Prozac

Dista Products Company
Eli Lilly and Company

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use PROZAC safely and effectively. See full prescribing information for PROZAC. PROZAC (fluoxetine hydrochloride) Pulvules for oral usePROZAC (fluoxetine hydrochloride) delayed-release capsules for oral useInitial U.S. Approval: 1987 RECENT MAJOR CHANGES Boxed Warning:  Warnings: Suicidal Thoughts and Behaviors 07/2013 Indications and Usage:  PROZAC and Olanzapine in Combination: Depressive Episodes Associated with Bipolar I Disorder (1.5) 07/2013 Dosage and Administration:   PROZAC and Olanzapine in Combination: Depressive Episodes Associated with Bipolar I Disorder (2.5) 07/2013   Dosing in Specific Populations (2.7) 07/2013 Contraindications:   Other Contraindications (4.2) 07/2013 Warnings and Precautions:   Clinical Worsening and Suicide Risk (5.1) 07/2013   QT Prolongation (5.10) 07/2013 BOXED WARNING WARNING: SUICIDAL THOUGHTS AND BEHAVIORS See full prescribing information for complete boxed warning. Increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants (5.1). Monitor for worsening and emergence of suicidal thoughts and behaviors (5.1). When using PROZAC and olanzapine in combination, also refer to Boxed Warning section of the package insert for Symbyax.INDICATIONS AND USAGEPROZAC® 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) PROZAC and olanzapine in combination for: Acute treatment of Depressive Episodes Associated with Bipolar I Disorder (1.5) Acute treatment of Treatment Resistant Depression in adults (1.6) DOSAGE AND ADMINISTRATION Indication Adult Pediatric MDD (2.1) 20 mg/day in am (initial dose) 10 to 20 mg/day (initial dose) OCD (2.2) 20 mg/day in am (initial dose) 10 mg/day (initial dose) Bulimia Nervosa (2.3) 60 mg/day in am Panic Disorder (2.4) 10 mg/day (initial dose) Depressive Episodes Associated with Bipolar I Disorder (2.5) Oral in combination with olanzapine: 5 mg of oral olanzapine and 20 mg of fluoxetine once daily (initial dose) Oral in combination with olanzapine: 2.5 mg of oral olanzapine and 20 mg of fluoxetine once daily (initial dose) Treatment Resistant Depression (2.6) Oral in combination with olanzapine: 5 mg of oral olanzapine and 20 mg of fluoxetine once daily (initial dose) A lower or less frequent dosage should be used in patients with hepatic impairment, the elderly, and for patients with concurrent disease or on multiple concomitant medications (2.7) Dosing with PROZAC Weekly capsules - initiate 7 days after the last daily dose of PROZAC 20 mg (2.1) PROZAC and olanzapine in combination: Dosage adjustments should be made with the individual components according to efficacy and tolerability (2.5, 2.6) Fluoxetine monotherapy is not indicated for the treatment of Depressive Episodes associated with Bipolar I Disorder or treatment resistant depression (2.5, 2.6) Safety of the coadministration of doses above 18 mg olanzapine with 75 mg fluoxetine has not been evaluated in adults (2.5, 2.6) Safety of the coadministration of doses above 12 mg olanzapine with 50 mg fluoxetine has not been evaluated in children and adolescents ages 10 to 17 (2.5) DOSAGE FORMS AND STRENGTHS Pulvules: 10 mg, 20 mg, 40 mg (3) Weekly capsules: 90 mg (3) CONTRAINDICATIONS Serotonin Syndrome and MAOIs: Do not use MAOIs intended to treat psychiatric disorders with PROZAC or within 5 weeks of stopping treatment with PROZAC. Do not use PROZAC within 14 days of stopping an MAOI intended to treat psychiatric disorders. In addition, do not start PROZAC 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, 5.10, 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 PROZAC. Do not use thioridazine within 5 weeks of discontinuing PROZAC (4.2, 5.10, 7.7, 7.8) When using PROZAC and olanzapine in combination, also refer to the Contraindications section of the package insert for Symbyax (4) WARNINGS AND PRECAUTIONS Clinical Worsening and Suicide Risk: Monitor for clinical worsening and suicidal thinking and behavior (5.1) Serotonin Syndrome: Serotonin syndrome has been reported with SSRIs and SNRIs, including PROZAC, both when taken alone, but especially when co-administered with other serotonergic agents (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone and St. John's Wort). If such symptoms occur, discontinue PROZAC and initiate supportive treatment. If concomitant use of PROZAC with other serotonergic drugs is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases. (5.2) Allergic Reactions and Rash: Discontinue upon appearance of rash or allergic phenomena (5.3) Activation of Mania/Hypomania: Screen for Bipolar Disorder and monitor for mania/hypomania (5.4) Seizures: Use cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold (5.5) Altered Appetite and Weight: Significant weight loss has occurred (5.6) Abnormal Bleeding: May increase the risk of bleeding. Use with NSAIDs, aspirin, warfarin, or other drugs that affect coagulation may potentiate the risk of gastrointestinal or other bleeding (5.7) Hyponatremia: Has been reported with PROZAC in association with syndrome of inappropriate antidiuretic hormone (SIADH). Consider discontinuing if symptomatic hyponatremia occurs (5.8) Anxiety and Insomnia: May occur (5.9) QT Prolongation: QT prolongation and ventricular arrhythmia including Torsades de Pointes have been reported with PROZAC use. 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, 5.10, 6.2, 7.7, 7.8, 10.1) Potential for Cognitive and Motor Impairment: Has potential to impair judgment, thinking, and motor skills. Use caution when operating machinery (5.11) Long Half-Life: Changes in dose will not be fully reflected in plasma for several weeks (5.12) PROZAC and Olanzapine in Combination: When using PROZAC and olanzapine in combination, also refer to the Warnings and Precautions section of the package insert for Symbyax (5.14) Side EffectsMost 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) PROZAC and olanzapine in combination – Also refer to the Adverse Reactions section of the package insert for Symbyax (6) To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch DRUG INTERACTIONS Monoamine Oxidase Inhibitors (MAOIs): (2.9, 2.10, 4.1, 5.2) Drugs Metabolized by CYP2D6: Fluoxetine is a potent inhibitor of CYP2D6 enzyme pathway (7.7) Tricyclic Antidepressants (TCAs): Monitor TCA levels during coadministration with PROZAC or when PROZAC has been recently discontinued (5.2, 7.7) CNS Acting Drugs: Caution should be used when taken in combination with other centrally acting drugs (7.2) Benzodiazepines: Diazepam – increased t½, alprazolam - further psychomotor performance decrement due to increased levels (7.7) Antipsychotics: Potential for elevation of haloperidol and clozapine levels (7.7) Anticonvulsants: Potential for elevated phenytoin and carbamazepine levels and clinical anticonvulsant toxicity (7.7) Serotonergic Drugs: (2.9, 2.10, 4.1, 5.2) Drugs that Interfere with Hemostasis (e.g. NSAIDs, Aspirin, Warfarin): May potentiate the risk of bleeding (7.4) Drugs Tightly Bound to Plasma Proteins: May cause a shift in plasma concentrations (7.6, 7.7) Olanzapine: When used in combination with PROZAC, also refer to the Drug Interactions section of the package insert for Symbyax (7.7) Drugs that Prolong the QT Interval: Do not use Prozac with thioridazine or pimozide. Use with caution in combination with other drugs that prolong the QT interval (4.2, 5.10, 7.7, 7.8) USE IN SPECIFIC POPULATIONS Pregnancy: PROZAC should be used during pregnancy only if the potential benefit justifies the potential risks to the fetus (8.1) Nursing Mothers: Breast feeding is not recommended (8.3) Pediatric Use: Safety and effectiveness of PROZAC in patients

FULL PRESCRIBING INFORMATION: CONTENTS*

• WARNING: SUICIDAL THOUGHTS AND BEHAVIORS
• 1 PROZAC INDICATIONS AND USAGE
  • 1.1 Major Depressive Disorder
  • 1.2 Obsessive Compulsive Disorder
  • 1.3 Bulimia Nervosa
  • 1.4 Panic Disorder
  • 1.5 PROZAC and Olanzapine in Combination: Depressive Episodes Associated with Bipolar I Disorder
  • 1.6 PROZAC and Olanzapine in Combination: Treatment Resistant Depression
• 2 PROZAC DOSAGE AND ADMINISTRATION
  • 2.1 Major Depressive Disorder
  • 2.2 Obsessive Compulsive Disorder
  • 2.3 Bulimia Nervosa
  • 2.4 Panic Disorder
  • 2.5 PROZAC and Olanzapine in Combination: Depressive Episodes Associated with Bipolar I Disorder
  • 2.6 PROZAC and Olanzapine in Combination: Treatment Resistant Depression
  • 2.7 Dosing in Specific Populations
  • 2.8 Discontinuation of Treatment
  • 2.9 Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders
  • 2.10 Use of PROZAC with Other MAOIs such as Linezolid or Methylene Blue
• 3 DOSAGE FORMS AND STRENGTHS
• 4 PROZAC CONTRAINDICATIONS
  • 4.1 Monoamine Oxidase Inhibitors (MAOIs)
  • 4.2 Other Contraindications
• 5 WARNINGS AND PRECAUTIONS
  • 5.1 Clinical Worsening and Suicide Risk
  • 5.2 Serotonin Syndrome
  • 5.3 Allergic Reactions and Rash
  • 5.4 Screening Patients for Bipolar Disorder and Monitoring for Mania/Hypomania
  • 5.5 Seizures
  • 5.6 Altered Appetite and Weight
  • 5.7 Abnormal Bleeding
  • 5.8 Hyponatremia
  • 5.9 Anxiety and Insomnia
  • 5.10 QT Prolongation
  • 5.11 Use in Patients with Concomitant Illness
  • 5.12 Potential for Cognitive and Motor Impairment
  • 5.13 Long Elimination Half-Life
  • 5.14 Discontinuation Adverse Reactions
  • 5.15 PROZAC and Olanzapine in Combination
• 6 PROZAC ADVERSE REACTIONS
  • 6.1 Clinical Trials Experience
  • 6.2 Other Reactions
  • 6.3 Postmarketing Experience
• 7 DRUG INTERACTIONS
  • 7.1 Monoamine Oxidase Inhibitors (MAOI)
  • 7.2 CNS Acting Drugs
  • 7.3 Serotonergic Drugs
  • 7.4 Drugs that Interfere with Hemostasis (e.g., NSAIDS, Aspirin, Warfarin)
  • 7.5 Electroconvulsive Therapy (ECT)
  • 7.6 Potential for Other Drugs to affect PROZAC
  • 7.7 Potential for PROZAC to affect Other Drugs
  • 7.8 Drugs that Prolong the QT Interval
• 8 USE IN SPECIFIC POPULATIONS
  • 8.1 Pregnancy
  • 8.2 Labor and Delivery
  • 8.3 Nursing Mothers
  • 8.4 Pediatric Use
  • 8.5 Geriatric Use
  • 8.6 Hepatic Impairment
• 9 DRUG ABUSE AND DEPENDENCE
  • 9.3 Dependence
• 10 OVERDOSAGE
  • 10.1 Human Experience
  • 10.2 Animal Experience
  • 10.3 Management of Overdose
• 11 PROZAC DESCRIPTION
• 12 CLINICAL PHARMACOLOGY
  • 12.1 Mechanism of Action
  • 12.2 Pharmacodynamics
  • 12.3 Pharmacokinetics
  • 12.4 Specific Populations
• 13 NONCLINICAL TOXICOLOGY
  • 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
  • 13.2 Animal Toxicology and/or Pharmacology
• 14 CLINICAL STUDIES
  • 14.1 Major Depressive Disorder
  • 14.2 Obsessive Compulsive Disorder
  • 14.3 Bulimia Nervosa
  • 14.4 Panic Disorder
• 16 HOW SUPPLIED/STORAGE AND HANDLING
  • 16.1 How Supplied
  • 16.2 Storage and Handling
• 17 PATIENT COUNSELING INFORMATION
  • 17.1 General Information
  • 17.2 Clinical Worsening and Suicide Risk
  • 17.3 Serotonin Syndrome
  • 17.4 Allergic Reactions and Rash
  • 17.5 Abnormal Bleeding
  • 17.6 Hyponatremia
  • 17.7 QT Prolongation
  • 17.8 Potential for Cognitive and Motor Impairment
  • 17.9 Use of Concomitant Medications
  • 17.10 Discontinuation of Treatment
  • 17.11 Use in Specific Populations

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

1.1 Major Depressive Disorder

PROZAC^® is 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

PROZAC 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 PROZAC 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 PROZAC 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

PROZAC 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 PROZAC 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

PROZAC is indicated for the acute treatment of Panic Disorder, with or without agoraphobia, in adult patients [see Clinical Studies (14.4)].

The effectiveness of PROZAC 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 PROZAC 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 PROZAC and Olanzapine in Combination: Depressive Episodes Associated with Bipolar I Disorder

When using PROZAC and olanzapine in combination, also refer to the Clinical Studies section of the package insert for Symbyax ^® .

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

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

1.6 PROZAC and Olanzapine in Combination: Treatment Resistant Depression

When using PROZAC and olanzapine in combination, also refer to the Clinical Studies section of the package insert for Symbyax.

PROZAC and olanzapine in combination is indicated for the acute treatment of treatment resistant depression (Major Depressive Disorder in adult patients, who do not respond to 2 separate trials of different antidepressants of adequate dose and duration in the current episode).

PROZAC monotherapy is not indicated for the treatment of treatment resistant depression.

2 DOSAGE AND ADMINISTRATION

2.1 Major Depressive Disorder

Initial Treatment

Adult — In controlled trials used to support the efficacy of fluoxetine, patients were administered morning doses ranging from 20 to 80 mg/day. Studies comparing fluoxetine 20, 40, and 60 mg/day to placebo indicate that 20 mg/day is sufficient to obtain a satisfactory response in Major Depressive Disorder in most cases. Consequently, a dose of 20 mg/day, administered in the morning, is recommended as the initial dose.

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) — In the short-term (8 to 9 week) controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of Major Depressive Disorder, patients were administered fluoxetine doses of 10 to 20 mg/day [see Clinical Studies (14.1)]. 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.

All patients — As with other drugs effective in the treatment of Major Depressive Disorder, the full effect may be delayed until 4 weeks of treatment or longer.

Maintenance/Continuation/Extended Treatment — It is generally agreed that acute episodes of Major Depressive Disorder require several months or longer of sustained pharmacologic therapy. Whether the dose needed to induce remission is identical to the dose needed to maintain and/or sustain euthymia is unknown.

Daily Dosing — Systematic evaluation of PROZAC in adult patients has shown that its efficacy in Major Depressive Disorder is maintained for periods of up to 38 weeks following 12 weeks of open-label acute treatment (50 weeks total) at a dose of 20 mg/day [see Clinical Studies (14.1)].

Weekly Dosing — Systematic evaluation of PROZAC^® Weekly™ in adult patients has shown that its efficacy in Major Depressive Disorder is maintained for periods of up to 25 weeks with once-weekly dosing following 13 weeks of open-label treatment with PROZAC 20 mg once daily. However, therapeutic equivalence of PROZAC Weekly given on a once-weekly basis with PROZAC 20 mg given daily for delaying time to relapse has not been established [see Clinical Studies (14.1)].

Weekly dosing with PROZAC Weekly capsules is recommended to be initiated 7 days after the last daily dose of PROZAC 20 mg [see Clinical Pharmacology (12.3)].

If satisfactory response is not maintained with PROZAC Weekly, consider reestablishing a daily dosing regimen [see Clinical Studies (14.1)].

Switching Patients to a Tricyclic Antidepressant (TCA) — Dosage of a TCA may need to be reduced, and plasma TCA concentrations may need to be monitored temporarily when fluoxetine is coadministered or has been recently discontinued [see Warnings and Precautions (5.2) and Drug Interactions (7.7)].

2.2 Obsessive Compulsive Disorder

Initial Treatment

Adult — In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of OCD, patients were administered fixed daily doses of 20, 40, or 60 mg of fluoxetine or placebo [see Clinical Studies (14.2)]. In one of these studies, no dose-response relationship for effectiveness was demonstrated. Consequently, a dose of 20 mg/day, administered in the morning, is recommended as the initial dose. Since there was a suggestion of a possible dose-response relationship for effectiveness in the second study, a dose increase may be considered 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 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) — In the controlled clinical trial of fluoxetine supporting its effectiveness in the treatment of OCD, patients were administered fluoxetine doses in the range of 10 to 60 mg/day [see Clinical Studies (14.2)].

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 — While there are no systematic studies that answer the question of how long to continue PROZAC, OCD is a chronic condition and it is reasonable to consider continuation for a responding patient. Although the efficacy of PROZAC after 13 weeks has not been documented in controlled trials, adult patients have been continued in therapy under double-blind conditions for up to an additional 6 months without loss of benefit. However, dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for treatment.

2.3 Bulimia Nervosa

Initial Treatment — In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of Bulimia Nervosa, patients were administered fixed daily fluoxetine doses of 20 or 60 mg, or placebo [see Clinical Studies (14.3)]. Only the 60 mg dose was statistically significantly superior to placebo in reducing the frequency of binge-eating and vomiting. Consequently, the recommended dose is 60 mg/day, administered in the morning. For some patients it may be advisable to titrate up to this target dose over several days. Fluoxetine doses above 60 mg/day have not been systematically studied in patients with bulimia.

Maintenance/Continuation Treatment — Systematic evaluation of continuing PROZAC 60 mg/day for periods of up to 52 weeks in patients with bulimia who have responded while taking PROZAC 60 mg/day during an 8-week acute treatment phase has demonstrated a benefit of such maintenance treatment [see Clinical Studies (14.3)]. Nevertheless, patients should be periodically reassessed to determine the need for maintenance treatment.

2.4 Panic Disorder

Initial Treatment — In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of Panic Disorder, patients were administered fluoxetine doses in the range of 10 to 60 mg/day [see Clinical Studies (14.4)]. Treatment should be initiated with a dose of 10 mg/day. After one week, the dose should be increased to 20 mg/day. The most frequently administered dose in the 2 flexible-dose clinical trials was 20 mg/day.

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 — While there are no systematic studies that answer the question of how long to continue PROZAC, panic disorder is a chronic condition and it is reasonable to consider continuation for a responding patient. Nevertheless, patients should be periodically reassessed to determine the need for continued treatment.

2.5 PROZAC and Olanzapine in Combination: Depressive Episodes Associated with Bipolar I Disorder

When using PROZAC and olanzapine in combination, also refer to the Clinical Studies section of the package insert for Symbyax.

Adult — 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 12.5 mg. 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 of co-administration of doses above 18 mg olanzapine with 75 mg fluoxetine has not been evaluated in clinical studies.

Children and adolescents (10 -17 years of age) — Olanzapine and fluoxetine combination should be administered once daily in the evening, generally beginning with 2.5 mg of olanzapine and 20 mg of fluoxetine. Dosage adjustments, if indicated, can be made according to efficacy and tolerability. Safety of co-administration of doses above 12 mg of olanzapine with 50 mg of fluoxetine has not been evaluated in pediatric clinical studies.

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 PROZAC and olanzapine versus Symbyax. Dosage adjustments, if indicated, should be made with the individual components according to efficacy and tolerability.

While there is no body of evidence to answer the question of how long a patient treated with PROZAC 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.

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

2.6 PROZAC and Olanzapine in Combination: Treatment Resistant Depression

When using PROZAC 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 20 mg. Antidepressant efficacy was demonstrated with olanzapine and fluoxetine in combination with a dose range of olanzapine 6 to 18 mg and fluoxetine 25 to 50 mg.

Safety and efficacy of fluoxetine in combination with olanzapine was determined in clinical trials supporting approval of Symbyax (fixed dose combination of olanzapine and fluoxetine). Symbyax is dosed between 3 mg/25 mg (olanzapine/fluoxetine) per day and 12 mg/50 mg (olanzapine/fluoxetine) per day. Table 1 demonstrates the appropriate individual component doses of PROZAC and olanzapine versus Symbyax. Dosage adjustments, if indicated, should be made with the individual components according to efficacy and tolerability.

While there is no body of evidence to answer the question of how long a patient treated with PROZAC and olanzapine in combination should remain on it, it is generally accepted that treatment resistant depression (Major Depressive Disorder in adult patients who do not respond to 2 separate trials of different antidepressants of adequate dose and duration in the current episode) 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.

PROZAC monotherapy is not indicated for the treatment of treatment resistant depression (Major Depressive Disorder in patients who do not respond to 2 antidepressants of adequate dose and duration in the current episode).

2.7 Dosing in Specific Populations

Treatment of Pregnant Women — When treating pregnant women with PROZAC, the physician should carefully consider the potential risks and potential benefits of treatment. Neonates exposed to SSRIs or SNRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding [see Use in Specific Populations (8.1)].

Geriatric — 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 (12.4) and Use in Specific Populations (8.6)].

Concomitant Illness — Patients with concurrent disease or on multiple concomitant medications may require dosage adjustments [see Clinical Pharmacology (12.4) and Warnings and Precautions (5.10)].

PROZAC and Olanzapine in Combination — The starting dose of oral olanzapine 2.5 to 5 mg with fluoxetine 20 mg should be used for patients with a predisposition to hypotensive reactions, patients with hepatic impairment, or patients who exhibit a combination of factors that may slow the metabolism of olanzapine or fluoxetine in combination (female gender, geriatric age, non-smoking status), or those patients who may be pharmacodynamically sensitive to olanzapine. Dosing modifications may be necessary in patients who exhibit a combination of factors that may slow metabolism. When indicated, dose escalation should be performed with caution in these patients. PROZAC and olanzapine in combination have not been systematically studied in patients over 65 years of age or in patients less than 10 years of age [see Warnings and Precautions (5.14) and Drug Interactions (7.7)].

2.8 Discontinuation of Treatment

Symptoms associated with discontinuation of fluoxetine, SNRIs, and SSRIs, have been reported [see Warnings and Precautions (5.13)].

2.9 Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders

At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with PROZAC. Conversely, at least 5 weeks should be allowed after stopping PROZAC before starting an MAOI intended to treat psychiatric disorders [see Contraindications (4.1)].

2.10 Use of PROZAC with Other MAOIs such as Linezolid or Methylene Blue

Do not start PROZAC in a patient who is being treated with linezolid or intravenous methylene blue because there is an increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered [see Contraindications (4.1)].

In some cases, a patient already receiving PROZAC therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, PROZAC should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for five weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with PROZAC may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue [see Warnings and Precautions (5.2)].

The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with PROZAC is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use [see Warnings and Precautions (5.2)].

3 DOSAGE FORMS AND STRENGTHS

• 10 mg Pulvule is an opaque green cap and opaque green body, imprinted with DISTA 3104 on the cap and Prozac 10 mg on the body
• 20 mg Pulvule is an opaque green cap and opaque yellow body, imprinted with DISTA 3105 on the cap and Prozac 20 mg on the body
• 40 mg Pulvule is an opaque green cap and opaque orange body, imprinted with DISTA 3107 on the cap and Prozac 40 mg on the body
• 90 mg Prozac Weekly™ Capsule is an opaque green cap and clear body containing discretely visible white pellets through the clear body of the capsule, imprinted with Lilly on the cap and 3004 and 90 mg on the body

4 CONTRAINDICATIONS

When using PROZAC and olanzapine in combination, also refer to the Contraindications section of the package insert for Symbyax.

4.1 Monoamine Oxidase Inhibitors (MAOIs)

The use of MAOIs intended to treat psychiatric disorders with PROZAC or within 5 weeks of stopping treatment with PROZAC is contraindicated because of an increased risk of serotonin syndrome. The use of PROZAC 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 PROZAC 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 PROZAC is contraindicated with the following:

• Pimozide [see Warnings and Precautions (5.10) and Drug Interactions (7.7, 7.8)]
• Thioridazine [see Warnings and Precautions (5.10) and Drug Interactions (7.7, 7.8)]

Pimozide and thioridazine prolong the QT interval. PROZAC can increase the levels of pimozide and thioridazine through inhibition of CYP2D6. PROZAC can also prolong the QT interval.

5 WARNINGS AND PRECAUTIONS

When using PROZAC and olanzapine in combination, also refer to the Warnings and Precautions section of the package insert for Symbyax.

5.1 Clinical Worsening and Suicide Risk

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 18-24) 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 2.

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 (5.13)].

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 PROZAC 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 PROZAC is approved in the pediatric population for Major Depressive Disorder and Obsessive Compulsive Disorder; and PROZAC in combination with olanzapine for the acute treatment of depressive episodes associated with Bipolar I Disorder.

5.2 Serotonin Syndrome

The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including PROZAC, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John's Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, 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). Patients should be monitored for the emergence of serotonin syndrome.

The concomitant use of PROZAC with MAOIs intended to treat psychiatric disorders is contraindicated. PROZAC should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking PROZAC. PROZAC should be discontinued before initiating treatment with the MAOI [see Contraindications (4.1) and Dosage and Administration (2.9, 2.10)].

If concomitant use of PROZAC with other serotonergic drugs, i.e., triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan and St. John's Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.

Treatment with PROZAC and any concomitant serotonergic agents, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.

5.3 Allergic Reactions and Rash

In US fluoxetine clinical trials, 7% of 10,782 patients developed various types of rashes and/or urticaria. Among the cases of rash and/or urticaria reported in premarketing clinical trials, almost 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 premarketing clinical trials, 2 patients are known to have developed a serious cutaneous systemic illness. In neither patient was there an unequivocal diagnosis, but one 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 PROZAC, systemic reactions, possibly related to vasculitis and including lupus-like syndrome, have developed in patients with rash. Although these reactions are rare, they may be serious, involving the lung, kidney, or liver. Death has been reported to occur in association with these systemic reactions.

Anaphylactoid reactions, including bronchospasm, angioedema, laryngospasm, and urticaria alone and in combination, have been reported.

Pulmonary reactions, including inflammatory processes of varying histopathology and/or fibrosis, have been reported rarely. These reactions have occurred with dyspnea as the only preceding symptom.

Whether these systemic reactions and rash have 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 possibly allergic phenomena for which an alternative etiology cannot be identified, PROZAC should be discontinued.

5.4 Screening Patients for Bipolar Disorder and Monitoring for 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 mixed/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 PROZAC and olanzapine in combination is approved for the acute treatment of depressive episodes associated with Bipolar I Disorder [see Warnings and Precautions section of the package insert for Symbyax]. PROZAC monotherapy is not indicated for the treatment of depressive episodes associated with Bipolar I Disorder.

In US placebo-controlled clinical trials for Major Depressive Disorder, mania/hypomania was reported in 0.1% of patients treated with PROZAC and 0.1% of patients treated with placebo. Activation of mania/hypomania has also been reported in a small proportion of patients with Major Affective Disorder treated with other marketed drugs effective in the treatment of Major Depressive Disorder [see Use in Specific Populations (8.4)].

In US placebo-controlled clinical trials for OCD, mania/hypomania was reported in 0.8% of patients treated with PROZAC and no patients treated with placebo. No patients reported mania/hypomania in US placebo-controlled clinical trials for bulimia. In US PROZAC clinical trials, 0.7% of 10,782 patients reported mania/hypomania [see Use in Specific Populations (8.4)].

5.5 Seizures

In US placebo-controlled clinical trials for Major Depressive Disorder, convulsions (or reactions described as possibly having been seizures) were reported in 0.1% of patients treated with PROZAC and 0.2% of patients treated with placebo. No patients reported convulsions in US placebo-controlled clinical trials for either OCD or bulimia. In US PROZAC clinical trials, 0.2% of 10,782 patients reported convulsions. The percentage appears to be similar to that associated with other marketed drugs effective in the treatment of Major Depressive Disorder. PROZAC should be introduced with care in patients with a history of seizures.

5.6 Altered Appetite and Weight

Significant weight loss, especially in underweight depressed or bulimic patients, may be an undesirable result of treatment with PROZAC.

In US placebo-controlled clinical trials for Major Depressive Disorder, 11% of patients treated with PROZAC and 2% of patients treated with placebo reported anorexia (decreased appetite). Weight loss was reported in 1.4% of patients treated with PROZAC and in 0.5% of patients treated with placebo. However, only rarely have patients discontinued treatment with PROZAC because of anorexia or weight loss [see Use in Specific Populations (8.4)].

In US placebo-controlled clinical trials for OCD, 17% of patients treated with PROZAC and 10% of patients treated with placebo reported anorexia (decreased appetite). One patient discontinued treatment with PROZAC because of anorexia [see Use in Specific Populations (8.4)].

In US placebo-controlled clinical trials for Bulimia Nervosa, 8% of patients treated with PROZAC 60 mg and 4% of patients treated with placebo reported anorexia (decreased appetite). Patients treated with PROZAC 60 mg on average lost 0.45 kg compared with a gain of 0.16 kg by patients treated with placebo in the 16-week double-blind trial. Weight change should be monitored during therapy.

5.7 Abnormal Bleeding

SNRIs and SSRIs, including fluoxetine, may increase the risk of bleeding reactions. Concomitant use of aspirin, 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. Bleeding reactions related to SNRIs and SSRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages. Patients should be cautioned about the risk of bleeding associated with the concomitant use of fluoxetine and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation [see Drug Interactions (7.4)].

5.8 Hyponatremia

Hyponatremia has been reported during treatment with SNRIs and SSRIs, including PROZAC. 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 PROZAC was discontinued. Elderly patients may be at greater risk of developing hyponatremia with SNRIs and SSRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk [see Use in Specific Populations (8.5)]. Discontinuation of PROZAC 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.

5.9 Anxiety and Insomnia

In US placebo-controlled clinical trials for Major Depressive Disorder, 12% to 16% of patients treated with PROZAC and 7% to 9% of patients treated with placebo reported anxiety, nervousness, or insomnia.

In US placebo-controlled clinical trials for OCD, insomnia was reported in 28% of patients treated with PROZAC and in 22% of patients treated with placebo. Anxiety was reported in 14% of patients treated with PROZAC and in 7% of patients treated with placebo.

In US placebo-controlled clinical trials for Bulimia Nervosa, insomnia was reported in 33% of patients treated with PROZAC 60 mg, and 13% of patients treated with placebo. Anxiety and nervousness were reported, respectively, in 15% and 11% of patients treated with PROZAC 60 mg and in 9% and 5% of patients treated with placebo.

Among the most common adverse reactions associated with discontinuation (incidence at least twice that for placebo and at least 1% for PROZAC in clinical trials collecting only a primary reaction associated with discontinuation) in US placebo-controlled fluoxetine clinical trials were anxiety (2% in OCD), insomnia (1% in combined indications and 2% in bulimia), and nervousness (1% in Major Depressive Disorder) [see Table 5].

5.10 QT Prolongation

Post-marketing cases of QT interval prolongation and ventricular arrhythmia including Torsades de Pointes have been reported in patients treated with PROZAC. PROZAC 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). PROZAC is primarily metabolized by CYP2D6 [see Contraindications (4.2), Adverse Reactions (6.2), Drug Interactions (7.7, 7.8), Overdose (10.1), and Clinical Pharmacology (12.3)].

Pimozide and thioridazine are contraindicated for use with PROZAC. 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 PROZAC in patients with risk factors for QT prolongation and ventricular arrhythmia. Consider discontinuing PROZAC and obtaining a cardiac evaluation if patients develop signs or symptoms consistent with ventricular arrhythmia.

5.11 Use in Patients with Concomitant Illness

Clinical experience with PROZAC in patients with concomitant systemic illness is limited. Caution is advisable in using PROZAC in patients with diseases or conditions that could affect metabolism or hemodynamic responses.

Cardiovascular — Fluoxetine has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were systematically excluded from clinical studies during the product's premarket testing. However, the electrocardiograms of 312 patients who received PROZAC in double-blind trials were retrospectively evaluated; no conduction abnormalities that resulted in heart block were observed. The mean heart rate was reduced by approximately 3 beats/min.

Glycemic Control — In patients with diabetes, PROZAC may alter glycemic control. Hypoglycemia has occurred during therapy with PROZAC, and hyperglycemia has developed following discontinuation of the drug. As is true with many other types of medication when taken concurrently by patients with diabetes, insulin and/or oral hypoglycemic, dosage may need to be adjusted when therapy with PROZAC is instituted or discontinued.

Acute Narrow-Angle Glaucoma — Mydriasis has been reported in association with PROZAC; therefore, caution should be used when prescribing PROZAC in patients with raised intraocular pressure or those at risk of acute narrow-angle glaucoma.

5.12 Potential for Cognitive and Motor Impairment

As with any CNS-active drug, PROZAC has the potential to impair judgment, thinking, or motor skills. Patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that the drug treatment does not affect them adversely.

5.13 Long Elimination Half-Life

Because of the long elimination half-lives of the parent drug and its major active metabolite, changes in dose will not be fully reflected in plasma for several weeks, affecting both strategies for titration to final dose and withdrawal from treatment. This is of potential consequence when drug discontinuation is required or when drugs are prescribed that might interact with fluoxetine and norfluoxetine following the discontinuation of fluoxetine [see Clinical Pharmacology (12.3)].

5.14 Discontinuation Side Effects

During marketing of PROZAC, 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 PROZAC. 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 physician 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.

5.15 PROZAC and Olanzapine in Combination

When using PROZAC and olanzapine in combination, also refer to the Warnings and Precautions section of the package insert for Symbyax.

6 ADVERSE REACTIONS

When using PROZAC and olanzapine in combination, also refer to the Adverse Reactions section of the package insert for Symbyax.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect or predict the rates observed in practice.

Multiple doses of PROZAC have been administered to 10,782 patients with various diagnoses in US clinical trials. In addition, there have been 425 patients administered PROZAC 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.e., 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 enumerates the most common treatment-emergent adverse reactions associated with the use of PROZAC (incidence of at least 5% for PROZAC and at least twice that for placebo within at least 1 of the indications) for the treatment of Major Depressive Disorder, OCD, and bulimia in US controlled clinical trials and Panic Disorder in US plus non-US controlled trials. Table 5 enumerates treatment-emergent adverse reactions that occurred in 2% or more patients treated with PROZAC and with incidence greater than placebo who participated in US Major Depressive Disorder, OCD, and bulimia controlled clinical trials and US plus non-US Panic Disorder controlled clinical trials. Table 4 provides combined data for the pool of studies that are provided separately by indication in Table 3.

Associated with discontinuation in Major Depressive Disorder, OCD, bulimia, and Panic Disorder placebo-controlled clinical trials (excluding data from extensions of trials) — Table 5 lists the adverse reactions associated with discontinuation of PROZAC treatment (incidence at least twice that for placebo and at least 1% for PROZAC in clinical trials collecting only a primary reaction associated with discontinuation) in Major Depressive Disorder, OCD, bulimia, and Panic Disorder clinical trials, plus non-US Panic Disorder clinical trials.

Other adverse reactions in pediatric patients (children and adolescents) — Treatment-emergent adverse reactions were collected in 322 pediatric patients (180 fluoxetine-treated, 142 placebo-treated). The overall profile of adverse reactions was generally similar to that seen in adult studies, as shown in Tables 4 and 5. However, the following adverse reactions (excluding those which appear in the body or footnotes of Tables 4 and 5 and those for which the COSTART terms were uninformative or misleading) were reported at an incidence of at least 2% for fluoxetine and greater than placebo: thirst, hyperkinesia, agitation, personality disorder, epistaxis, urinary frequency, and menorrhagia.

The most common adverse reaction (incidence at least 1% for fluoxetine and greater than placebo) associated with discontinuation in 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.

Reactions observed in PROZAC Weekly clinical trials — Treatment-emergent adverse reactions in clinical trials with PROZAC Weekly were similar to the adverse reactions reported by patients in clinical trials with PROZAC daily. In a placebo-controlled clinical trial, more patients taking PROZAC Weekly reported diarrhea than patients taking placebo (10% versus 3%, respectively) or taking PROZAC 20 mg daily (10% versus 5%, respectively).

Male and female sexual dysfunction with SSRIs — Although changes in sexual desire, sexual performance, and sexual satisfaction often occur as manifestations of a psychiatric disorder, they may also be a consequence of pharmacologic treatment. In particular, some evidence suggests that SSRIs can cause such untoward sexual experiences. Reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance, and satisfaction are difficult to obtain, however, in part because patients and physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance, cited in product labeling, are likely to underestimate their actual incidence. In patients enrolled in US Major Depressive Disorder, OCD, and bulimia placebo-controlled clinical trials, decreased libido was the only sexual side effect reported by at least 2% of patients taking fluoxetine (4% fluoxetine, <1% placebo). There have been spontaneous reports in women taking fluoxetine of orgasmic dysfunction, including anorgasmia.

There are no adequate and well-controlled studies examining sexual dysfunction with fluoxetine treatment.

Symptoms of sexual dysfunction occasionally persist after discontinuation of fluoxetine treatment.

Priapism has been reported with all SSRIs.

While it is difficult to know the precise risk of sexual dysfunction associated with the use of SSRIs, physicians should routinely inquire about such possible side effects.

6.2 Other Reactions

Following is a list of treatment-emergent adverse reactions reported by patients treated with fluoxetine in clinical trials. This listing is not intended to include reactions (1) already listed in previous tables or elsewhere in labeling, (2) for which a drug cause was remote, (3) which were so general as to be uninformative, (4) which were not considered to have significant clinical implications, or (5) which occurred at a rate equal to or less than placebo.

Reactions are classified by body system using the following definitions: frequent adverse reactions are those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in fewer than 1/1000 patients.

Body as a Whole — Frequent: chills; Infrequent: suicide attempt; Rare: acute abdominal syndrome, photosensitivity reaction.

Cardiovascular System — Frequent: palpitation; Infrequent: arrhythmia, hypotension¹.

Digestive System — Infrequent: dysphagia, gastritis, gastroenteritis, melena, stomach ulcer; Rare: bloody diarrhea, duodenal ulcer, esophageal ulcer, gastrointestinal hemorrhage, hematemesis, hepatitis, peptic ulcer, stomach ulcer hemorrhage.

Hemic and Lymphatic System — Infrequent: ecchymosis; Rare: petechia, purpura.

Investigations — Frequent: QT interval prolongation (QT_cF ≥450 msec)³

Nervous System — Frequent: emotional lability; Infrequent: akathisia, ataxia, balance disorder¹, bruxism¹, buccoglossal syndrome, depersonalization, euphoria, hypertonia, libido increased, myoclonus, paranoid reaction; Rare: delusions.

Respiratory System — Rare: larynx edema.

Skin and Appendages — Infrequent: alopecia; Rare: purpuric rash.

Special Senses — Frequent: taste perversion; Infrequent: mydriasis.

Urogenital System — Frequent: micturition disorder; Infrequent: dysuria, gynecological bleeding².

¹ MedDRA dictionary term from integrated database of placebo controlled trials of 15870 patients, of which 9673 patients received fluoxetine.

² Group term that includes individual MedDRA terms: cervix hemorrhage uterine, dysfunctional uterine bleeding, genital hemorrhage, menometrorrhagia, menorrhagia, metrorrhagia, polymenorrhea, postmenopausal hemorrhage, uterine hemorrhage, vaginal hemorrhage. Adjusted for gender.

³ QT prolongation data are based on routine ECG measurements in clinical trials.

6.3 Postmarketing Experience

The following adverse reactions have been identified during post approval use of PROZAC. 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 PROZAC that have been received since market introduction and that may have no causal relationship with the drug include the following: aplastic anemia, atrial fibrillation¹, cataract, cerebrovascular accident¹, cholestatic jaundice, dyskinesia (including, for example, a case of buccal-lingual-masticatory syndrome with involuntary tongue protrusion reported to develop in a 77-year-old female after 5 weeks of fluoxetine therapy and which completely resolved over the next few months following drug discontinuation), eosinophilic pneumonia¹, epidermal necrolysis, erythema multiforme, erythema nodosum, exfoliative dermatitis, galactorrhea, gynecomastia, heart arrest¹, hepatic failure/necrosis, hyperprolactinemia, hypoglycemia, immune-related hemolytic anemia, kidney failure, memory impairment, movement disorders developing in patients with risk factors including drugs associated with such reactions and worsening of pre-existing movement disorders, optic neuritis, pancreatitis¹, pancytopenia, pulmonary embolism, pulmonary hypertension, QT prolongation, Stevens-Johnson syndrome, thrombocytopenia¹, thrombocytopenic purpura, ventricular tachycardia (including Torsades de Pointes–type arrhythmias), vaginal bleeding, and violent behaviors¹.

¹ These terms represent serious adverse events, but do not meet the definition for adverse drug reactions. They are included here because of their seriousness.

7 DRUG INTERACTIONS

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

7.1 Monoamine Oxidase Inhibitors (MAOI)

[see Dosage and Administration (2.9, 2.10), Contraindications (4.1), and Warnings and Precautions (5.2)].

7.2 CNS Acting Drugs

Caution is advised if the concomitant administration of PROZAC and such drugs is required. In evaluating individual cases, consideration should be given to using lower initial doses of the concomitantly administered drugs, using conservative titration schedules, and monitoring of clinical status [see Clinical Pharmacology (12.3)].

7.3 Serotonergic Drugs

[see Dosage and Administration (2.9, 2.10), Contraindications (4.1), and Warnings and Precautions (5.2)].

7.4 Drugs that Interfere with Hemostasis (e.g., NSAIDS, Aspirin, Warfarin)

Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SNRIs or SSRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when fluoxetine is initiated or discontinued [see Warnings and Precautions (5.7)].

7.5 Electroconvulsive Therapy (ECT)

There are no clinical studies establishing the benefit of the combined use of ECT and fluoxetine. There have been rare reports of prolonged seizures in patients on fluoxetine receiving ECT treatment.

7.6 Potential for Other Drugs to affect PROZAC

Drugs Tightly Bound to Plasma Proteins — Because fluoxetine is tightly bound to plasma proteins, adverse effects may result from displacement of protein-bound fluoxetine by other tightly-bound drugs [see Clinical Pharmacology (12.3)].

7.7 Potential for PROZAC 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 PROZAC [see Contraindications (4.2), Warnings and Precautions (5.10), and Drug Interactions (7.8)].

Thioridazine — Thioridazine should not be administered with PROZAC or within a minimum of 5 weeks after PROZAC has been discontinued, because of the risk of QT Prolongation [see Contraindications (4.2), Warnings and Precautions (5.10), and Drug Interactions (7.8)].

In a study of 19 healthy male subjects, which included 6 slow and 13 rapid hydroxylators of debrisoquin, a single 25 mg oral dose of thioridazine produced a 2.4-fold higher C_max and a 4.5-fold higher AUC for thioridazine in the slow hydroxylators compared with the rapid hydroxylators. The rate of debrisoquin hydroxylation is felt to depend on the level of CYP2D6 isozyme activity. Thus, this study suggests that drugs which inhibit CYP2D6, such as certain SSRIs, including fluoxetine, will produce elevated plasma levels of thioridazine.

Thioridazine 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. Coadministration of fluoxetine with other drugs that are metabolized by CYP2D6, including certain antidepressants (e.g., TCAs), antipsychotics (e.g., phenothiazines and most atypicals), and antiarrhythmics (e.g., propafenone, flecainide, and others) should be approached with caution. Therapy with medications that are predominantly metabolized by the CYP2D6 system and that have 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 coadministered or has been recently discontinued [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)].

Benzodiazepines — The half-life of concurrently administered diazepam may be prolonged in some patients [see Clinical Pharmacology (12.3)]. Coadministration of alprazolam and fluoxetine has resulted in increased alprazolam plasma concentrations and in further psychomotor performance decrement due to increased alprazolam levels.

Antipsychotics — Some clinical data suggests 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 coadministration of fluoxetine with single doses of terfenadine (a CYP3A4 substrate), no increase in plasma terfenadine concentrations occurred with concomitant fluoxetine.

Additionally, in vitro studies have shown ketoconazole, 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.

When using PROZAC and olanzapine and in combination, also refer to the Drug Interactions section of the package insert for Symbyax.

7.8 Drugs that Prolong the QT Interval

Do not use PROZAC in combination with thioridazine or pimozide. Use PROZAC 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 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). PROZAC is primarily metabolized by CYP2D6. Concomitant treatment with CYP2D6 inhibitors can increase the concentration of PROZAC. Concomitant use of other highly protein-bound drugs can increase the concentration of PROZAC [see Contraindications (4.2), Warnings and Precautions (5.10), Drug Interactions (7.7), and Clinical Pharmacology (12.3)].

8 USE IN SPECIFIC POPULATIONS

When using PROZAC and olanzapine in combination, also refer to the Use in Specific Populations section of the package insert for Symbyax.

8.1 Pregnancy

Pregnancy Category C — PROZAC should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. All pregnancies have a background risk of birth defects, loss, or other adverse outcome regardless of drug exposure.

Treatment of Pregnant Women during the First Trimester — There are no adequate and well-controlled clinical studies on the use of fluoxetine in pregnant women. Results of a number of published epidemiological studies assessing the risk of fluoxetine exposure during the first trimester of pregnancy have demonstrated inconsistent results. More than 10 cohort studies and case-control studies failed to demonstrate an increased risk for congenital malformations overall. However, one prospective cohort study conducted by the European Network of Teratology Information Services reported an increased risk of cardiovascular malformations in infants born to women (N = 253) exposed to fluoxetine during the first trimester of pregnancy compared to infants of women (N = 1359) who were not exposed to fluoxetine. There was no specific pattern of cardiovascular malformations. Overall, however, a causal relationship has not been established.

Nonteratogenic Effects — Neonates exposed to PROZAC and other SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs), late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome [see Warnings and Precautions (5.2)].

Infants exposed to SSRIs in pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 - 2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. Several recent epidemiological studies suggest a positive statistical association between SSRI use (including PROZAC) in pregnancy and PPHN. Other studies do not show a significant statistical association.

Physicians should also note the results of a prospective longitudinal study of 201 pregnant women with a history of major depression, who were either on antidepressants or had received antidepressants less than 12 weeks prior to their last menstrual period, and were in remission. Women who discontinued antidepressant medication during pregnancy showed a significant increase in relapse of their major depression compared to those women who remained on antidepressant medication throughout pregnancy.

When treating a pregnant woman with PROZAC, the physician should carefully consider both the potential risks of taking an SSRI, along with the established benefits of treating depression with an antidepressant. The decision can only be made on a case by case basis [see Dosage and Administration (2.7)].

Animal Data — In embryo-fetal development studies in rats and rabbits, there was no evidence of teratogenicity following administration of fluoxetine at doses up to 12.5 and 15 mg/kg/day, respectively (1.5 and 3.6 times, respectively, the maximum recommended human dose (MRHD) of 80 mg on a mg/m² basis) throughout organogenesis. However, in rat reproduction studies, an increase in stillborn pups, a decrease in pup weight, and an increase in pup deaths during the first 7 days postpartum occurred following maternal exposure to 12 mg/kg/day (1.5 times the MRHD on a mg/m² basis) during gestation or 7.5 mg/kg/day (0.9 times the MRHD on a mg/m² basis) during gestation and lactation. There was no evidence of developmental neurotoxicity in the surviving offspring of rats treated with 12 mg/kg/day during gestation. The no-effect dose for rat pup mortality was 5 mg/kg/day (0.6 times the MRHD on a mg/m² basis).

8.2 Labor and Delivery

The effect of PROZAC on labor and delivery in humans is unknown. However, because fluoxetine crosses the placenta and because of the possibility that fluoxetine may have adverse effects on the newborn, fluoxetine should be used during labor and delivery only if the potential benefit justifies the potential risk to the fetus.

8.3 Nursing Mothers

Because PROZAC is excreted in human milk, nursing while on PROZAC is not recommended. In one breast-milk sample, the concentration of fluoxetine plus norfluoxetine was 70.4 ng/mL. The concentration in the mother's plasma was 295.0 ng/mL. No adverse effects on the infant were reported. In another case, an infant nursed by a mother on PROZAC 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.

8.4 Pediatric Use

Use of PROZAC in children - The efficacy of PROZAC 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 PROZAC 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)].

PROZAC is approved for use in pediatric patients with MDD and OCD [see Box Warning and Warnings and Precautions (5.1)]. Anyone considering the use of PROZAC in a child or adolescent must balance the potential risks with the clinical need.

Animal Data - Significant toxicity on muscle tissue, neurobehavior, reproductive organs, and bone development has been observed following exposure of juvenile rats to fluoxetine from weaning through maturity. Oral administration of fluoxetine to rats from weaning postnatal day 21 through adulthood day 90 at 3, 10, or 30 mg/kg/day was associated with testicular degeneration and necrosis, epididymal vacuolation and hypospermia (at 30 mg/kg/day corresponding to plasma exposures [AUC] approximately 5-10 times the average AUC in pediatric patients at the MRHD of 20 mg/day), increased serum levels of creatine kinase (at AUC as low as 1-2 times the average AUC in pediatric patients at the MRHD of 20 mg/day), skeletal muscle degeneration and necrosis, decreased femur length/growth and body weight gain (at AUC 5-10 times the average AUC in pediatric patients at the MRHD of 20 mg/day). The high dose of 30 mg/kg/day exceeded a maximum tolerated dose. When animals were evaluated after a drug-free period (up to 11 weeks after cessation of dosing), fluoxetine was associated with neurobehavioral abnormalities (decreased reactivity at AUC as low as approximately 0.1-0.2 times the average AUC in pediatric patients at the MRHD and learning deficit at the high dose), and reproductive functional impairment (decreased mating at all doses and impaired fertility at the high dose). In addition, the testicular and epididymal microscopic lesions and decreased sperm concentrations found in high dose group were also observed, indicating that the drug effects on reproductive organs are irreversible. The reversibility of fluoxetine-induced muscle damage was not assessed.

These fluoxetine toxicities in juvenile rats have not been observed in adult animals. Plasma exposures (AUC) to fluoxetine in juvenile rats receiving 3, 10, or 30 mg/kg/day doses in this study are approximately 0.1-0.2, 1-2, and 5-10 times, respectively, the average exposure in pediatric patients receiving the MRHD of 20 mg/day. Rat exposures to the major metabolite, norfluoxetine, are approximately 0.3-0.8, 1-8, and 3-20 times, respectively, the pediatric exposure at the MRHD.

A specific effect on bone development was reported in juvenile mice administered fluoxetine by the intraperitoneal route to 4 week old mice for 4 weeks at doses 0.5 and 2 times the oral MRHD of 20 mg/day on mg/m² basis. There was a decrease in bone mineralization and density at both doses, but the overall growth (body weight gain or femur length) was not affected.

Use of PROZAC in combination with olanzapine in children and adolescents: Safety and efficacy of PROZAC and olanzapine in combination in patients 10 to 17 years of age have been established for the acute treatment of depressive episodes associated with Bipolar I Disorder. Safety and effectiveness of PROZAC and olanzapine in combination in patients less than 10 years of age have not been established.

8.5 Geriatric Use

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)]. For pharmacokinetic information in geriatric patients, [see Clinical Pharmacology (12.4)]. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. SNRIs and SSRIs, including fluoxetine, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse reaction [see Warnings and Precautions (5.8)].

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.

8.6 Hepatic Impairment

In subjects with cirrhosis of the liver, the clearances of fluoxetine and its active metabolite, norfluoxetine, were decreased, thus increasing the elimination half-lives of these substances. A lower or less frequent dose of fluoxetine should be used in patients with cirrhosis. Caution is advised when using PROZAC in patients with diseases or conditions that could affect its metabolism [see Dosage and Administration (2.7) and Clinical Pharmacology (12.4)].

9 DRUG ABUSE AND DEPENDENCE

9.3 Dependence

PROZAC has not been systematically studied, in animals or humans, for its potential for abuse, tolerance, or physical dependence. While the premarketing clinical experience with PROZAC did not reveal any tendency for a withdrawal syndrome or any drug seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of PROZAC (e.g., development of tolerance, incrementation of dose, drug-seeking behavior).

10 OVERDOSAGE

10.1 Human Experience

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 nodal rhythm, QT interval prolongation and ventriculararrhythmias, including Torsades de Pointes-type arrhythmias), hypotension, mania, neuroleptic malignant syndrome-like reactions, pyrexia, stupor, and syncope.

10.2 Animal Experience

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)].

10.3 Management of Overdose

For current information on the management of PROZAC overdose, contact a certified poison control center (1-800-222-1222 or www.poison.org). Treatment should consist of those general measures employed in the management of overdosage with any drug. Consider the possibility of multi-drug overdose.

Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. Use general supportive and symptomatic measures. Induction of emesis is not recommended.

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 (7.7)].

For specific information about overdosage with olanzapine and fluoxetine in combination, refer to the Overdosage section of the Symbyax package insert.

11 DESCRIPTION

PROZAC^® (fluoxetine capsules, USP) is a selective serotonin reuptake inhibitor for oral administration. It is also marketed for the treatment of premenstrual dysphoric disorder (Sarafem^®, fluoxetine hydrochloride). It is designated (±)-N-methyl-3-phenyl-3-[(α,α,α-trifluoro-p-tolyl)oxy]propylamine hydrochloride and has the empirical formula of C₁₇H₁₈F₃NO•HCl. Its molecular weight is 345.79. The structural formula is: