Olanzapine and Fluoxetine Capsules, USP combines an atypical antipsychotic and a selective serotonin reuptake inhibitor, olanzapine (the active ingredient in Zyprexa, and Zyprexa Zydis) and fluoxetine hydrochloride (the active ingredient in Prozac and Sarafem). Olanzapine belongs to the thienobenzodiazepine class. The chemical designation is 2-methyl-4-(4-methyl-1-piperazinyl)-10 H- thieno[2,3- b ] [1,5]benzodiazepine. The molecular formula is C 17 H 20 N 4 S, which corresponds to a molecular weight of 312.44. Fluoxetine hydrochloride is a selective serotonin reuptake inhibitor (SSRI). The chemical designation is (±)-N-methyl-3-phenyl-3-[(α,α,α-trifluoro- p -tolyl)oxy]propylamine hydrochloride. The molecular formula is C 17 H 18 F 3 NO•HCl, which corresponds to a molecular weight of 345.79. The chemical structures are: Olanzapine is a yellow crystalline solid, which is practically insoluble in water. Fluoxetine hydrochloride is a white to off-white crystalline solid with a solubility of 14 mg/mL in water. Olanzapine and Fluoxetine Capsules, USP are available for oral administration in the following strength combinations: 3 mg/25 mg 6 mg/25 mg 6 mg/50 mg 12 mg/25 mg 12 mg/50 mg Olanzapine 3 6 6 12 12 Fluoxetine base equivalent 25 25 50 25 50 Each capsule consists of gelatin, magnesium stearate, partially pregelatinized starch, titanium dioxide, and yellow iron oxide. In addition, the 3 mg/25 mg capsule also contains red iron oxide; the 6 mg/50 mg capsule also contains FD&C blue No. 2, FD&C red No. 3, and FD&C yellow No. 6; the 12 mg/25 mg capsule also contains D&C red No. 28, FD&C blue No. 1, FD&C red No. 40, and red iron oxide; and the 12 mg/50 mg capsule also contains D&C red No. 28, FD&C blue No. 1 FD&C blue No. 2, FD&C red No. 3, FD&C red No. 40, and FD&C yellow No. 6. The capsules also have printing in edible black ink which contains the following ingredients: D&C yellow No. 10, ethanol, FD&C blue No. 1, FD&C blue No. 2, FD&C red No. 40, iron oxide black, methanol, n-Butyl alcohol, propylene glycol, and shellac glaze in alcohol. This is the structure

AND USAGE Fluoxetine Capsules USP are 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

Capsules USP and olanzapine in combination for:

Acute treatment of Depressive Episodes Associated with Bipolar I Disorder ( 1.5 )

1.1 Major Depressive Disorder Fluoxetine Capsules USP are indicated for the acute and maintenance treatment of Major Depressive Disorder in adult patients and in pediatric patients aged 8 to 18 years [ see Clinical Studies ( 14.1 ) ] . The usefulness of the drug in adult and pediatric patients receiving fluoxetine for extended periods should periodically be re-evaluated [ see Dosage and Administration ( 2.1 ) ] .

1.2 Obsessive Compulsive Disorder Fluoxetine Capsules USP are 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 capsules USP in long-term use, i.e., for more than 13 weeks, has not been systematically evaluated in placebo-controlled trials. Therefore, the physician who elects to use fluoxetine capsules USP for extended periods, should periodically re-evaluate the long-term usefulness of the drug for the individual patient [ see Dosage and Administration ( 2.2 ) ] .

1.3 Bulimia Nervosa Fluoxetine Capsules USP are 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 capsules USP for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient [ see Dosage and Administration ( 2.3 ) ] .

1.4 Panic Disorder Fluoxetine Capsules USP are indicated for the acute treatment of Panic Disorder, with or without agoraphobia, in adult patients [ see Clinical Studies ( 14.4 ) ] . The effectiveness of fluoxetine capsules USP in long-term use, i.e., for more than 12 weeks, has not been established in placebo-controlled trials. Therefore, the physician who elects to use fluoxetine capsules USP for extended periods, should periodically re-evaluate the long-term usefulness of the drug for the individual patient [ see Dosage and Administration ( 2.4 ) ].

1.5 Fluoxetine Capsules USP and Olanzapine in Combination: Depressive Episodes Associated With Bipolar I Disorder When using fluoxetine capsules USP and olanzapine in combination, also refer to the Clinical Studies section of the package insert for Symbyax ® .

Fluoxetine

Capsules USP and olanzapine in combination is indicated for the acute treatment of depressive episodes associated with Bipolar I Disorder.

Fluoxetine

Capsules USP monotherapy is not indicated for the treatment of depressive episodes associated with Bipolar I Disorder.

AND ADMINISTRATION This product is only available in a 60 mg dosage form. A 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: Indication Adult Pediatric MDD (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 a 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 Treatment Adult —Initiate fluoxetine tablets 20 mg/day orally in the morning. Consider a dose increase after several weeks if insufficient clinical improvement is observed. Administer doses above 20 mg/day once daily in the morning or twice daily (i.e., morning and noon). The maximum fluoxetine tablets dose should not exceed 80 mg/day. In controlled trials used to support the efficacy of fluoxetine tablets, patients were administered morning doses ranging from 20 to 80 mg/day. Studies comparing fluoxetine tablets 20, 40, and 60 mg/day to placebo indicate that 20 mg/day is sufficient to obtain a satisfactory response in MDD in most cases [see Clinical Studies (14.1)]. Pediatric (children and adolescents) —Treatment should be initiated with a dose of 10 or 20 mg/day.

After

1 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. A 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 tablets supporting its effectiveness in the treatment of MDD, patients were administered fluoxetine tablets 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 a 60 mg dosage form. Administration of doses with demonstrated efficacy of fluoxetine tablets 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 4 weeks of treatment or longer. Periodically reassess to determine the need for maintenance treatment.

Switching

Patients to a Tricyclic Antidepressant (TCA) —Dosage of a TCA may need to be reduced, and plasma TCA concentrations may need to be monitored temporarily when fluoxetine tablets are co-administered or has been recently discontinued [see Warnings and Precautions (5.2) and Drug Interactions (7.6)].

2.2 Obsessive Compulsive Disorder Initial Treatment Adults —Initiate fluoxetine tablets 20 mg/day, orally in the morning. Consider a dose increase after several weeks if insufficient clinical improvement is observed. The full therapeutic effect may be delayed until 5 weeks of treatment or longer. Doses above 20 mg/day may be administered on a once daily (i.e., morning) or twice daily 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 tablets dose should not exceed 80 mg/day. In the controlled clinical trials of fluoxetine tablets supporting its effectiveness in the treatment of OCD, patients were administered fixed daily doses of 20, 40, or 60 mg of fluoxetine tablets 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 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. In the controlled clinical trial of fluoxetine tablets supporting its effectiveness in the treatment of OCD, patients were administered fluoxetine tablets 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 tablets 60 mg/day in the morning. For some patients it may be advisable to titrate up to this target dose over several days. Fluoxetine tablets doses above 60 mg/day have not been systematically studied in patients with Bulimia Nervosa. In the controlled clinical trials of fluoxetine tablets supporting its effectiveness in the treatment of Bulimia Nervosa, patients were administered fixed daily fluoxetine tablets 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 a dose of 10 mg/day.

2.3 Bulimia Nervosa Initial Treatment —Administer fluoxetine tablets 60 mg/day in the morning. For some patients it may be advisable to titrate up to this target dose over several days. Fluoxetine tablets doses above 60 mg/day have not been systematically studied in patients with Bulimia Nervosa. In the controlled clinical trials of fluoxetine tablets supporting its effectiveness in the treatment of Bulimia Nervosa, patients were administered fixed daily fluoxetine tablets 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 a dose of 10 mg/day.

After

1 week, the dose should be increased to 20 mg/day. A dose increase may be considered after several weeks if no clinical improvement is observed. Fluoxetine tablets doses above 60 mg/day have not been systematically evaluated in patients with Panic Disorder. In the controlled clinical trials of fluoxetine tablets supporting its effectiveness in the treatment of Panic Disorder, patients were administered fluoxetine tablets doses in the range of 10 to 60 mg/day [see Clinical Studies (14.4)]. The most frequently administered dose in the 2 flexible-dose clinical trials was 20 mg/day. Periodically reassess to determine the need for continued treatment.

2.5 Dosing in Specific Populations 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, a 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)].

4.

Contraindications

When using fluoxetine and olanzapine in combination, also refer to the Contraindications section of the package insert for olanzapine and fluoxetine hydrochloride capsules .

Serotonin

Syndrome and MAOIs: Do not use MAOIs intended to treat psychiatric disorders with fluoxetine or within 5 weeks of stopping treatment with fluoxetine. Do not use fluoxetine within 14 days of stopping an MAOI intended to treat psychiatric disorders. In addition, do not start fluoxetine in a patient who is being treated with linezolid or intravenous methylene blue (4.1) Pimozide: Do not use. Risk of QT prolongation and drug interaction (4.2, 5.11,7.7, 7.8) Thioridazine: Do not use. Risk of QT interval prolongation and elevated thioridazine plasma levels. Do not use thioridazine within 5 weeks of discontinuing fluoxetine Do not use thioridazine within 5 weeks of discontinuing fluoxetine (4.2, 5.11,7.7, 7.8). When using fluoxetine and olanzapine in combination, also refer to the Contraindications section of the package insert for olanzapine and fluoxetine hydrochloride capsules (4)

4.1 Monoamine Oxidase Inhibitors (MAOIs) The use of MAOIs intended to treat psychiatric disorders with fluoxetine or within 5 weeks of stopping treatment with fluoxetine is contraindicated because of an increased risk of serotonin syndrome. The use of fluoxetine within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated [see Dosage and Administration (2.9) and Warnings and Precautions (5.2)]. Starting fluoxetine in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome [see Dosage and Administration (2.10) and Warnings and Precautions (5.2)].

4.2 Other Contraindications The use of fluoxetine is contraindicated with the following:

Pimozide [see Warnings and Precautions (5.11) and Drug Interactions (7.7, 7.8)]
Thioridazine [see Warnings and Precautions (5.11) and Drug Interactions (7.7, 7.8)] Pimozide and thioridazine prolong the QT interval. Fluoxetine can increase the levels of pimozide and thioridazine through inhibition of CYP2D6. Fluoxetine can also prolong the QT interval.

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)]

Increased

Risk of Bleeding [see Warnings and Precautions (5.7)] Angle-closure Glaucoma [see Warnings and Precautions (5.8)] Hyponatremia [see Warnings and Precautions (5.9)] Anxiety and Insomnia [see Warnings and Precautions (5.10)] QT Prolongation [see Warnings and Precautions (5.11)] Potential for Cognitive and Motor Impairment [see Warnings and Precautions (5.13)]

Discontinuation Adverse

Reactions [see Warnings and Precautions (5.15)] 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 Par Pharmaceutical at 1-800-828-9393 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

Risk of Bleeding : SSRIs increase the risk of bleeding. Use with NSAIDs, aspirin, warfarin, or other drugs that affect coagulation may potentiate the risk of gastrointestinal or other bleeding (5.16) Hyponatremia : Can occur in association with syndrome of inappropriate antidiuretic hormone (SIADH). Consider discontinuing Olanzapine and Fluoxetine capsules if symptomatic hyponatremia occurs (SIADH) (5.17) Potential for Cognitive and Motor Impairment : Has potential to impair judgment, thinking, and motor skills. Caution patients about operating machinery (5.18) QT Prolongation : QT prolongation and ventricular arrhythmia including Torsade de Pointes have been reported with fluoxetine. Use with caution in conditions that predispose to arrhythmias or increased fluoxetine exposure. Use cautiously in patients with risk factors for QT prolongation (4.2, 5.20) Anticholinergic (antimuscarinic) Effects : Use with caution with other anticholinergic drugs and in patients with urinary retention, prostatic hypertrophy, constipation, history of paralytic ileus or related conditions (5.21) Hyperprolactinemia : May elevate prolactin levels (5.22)

Long Elimination

Half-Life of Fluoxetine : Changes in dose will not be fully reflected in plasma for several weeks (5.24)

Sexual

Dysfunction: Olanzapine and Fluoxetine capsules use may cause symptoms of sexual dysfunction (5.26)

5.1 Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults Patients with Major Depressive Disorder (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 a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a 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 Major Depressive Disorder (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 a 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, Obsessive Compulsive Disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a 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: Suicidality per 1000 Patients Treated Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Increases Compared to Placebo <18 14 additional cases 18 to 24 5 additional cases Decreases Compared to Placebo 25 to 64 1 fewer case ≥65 6 fewer cases No 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 a 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 Major Depressive Disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a 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 patient's 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 (5.25)] . Families and caregivers of patients being treated with antidepressants for Major Depressive Disorder 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 olanzapine and fluoxetine should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose. It should be noted that olanzapine and fluoxetine capsules are not approved for use in treating any indications in patients less than 10 years of age [see Use in Specifi c Populations (8.4)] .

5.2 Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Olanzapine and Fluoxetine capsules are not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning and Use in Specific Populations (8.5)]. In olanzapine placebo-controlled clinical trials of elderly patients with dementia-related psychosis, the incidence of death in olanzapine-treated patients was significantly greater than placebo-treated patients (3.5% vs 1.5%, respectively). Meta-Analysis of Antipsychotic Use in Dementia-Related Psychosis — Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of seventeen placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. Olanzapine and Fluoxetine Capsules are not approved for the treatment of patients with dementia-related psychosis [see Use in Specific Populations (8.5)] .

Cerebrovascular Adverse

Events (CVAE), Including Stroke — Cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, were reported in patients in trials of olanzapine in elderly patients with dementia-related psychosis. In placebo-controlled trials, there was a significantly higher incidence of cerebrovascular adverse events in patients treated with olanzapine compared to patients treated with placebo. Olanzapine and olanzapine and fluoxetine capsules are not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning] .

5.3 Neuroleptic Malignant Syndrome (NMS) A potentially fatal symptom complex sometimes referred to as NMS has been reported in association with administration of antipsychotic drugs, including olanzapine. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to exclude cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology. The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, 2) intensive symptomatic treatment and medical monitoring, and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for NMS. If after recovering from NMS, a patient requires treatment with an antipsychotic, the patient should be carefully monitored, since recurrences of NMS have been reported [see Warnings and Precautions (5.5)] .

5.4 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)

Drug

Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported with olanzapine exposure. DRESS may present with a cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, and/or lymphadenopathy with systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and/or pericarditis. DRESS is sometimes fatal. Discontinue olanzapine and fluoxetine capsules if DRESS is suspected.

3% of olanzapine and fluoxetine-treated patients gained at least 15% of their baseline weight, with a median exposure to event of 8 weeks. This was greater than in placebo-treated patients (0%). Clinically significant weight gain was observed across all baseline Body Mass Index (BMI) categories. Discontinuation due to weight gain occurred in 2.5% of olanzapine and fluoxetine-treated patients and 0% of placebo-treated patients. In long-term olanzapine and fluoxetine in combination studies (at least 48 weeks), the mean weight gain was 6.7 kg (14.7 lb) (median exposure of 448 days, N=431). The percentages of patients who gained at least 7%, 15% or 25% of their baseline body weight with long-term exposure were 66%, 33%, and 10%, respectively. Discontinuation due to weight gain occurred in 1.2% of patients treated with olanzapine and fluoxetine in combination following at least 48 weeks of exposure.

Table

11 presents the distribution of weight gain in a single long-term relapse prevention study of patients treated for up to 47 weeks with olanzapine and fluoxetine [see Clinical Studies (14.2)].

Table

11: Weight Gain with Olanzapine and Fluoxetine Use in a Single Relapse Prevention Study in Adults Amount Gained kg (lb) Up to 8 Weeks (N=881) (%) Up to 20 Weeks (N=651) (%) Up to 47 Weeks (N=220) (%) ≤0 19.8 14.9 19.1 0 to ≤5 (0 to 11 lb) 64.1 47.2 37.7 >5 to ≤10 (11 to 22 lb) 15.1 30.3 27.7 >10 to ≤15 (22 to 33 lb) 0.9 5.8 10.0 >15 to ≤20 (33 to 44 lb) 0.1 1.2 3.2 >20 to ≤25 (44 to 55 lb) 0.0 0.6 1.4 >25 to ≤30 (55 to 66 lb) 0.0 0.0 0.5 >30 (>66 lb) 0.0 0.0

0.5 In long-term olanzapine studies (at least 48 weeks), the mean weight gain was 5.6 kg (12.3 lb) (median exposure of 573 days, N=2021). The percentages of patients who gained at least 7%, 15%, or 25% of their baseline body weight with long-term exposure were 64%, 32%, and 12%, respectively. Discontinuation due to weight gain occurred in 0.4% of olanzapine-treated patients following at least 48 weeks of exposure.

0.5 In long-term olanzapine studies (at least 48 weeks), the mean weight gain was 5.6 kg (12.3 lb) (median exposure of 573 days, N=2021). The percentages of patients who gained at least 7%, 15%, or 25% of their baseline body weight with long-term exposure were 64%, 32%, and 12%, respectively. Discontinuation due to weight gain occurred in 0.4% of olanzapine-treated patients following at least 48 weeks of exposure.

5.6 Serotonin Syndrome Selective serotonin reuptake inhibitors (SSRIs), including olanzapine and fluoxetine, can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, meperidine, methadone, tryptophan, buspirone, amphetamines, and St. John’s Wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs [see Contraindications ( 4.1 ), Drug Interactions ( 7.1 )]. Serotonin syndrome can also occur when these drugs are used alone. Serotonin syndrome signs and symptoms 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 symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The concomitant use of olanzapine and fluoxetine with MAOIs is contraindicated. In addition, do not initiate olanzapine and fluoxetine in a patient being treated with MAOIs such as linezolid or intravenous methylene blue. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection). If it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking olanzapine and fluoxetine, discontinue olanzapine and fluoxetine before initiating treatment with the MAOI [see Contraindications ( 4.1 ) and Drug Interactions ( 7.1 )] . Monitor all patients taking olanzapine and fluoxetine for the emergence of serotonin syndrome. Discontinue treatment with olanzapine and fluoxetine and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of olanzapine and fluoxetine with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms.

5.7 Angle-Closure Glaucoma Angle-Closure Glaucoma – The pupillary dilation that occurs following use of many antidepressant drugs including olanzapine and fluoxetine may trigger an angle-closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.

5.8 Allergic Reactions and Rash In olanzapine and fluoxetine premarketing controlled clinical studies, the overall incidence of rash or allergic reactions in olanzapine and fluoxetine-treated patients [4.6% (26/571)] was similar to that of placebo [5.2% (25/477)]. The majority of the cases of rash and/or urticaria were mild; however, 3 patients discontinued (1 due to rash, which was moderate in severity and 2 due to allergic reactions, 1 of which included face edema). In fluoxetine U.S. clinical studies, 7% of 10,782 fluoxetine-treated patients developed various types of rashes and/or urticaria. Among the cases of rash and/or urticaria reported in premarketing clinical studies, almost a 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 fluoxetine premarketing clinical studies, 2 patients are known to have developed a serious cutaneous systemic illness. In neither patient was there an unequivocal diagnosis, but 1 was considered to have a leukocytoclastic vasculitis, and the other, a severe desquamating syndrome that was considered variously to be a 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, 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, 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 a common underlying cause or are due to different etiologies or pathogenic processes is not known. Furthermore, a specific underlying immunologic basis for these reactions has not been identified. Upon the appearance of rash or of other possible allergic phenomena for which an alternative etiology cannot be identified, olanzapine and fluoxetine capsules should be discontinued.

5.9 Activation of Mania/Hypomania A 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 a manic episode in patients at risk for Bipolar Disorder. Whether any of the symptoms described for clinical worsening and suicide risk represent such a 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 a detailed psychiatric history, including a family history of suicide, Bipolar Disorder, and depression. It should be noted that olanzapine and fluoxetine capsules are approved for the acute treatment of depressive episodes associated with Bipolar I Disorder. In the 3 controlled bipolar depression studies (2 in adults and 1 in children and adolescents [10 to 17 years of age]) there was no statistically significant difference in the incidence of manic reactions (manic reaction or manic depressive reaction) between olanzapine and fluoxetine- and placebo-treated patients.

In

1 adult study, the incidence of manic reactions was (7% [3/43]) in olanzapine and fluoxetine-treated patients compared to (3% [5/184]) in placebo-treated patients. In the other adult study, the incidence of manic reactions was (2% [1/43]) in olanzapine and fluoxetine-treated patients compared to (8% [15/193]) in placebo-treated patients. In a single, 8-week, randomized, placebo-controlled clinical trial investigating olanzapine and fluoxetine for the treatment of bipolar I depression in patients 10 to 17 years of age, the incidence of manic reactions was (1% [2/170]) in olanzapine and fluoxetine-treated patients compared to (0% [0/84]) in placebo-treated patients. Because of the cyclical nature of Bipolar I Disorder, patients should be monitored closely for the development of symptoms of mania/hypomania during treatment with olanzapine and fluoxetine.

5.10 Tardive Dyskinesia A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown. The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses or may even arise after discontinuation of treatment. Tardive dyskinesia may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown. The incidence of dyskinetic movement in olanzapine and fluoxetine-treated patients was infrequent. The mean score on the Abnormal Involuntary Movement Scale (AIMS) in the olanzapine and fluoxetine-controlled database across clinical studies involving olanzapine and fluoxetine-treated patients decreased from baseline. Nonetheless, olanzapine and fluoxetine should be prescribed in a manner that is most likely to minimize the risk of tardive dyskinesia. If signs and symptoms of tardive dyskinesia appear in a patient on olanzapine and fluoxetine capsules, drug discontinuation should be considered. However, some patients may require treatment with olanzapine and fluoxetine despite the presence of the syndrome. The need for continued treatment should be reassessed periodically.

5.11 Orthostatic Hypotension Olanzapine and Fluoxetine may induce orthostatic hypotension associated with dizziness, tachycardia, bradycardia, and in some patients, syncope, especially during the initial dose-titration period. In the olanzapine and fluoxetine-controlled clinical trials across all indications, there were no significant differences between olanzapine and fluoxetine-treated patients and olanzapine, fluoxetine- or placebo-treated patients in exposure-adjusted rates of orthostatic systolic blood pressure decreases of at least 30 mm Hg. Orthostatic systolic blood pressure decreases of at least 30 mm Hg occurred in 4.0% (28/705), 2.3% (19/831), 4.5% (18/399), and 1.8% (8/442) of the olanzapine and fluoxetine, olanzapine, fluoxetine, and placebo groups, respectively. In this group of studies, the incidence of syncope-related adverse reactions (i.e., syncope and/or loss of consciousness) in olanzapine and fluoxetine-treated patients was 0.4% (3/771) compared to placebo 0.2% (1/477). In a clinical pharmacology study of olanzapine and fluoxetine, 3 healthy subjects were discontinued from the trial after experiencing severe, but self-limited, hypotension and bradycardia that occurred 2 to 9 hours following a single 12 mg/50 mg dose of olanzapine and fluoxetine capsules. Reactions consisting of this combination of hypotension and bradycardia (and also accompanied by sinus pause) have been observed in at least 3 other healthy subjects treated with various formulations of olanzapine (1 oral, 2 intramuscular). In controlled clinical studies, the incidence of patients with a ≥20 bpm decrease in orthostatic pulse concomitantly with a ≥20 mm Hg decrease in orthostatic systolic blood pressure was 0.3% (2/706) in the olanzapine and fluoxetine group, 0.2% (1/445) in the placebo group, 0.7% (6/837) in the olanzapine group, and 0% (0/404) in the fluoxetine group. Olanzapine and Fluoxetine should be used with particular caution in patients with known cardiovascular disease (history of myocardial infarction or ischemia, heart failure, or conduction abnormalities), cerebrovascular disease, or conditions that would predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medications).

5.12 Falls Olanzapine and fluoxetine may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

5.13 Leukopenia, Neutropenia, and Agranulocytosis Class Effect - In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents, including olanzapine and fluoxetine. Agranulocytosis has also been reported. Possible risk factors for leukopenia/neutropenia include preexisting low white blood cell count (WBC) and history of drug induced leukopenia/neutropenia. Patients with a history of a clinically significant low WBC or drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of olanzapine and fluoxetine capsules should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors. Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm 3 ) should discontinue olanzapine and fluoxetine capsules and have their WBC followed until recovery.

5.14 Dysphagia Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced Alzheimer's disease. Olanzapine and Fluoxetine capsules are not approved for the treatment of patients with Alzheimer's disease.

5.15 Seizures Seizures occurred in 0.2% (4/2547) of olanzapine and fluoxetine-treated patients during open-label clinical studies. No seizures occurred in the controlled olanzapine and fluoxetine studies. Seizures have also been reported with both olanzapine and fluoxetine monotherapy. Olanzapine and Fluoxetine should be used cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold, e.g., Alzheimer's dementia. Olanzapine and Fluoxetine capsules are not approved for the treatment of patients with Alzheimer's disease. Conditions that lower the seizure threshold may be more prevalent in a population of ≥65 years of age.

5.16 Increased Risk of Bleeding SNRIs and SSRIs, including fluoxetine, may increase the risk of bleeding reactions. Concomitant use of aspirin, nonsteroidal 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. Based on data from the published observational studies, exposure to SSRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [see Use in Specific Populations (8.1)]. 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 increased risk of bleeding associated with the concomitant use of olanzapine and fluoxetine and NSAIDs, aspirin, or other drugs that affect coagulation [see Drug Interactions (7.4)].

5.17 Hyponatremia Hyponatremia has been reported during treatment with SNRIs and SSRIs, including fluoxetine and olanzapine and 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 [see Use in Specific Populations (8.5)] olanzapine and fluoxetine capsules were 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. Discontinuation of olanzapine and fluoxetine capsules 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.

5.18 Potential for Cognitive and Motor Impairment Olanzapine and 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 olanzapine and fluoxetine therapy does not affect them adversely. Adults — Sedation-related adverse reactions were commonly reported with olanzapine and fluoxetine treatment occurring at an incidence of 26.6% in olanzapine and fluoxetine-treated patients compared with 10.9% in placebo-treated patients. Sedation-related adverse reactions (sedation, somnolence, hypersomnia, and lethargy) led to discontinuation in 2% (15/771) of patients in the controlled clinical studies. Children and Adolescents — In a single, 8-week, randomized, placebo-controlled clinical trial investigating olanzapine and fluoxetine for the treatment of bipolar I depression in patients 10 to 17 years of age, somnolence-related adverse events were commonly reported with olanzapine and fluoxetine treatment occurring at an incidence of 23.5% in olanzapine and fluoxetine-treated patients compared with 2.4% in placebo-treated patients. Somnolence-related adverse events led to discontinuation in 1.2% (2/170) of patients.

5.19 Body Temperature Dysregulation Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic drugs. Appropriate care is advised when prescribing olanzapine and fluoxetine capsules for patients who will be experiencing conditions which may contribute to an elevation in core body temperature (e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration).

5.20 QT Prolongation Post-marketing cases of QT interval prolongation and ventricular arrhythmia including Torsade de Pointes have been reported in patients treated with fluoxetine. Olanzapine and fluoxetine should be used with caution in patients with congenital long QT syndrome; a previous history of QT prolongation; a 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), Adverse Reactions (6), Drug Interactions (7.7, 7.8), Overdosage (10.1), and Clinical Pharmacology (12.3)]. Pimozide and thioridazine are contraindicated for use with olanzapine and 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 1A antiarrhythmic medications (e.g., quinidine, procainamide); Class III antiarrhythmics (e.g., amiodarone, sotalol); and others (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus) [see Drug Interactions (7.7, 7.8) and Clinical Pharmacology (12.3) ]. Consider ECG assessment and periodic ECG monitoring if initiating treatment with olanzapine and fluoxetine in patients with risk factors for QT prolongation and ventricular arrhythmia. Consider discontinuing olanzapine and fluoxetine and obtaining a cardiac evaluation if patients develop signs or symptoms consistent with ventricular arrhythmia. In a single, 8-week, randomized, placebo-controlled clinical trial investigating olanzapine and fluoxetine for the treatment of bipolar I depression in patients 10 to 17 years of age, there was a statistically significant difference in QT c interval for patients treated with olanzapine and fluoxetine compared with patients on placebo: mean change in QT c F (Fridericia correction factor) from baseline to endpoint in patients treated with olanzapine and fluoxetine was 8.2 msec (95% CI 6.2, 10.2). No patient developed QT c increases ≥60 msec or QT c ≥480 msec. Clinicians should use olanzapine and fluoxetine with caution in those children or adolescents who are known to be particularly at risk for QT prolongation [see Adverse Reactions (6.1)] .

5.21 Anticholinergic (antimuscarinic)

Effects

The following precautions for the individual components may be applicable to olanzapine and fluoxetine capsules. Olanzapine exhibits in vitro muscarinic receptor affinity. In premarketing clinical studies, olanzapine and fluoxetine was associated with constipation, dry mouth, and tachycardia, all adverse reactions possibly related to cholinergic antagonism. Such adverse reactions were not often the basis for study discontinuations; olanzapine and fluoxetine capsules should be used with caution in patients with a current diagnosis or prior history of urinary retention, clinically significant prostatic hypertrophy, constipation, a history of paralytic ileus, or related conditions.

5.22 Hyperprolactinemia As with other drugs that antagonize dopamine D 2 receptors, olanzapine and fluoxetine elevates prolactin levels, and the elevation persists during administration. Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and erectile dysfunction have been reported in patients receiving prolactin-elevating compounds. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male subjects. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro , a factor of potential importance if the prescription of these drugs is contemplated in a patient with previously detected breast cancer. As is common with compounds that increase prolactin release, an increase in mammary gland neoplasia was observed in the olanzapine carcinogenicity studies conducted in mice and rats [see Nonclinical Toxicology (13.1)] . Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans; the available evidence is considered too limited to be conclusive at this time. Adults — In controlled clinical studies of olanzapine and fluoxetine (up to 12 weeks), changes from normal to high in prolactin concentrations were observed in 28% of adults treated with olanzapine and fluoxetine as compared to 5% of placebo-treated patients. The elevations persisted throughout administration of olanzapine and fluoxetine. In a pooled analysis from clinical studies including 2929 adults treated with olanzapine and fluoxetine, potentially associated clinical manifestations included menstrual-related events 1 (1% [20/1946] of females), sexual function-related events 2 (7% [192/2929] of females and males), and breast-related events 3 (0.8% [16/1946] of females, 0.2% [2/983] of males). Children and Adolescents —In a single, 8-week, randomized, placebo-controlled clinical trial investigating olanzapine and fluoxetine for the treatment of bipolar I depression in patients 10 to 17 years of age, olanzapine and fluoxetine was associated with a statistically significant greater mean change from baseline in prolactin levels compared to placebo (8.7 mcg/L vs 0.7 mcg/L, respectively). Although prolactin concentrations were very commonly (>10%) elevated above normal in both the olanzapine and fluoxetine and placebo groups, more than twice as many olanzapine and fluoxetine-treated patients were seen with these elevations compared to placebo-treated patients. Five patients experienced an adverse event potentially associated with elevated prolactin; these events included dysmenorrhea, galactorrhea, and ovulation disorder. The magnitude and frequency of change in prolactin in children and adolescents was larger than observed in adult patients treated with olanzapine and fluoxetine, but was similar to that observed in adolescents treated with olanzapine monotherapy.

Olanzapine

Monotherapy In placebo-controlled olanzapine clinical studies (up to 12 weeks), changes from normal to high in prolactin concentrations were observed in 30% of adults treated with olanzapine as compared to 10.5% of adults treated with placebo. In a pooled analysis from clinical studies including 8136 adults treated with olanzapine, potentially associated clinical manifestations included menstrual-related events 1 (2% [49/3240] of females), sexual function-related events 2 (2% [150/8136] of females and males), and breast-related events 3 (0.7% [23/3240] of females, 0.2% [9/4896] of males). In placebo-controlled olanzapine monotherapy studies in adolescent patients (up to 6 weeks) with schizophrenia or bipolar I disorder (manic or mixed episodes), changes from normal to high in prolactin concentrations were observed in 47% of olanzapine-treated patients compared to 7% of placebo-treated patients. In a pooled analysis from clinical trials including 454 adolescents treated with olanzapine, potentially associated clinical manifestations included menstrual-related events 1 (1% [2/168] of females), sexual function-related events 2 (0.7% [3/454] of females and males), and breast-related events 3 (2% [3/168] of females, 2% [7/286] of males), [se e Use in Specific Populations (8.4)] . 1. Based on a search of the following terms: amenorrhea, hypomenorrhea, menstruation delayed, and oligomenorrhea. 2. Based on a search of the following terms: anorgasmia, delayed ejaculation, erectile dysfunction, decreased libido, loss of libido, abnormal orgasm, and sexual dysfunction. 3. Based on a search of the following terms: breast discharge, enlargement or swelling, galactorrhea, gynecomastia, and lactation disorder. Dose group differences with respect to prolactin elevation have been observed. In a single 8-week randomized, double-blind, fixed-dose study comparing 10 (n=199), 20 (n=200) and 40 (n=200) mg/day of oral olanzapine in adult patients with schizophrenia or schizoaffective disorder, incidence of prolactin elevation >24.2 ng/mL (female) or >18.77 ng/mL (male) at any time during the trial (10 mg/day: 31.2%; 20 mg/day: 42.7%; 40 mg/day: 61.1%) indicated significant differences between 10 vs 40 mg/day and 20 vs 40 mg/day.

5.23 Concomitant Use of Olanzapine and Fluoxetine Products Olanzapine and Fluoxetine capsules contain the same active ingredients that are in Zyprexa ® , Zyprexa ® Zydis ® , Zyprexa ® Relprevv TM (olanzapine), and in Prozac ® , and Sarafem ® (fluoxetine HCl). Caution should be exercised when prescribing these medications concomitantly with olanzapine and fluoxetine capsules [see Overdosage (10)] .

5.24 Long Elimination Half-Life of Fluoxetine Because of the long elimination half-lives of fluoxetine 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)] .

5.25 Discontinuation Adverse Reactions During marketing of fluoxetine, a component of olanzapine and 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. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the healthcare provider may continue decreasing the dose but at a 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 [see Dosage and Administration (2.4)].

5.26 Sexual Dysfunction Use of SSRIs, including fluoxetine a component of olanzapine and fluoxetine, may cause symptoms of sexual dysfunction [see Adverse Reactions (6.1)]. In male patients, olanzapine and fluoxetine use may result in ejaculatory delay or failure, decreased libido, and erectile dysfunction. In female patients, olanzapine and fluoxetine use may result in decreased libido and delayed or absent orgasm. It is important for prescribers to inquire about sexual function prior to initiation of olanzapine and fluoxetine and to inquire specifically about changes in sexual function during treatment, because sexual function may not be spontaneously reported. When evaluating changes in sexual function, obtaining a detailed history (including timing of symptom onset) is important because sexual symptoms may have other causes, including the underlying psychiatric disorder. Discuss potential management strategies to support patients in making informed decisions about treatment.

INTERACTIONS As with all drugs, the potential for interaction by a variety of mechanisms (e.g., pharmacodynamic, pharmacokinetic drug inhibition or enhancement, etc.) is a possibility.

Drugs

Metabolized by CYP2D6: Fluoxetine is a potent inhibitor of CYP2D6 enzyme pathway (7.6)

Tricyclic

Antidepressants (TCAs): Monitor TCA levels during co-administration with fluoxetine or when fluoxetine has been recently discontinued (5.2, 7.6) Benzodiazepines: Diazepam—increased t½, 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 Other Serotonergic Drugs The concomitant use of serotonergic drugs (including other SSRIs, SNRIs, triptans, tricyclic antidepressants, opioids, lithium, buspirone, amphetamines, tryptophan, and St. John's Wort) with fluoxetine increases the risk of serotonin syndrome. Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of fluoxetine and/or concomitant serotonergic drugs [see Warnings and Precautions (5.2)].

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 co-administered 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 a specific study with pimozide and fluoxetine has not been conducted, the potential for drug interactions or QT prolongation warrants restricting the concurrent use of pimozide and fluoxetine [see Contraindications (4.2), Warnings and Precautions (5.11), and Drug Interactions (7.7)]. Thioridazine —Thioridazine should not be administered with fluoxetine or within a minimum of 5 weeks after fluoxetine has been discontinued, because of the risk of QT prolongation [see Contraindications (4.2), Warnings and Precautions (5.11), and Drug Interactions (7.7)]. In a study of 19 healthy male subjects, which included 6 slow and 13 rapid hydroxylators of debrisoquin, a single 25 mg oral dose of thioridazine produced a 2.4-fold higher C max and a 4.5-fold higher 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 a dose-related prolongation of the QT interval, which is associated with serious ventricular arrhythmias, such as Torsades de Pointes-type arrhythmias, and sudden death. This risk is expected to increase with fluoxetine-induced inhibition of thioridazine metabolism. Drugs metabolized by CYP2D6 —Fluoxetine inhibits the activity of CYP2D6, and may make individuals with normal CYP2D6 metabolic activity resemble a poor metabolizer. Co-administration of fluoxetine with other drugs that are metabolized by CYP2D6, including certain antidepressants (e.g., TCAs), antipsychotics (e.g., phenothiazines and most atypicals), and antiarrhythmics (e.g., propafenone, flecainide, and others) should be approached with caution. Therapy with medications that are predominantly metabolized by the CYP2D6 system and that have a relatively narrow therapeutic index (see list below) should be initiated at the low end of the dose range if a patient is receiving fluoxetine concurrently or has taken it in the previous 5 weeks. Thus, his/her dosing requirements resemble those of poor metabolizers. If fluoxetine is added to the treatment regimen of a patient already receiving a drug metabolized by CYP2D6, the need for decreased dose of the original medication should be considered. Drugs with a narrow therapeutic index represent the greatest concern (e.g., flecainide, propafenone, vinblastine, and TCAs). Due to the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, thioridazine should not be administered with fluoxetine or within a minimum of 5 weeks after fluoxetine has been discontinued [see Contraindications (4.2)]. Tricyclic antidepressants (TCAs) —In 2 studies, previously stable plasma levels of imipramine and desipramine have increased greater than 2- to 10-fold when fluoxetine has been administered in combination. This influence may persist for 3 weeks or longer after fluoxetine is discontinued. Thus, the dose of TCAs may need to be reduced and plasma TCA concentrations may need to be monitored temporarily when fluoxetine is co-administered 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)]. Co-administration of alprazolam and fluoxetine has resulted in increased alprazolam plasma concentrations and in further psychomotor performance decrement due to increased alprazolam levels. Antipsychotics —Some clinical data suggests a possible pharmacodynamic and/or pharmacokinetic interaction between SSRIs and antipsychotics. Elevation of blood levels of haloperidol and clozapine has been observed in patients receiving concomitant fluoxetine. Anticonvulsants —Patients on stable doses of phenytoin and carbamazepine have developed elevated plasma anticonvulsant concentrations and clinical anticonvulsant toxicity following initiation of concomitant fluoxetine treatment. Lithium —There have been reports of both increased and decreased lithium levels when lithium was used concomitantly with fluoxetine. Cases of lithium toxicity and increased serotonergic effects have been reported. Lithium levels should be monitored when these drugs are administered concomitantly [see Warnings and Precautions (5.2)]. Drugs tightly bound to plasma proteins —Because fluoxetine is tightly bound to plasma proteins, the administration of fluoxetine to a patient taking another drug that is tightly bound to protein (e.g., Coumadin, digitoxin) may cause a shift in plasma concentrations potentially resulting in an adverse effect [see Clinical Pharmacology (12.3)]. Drugs metabolized by CYP3A4 —In an in vivo interaction study involving co-administration of fluoxetine with single doses of terfenadine (a CYP3A4 substrate), no increase in plasma terfenadine concentrations occurred with concomitant fluoxetine. Additionally, in vitro studies have shown ketoconazole, a potent inhibitor of CYP3A4 activity, to be at least 100 times more potent than fluoxetine or norfluoxetine as an inhibitor of the metabolism of several substrates for this enzyme, including astemizole, cisapride, and midazolam. These data indicate that fluoxetine’s extent of inhibition of CYP3A4 activity is not likely to be of clinical significance. Olanzapine —Fluoxetine (60 mg single dose or 60 mg daily dose for 8 days) causes a small (mean 16%) increase in the maximum concentration of olanzapine and a 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)].

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 Other Serotonergic Drugs The concomitant use of serotonergic drugs (including other SSRIs, SNRIs, triptans, tricyclic antidepressants, opioids, lithium, buspirone, amphetamines, tryptophan, and St. John's Wort) with fluoxetine increases the risk of serotonin syndrome. Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of fluoxetine and/or concomitant serotonergic drugs [see Warnings and Precautions (5.2)].

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 co-administered 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 a specific study with pimozide and fluoxetine has not been conducted, the potential for drug interactions or QT prolongation warrants restricting the concurrent use of pimozide and fluoxetine [see Contraindications (4.2), Warnings and Precautions (5.11), and Drug Interactions (7.7)]. Thioridazine —Thioridazine should not be administered with fluoxetine or within a minimum of 5 weeks after fluoxetine has been discontinued, because of the risk of QT prolongation [see Contraindications (4.2), Warnings and Precautions (5.11), and Drug Interactions (7.7)]. In a study of 19 healthy male subjects, which included 6 slow and 13 rapid hydroxylators of debrisoquin, a single 25 mg oral dose of thioridazine produced a 2.4-fold higher C max and a 4.5-fold higher 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 a dose-related prolongation of the QT interval, which is associated with serious ventricular arrhythmias, such as Torsades de Pointes-type arrhythmias, and sudden death. This risk is expected to increase with fluoxetine-induced inhibition of thioridazine metabolism. Drugs metabolized by CYP2D6 —Fluoxetine inhibits the activity of CYP2D6, and may make individuals with normal CYP2D6 metabolic activity resemble a poor metabolizer. Co-administration of fluoxetine with other drugs that are metabolized by CYP2D6, including certain antidepressants (e.g., TCAs), antipsychotics (e.g., phenothiazines and most atypicals), and antiarrhythmics (e.g., propafenone, flecainide, and others) should be approached with caution. Therapy with medications that are predominantly metabolized by the CYP2D6 system and that have a relatively narrow therapeutic index (see list below) should be initiated at the low end of the dose range if a patient is receiving fluoxetine concurrently or has taken it in the previous 5 weeks. Thus, his/her dosing requirements resemble those of poor metabolizers. If fluoxetine is added to the treatment regimen of a patient already receiving a drug metabolized by CYP2D6, the need for decreased dose of the original medication should be considered. Drugs with a narrow therapeutic index represent the greatest concern (e.g., flecainide, propafenone, vinblastine, and TCAs). Due to the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, thioridazine should not be administered with fluoxetine or within a minimum of 5 weeks after fluoxetine has been discontinued [see Contraindications (4.2)]. Tricyclic antidepressants (TCAs) —In 2 studies, previously stable plasma levels of imipramine and desipramine have increased greater than 2- to 10-fold when fluoxetine has been administered in combination. This influence may persist for 3 weeks or longer after fluoxetine is discontinued. Thus, the dose of TCAs may need to be reduced and plasma TCA concentrations may need to be monitored temporarily when fluoxetine is co-administered 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)]. Co-administration of alprazolam and fluoxetine has resulted in increased alprazolam plasma concentrations and in further psychomotor performance decrement due to increased alprazolam levels. Antipsychotics —Some clinical data suggests a possible pharmacodynamic and/or pharmacokinetic interaction between SSRIs and antipsychotics. Elevation of blood levels of haloperidol and clozapine has been observed in patients receiving concomitant fluoxetine. Anticonvulsants —Patients on stable doses of phenytoin and carbamazepine have developed elevated plasma anticonvulsant concentrations and clinical anticonvulsant toxicity following initiation of concomitant fluoxetine treatment. Lithium —There have been reports of both increased and decreased lithium levels when lithium was used concomitantly with fluoxetine. Cases of lithium toxicity and increased serotonergic effects have been reported. Lithium levels should be monitored when these drugs are administered concomitantly [see Warnings and Precautions (5.2)]. Drugs tightly bound to plasma proteins —Because fluoxetine is tightly bound to plasma proteins, the administration of fluoxetine to a patient taking another drug that is tightly bound to protein (e.g., Coumadin, digitoxin) may cause a shift in plasma concentrations potentially resulting in an adverse effect [see Clinical Pharmacology (12.3)]. Drugs metabolized by CYP3A4 —In an in vivo interaction study involving co-administration of fluoxetine with single doses of terfenadine (a CYP3A4 substrate), no increase in plasma terfenadine concentrations occurred with concomitant fluoxetine. Additionally, in vitro studies have shown ketoconazole, a potent inhibitor of CYP3A4 activity, to be at least 100 times more potent than fluoxetine or norfluoxetine as an inhibitor of the metabolism of several substrates for this enzyme, including astemizole, cisapride, and midazolam. These data indicate that fluoxetine’s extent of inhibition of CYP3A4 activity is not likely to be of clinical significance. Olanzapine —Fluoxetine (60 mg single dose or 60 mg daily dose for 8 days) causes a small (mean 16%) increase in the maximum concentration of olanzapine and a 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)].

Side Effect	Reports	% of Total	Deaths	Hosp.
Toxicity to various agents	3,172	10.2%	1,830	1,573
Drug ineffective	2,471	7.9%	23	817
Completed suicide	2,345	7.5%	2,338	738
Drug interaction	2,054	6.6%	248	1,053
Intentional overdose	2,026	6.5%	173	1,570
Foetal exposure during pregnancy	1,670	5.4%	73	469
Off label use	1,472	4.7%	103	635
Serotonin syndrome	1,457	4.7%	81	817
Suicide attempt	1,441	4.6%	28	1,022
Anxiety	1,347	4.3%	19	353
Suicidal ideation	1,298	4.2%	58	489
Drug abuse	1,295	4.2%	569	549
Nausea	1,171	3.8%	133	313
Fatigue	1,150	3.7%	167	309
Insomnia	1,150	3.7%	187	160
Somnolence	1,102	3.5%	213	515
Depression	1,096	3.5%	30	265
Dizziness	1,017	3.3%	181	283
Headache	954	3.1%	179	194
Tremor	919	3.0%	37	327

Year	Reports	Deaths	Hosp.
2000	46	4	17
2001	53	2	26
2002	40	1	11
2003	43	5	20
2004	42	1	15
2005	76	7	25
2006	83	6	43
2007	79	5	13
2008	105	16	28
2009	197	23	51
2010	181	17	48
2011	226	17	68
2012	283	125	61
2013	316	28	144
2014	592	112	203
2015	694	124	266
2016	930	118	354
2017	1,142	220	524
2018	1,531	190	827
2019	1,260	163	593
2020	1,135	164	406
2021	1,070	199	431
2022	949	150	364
2023	871	141	433
2024	707	23	355
2025	370	23	176

Indication	Reports
Product used for unknown indication	13,207
Depression	7,035
Anxiety	1,541
Major depression	838
Obsessive-compulsive disorder	637
Suicide attempt	392
Bipolar disorder	385
Schizophrenia	351
Antidepressant therapy	267
Mixed anxiety and depressive disorder	198

FLUOXETINE: 31,181 Adverse Event Reports & Safety Profile

What Are the Most Common FLUOXETINE Side Effects?

All FLUOXETINE Side Effects by Frequency

Who Reports FLUOXETINE Side Effects? Age & Gender Data

Is FLUOXETINE Getting Safer? Reports by Year

What Is FLUOXETINE Used For?

FLUOXETINE vs Alternatives: Which Is Safer?

Other Drugs in Same Class: Serotonin Reuptake Inhibitor [EPC]

Official FDA Label for FLUOXETINE

Drug Description

FDA Approved Uses (Indications)

Fluoxetine

1.5 Fluoxetine Capsules USP and Olanzapine in Combination: Depressive Episodes Associated With Bipolar I Disorder When using fluoxetine capsules USP and olanzapine in combination, also refer to the Clinical Studies section of the package insert for Symbyax ® .

Fluoxetine

Fluoxetine

Dosage & Administration

Bulimia

After

Switching

After

2.4 Panic Disorder Initial Treatment —Treatment should be initiated with a dose of 10 mg/day.

After

2.5 Dosing in Specific Populations Geriatrics —A lower or less frequent dosage should be considered for the elderly <span class="opacity-50 text-xs">[see Use in Specific Populations (8.5)]</span>.

Hepatic

After

Switching

After

2.4 Panic Disorder Initial Treatment —Treatment should be initiated with a dose of 10 mg/day.

After

2.5 Dosing in Specific Populations Geriatrics —A lower or less frequent dosage should be considered for the elderly <span class="opacity-50 text-xs">[see Use in Specific Populations (8.5)]</span>.

Hepatic

Contraindications

Contraindications

Serotonin

4.2 Other Contraindications The use of fluoxetine is contraindicated with the following:

Known Adverse Reactions

Serotonin

Allergic

Screening

Altered

Increased

Discontinuation Adverse

Table

Table

Most Common Adverse

Table

Adverse

Panic

Table

Most Common Adverse Reactions

Panic

Cardiovascular

Digestive

Nervous

Respiratory

Special

Urogenital

Table

Table

Most Common Adverse

Table

Adverse

Panic

Table

Most Common Adverse Reactions

Panic

Cardiovascular

Digestive

Nervous

Respiratory

Special

Urogenital

FDA Boxed Warning

Symbyax

Warnings

Drug

Metabolic

Serotonin

Allergic

Tardive