FLUOXETINE HYDROCHLORIDE- fluoxetine hydrochloride_capsule

Although the exact mechanism of fluoxetine is unknown, it is presumed to be linked to its inhibition of CNS neuronal uptake of serotonin. Studies at clinically relevant doses in man have demonstrated that fluoxetine blocks the uptake of serotonin into human platelets. Studies in animals also suggest that fluoxetine is a much more potent uptake inhibitor of serotonin than of norepinephrine. Antagonism of muscarinic, histaminergic, and alpha1-adrenergic receptors has been hypothesized to be associated with various anticholinergic, sedative, and cardiovascular effects of classical tricyclic antidepressant (TCA) drugs. Fluoxetine binds to these and other membrane receptors from brain tissue much less potently in vitro Systemic Bioavailability The capsule, tablet and oral solution dosage forms of fluoxetine are bioequivalent. Food does not appear to affect the systemic bioavailability of fluoxetine, although it may delay its absorption by 1 to 2 hours, which is probably not clinically significant. Thus, fluoxetine may be administered with or without food. Protein Binding in vitro Enantiomers R S S Metabolism S R S R Variability in Metabolism S S S R Because fluoxetine’s metabolism, like that of a number of other compounds including TCAs and other selective serotonin reuptake inhibitors (SSRIs), involves the CYP2D6 system, concomitant therapy with drugs also metabolized by this enzyme system (such as the TCAs) may lead to drug interactions [see DRUG INTERACTIONS ( 7. 9 Accumulation and Slow Elimination WARNINGS AND PRECAUTIONS ( 5. 12 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 DOSAGE AND ADMINISTRATION ( 2. 6 Renal Disease Geriatric Pharmacokinetics Pediatric Pharmacokinetics (children and adolescents Higher average steady-state fluoxetine and norfluoxetine concentrations were observed in children relative to adults; however, these concentrations were within the range of concentrations observed in the adult population. As in adults, fluoxetine and norfluoxetine accumulated extensively following multiple oral dosing; steady-state concentrations were achieved within 3 to 4 weeks of daily dosing.

Fluoxetine is a selective serotonin reuptake inhibitor indicated for: Acute and maintenance treatment of Major Depressive Disorder (MDD) in adult and pediatric patients aged 8 to 18 years ( 1. 1 Acute and maintenance treatment of Obsessive Compulsive Disorder (OCD) in adult and pediatric patients aged 7 to 17 years ( 1. 2 Acute and maintenance treatment of Bulimia Nervosa in adult patients ( 1. 3 Acute treatment of Panic Disorder, with or without agoraphobia, in adult patients ( 1. 4 Fluoxetine and olanzapine in combination Acute treatment of Depressive Episodes Associated with Bipolar I Disorder in adults ( 1. 5 Fluoxetine hydrochloride is indicated for the acute and maintenance treatment of Major Depressive Disorder in adult patients and in pediatric patients aged 8 to18 years [see CLINICAL STUDIES ( 14. 1 The usefulness of the drug in adult and pediatric patients receiving fluoxetine for extended periods, should periodically be reevaluated [see DOSAGE AND ADMINISTRATION ( 2. 1 Fluoxetine is indicated for the acute and maintenance treatment of obsessions and compulsions in adult patients and in pediatric patients aged 7 to 17 years with Obsessive Compulsive Disorder (OCD) [see CLINICAL STUDIES ( 14. 2 The effectiveness of fluoxetine in long-term use, i. , for more than 13 weeks, has not been systematically evaluated in placebo-controlled trials. Therefore, the physician who elects to use fluoxetine for extended periods, should periodically re-evaluate the long-term usefulness of the drug for the individual patient [see DOSAGE AND ADMINISTRATION ( 2. 2 Fluoxetine is indicated for the acute and maintenance treatment of binge-eating and vomiting behaviors in adult patients with moderate to severe Bulimia Nervosa [see CLINICAL STUDIES ( 14. 3 The physician who elects to use fluoxetine for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient [see DOSAGE AND ADMINISTRATION ( 2. 3 Fluoxetine is indicated for the acute treatment of Panic Disorder, with or without agoraphobia, in adult patients [see CLINICAL STUDIES ( 14. 4 The effectiveness of fluoxetine in long-term use, i. , for more than 12 weeks, has not been established in placebo-controlled trials. 4 When using fluoxetine and olanzapine in combination, also refer to the Clinical Studies section of the package insert for Symbyax registered. Fluoxetine and olanzapine in combination is indicated for the acute treatment of depressive episodes associated with Bipolar I Disorder in adult patients. Fluoxetine monotherapy is not indicated for the treatment of depressive episodes associated with Bipolar I Disorder.

DOSAGE AND ADMINISTRATION
Indication Adult Pediatric MDD ( 2. 1 20 mg/day in am (initial dose) 10 to 20 mg/day (initial dose) OCD ( 2. 2 20 mg/day in am (initial dose) 10 mg/day (initial dose) Bulimia Nervosa ( 2. 3 60 mg/day in am en dash Panic Disorder ( 2. 4 10 mg/day (initial dose) en dash Depressive Episodes Associated with Bipolar I Disorder ( 2. 5 Oral in combination with olanzapine: 5 mg of oral olanzapine and 20 mg of fluoxetine once daily (initial dose) en dash Consider tapering the dose of fluoxetine for pregnant women during the third trimester ( 2. 7 A lower or less frequent dosage should be used in patients with hepatic impairment, the elderly, and for patients with concurrent disease or on multiple concomitant medications ( 2. 7 Fluoxetine and olanzapine in combination Dosage adjustments, if indicated, should be made with the individual components according to efficacy and tolerability ( 2. 5 Fluoxetine monotherapy is not indicated for the treatment of Depressive Episodes associated with Bipolar I Disorder ( 2. 5 Safety of the coadministration of doses above 18 mg olanzapine with 75 mg fluoxetine has not been evaluated ( 2. 5 Adult A dose increase may be considered after several weeks if insufficient clinical improvement is observed. Doses above 20 mg/day may be administered on a once-a-day (morning) or BID schedule (i. , morning and noon) and should not exceed a maximum dose of 80 mg/day. Pediatric (children and adolescents) CLINICAL STUDIES ( 14. 1 However, due to higher plasma levels in lower weight children, the starting and target dose in this group may be 10 mg/day. A dose increase to 20 mg/day may be considered after several weeks if insufficient clinical improvement is observed. All patients Maintenance/Continuation/Extended Treatment Daily Dosing CLINICAL STUDIES ( 14. 1 Switching Patients to a Tricyclic Antidepressant (TCA) DRUG INTERACTIONS ( 7. 9 Switching Patients to or from a Monoamine Oxidase Inhibitor (MAOI) CONTRAINDICATIONS ( 4 DRUG INTERACTIONS ( 7. 1 Adult CLINICAL STUDIES ( 14. 2 Doses above 20 mg/day may be administered on a once daily (i. , morning) or BID schedule (i. , morning and noon). A dose range of 20 to 60 mg/day is recommended; however, doses of up to 80 mg/day have been well tolerated in open studies of OCD. The maximum fluoxetine dose should not exceed 80 mg/day. 2 In adolescents and higher weight children, treatment should be initiated with a dose of 10 mg/day. After 2 weeks, the dose should be increased to 20 mg/day. Additional dose increases may be considered after several more weeks if insufficient clinical improvement is observed. A dose range of 20 to 60 mg/day is recommended. In lower weight children, treatment should be initiated with a dose of 10 mg/day. A dose range of 20 to 30 mg/day is recommended. Experience with daily doses greater than 20 mg is very minimal, and there is no experience with doses greater than 60 mg. Maintenance/Continuation Treatment) Initial Treatment) CLINICAL STUDIES ( 14. 3 Maintenance/Continuation Treatment) CLINICAL STUDIES ( 14. 3 Initial Treatment) CLINICAL STUDIES ( 14. 4 A 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. Maintenance/Continuation Treatment) When using fluoxetine and olanzapine in combination, also refer to the Clinical Studies section of the package insert for Symbyax Fluoxetine should be administered in combination with oral olanzapine once daily in the evening, without regard to meals, generally beginning with 5 mg of oral olanzapine and 20 mg of fluoxetine. Dosage adjustments, if indicated, can be made according to efficacy and tolerability within dose ranges of fluoxetine 20 to 50 mg and oral olanzapine 5 to 12. Antidepressant efficacy was demonstrated with olanzapine and fluoxetine in combination with a dose range of olanzapine 6 to 12 mg and fluoxetine 25 to 50 mg. Safety and efficacy of fluoxetine in combination with olanzapine was determined in clinical trials supporting approval of Symbyax (fixed-dose combination of olanzapine and fluoxetine). Symbyax is dosed between 3 mg/25 mg (olanzapine/fluoxetine) per day and 12 mg/50 mg (olanzapine/fluoxetine) per day. The following table demonstrates the appropriate individual component doses of fluoxetine and olanzapine versus Symbyax. Dosage adjustments, if indicated, should be made with the individual components according to efficacy and tolerability. Table 1: Approximate Dose Correspondence Between Symbyax Symbyax (olanzapine/fluoxetine HCl) is a fixed-dose combination of fluoxetine and olanzapine. For Use in Combination Olanzapine fluoxetine 3 mg olanzapine/25 mg fluoxetine 2. 5 20 6 mg olanzapine/25 mg fluoxetine 5 20 12 mg olanzapine/25 mg fluoxetine 10+2. 5 20 6 mg olanzapine/50 mg fluoxetine 5 40+10 12 mg olanzapine/50 mg fluoxetine 10+2. 5 40+10 While there is no body of evidence to answer the question of how long a patient treated with fluoxetine and olanzapine in combination should remain on it, it is generally accepted that Bipolar I Disorder, including the depressive episodes associated with Bipolar I Disorder, is a chronic illness requiring chronic treatment. The physician should periodically re-examine the need for continued pharmacotherapy. Safety of coadministration of doses above 18 mg olanzapine with 75 mg fluoxetine has not been evaluated in clinical studies. Fluoxetine monotherapy is not indicated for the treatment of depressive episodes associated with Bipolar I Disorder. Treatment of pregnant Women During the Third Trimester) USE IN SPECIFIC POPULATIONS ( 8. 1 Geriatrics) USE IN SPECIFIC POPULATIONS ( 8. 5 Hepatic Impairment) CLINICAL PHARMACOLOGY ( 12. 4 USE IN SPECIFIC POPULATIONS ( 8. 6 Concomitant Illness) CLINICAL PHARMACOLOGY ( 12. 4 WARNINGS AND PRECAUTIONS ( 5. 1 Fluoxetine and Olanzapine in Combination) [see Warnings and Precautions ( 5. 9 Symptoms associated with discontinuation of fluoxetine, SNRIs, and SSRIs, have been reported [see WARNINGS AND PRECAUTIONS ( 5.
Initial Treatment
Adult A dose increase may be considered after several weeks if insufficient clinical improvement is observed. Doses above 20 mg/day may be administered on a once-a-day (morning) or BID schedule (i.e., morning and noon) and should not exceed a maximum dose of 80 mg/day. Pediatric (children and adolescents) CLINICAL STUDIES ( 14.1 However, due to higher plasma levels in lower weight children, the starting and target dose in this group may be 10 mg/day. A dose increase to 20 mg/day may be considered after several weeks if insufficient clinical improvement is observed. All patients Maintenance/Continuation/Extended Treatment Daily Dosing CLINICAL STUDIES ( 14.1 Switching Patients to a Tricyclic Antidepressant (TCA) DRUG INTERACTIONS ( 7.9 Switching Patients to or from a Monoamine Oxidase Inhibitor (MAOI) CONTRAINDICATIONS ( 4 DRUG INTERACTIONS ( 7.1
Initial Treatment
Adult CLINICAL STUDIES ( 14.2 Doses above 20 mg/day may be administered on a once daily (i.e., morning) or BID schedule (i.e., morning and noon). A dose range of 20 to 60 mg/day is recommended; however, doses of up to 80 mg/day have been well tolerated in open studies of OCD. The maximum fluoxetine dose should not exceed 80 mg/day. Pediatric (children and adolescents) CLINICAL STUDIES ( 14.2 In adolescents and higher weight children, treatment should be initiated with a dose of 10 mg/day. After 2 weeks, the dose should be increased to 20 mg/day. Additional dose increases may be considered after several more weeks if insufficient clinical improvement is observed. A dose range of 20 to 60 mg/day is recommended. In lower weight children, treatment should be initiated with a dose of 10 mg/day. Additional dose increases may be considered after several more weeks if insufficient clinical improvement is observed. A dose range of 20 to 30 mg/day is recommended. Experience with daily doses greater than 20 mg is very minimal, and there is no experience with doses greater than 60 mg. Maintenance/Continuation Treatment)
Daily Dosing
Adult Two 6-week controlled studies (N=671, randomized) comparing fluoxetine 20 mg and placebo have shown fluoxetine 20 mg daily to be effective in the treatment of elderly patients (>=60 years of age) with Major Depressive Disorder. In these studies, fluoxetine produced a significantly higher rate of response and remission as defined, respectively, by a 50% decrease in the HAM-D score and a total endpoint HAM-D score of <=8. fluoxetine was well tolerated and the rate of treatment discontinuations due to adverse reactions did not differ between fluoxetine (12%) and placebo (9%). A study was conducted involving depressed outpatients who had responded (modified HAMD-17 score of <=7 during each of the last 3 weeks of open-label treatment and absence of Major Depressive Disorder by DSM-III-R criteria) by the end of an initial 12-week open-treatment phase on fluoxetine 20 mg/day. These patients (N=298) were randomized to continuation on double-blind fluoxetine 20 mg/day or placebo. At 38 weeks (50 weeks total), a statistically significantly lower relapse rate (defined as symptoms sufficient to meet a diagnosis of Major Depressive Disorder for 2 weeks or a modified HAMD-17 score of >=14 for 3 weeks) was observed for patients taking fluoxetine compared with those on placebo. Pediatric (children and adolescents) In both studies independently, fluoxetine produced a statistically significantly greater mean change on the Childhood Depression Rating Scale-Revised (CDRS-R) total score from baseline to endpoint than did placebo. Subgroup analyses on the CDRS-R total score did not suggest any differential responsiveness on the basis of age or gender.

When using fluoxetine and olanzapine in combination, also refer to the Adverse Reactions section of the package insert for Symbyax. Most common adverse reactions (>=5% and at least twice that for placebo) associated with: Major Depressive Disorder, Obsessive Compulsive Disorder, Bulimia, and Panic Disorder: abnormal dreams, abnormal ejaculation, anorexia, anxiety, asthenia, diarrhea, dry mouth, dyspepsia, flu syndrome, impotence, insomnia, libido decreased, nausea, nervousness, pharyngitis, rash, sinusitis, somnolence, sweating, tremor, vasodilatation, and yawn ( 6. 1 Fluoxetine and olanzapine in combination en dash Also refer to the Adverse Reactions section of the package insert for Symbyax ( 6 To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www. gov/medwatch Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect or predict the rates observed in practice. Multiple doses of fluoxetine had been administered to 10,782 patients with various diagnoses in US clinical trials as of May 8, 1995. In addition, there have been 425 patients administered fluoxetine in panic clinical trials. Adverse reactions were recorded by clinical investigators using descriptive terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse reactions without first grouping similar types of reactions into a limited (i. , reduced) number of standardized reaction categories. In the tables and tabulations that follow, COSTART Dictionary terminology has been used to classify reported adverse reactions. The stated frequencies represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse reaction of the type listed. A reaction was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. It is important to emphasize that reactions reported during therapy were not necessarily caused by it. The prescriber should be aware that the figures in the tables and tabulations cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the population studied. Incidence in Major Depressive Disorder, OCD, bulimia, and Panic Disorder placebo-controlled clinical trials (excluding data from extensions of trials) Table 3. Most Common Treatment-Emergent Adverse Reactions: Incidence in Major Depressive Disorder, OCD, Bulimia, and Panic Disorder Placebo-Controlled Clinical Trials Incidence less than 1%. Includes US data for Major Depressive Disorder, OCD, Bulimia, and Panic Disorder clinical trials, plus non-US data for Panic Disorder clinical trials. Percentage of Patients Reporting Event Major Depressive Disorder OCD Bulimia Panic Disorder Body System/ Adverse Reaction Fluoxetine (N=1728) Placebo (N=975) Fluoxetine (N=266) Placebo (N=89) Fluoxetine (N=450) Placebo (N=267) Fluoxetine (N=425) Placebo (N=342) Body as a Whole Asthenia 9 5 15 11 21 9 7 7 Flu syndrome 3 4 10 7 8 3 5 5 Cardiovascular System Vasodilatation 3 2 5 en dash 2 1 1 en dash Digestive System Nausea 21 9 26 13 29 11 12 7 Diarrhea 12 8 18 13 8 6 9 4 Anorexia 11 2 17 10 8 4 4 1 Dry mouth 10 7 12 3 9 6 4 4 Dyspepsia 7 5 10 4 10 6 6 2 Nervous System Insomnia 16 9 28 22 33 13 10 7 Anxiety 12 7 14 7 15 9 6 2 Nervousness 14 9 14 15 11 5 8 6 Somnolence 13 6 17 7 13 5 5 2 Tremor 10 3 9 1 13 1 3 1 Table 3 (continued). Percentage of Patients Reporting Event Major Depressive Disorder OCD Bulimia Panic Disorder Body System/ Adverse Reaction Fluoxetine (N=1728) Placebo (N=975) Fluoxetine (N=266) Placebo (N=89) Fluoxetine (N=450) Placebo (N=267) Fluoxetine (N=425) Placebo (N=342) Nervous System Libido decreased 3 en dash 11 2 5 1 1 2 Abnormal dreams 1 1 5 2 5 3 1 1 Respiratory System Pharyngitis 3 3 11 9 10 5 3 3 Sinusitis 1 4 5 2 6 4 2 3 Yawn en dash en dash 7 en dash 11 en dash 1 en dash Skin and Appendages Sweating 8 3 7 en dash 8 3 2 2 Rash 4 3 6 3 4 4 2 2 Urogenital System Impotence Denominator used was for males only (N=690 fluoxetine Major Depressive Disorder; N=410 placebo Major Depressive Disorder; N=116 fluoxetine OCD; N=43 placebo OCD; N=14 fluoxetine bulimia; N=1 placebo bulimia; N=162 fluoxetine panic; N=121 placebo panic). 2 en dash en dash en dash 7 en dash 1 en dash Abnormal ejaculation en dash en dash 7 en dash 7 en dash 2 1 Table 4. Treatment-Emergent Adverse Reactions: Incidence in Major Depressive Disorder, OCD, Bulimia, and Panic Disorder Placebo-Controlled Clinical Trials Incidence less than 1%. Percentage of Patients Reporting Event Major Depressive Disorder, OCD, Bulimia, and Panic Disorder Combined Body System/ Adverse Reaction Fluoxetine (N=2869) Placebo (N=1673) Body as a Whole Headache 21 19 Asthenia 11 6 Flu syndrome 5 4 Fever 2 1 Cardiovascular System Vasodilatation 2 1 Digestive System Nausea 22 9 Diarrhea 11 7 Anorexia 10 3 Dry mouth 9 6 Dyspepsia 8 4 Constipation 5 4 Flatulence 3 2 Vomiting 3 2 Metabolic and Nutritional Disorders Weight loss 2 1 Nervous System Insomnia 19 10 Nervousness 13 8 Anxiety 12 6 Somnolence 12 5 Dizziness 9 6 Tremor 9 2 Libido decreased 4 1 Thinking abnormal 2 1 Respiratory System Yawn 3 en dash Skin and Appendages Sweating 7 3 Rash 4 3 Pruritus 3 2 Special Senses Abnormal vision 2 1 Associated with discontinuation in Major Depressive Disorder, OCD, bulimia, and Panic Disorder placebo-controlled clinical trials (excluding data from extensions of trials) Table 5: Most Common Adverse Reactions Associated with Discontinuation in Major Depressive Disorder, OCD, Bulimia, and Panic Disorder Placebo-Controlled Clinical Trials Includes US Major Depressive Disorder, OCD, Bulimia, and Panic Disorder clinical trials, plus non-US Panic Disorder clinical trials. Major Depressive Disorder, OCD, Bulimia, and Panic Disorder Combined (N=1533) Major Depressive Disorder (N=392) OCD (N=266) Bulimia (N=450) Panic Disorder (N=425) Anxiety en dash Anxiety en dash Anxiety en dash en dash en dash Insomnia en dash en dash Nervousness en dash en dash Nervousness en dash en dash Rash en dash en dash Other adverse reactions in pediatric patients (children and adolescents) The most common adverse reaction (incidence at least 1% for fluoxetine and greater than placebo) associated with discontinuation in 3 pediatric placebo-controlled trials (N=418 randomized; 228 fluoxetine-treated; 190 placebo-treated) was mania/hypomania (1. 8% for fluoxetine-treated, 0% for placebo-treated). In these clinical trials, only a primary reaction associated with discontinuation was collected. Male and female sexual dysfunction with SSRIs There are no adequate and well-controlled studies examining sexual dysfunction with fluoxetine treatment. 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 side effects. Following is a list of treatment-emergent adverse reactions reported by patients treated with fluoxetine in clinical trials. This listing is not intended to include reactions (1) already listed in previous tables or elsewhere in labeling, (2) for which a drug cause was remote, (3) which were so general as to be uninformative, (4) which were not considered to have significant clinical implications, or (5) which occurred at a rate equal to or less than placebo. Reactions are classified by body system using the following definitions: frequent adverse reactions are those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in fewer than 1/1000 patients. Body as a Whole Frequent: Infrequent: Rare: Cardiovascular System Frequent: Infrequent: Digestive System Infrequent: Rare: Hemic and Lymphatic System Infrequent: Rare: Nervous System Frequent: Infrequent: Rare: Respiratory System Rare: Skin and Appendages Rare: Special Senses Frequent: Infrequent: The following adverse reactions have been identified during post approval use of fluoxetine. Because these reactions are reported voluntarily from a population of uncertain size, it is difficult to reliably estimate their frequency or evaluate a causal relationship to drug exposure. Voluntary reports of adverse reactions temporally associated with fluoxetine that have been received since market introduction and that may have no causal relationship with the drug include the following: aplastic anemia, atrial fibrillation These terms represent serious adverse events, but do not meet the definition for adverse drug reactions. They are included here because of their seriousness. 1 1 1 1 1 1.

When using fluoxetine and olanzapine in combination, also refer to the Contraindications section of the package insert for Symbyax. The use of fluoxetine is contraindicated with the following: Monoamine Oxidase Inhibitors [see DRUG INTERACTIONS ( 7. 1 Pimozide [see DRUG INTERACTIONS ( 7. 9 Thioridazine [see DRUG INTERACTIONS ( 7. 9 Do not use with an MAOI or within 14 days of discontinuing an MAOI due to risk of drug interaction. At least 5 weeks should be allowed after stopping fluoxetine before treatment with an MAOI ( 4 7. 1 Do not use with pimozide due to risk of drug interaction or QTc prolongation ( 4 7. 9 Do not use with thioridazine due to QTc interval prolongation or potential for elevated thioridazine plasma levels. Do not use thioridazine within 5 weeks of discontinuing fluoxetine ( 4 7. 9 When using fluoxetine and olanzapine in combination, also refer to the Contraindications section of the package insert for Symbyax (4).

USE IN SPECIFIC POPULATIONS
When using fluoxetine and olanzapine and in combination, also refer to the Specific Populations section of the package insert for Symbyax. Pregnancy: 8. 1 Nursing Mothers: 8. 3 Pediatric Use: 8. 4 Hepatic Impairment: 8. 6 In embryo-fetal development studies in rats and rabbits, there was no evidence of teratogenicity following administration of up to 12. 5 and 15 mg/kg/day, respectively (1. 6 times, respectively, the MRHD of 80 mg on a mg/m 2 2 2 2 Treatment of Pregnant Women During the Third Trimester Infants exposed to SSRIs in late pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 to 2 per 1000 live births in the general population and is associated with substantial neonatal morbidity and mortality. In a retrospective case-control study of 377 women whose infants were born with PPHN and 836 women whose infants were born healthy, the risk for developing PPHN was approximately six-fold higher for infants exposed to SSRIs after the 20th week of gestation compared to infants who had not been exposed to antidepressants during pregnancy. There is currently no corroborative evidence regarding the risk for PPHN following exposure to SSRIs in pregnancy; this is the first study that has investigated the potential risk. The study did not include enough cases with exposure to individual SSRIs to determine if all SSRIs posed similar levels of PPHN risk. When treating pregnant women with fluoxetine during the third trimester, the physician should carefully consider both the potential risks and potential benefits of treatment. Physicians should note that in a prospective longitudinal study of 201 women with a history of major depression who were euthymic at the beginning of pregnancy, women who discontinued antidepressant medication during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressant medication. The physician may consider tapering fluoxetine in the third trimester. 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. 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. The concentration in the mother’s plasma was 295. No adverse effects on the infant were reported. In another case, an infant nursed by a mother on fluoxetine developed crying, sleep disturbance, vomiting, and watery stools. The infant’s plasma drug levels were 340 ng/mL of fluoxetine and 208 ng/mL of norfluoxetine on the second day of feeding. The efficacy of fluoxetine for the treatment of Major Depressive Disorder was demonstrated in two 8- to 9-week placebo-controlled clinical trials with 315 pediatric outpatients ages 8 to <=18 [see CLINICAL STUDIES ( 14. 1 The efficacy of fluoxetine for the treatment of OCD was demonstrated in one 13-week placebo-controlled clinical trial with 103 pediatric outpatients ages 7 to <18 [see CLINICAL STUDIES ( 14. 2 The safety and effectiveness in pediatric patients <8 years of age in Major Depressive Disorder and <7 years of age in OCD have not been established. Fluoxetine pharmacokinetics were evaluated in 21 pediatric patients (ages 6 to <=18) with Major Depressive Disorder or OCD [see CLINICAL PHARMACOLOGY ( 12. 3 The acute adverse reaction profiles observed in the 3 studies (N=418 randomized; 228 fluoxetine-treated, 190 placebo-treated) were generally similar to that observed in adult studies with fluoxetine. The longer-term adverse reaction profile observed in the 19-week Major Depressive Disorder study (N=219 randomized; 109 fluoxetine-treated, 110 placebo-treated) was also similar to that observed in adult trials with fluoxetine [see ADVERSE REACTIONS ( 6. 1 Manic reaction, including mania and hypomania, was reported in 6 (1 mania, 5 hypomania) out of 228 (2. 6%) fluoxetine-treated patients and in 0 out of 190 (0%) placebo-treated patients. Mania/hypomania led to the discontinuation of 4 (1. 8%) fluoxetine-treated patients from the acute phases of the 3 studies combined. Consequently, regular monitoring for the occurrence of mania/hypomania is recommended. As with other SSRIs, decreased weight gain has been observed in association with the use of fluoxetine in children and adolescent patients. After 19 weeks of treatment in a clinical trial, pediatric subjects treated with fluoxetine gained an average of 1. 1 cm less in height and 1. 1 kg less in weight than subjects treated with placebo. In addition, fluoxetine treatment was associated with a decrease in alkaline phosphatase levels. The safety of fluoxetine treatment for pediatric patients has not been systematically assessed for chronic treatment longer than several months in duration. In particular, there are no studies that directly evaluate the longer-term effects of fluoxetine on the growth, development and maturation of children and adolescent patients. Therefore, height and weight should be monitored periodically in pediatric patients receiving fluoxetine. [see WARNINGS AND PRECAUTIONS ( 5. 6 Fluoxetine is approved for use in pediatric patients with MDD and OCD [see Box Warning WARNINGS AND PRECAUTIONS ( 5. 1 Significant toxicity, including myotoxicity, long-term neurobehavioral and reproductive toxicity, and impaired bone development, has been observed following exposure of juvenile animals to fluoxetine. Some of these effects occurred at clinically relevant exposures. In a study in which fluoxetine (3, 10, or 30 mg/kg) was orally administered to young rats from weaning (Postnatal Day 21) through adulthood (Day 90), male and female sexual development was delayed at all doses, and growth (body weight gain, femur length) was decreased during the dosing period in animals receiving the highest dose. At the end of the treatment period, serum levels of creatine kinase (marker of muscle damage) were increased at the intermediate and high doses, and abnormal muscle and reproductive organ histopathology (skeletal muscle degeneration and necrosis, testicular degeneration and necrosis, epididymal vacuolation and hypospermia) was observed at the high dose. When animals were evaluated after a recovery period (up to 11 weeks after cessation of dosing), neurobehavioral abnormalities (decreased reactivity at all doses and learning deficit at the high dose) and reproductive functional impairment (decreased mating at all doses and impaired fertility at the high dose) were seen; in addition, testicular and epididymal microscopic lesions and decreased sperm concentrations were found in the high dose group, indicating that the reproductive organ effects seen at the end of treatment were irreversible. The reversibility of fluoxetine-induced muscle damage was not assessed. Adverse effects similar to those observed in rats treated with fluoxetine during the juvenile period have not been reported after administration of fluoxetine to adult animals. Plasma exposures (AUC) to fluoxetine in juvenile rats receiving the low, intermediate, and high dose in this study were approximately 0. 2, 1 to 2, and 5 to 10 times, respectively, the average exposure in pediatric patients receiving the maximum recommended dose (MRD) of 20 mg/day. Rat exposures to the major metabolite, norfluoxetine, were approximately 0. 8, 1 to 8, and 3 to 20 times, respectively, pediatric exposure at the MRD. A specific effect of fluoxetine on bone development has been reported in mice treated with fluoxetine during the juvenile period. When mice were treated with fluoxetine (5 or 20 mg/kg, intraperitoneal) for 4 weeks starting at 4 weeks of age, bone formation was reduced resulting in decreased bone mineral content and density. These doses did not affect overall growth (body weight gain or femoral length). The doses administered to juvenile mice in this study are approximately 0. 5 and 2 times the MRD for pediatric patients on a body surface area (mg/m 2 In another mouse study, administration of fluoxetine (10 mg/kg intraperitoneal) during early postnatal development (Postnatal Days 4 to 21) produced abnormal emotional behaviors (decreased exploratory behavior in elevated plus-maze, increase shock avoidance latency) in adulthood (12 weeks of age). The dose used in this study is approximately equal to the pediatric MRD on a mg/m 2 Safety and effectiveness of fluoxetine and olanzapine in combination in patients less than 18 years of age have not been established. US fluoxetine clinical trials included 687 patients >=65 years of age and 93 patients >=75 years of age. The efficacy in geriatric patients has been established [see CLINICAL STUDIES ( 14. 1 CLINICAL PHARMACOLOGY ( 12. 4 WARNINGS AND PRECAUTIONS ( 5. 8 Clinical studies of olanzapine and fluoxetine in combination did not include sufficient numbers of patients >= 65 years of age to determine whether they respond differently from younger patients. In subjects with cirrhosis of the liver, the clearances of fluoxetine and its active metabolite, norfluoxetine, were decreased, thus increasing the elimination half-lives of these substances. A lower or less frequent dose of fluoxetine should be used in patients with cirrhosis. Caution is advised when using fluoxetine in patients with diseases or conditions that could affect its metabolism [see DOSAGE AND ADMINISTRATION ( 2. 7 CLINICAL PHARMACOLOGY ( 12.
Pregnancy Category C
In embryo-fetal development studies in rats and rabbits, there was no evidence of teratogenicity following administration of up to 12.5 and 15 mg/kg/day, respectively (1.5 and 3.6 times, respectively, the MRHD of 80 mg on a mg/m 2 2 2 2 Treatment of Pregnant Women During the Third Trimester Infants exposed to SSRIs in late pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 to 2 per 1000 live births in the general population and is associated with substantial neonatal morbidity and mortality. In a retrospective case-control study of 377 women whose infants were born with PPHN and 836 women whose infants were born healthy, the risk for developing PPHN was approximately six-fold higher for infants exposed to SSRIs after the 20th week of gestation compared to infants who had not been exposed to antidepressants during pregnancy. There is currently no corroborative evidence regarding the risk for PPHN following exposure to SSRIs in pregnancy; this is the first study that has investigated the potential risk. The study did not include enough cases with exposure to individual SSRIs to determine if all SSRIs posed similar levels of PPHN risk. When treating pregnant women with fluoxetine during the third trimester, the physician should carefully consider both the potential risks and potential benefits of treatment. Physicians should note that in a prospective longitudinal study of 201 women with a history of major depression who were euthymic at the beginning of pregnancy, women who discontinued antidepressant medication during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressant medication. The physician may consider tapering fluoxetine in the third trimester.

As with all drugs, the potential for interaction by a variety of mechanisms (e. , pharmacodynamic, pharmacokinetic drug inhibition or enhancement, etc. ) is a possibility. Monoamine Oxidase Inhibitors (MAOI): 4 7. 1 Pimozide: 4 7. 9 Thioridazine: 4 7. 9 Drugs Metabolized by CYP2D6: 7. 9 Tricyclic Antidepressants (TCAs): 7. 9 CNS Acting Drugs: 7. 2 Benzodiazepines: 7. 9 Antipsycotics: 7. 9 Anticonvulsants: 7. 9 Serotonergic Drugs: 5. 3 Triptans: 5. 4 Tryptophan: 5. 5 Drugs that Interfere with Hemostasis (e. NSAIDs, Aspirin, Warfarin): 7. 6 Drugs Tightly Bound to Plasma Proteins: 7. 9 Olanzapine: 7. 9 There have been reports of serious, sometimes fatal, reactions (including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma) in patients receiving fluoxetine in combination with a monoamine oxidase inhibitor (MAOI), and in patients who have recently discontinued fluoxetine and are then started on an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. Therefore, fluoxetine should not be used in combination with an MAOI, or within a minimum of 14 days of discontinuing therapy with an MAOI [see CONTRAINDICATIONS ( 4 CLINICAL PHARMACOLOGY ( 12. 3 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 Based on the mechanism of action of SNRIs and SSRIs, including fluoxetine, and the potential for serotonin syndrome, caution is advised when fluoxetine is coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, tramadol, or St. John’s Wort [see WARNINGS AND PRECAUTIONS ( 5. 2 DRUG INTERACTIONS ( 7. 5 There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of fluoxetine with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases [see WARNINGS AND PRECAUTIONS ( 5. 3 Five patients receiving fluoxetine in combination with tryptophan experienced adverse reactions, including agitation, restlessness, and gastrointestinal distress. The concomitant use with tryptophan is not recommended [see WARNINGS AND PRECAUTIONS ( 5. 3 Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SNRIs or SSRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when fluoxetine is initiated or discontinued [see WARNINGS AND PRECAUTIONS ( 5. 7 There are no clinical studies establishing the benefit of the combined use of ECT and fluoxetine. There have been rare reports of prolonged seizures in patients on fluoxetine receiving ECT treatment. Drugs Tightly Bound to Plasma Proteins CLINICAL PHARMACOLOGY ( 12. 3 Pimozide CONTRAINDICATIONS ( 4 Thioridazine CONTRAINDICATIONS ( 4 In a study of 19 healthy male subjects, which included 6 slow and 13 rapid hydroxylators of debrisoquin, a single 25 mg oral dose of thioridazine produced a 2. 4-fold higher C max Thioridazine administration produces a dose-related prolongation of the QTc 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 CONTRAINDICATIONS ( 4 Tricyclic Antidepressants (TCAs) CLINICAL PHARMACOLOGY ( 12. 3 Benzodiazapines CLINICAL PHARMACOLOGY ( 12. 3 Antipsychotics CONTRAINDICATIONS ( 4 Anticonvulsants Lithium Drugs Tightly Bound to Plasma Proteins CLINICAL PHARMACOLOGY ( 12. 3 Drugs Metabolized by CYP3A4 in vivo Additionally, in vitro Olanzapine When using fluoxetine and olanzapine and in combination, also refer to the Drug Interactions section of the package insert for Symbyax.

Teratogenic Effects
In embryo-fetal development studies in rats and rabbits, there was no evidence of teratogenicity following administration of up to 12.5 and 15 mg/kg/day, respectively (1.5 and 3.6 times, respectively, the MRHD of 80 mg on a mg/m 2 2 2 2 Treatment of Pregnant Women During the Third Trimester Infants exposed to SSRIs in late pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 to 2 per 1000 live births in the general population and is associated with substantial neonatal morbidity and mortality. In a retrospective case-control study of 377 women whose infants were born with PPHN and 836 women whose infants were born healthy, the risk for developing PPHN was approximately six-fold higher for infants exposed to SSRIs after the 20th week of gestation compared to infants who had not been exposed to antidepressants during pregnancy. There is currently no corroborative evidence regarding the risk for PPHN following exposure to SSRIs in pregnancy; this is the first study that has investigated the potential risk. The study did not include enough cases with exposure to individual SSRIs to determine if all SSRIs posed similar levels of PPHN risk. When treating pregnant women with fluoxetine during the third trimester, the physician should carefully consider both the potential risks and potential benefits of treatment. Physicians should note that in a prospective longitudinal study of 201 women with a history of major depression who were euthymic at the beginning of pregnancy, women who discontinued antidepressant medication during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressant medication. The physician may consider tapering fluoxetine in the third trimester.
OVERDOSAGE
Worldwide exposure to fluoxetine hydrochloride is estimated to be over 38 million patients (circa 1999). Of the 1578 cases of overdose involving fluoxetine hydrochloride, alone or with other drugs, reported from this population, there were 195 deaths. Among 633 adult patients who overdosed on fluoxetine hydrochloride alone, 34 resulted in a fatal outcome, 378 completely recovered, and 15 patients experienced sequelae after overdosage, including abnormal accommodation, abnormal gait, confusion, unresponsiveness, nervousness, pulmonary dysfunction, vertigo, tremor, elevated blood pressure, impotence, movement disorder, and hypomania. The remaining 206 patients had an unknown outcome. The most common signs and symptoms associated with non-fatal overdosage were seizures, somnolence, nausea, tachycardia, and vomiting. The largest known ingestion of fluoxetine hydrochloride in adult patients was 8 grams in a patient who took fluoxetine alone and who subsequently recovered. However, in an adult patient who took fluoxetine alone, an ingestion as low as 520 mg has been associated with lethal outcome, but causality has not been established. Among pediatric patients (ages 3 months to 17 years), there were 156 cases of overdose involving fluoxetine alone or in combination with other drugs. Six patients died, 127 patients completely recovered, 1 patient experienced renal failure, and 22 patients had an unknown outcome. One of the six fatalities was a 9-year-old boy who had a history of OCD, Tourette’s syndrome with tics, attention deficit disorder, and fetal alcohol syndrome. He had been receiving 100 mg of fluoxetine daily for 6 months in addition to clonidine, methylphenidate, and promethazine. Mixed-drug ingestion or other methods of suicide complicated all 6 overdoses in children that resulted in fatalities. The largest ingestion in pediatric patients was 3 grams which was nonlethal. Other important adverse reactions reported with fluoxetine overdose (single or multiple drugs) include coma, delirium, ECG abnormalities (such as QT interval prolongation and ventricular tachycardia, including torsades de pointes-type arrhythmias), hypotension, mania, neuroleptic malignant syndrome-like reactions, pyrexia, stupor, and syncope. Studies in animals do not provide precise or necessarily valid information about the treatment of human overdose. However, animal experiments can provide useful insights into possible treatment strategies. The oral median lethal dose in rats and mice was found to be 452 and 248 mg/kg, respectively. Acute high oral doses produced hyperirritability and convulsions in several animal species. Among 6 dogs purposely overdosed with oral fluoxetine, 5 experienced grand mal seizures. Seizures stopped immediately upon the bolus intravenous administration of a standard veterinary dose of diazepam. In this short-term study, the lowest plasma concentration at which a seizure occurred was only twice the maximum plasma concentration seen in humans taking 80 mg/day, chronically. In a separate single-dose study, the ECG of dogs given high doses did not reveal prolongation of the PR, QRS, or QT intervals. Tachycardia and an increase in blood pressure were observed. Consequently, the value of the ECG in predicting cardiac toxicity is unknown. Nonetheless, the ECG should ordinarily be monitored in cases of human overdose [see OVERDOSAGE ( 10. 3 Treatment should consist of those general measures employed in the management of overdosage with any drug effective in the treatment of Major Depressive Disorder. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion, or in symptomatic patients. Activated charcoal should be administered. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit. No specific antidotes for fluoxetine are known. A specific caution involves patients who are taking or have recently taken fluoxetine and might ingest excessive quantities of a TCA. In such a case, accumulation of the parent tricyclic and/or an active metabolite may increase the possibility of clinically significant sequelae and extend the time needed for close medical observation [see DRUG INTERACTIONS ( 7. 9 Based on experience in animals, which may not be relevant to humans, fluoxetine-induced seizures that fail to remit spontaneously may respond to diazepam. In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians’ Desk Reference (PDR) For specific information about overdosage with olanzapine and fluoxetine in combination, refer to the Overdosage section of the Symbyax package insert.
NONCLINICAL TOXICOLOGY
Carcinogenicity 2 Mutagenicity in vivo Impairment of Fertility 2 USE IN SPECIFIC POPULATIONS ( 8. 4 Phospholipids are increased in some tissues of mice, rats, and dogs given fluoxetine chronically. This effect is reversible after cessation of fluoxetine treatment. Phospholipid accumulation in animals has been observed with many cationic amphiphilic drugs, including fenfluramine, imipramine, and ranitidine. The significance of this effect in humans is unknown.
CLINICAL STUDIES
When using fluoxetine and olanzapine in combination, also refer to the Clinical Studies section of the package insert for Symbyax. Adult Two 6-week controlled studies (N=671, randomized) comparing fluoxetine 20 mg and placebo have shown fluoxetine 20 mg daily to be effective in the treatment of elderly patients (>=60 years of age) with Major Depressive Disorder. In these studies, fluoxetine produced a significantly higher rate of response and remission as defined, respectively, by a 50% decrease in the HAM-D score and a total endpoint HAM-D score of <=8. fluoxetine was well tolerated and the rate of treatment discontinuations due to adverse reactions did not differ between fluoxetine (12%) and placebo (9%). A study was conducted involving depressed outpatients who had responded (modified HAMD-17 score of <=7 during each of the last 3 weeks of open-label treatment and absence of Major Depressive Disorder by DSM-III-R criteria) by the end of an initial 12-week open-treatment phase on fluoxetine 20 mg/day. These patients (N=298) were randomized to continuation on double-blind fluoxetine 20 mg/day or placebo. At 38 weeks (50 weeks total), a statistically significantly lower relapse rate (defined as symptoms sufficient to meet a diagnosis of Major Depressive Disorder for 2 weeks or a modified HAMD-17 score of >=14 for 3 weeks) was observed for patients taking fluoxetine compared with those on placebo. Pediatric (children and adolescents) In both studies independently, fluoxetine produced a statistically significantly greater mean change on the Childhood Depression Rating Scale-Revised (CDRS-R) total score from baseline to endpoint than did placebo. Subgroup analyses on the CDRS-R total score did not suggest any differential responsiveness on the basis of age or gender. Adult Table 6. Outcome Classification (%) on CGI Improvement Scale for Completers in Pool of Two OCD Studies Fluoxetine Outcome Classification Placebo 20 mg 40 mg 60 mg Worse 8% 0% 0% 0% No change 64% 41% 33% 29% Minimally improved 17% 23% 28% 24% Much improved 8% 28% 27% 28% Very much improved 3% 8% 12% 19% Exploratory analyses for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or sex. Pediatric (children and adolescents) Subgroup analyses on outcome did not suggest any differential responsiveness on the basis of age or gender. The effectiveness of fluoxetine for the treatment of bulimia was demonstrated in two 8-week and one 16-week, multicenter, parallel group studies of adult outpatients meeting DSM-III-R criteria for bulimia. Patients in the 8-week studies received either 20 or 60 mg/day of fluoxetine or placebo in the morning. Patients in the 16-week study received a fixed fluoxetine dose of 60 mg/day (once a day) or placebo. Patients in these 3 studies had moderate to severe bulimia with median binge-eating and vomiting frequencies ranging from 7 to 10 per week and 5 to 9 per week, respectively. In these 3 studies, fluoxetine 60 mg, but not 20 mg, was statistically significantly superior to placebo in reducing the number of binge-eating and vomiting episodes per week. The statistically significantly superior effect of 60 mg versus placebo was present as early as Week 1 and persisted throughout each study. The fluoxetine-related reduction in bulimic episodes appeared to be independent of baseline depression as assessed by the Hamilton Depression Rating Scale. In each of these 3 studies, the treatment effect, as measured by differences between fluoxetine 60 mg and placebo on median reduction from baseline in frequency of bulimic behaviors at endpoint, ranged from 1 to 2 episodes per week for binge-eating and 2 to 4 episodes per week for vomiting. The size of the effect was related to baseline frequency, with greater reductions seen in patients with higher baseline frequencies. Although some patients achieved freedom from binge-eating and purging as a result of treatment, for the majority, the benefit was a partial reduction in the frequency of binge-eating and purging. In a longer-term trial, 150 patients meeting DSM-IV criteria for Bulimia Nervosa, purging subtype, who had responded during a single-blind, 8-week acute treatment phase with fluoxetine 60 mg/day, were randomized to continuation of fluoxetine 60 mg/day or placebo, for up to 52 weeks of observation for relapse. Response during the single-blind phase was defined by having achieved at least a 50% decrease in vomiting frequency compared with baseline. Relapse during the double-blind phase was defined as a persistent return to baseline vomiting frequency or physician judgment that the patient had relapsed. Patients receiving continued fluoxetine 60 mg/day experienced a significantly longer time to relapse over the subsequent 52 weeks compared with those receiving placebo. The effectiveness of fluoxetine in the treatment of Panic Disorder was demonstrated in 2 double-blind, randomized, placebo-controlled, multicenter studies of adult outpatients who had a primary diagnosis of Panic Disorder (DSM-IV), with or without agoraphobia. Study 1 (N=180 randomized) was a 12-week flexible-dose study. Fluoxetine was initiated at 10 mg/day for the first week, after which patients were dosed in the range of 20 to 60 mg/day on the basis of clinical response and tolerability. A statistically significantly greater percentage of fluoxetine-treated patients were free from panic attacks at endpoint than placebo-treated patients, 42% versus 28%, respectively. Study 2 (N=214 randomized) was a 12-week flexible-dose study. Fluoxetine was initiated at 10 mg/day for the first week, after which patients were dosed in a range of 20 to 60 mg/day on the basis of clinical response and tolerability. A statistically significantly greater percentage of fluoxetine-treated patients were free from panic attacks at endpoint than placebo-treated patients, 62% versus 44%, respectively.
MEDICATION GUIDE
Fluoxetine Capsules Read the Medication Guide that comes with fluoxetine capsules before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your doctor about your medical condition or treatment. Talk with your doctor or pharmacist if there is something you do not understand or you want to learn more about fluoxetine capsules. What is the most important information I should know about fluoxetine capsules? Antidepressant medicines, depression and other serious mental illnesses, and suicidal thoughts or actions: Talk to your, or your family member’s, healthcare provider about: all risks and benefits of treatment with antidepressant medicines all treatment choices for depression or other serious mental illness Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment. Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a particularly high risk of having suicidal thoughts or actions. How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member? Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is very important when an antidepressant medicine is started or when the dose is changed. Call the healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings. Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare provider between visits as needed, especially if you have concerns about symptoms. Call a healthcare provider right away if you or your family member has any of the following symptoms, especially if they are new, worse, or worry you: thoughts about suicide or dying attempts to commit suicide new or worse depression new or worse anxiety feeling very agitated or restless panic attacks trouble sleeping (insomnia) new or worse irritability acting aggressive, being angry, or violent acting on dangerous impulses an extreme increase in activity and talking (mania) or other unusual changes in behavior or mood What else do I need to know about antidepressant medicines? Never stop an antidepressant medicine without first talking to a healthcare provider. Antidepressants are medicines used to treat depression and other illnesses. Antidepressant medicines have other side effects. Antidepressant medicines can interact with other medicines. Not all antidepressant medicines prescribed for children are FDA approved for use in children. What are fluoxetine capsules? Fluoxetine capsules are a prescription medicine used: for short and long-term treatment of depression in adults and children over the age of 8. for short and long-term treatment of Obsessive Compulsive Disorder (OCD) in adults and children over the age of 7. for short and long-term treatment of Bulimia Nervosa in adults. for short-term treatment of Panic Disorder, with or without agoraphobia, in adults. with the medicine olanzapine (Zyprexa), for the short-term treatment of episodes of depression that happen with Bipolar I Disorder. It is not known if fluoxetine capsules and olanzapine (Zyprexa) taken together is safe and works in children under 18 years of age. The symptoms of depression (Major Depressive Disorder, Bipolar I Disorder) include decreased mood, decreased interest, increased guilty feelings, decreased energy, decreased concentration, changes in appetite, and suicidal thoughts or behavior. With treatment, some of your symptoms of depression may improve. OCD is an anxiety disorder and is characterized by recurrent, unwanted thoughts (obsessions) and/or repetitive behaviors (compulsions). With treatment, some of your symptoms of OCD may improve. Panic Disorder is an anxiety disorder that includes panic attacks, which are sudden feelings of terror for no reason. You may also have physical symptoms, such as; fast heartbeat, chest pain, breathing difficulty, dizziness. With treatment, some of your symptoms of Panic Disorder may improve. Bulimia Nervosa, involves periods of overeating followed by purging (e. vomiting, excessive laxative use). With treatment, some of your symptoms of Bulimia Nervosa may improve. If you do not think you are getting better, call your doctor. Who should not take fluoxetine capsules? Do not take fluoxetine capsules if you take a Monoamine Oxidase Inhibitor (MAOI) or if you stopped taking an MAOI in the last 2 Do not take an MAOI within 5 weeks of stopping fluoxetine capsules high fever continued muscle spasms that you can not control rigid muscles changes in heart rate and blood pressure that happen fast confusion unconsciousness Ask your doctor or pharmacist if you are not sure if your medicine is an MAOI. Do not take fluoxetine capsules if you take Mellarilregistered (thioridazine). Do not take Mellaril within 5 weeks of stopping fluoxetine capsules Mellaril can cause serious heart rhythm problems and you could die suddenly. Do not take fluoxetine capsules if you take the antipsychotic medicine pimozide (Orapregistered). What should I tell my doctor before taking fluoxetine capsules? Fluoxetine capsules may not be right for you. Before starting fluoxetine capsules, tell your doctor about all your medical conditions, including if you have or had any of the following: seizures (convulsions) bipolar disorder (mania) are pregnant or plan to become pregnant. It is not known if fluoxetine capsules will harm your unborn baby. are breast-feeding or plan to breast-feed. fluoxetine capsules can pass into your breast milk and may harm your baby. You should not breast-feed while taking fluoxetine capsules. Talk to your doctor about the best way to feed your baby if you take fluoxetine capsules. Tell your doctor about all the medicines that you take, If you take fluoxetine capsules, you should not take any other medicines that contain fluoxetine hydrochloride: Symbyaxregistered Sarafemregistered Prozacregistered Weeklytrademark You could take too much medicine (overdose). How should I take fluoxetine capsules? Take fluoxetine capsules exactly as prescribed. Your doctor may need to change (adjust) the dose of fluoxetine capsules until it is right for you. If you miss a dose of fluoxetine capsules, 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 capsules at the same time. To prevent serious side effects, do not stop taking fluoxetine capsules suddenly. If you need to stop taking fluoxetine capsules, your doctor can tell you how to safely stop taking it. If you take too much fluoxetine capsules, call your doctor or poison control center right away, or get emergency treatment. Fluoxetine capsules can be taken with or without food. Fluoxetine capsules are usually taken once a day. If you do not think you are getting better or have any concerns about your condition while taking fluoxetine capsules, call your doctor. What should I avoid while taking fluoxetine capsules? Fluoxetine capsules can cause sleepiness and 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 capsules affects you. What are the possible side effects of fluoxetine capsules? Fluoxetine capsules may be associated with the following serious risks: Serotonin Syndrome: agitation hallucinations problems with coordination racing heart beat over-active reflexes fever nausea, vomiting, and diarrhea Severe allergic reactions: swelling of your face, eyes, or mouth trouble breathing Abnormal bleeding: the blood thinner warfarin (Coumadinregistered, Jantovenregistered) a non-steroidal anti-inflammatory drug (NSAID) aspirin Mania: Seizures Loss of appetite Low salt (sodium) levels in the blood (hyponatremia): headache feel weak confusion problems concentrating memory problems feel unsteady Common possible side effects of fluoxetine capsules include: Tell your doctor about any side effect that bothers you or that does not go away. These are not all the possible side effects with fluoxetine capsules. For more information, ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store fluoxetine capsules? Store at 20°-25°C (68°-77°F) (see USP Controlled Room Temperature). Keep fluoxetine capsules away from light. Keep fluoxetine capsules bottle closed tightly. Keep fluoxetine capsules and all medicines out of the reach of children. General information about fluoxetine capsules Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use fluoxetine capsules for a condition for which it was not prescribed. Do not give fluoxetine capsules to other people, even if they have the same condition. It may harm them. This Medication Guide summarizes the most important information about fluoxetine capsules. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about fluoxetine capsules that was written for healthcare professionals. What are the ingredients in fluoxetine capsules? Active ingredients: Inactive ingredients: The following are registered trademarks of their respective manufacturers: Symbyaxregistered, Sarafemregistered, Prozacregistered Weeklytrademark/Eli Lilly and Company; Mellarilregistered/Novartis AG Corporation; Orapregistered/Teva Pharmaceuticals USA; Coumadinregistered/Bristol Myers Squibb; Jantovenregistered/Upsher-Smith Laboratories Inc. This Medication Guide has been approved by the U. Food and Drug Administration. 07-2010M 7269 Sandoz Inc. Princeton, NJ 08540.

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