HIGHLIGHTS OF PRESCRIBING INFORMATION
`These 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 use
`
`PROZAC (fluoxetine hydrochloride) delayed-release capsules for oral use
`
`Initial U.S. Approval: 1987
`WARNING: SUICIDALITY AND ANTIDEPRESSANT DRUGS
`
`
`See full prescribing information for complete boxed warning.
`
`
`
`Increased risk of suicidal thinking and behavior in children, adolescents,
`
`and young adults taking antidepressants for Major Depressive
`Disorder (MDD) and other psychiatric disorders (5.1).
`
`
`When using PROZAC and olanzapine in combination, also refer to Boxed
`Warning section of the package insert for Symbyax.
`
`
`
`
`
`
`
`•
`
`
`•
`
`•
`
`•
`
`OCD (2.2)
`
`20 mg/day in am (initial dose)
`
`
`--------------------------- RECENT MAJOR CHANGES --------------------------
`
`------------------------INDICATIONS AND USAGE ---------------------------
`
`PROZAC® 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 in adults (1.5)
`
`Acute treatment of Treatment Resistant Depression in adults (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) (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)
`
`10 mg/day (initial
`
`dose)
`-
`
`60 mg/day in am
`
`
`Bulimia Nervosa
`(2.3)
`Panic Disorder (2.4)
`Depressive Episodes
`Associated with
`
`Bipolar I Disorder
`
`(2.5)
`
`-
`-
`
`-
`
`10 mg/day (initial dose)
`
`Oral in combination with
`olanzapine: 5 mg of oral
`
`
`olanzapine and 20 mg of
`
`fluoxetine once daily (initial
`
`dose)
`Oral in combination with
`olanzapine: 5 mg of oral
`
`
`olanzapine and 20 mg of
`
`fluoxetine once daily (initial
`
`dose)
`Consider tapering the dose of fluoxetine for pregnant women during the
`
`third trimester (2.7)
`A lower or less frequent dosage should be used in patients with hepatic
`impairment, the elderly, and for patients with concurrent disease or on
`multiple concomitant medications (2.7)
`
`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, if indicated, 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)
`
`Treatment Resistant
`
`Depression (2.6)
`
`
`•
`
`•
`
`
`•
`
`•
`
`
`
`Reference ID: 2927282
`
`
`
`
`
`
`
`1
`Safety of the coadministration of doses above 18 mg olanzapine with 75
`
`
`
`mg fluoxetine has not been evaluated (2.5, 2.6)
`---------------------- DOSAGE FORMS AND STRENGTHS ---------------------
`•
`Pulvules: 10 mg, 20 mg, 40 mg (3)
`
`
`• Weekly capsules: 90 mg (3)
`
`
`-------------------------------CONTRAINDICATIONS------------------------------
`Do not use with an MAOI or within 14 days of discontinuing an MAOI
`•
`
`due to risk of drug interaction. At least 5 weeks should be allowed after
`
`stopping PROZAC before treatment with an MAOI (4, 7.1)
`
`Do not use with pimozide due to risk of drug interaction or QTc
`
`prolongation (4, 7.9)
`Do not use with thioridazine due to QTc interval prolongation or
`
`potential for elevated thioridazine plasma levels. Do not use thioridazine
`within 5 weeks of discontinuing PROZAC (4, 7.9)
`
`• 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 or Neuroleptic Malignant Syndrome (NMS)-like
`
`Reactions: Have been reported with PROZAC. Discontinue PROZAC
`
`and initiate supportive treatment (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 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) (5.8)
`
`
`Anxiety and Insomnia: May occur (5.9)
`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)
`-------------------------------ADVERSE REACTIONS ------------------------------
`Most common adverse reactions (≥5% and at least twice that for placebo)
`
`
`associated with:
`
`Major Depressive Disorder, Obsessive Compulsive Disorder, Bulimia, and
`
`
`Panic Disorder: abnormal dreams, abnormal ejaculation, anorexia, anxiety,
`
`asthenia, diarrhea, dry mouth, dyspepsia, flu syndrome, impotence, insomnia,
`
`
`libido decreased, nausea, nervousness, pharyngitis, rash, sinusitis,
`
`somnolence, sweating, tremor, vasodilatation, and yawn (6.1)
`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 (MAOI): PROZAC is contraindicated for
`use with MAOI’s, or within 14 days of discontinuing an MAOI due to
`
`risk of drug interaction. At least 5 weeks should be allowed after
`stopping PROZAC before starting treatment with an MAOI (4, 7.1)
`
`Pimozide: PROZAC is contraindicated for use with pimozide due to risk
`
`of drug interaction or QTc prolongation (4, 7.9)
`Thioridazine: PROZAC is contraindicated for use with thioridazine due
`
`to QTc interval prolongation or potential for elevated thioridazine plasma
`
`levels. Do not use thioridazine within 5 weeks of discontinuing
`
`PROZAC (4, 7.9)
`
`Drugs Metabolized by CYP2D6: Fluoxetine is a potent inhibitor of
`
`
`
`CYP2D6 enzyme pathway (7.9)
`
`
`•
`
`
`•
`
`•
`
`•
`
`•
`
`•
`
`•
`
`•
`•
`
`•
`
`•
`•
`
`•
`
`•
`
`•
`
`•
`
`•
`
`

`

`•
`
`•
`
`•
`
`•
`
`•
`
`•
`•
`
`•
`
`•
`
`Tricyclic Antidepressants (TCAs): Monitor TCA levels during
`coadministration with PROZAC or when PROZAC has been recently
`
`
`discontinued (7.9)
`CNS Acting Drugs: Caution should be used when taken in combination
`with other centrally acting drugs (7.2)
`Benzodiazepines: Diazepam – increased t ½ , alprazolam - further
`psychomotor performance decrement due to increased levels (7.9)
`Antipsycotics: Potential for elevation of haloperidol and clozapine levels
`
`(7.9)
`Anticonvulsants: Potential for elevated phenytoin and carbamazepine
`levels and clinical anticonvulsant toxicity (7.9)
`
`
`
`Serotonergic Drugs: Potential for Serotonin Syndrome (5.2, 7.3)
`
`Triptans: There have been rare postmarketing reports of Serotonin
`
`Syndrome with use of an SSRI and a triptan (5.2, 7.4)
`Tryptophan: Concomitant use with tryptophan is not recommended (5.2,
`
`
`7.5)
`Drugs that Interfere with Hemostasis (e.g. NSAIDs, Aspirin, Warfarin):
`
`
`
`May potentiate the risk of bleeding (7.6)
`
`
`•
`
`•
`
`•
`•
`
`•
`
`
`
`Drugs Tightly Bound to Plasma Proteins: May cause a shift in plasma
`concentrations (7.8, 7.9)
`Olanzapine: When used in combination with PROZAC, also refer to the
`Drug Interactions section of the package insert for Symbyax (7.9)
`
`------------------------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 and olanzapine in
`
`
`combination have not been established in patients less than 18 years of
`age (8.4)
`Hepatic Impairment: Lower or less frequent dosing may be appropriate
`
`
`in patients with cirrhosis (8.6)
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`approved Medication Guide
`
`2
`
`
`
`Revised: [00/0000]
`
`
`1.6
`
`2.6
`
`5.3
`5.4
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`WARNING — SUICIDALITY AND ANTIDEPRESSANT DRUGS
`
`
`
`INDICATIONS AND USAGE
`1
`Major Depressive Disorder
`1.1
`
`Obsessive Compulsive Disorder
`1.2
`
`1.3
` Bulimia Nervosa
` Panic Disorder
`1.4
`
`PROZAC and Olanzapine in Combination: Depressive Episodes
`1.5
`Associated with Bipolar I Disorder
`
`PROZAC and Olanzapine in Combination: Treatment Resistant
`
`Depression
`
`DOSAGE AND ADMINISTRATION
`
`Major Depressive Disorder
`2.1
`
`Obsessive Compulsive Disorder
`2.2
`
`2.3
` Bulimia Nervosa
` Panic Disorder
`2.4
`
`PROZAC and Olanzapine in Combination: Depressive Episodes
`2.5
`Associated with Bipolar I Disorder
`
`PROZAC and Olanzapine in Combination: Treatment Resistant
`
`Depression
`
`
`Dosing in Specific Populations
`2.7
`
`
`Discontinuation of Treatment
`2.8
`
`
`DOSAGE FORMS AND STRENGTHS
`
`CONTRAINDICATIONS
`
` WARNINGS AND PRECAUTIONS
`
`Clinical Worsening and Suicide Risk
`5.1
`5.2
`Serotonin Syndrome or Neuroleptic Malignant Syndrome
`
`(NMS)-like Reactions
`
`Allergic Reactions and Rash
`
`Screening Patients for Bipolar Disorder and Monitoring for
`
`Mania/Hypomania
` Seizures
`5.5
`
`Altered Appetite and Weight
`5.6
`
`
` Abnormal Bleeding
`5.7
`
`
`Hyponatremia
`5.8
`Anxiety and Insomnia
`5.9
`
`
`5.10 Use in Patients with Concomitant Illness
`
`Potential for Cognitive and Motor Impairment
`5.11
`
`5.12
`Long Elimination Half-Life
`
`
`5.13 Discontinuation of Treatment
`
`5.14
`PROZAC and Olanzapine in Combination
`
`
` ADVERSE REACTIONS
`Clinical Trials Experience
`6.1
`
`Other Reactions
`6.2
`Postmarketing Experience
`6.3
`
`DRUG INTERACTIONS
`
`Monoamine Oxidase Inhibitors (MAOI)
`7.1
`
` CNS Acting Drugs
`7.2
`
`
` Serotonergic Drugs
`7.3
`
` Triptans
`7.4
`Tryptophan
`7.5
`
`2
`
`3
`4
`5
`
`6
`
`7
`
`
`
`Reference ID: 2927282
`
`7.6
`
`
`8
`
`9
`
`
`Drugs that Interfere with Hemostasis (e.g., NSAIDS, Aspirin,
`Warfarin)
`
`Electroconvulsive Therapy (ECT)
`7.7
`
`
`Potential for Other Drugs to affect PROZAC
`7.8
`
`Potential for PROZAC to affect Other Drugs
`7.9
`
`
`USE IN SPECIFIC POPULATIONS
`
`Pregnancy
`8.1
`
`
`Labor and Delivery
`8.2
`8.3
`Nursing Mothers
`8.4
` Pediatric Use
`
`
` Geriatric Use
`8.5
`
`Hepatic Impairment
`8.6
`DRUG ABUSE AND DEPENDENCE
`9.3
` Dependence
`
`10 OVERDOSAGE
`10.1 Human Experience
`
`10.2 Animal Experience
`
`
`10.3 Management of Overdose
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`
`Pharmacodynamics
`12.2
`
`Pharmacokinetics
`12.3
`
` Specific Populations
`12.4
`
`
`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
`
`
`
`Bulimia Nervosa
`
`14.3
`Panic Disorder
`14.4
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`16.1 How Supplied
`
`
`Storage and Handling
`16.2
`
`
`
`17 PATIENT COUNSELING INFORMATION
`17.1 General Information
`
`
`17.2
`Clinical Worsening and Suicide Risk
`17.3
`Serotonin Syndrome or Neuroleptic Malignant Syndrome
`
`(NMS)-like Reactions
`
`
`17.4 Allergic Reactions and Rash
`
`
`17.5 Abnormal Bleeding
`17.6 Hyponatremia
`
`Potential for Cognitive and Motor Impairment
`17.7
`
`17.8 Use of Concomitant Medications
`
`
`17.9 Discontinuation of Treatment
`
`17.10 Use in Specific Populations
`
`
`*Sections or subsections omitted from the full prescribing information are not
`listed
`
`
`
`

`

`
`FULL PRESCRIBING INFORMATION
`
`
`
`3
`
`
`WARNING: SUICIDALITY AND ANTIDEPRESSANT DRUGS
`Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children,
`
`adolescents, and young adults in short-term studies of Major Depressive Disorder (MDD) and other psychiatric disorders.
`
`
`
`Anyone considering the use of PROZAC or any other antidepressant in a child, adolescent, or young adult must balance this
`
`
`
`risk with the clinical need. 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 in risk with antidepressants compared to placebo in
`adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the
`
`risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed
`closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the
`need for close observation and communication with the prescriber. PROZAC is approved for use in pediatric patients with
`
`MDD and Obsessive Compulsive Disorder (OCD) [see Warnings and Precautions (5.1) and Use in Specific Populations (8.4)].
`When using PROZAC and olanzapine in combination, also refer to Boxed Warning section of the package insert for
`
`Symbyax.
`
`
`INDICATIONS AND USAGE
`1
`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)].
`
`
`
`Bulimia Nervosa
`1.3
`
`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)].
`
`
`Panic Disorder
`1.4
`
`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)].
`
`
`PROZAC and Olanzapine in Combination: Depressive Episodes Associated with Bipolar I Disorder
`1.5
`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 in adult patients.
`PROZAC monotherapy is not indicated for the treatment of depressive episodes associated with Bipolar I Disorder.
`
`
`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.
`DOSAGE AND ADMINISTRATION
`2
`2.1 Major Depressive Disorder
`Initial Treatment
`
`
`1.6
`
`
`
`Reference ID: 2927282
`
`

`

`
`
`4
`
`
`
` 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 Drug
`
`Interactions (7.9)].
`Switching Patients to or from a Monoamine Oxidase Inhibitor (MAOI) — At least 14 days should elapse between
`
`
`
`discontinuation of an MAOI and initiation of therapy with PROZAC. In addition, at least 5 weeks, perhaps longer, should be allowed
`
`after stopping PROZAC before starting an MAOI [see Contraindications (4) and Drug Interactions (7.1)].
`
`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
`
`
`
`Reference ID: 2927282
`
`

`

`5
`
`
`
`PROZAC
`
`(mg/day)
`20
`20
`20
`
`40+10
`
`40+10
`
`
` 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.
`
`Panic Disorder
`2.4
`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.
`PROZAC and Olanzapine in Combination: Depressive Episodes Associated with Bipolar I Disorder
`2.5
`
`
`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 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 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.
`
`Table 1: Approximate Dose Correspondence Between Symbyax1 and the Combination of PROZAC and Olanzapine
`For
`Use in Combination
`Symbyax
`Olanzapine
`
`(mg/day)
`
`(mg/day)
`
`
`2.5
`3 mg olanzapine/25 mg fluoxetine
`
`
`5
`6 mg olanzapine/25 mg fluoxetine
`
`
`10+2.5
`12 mg olanzapine/25 mg fluoxetine
`
`
`5
`6 mg olanzapine/50 mg fluoxetine
`
`
`10+2.5
`12 mg olanzapine/50 mg fluoxetine
` Symbyax (olanzapine/fluoxetine HCL) is a fixed-dose combination of PROZAC and olanzapine.
`
`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.
`
`
`
`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 depressive episodes associated with Bipolar I Disorder.
`
`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
`
`
`
`
`1
`
`
`2.6
`
`Reference ID: 2927282
`
`

`

`6
`
`
`
`•
`
`•
`
`•
`
`
` 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 during the Third Trimester — When treating pregnant women with PROZAC during the third
`trimester, the physician should carefully consider the potential risks and potential benefits of treatment. Neonates exposed to SNRIs or
`
`SSRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube
`
`feeding. The physician may consider tapering PROZAC in the third trimester [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