monitored for these symptoms when discontinuing treatment with fluoxetine. gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at more gradual rate. Plasma fluoxetine and norfluoxetine concentration decrease gradually at the conclusion of therapy which may minimize the risk of discontinuation symptoms with this drug.