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 capsules) for oral use
`Initial U.S. Approval: 1987
`
`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.
`
` --------------------------- RECENT MAJOR CHANGES --------------------------
`
`Warnings and Precautions (5.2, 5.7) 8/2023
`
` ---------------------------- INDICATIONS AND USAGE ---------------------------
`PROZAC® is a selective serotonin reuptake inhibitor indicated for:
`•
`Acute and maintenance treatment of Major Depressive Disorder
`(MDD) (1)
`Acute and maintenance treatment of Obsessive Compulsive
`Disorder (OCD) (1)
`Acute and maintenance treatment of Bulimia Nervosa (1)
`Acute treatment of Panic Disorder, with or without agoraphobia
`(1)
`
`•
`•
`
`•
`
`PROZAC and olanzapine in combination for treatment of:
`•
`Acute Depressive Episodes Associated with Bipolar I Disorder (1)
`•
`Treatment Resistant Depression (1)
`
` ------------------------ DOSAGE AND ADMINISTRATION -----------------------
`
`Indication
`
`MDD (2.1)
`
`OCD (2.2)
`
`Adult
`
`Pediatric
`
`20 mg/day in am (initial
`dose)
`
`10 to 20 mg/day
`(initial dose)
`
`20 mg/day in am (initial
`dose)
`
`10 mg/day (initial
`dose)
`
`Bulimia Nervosa
`(2.3)
`
`Panic Disorder
`(2.4)
`
`Depressive
`Episodes
`Associated with
`Bipolar I Disorder
`(2.5)
`
`60 mg/day in am
`
`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:
`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)
`
`•
`
`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)
`
`Reference ID: 5229460
`
`1
` ------------------------------- 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, 5.11, 7.7, 7.8)
`Thioridazine: Do not use. Risk of QT interval prolongation and
`elevated thioridazine plasma levels. Do not use thioridazine within
`5 weeks of discontinuing PROZAC. Do not use thioridazine within
`5 weeks of discontinuing PROZAC (4.2, 5.11, 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 -----------------------
`Suicidal Thoughts and Behaviors in Children, Adolescents, and
`•
`Young Adults: Monitor for clinical worsening and suicidal thinking
`and behavior (5.1)
`Serotonin Syndrome: Serotonin syndrome has been reported with
`SSRIs and SNRIs, including PROZAC, both when taken alone,
`but especially when co-administered with other serotonergic
`agents. If such symptoms occur, discontinue PROZAC and
`serotonergic agents 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)
`Increased Risk of 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)
`Angle-Closure Glaucoma: Angle-closure glaucoma has occurred
`in patients with untreated anatomically narrow angles treated with
`antidepressants (5.8)
`Hyponatremia: Has been reported with PROZAC in association
`with syndrome of inappropriate antidiuretic hormone (SIADH).
`Consider discontinuing if symptomatic hyponatremia occurs (5.9)
`Anxiety and Insomnia: May occur (5.10)
`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, 5.11)
`Potential for Cognitive and Motor Impairment: Has potential to
`impair judgment, thinking, and motor skills. Use caution when
`operating machinery (5.13)
`Long Half-Life: Changes in dose will not be fully reflected in
`plasma for several weeks (5.14)
`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 (5.16)
`Sexual Dysfunction: PROZAC may cause symptoms of sexual
`dysfunction (5.17)
`
`•
`
`•
`
`•
`•
`
`•
`
`•
`
`•
`
`•
`
` ------------------------------- 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)
`
`

`

`•
`
`•
`
`2
`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, 5.11, 7.7, 7.8)
`
`•
`
` ------------------------ USE IN SPECIFIC POPULATIONS -----------------------
`•
`Pregnancy: SSRI use, particularly later in pregnancy, may
`increase risk for persistent pulmonary hypertension and
`symptoms of poor adaptation (respiratory distress, temperature
`instability, feeding difficulty, hypotonia, tremor, irritability) in the
`neonate (8.1)
`Pediatric Use: Safety and effectiveness of PROZAC in patients
`<8 years of age with Major Depressive Disorder and <7 years of
`age with OCD have not been established. Safety and
`effectiveness of PROZAC and olanzapine in combination in
`patients <10 years of age for depressive episodes associated with
`Bipolar I Disorder have not been established (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 Medication
`Guide.
`
`Revised: 8/2023
`
`7.2
`7.3
`7.4
`
`7.5
`7.6
`7.7
`7.8
`
`CNS Acting Drugs
`Other Serotonergic Drugs
`Drugs that Interfere with Hemostasis (e.g., NSAIDS,
`Aspirin, Warfarin)
`Electroconvulsive Therapy (ECT)
`Potential for Other Drugs to affect PROZAC
`Potential for PROZAC to affect Other Drugs
`Drugs that Prolong the QT Interval
`
`8 USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`8.2
`Lactation
`8.4
`Pediatric Use
`8.5
`Geriatric Use
`8.6
`Hepatic Impairment
`
`9 DRUG ABUSE AND DEPENDENCE
`9.3
`Dependence
`
`10 OVERDOSAGE
`
`11 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
`
`*Sections or subsections omitted from the full prescribing information
`are not listed.
`
`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)
`
`•
`
`•
`
`•
`•
`
`•
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`WARNING: SUICIDAL THOUGHTS AND BEHAVIORS
`
`1
`
`INDICATIONS AND USAGE
`
`2 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
`PROZAC and Olanzapine in Combination: Treatment
`Resistant Depression
`Dosing in Specific Populations
`Discontinuation of Treatment
`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
`
`2.7
`2.8
`2.9
`
`2.6
`
`3 DOSAGE FORMS AND STRENGTHS
`
`4 CONTRAINDICATIONS
`4.1
`Monoamine Oxidase Inhibitors (MAOIs)
`4.2
`Other Contraindications
`
`5.2
`5.3
`5.4
`
`5 WARNINGS AND PRECAUTIONS
`5.1
`Suicidal Thoughts and Behaviors in Children,
`Adolescents, and Young Adults
`Serotonin Syndrome
`Allergic Reactions and Rash
`Screening Patients for Bipolar Disorder and Monitoring for
`Mania/Hypomania
`Seizures
`5.5
`Altered Appetite and Weight
`5.6
`Increased Risk of Bleeding
`5.7
`Angle-Closure Glaucoma
`5.8
`Hyponatremia
`5.9
`5.10 Anxiety and Insomnia
`5.11 QT Prolongation
`5.12 Use in Patients with Concomitant Illness
`5.13 Potential for Cognitive and Motor Impairment
`5.14
`Long Elimination Half-Life
`5.15 Discontinuation Adverse Reactions
`5.16 PROZAC and Olanzapine in Combination
`5.17 Sexual Dysfunction
`
`6 ADVERSE REACTIONS
`6.1
`Clinical Trials Experience
`6.2
`Postmarketing Experience
`
`7 DRUG INTERACTIONS
`7.1
`Monoamine Oxidase Inhibitors (MAOI)
`
`Reference ID: 5229460
`
`

`

`3
`
`FULL PRESCRIBING INFORMATION
`
`
`WARNING: SUICIDAL THOUGHTS AND BEHAVIORS
`• Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young
`adults in short-term studies. These studies did not show an increase in the risk of suicidal thoughts and
`behavior with antidepressant use in patients over age 24; there was a reduction in risk with antidepressant use
`in patients aged 65 and older [see Warnings and Precautions (5.1)].
`
` •
`
` In patients of all ages who are started on antidepressant therapy, monitor closely for worsening and for
`emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close
`observation and communication with the prescriber [see Warnings and Precautions (5.1)].
`
` •
`
` PROZAC is not approved for use in children less than 7 years of age [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.
`
`•
`
`1
`
`INDICATIONS AND USAGE
`PROZAC® is indicated for the treatment of:
`•
`Acute and maintenance treatment of Major Depressive Disorder [see Clinical Studies (14.1)].
`•
`Acute and maintenance treatment of obsessions and compulsions in patients with Obsessive Compulsive
`Disorder (OCD) [see Clinical Studies (14.2)].
`Acute and maintenance treatment of binge-eating and vomiting behaviors in patients with moderate to severe
`Bulimia Nervosa [see Clinical Studies (14.3)].
`Acute treatment of Panic Disorder, with or without agoraphobia [see Clinical Studies (14.4)].
`•
`PROZAC and Olanzapine in Combination is indicated for the treatment of:
`•
`Acute treatment of depressive episodes associated with Bipolar I Disorder.
`•
`Treatment resistant depression (Major Depressive Disorder in 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 depressive episodes associated with Bipolar I Disorder
`or the treatment of treatment resistant depression.
`When using PROZAC and olanzapine in combination, also refer to the Clinical Studies section of the package
`insert for Symbyax®.
`
`2
`
`DOSAGE AND ADMINISTRATION
`
`2.1 Major Depressive Disorder
`Initial Treatment
`Adult — Initiate PROZAC 20 mg/day orally in the morning. Consider a dose increase after several weeks if
`insufficient clinical improvement is observed. Administer doses above 20 mg/day once daily in the morning or twice daily
`(i.e., morning and noon).The maximum fluoxetine dose should not exceed 80 mg/day.
`In controlled trials used to support the efficacy of fluoxetine, patients were administered morning doses ranging
`from 20 to 80 mg/day. Studies comparing fluoxetine 20, 40, and 60 mg/day to placebo indicate that 20 mg/day is sufficient
`to obtain a satisfactory response in Major Depressive Disorder in most cases [see Clinical Studies (14.1)].
`Pediatric (children and adolescents) — Initiate PROZAC 10 or 20 mg/day. After 1 week at 10 mg/day, increase the
`dose 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. Consider a dose increase to 20 mg/day after several weeks if insufficient clinical improvement
`is observed. In the short-term (8 to 9 week) controlled clinical trials of fluoxetine supporting its effectiveness in the
`treatment of Major Depressive Disorder, patients were administered fluoxetine doses of 10 to 20 mg/day [see Clinical
`Studies (14.1)].
`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.
`Periodically reassess to determine the need for maintenance treatment.
`Switching Patients to a Tricyclic Antidepressant (TCA) — Dosage of a TCA may need to be reduced, and plasma
`TCA concentrations may need to be monitored temporarily when fluoxetine 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
`
`Reference ID: 5229460
`
`

`

`4
`
`Adult — Initiate PROZAC 20 mg/day, orally in the morning. Consider a dose increase after several weeks if
`insufficient clinical improvement is observed. The full therapeutic effect may be delayed until 5 weeks of treatment or
`longer. Administer doses above 20 mg/day once daily in the morning or twice daily (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.
`In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of OCD, patients were
`administered fixed daily doses of 20, 40, or 60 mg of fluoxetine or placebo [see Clinical Studies (14.2)]. In one of these
`studies, no dose-response relationship for effectiveness was demonstrated.
`Pediatric (children and adolescents) — In adolescents and higher weight children, initiate treatment with a dose of
`10 mg/day. After 2 weeks, increase the dose to 20 mg/day. Consider additional dose increases 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, initiate treatment with a dose of 10 mg/day. Consider additional dose increases after
`several more weeks if insufficient clinical improvement is observed. A dose range of 20 to 30 mg/day is recommended.
`Experience with daily doses greater than 20 mg is very minimal, and there is no experience with doses greater than
`60 mg.
`In the controlled clinical trial of fluoxetine supporting its effectiveness in the treatment of OCD, patients were
`administered fluoxetine doses in the range of 10 to 60 mg/day [see Clinical Studies (14.2)].
`Periodically reassess to determine the need for treatment.
`
`2.3
`
`Bulimia Nervosa
`Initial Treatment — Administer PROZAC 60 mg/day in the morning. For some patients it may be advisable to titrate
`up to this target dose over several days. Fluoxetine doses above 60 mg/day have not been systematically studied in
`patients with bulimia. In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of Bulimia
`Nervosa, patients were administered fixed daily fluoxetine doses of 20 or 60 mg, or placebo [see Clinical Studies (14.3)].
`Only the 60 mg dose was statistically significantly superior to placebo in reducing the frequency of binge-eating and
`vomiting.
`Periodically reassess to determine the need for maintenance treatment.
`
`2.4
`
`Panic Disorder
`Initial Treatment — Initiate treatment with PROZAC 10 mg/day. After one week, increase the dose to 20 mg/day.
`Consider a dose increase after several weeks if no clinical improvement is observed. Fluoxetine doses above 60 mg/day
`have not been systematically evaluated in patients with Panic Disorder. In the controlled clinical trials of fluoxetine
`supporting its effectiveness in the treatment of Panic Disorder, patients were administered fluoxetine doses in the range of
`10 to 60 mg/day [see Clinical Studies (14.4)]. The most frequently administered dose in the 2 flexible-dose clinical trials
`was 20 mg/day.
`Periodically reassess 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 — Administer fluoxetine 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. Make dosage adjustments, if indicated,
`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. Periodically re-examine the need for continued pharmacotherapy.
`Children and adolescents (10 -17 years of age) — Administer olanzapine and fluoxetine combination once daily in
`the evening, generally beginning with 2.5 mg of olanzapine and 20 mg of fluoxetine. Make dosage adjustments, if
`indicated, 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. Periodically re-examine the need for continued
`pharmacotherapy.
`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. Adjust dosage, if indicated, with
`the individual components according to efficacy and tolerability.
`
`
`Reference ID: 5229460
`
`

`

`Table 1: Approximate Dose Correspondence Between Symbyax1 and the Combination of PROZAC and
`Olanzapine
`
`5
`
`Use in Combination
`
`For
`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
`1 Symbyax (olanzapine/fluoxetine HCL) is a fixed-dose combination of PROZAC and olanzapine.
`
`PROZAC monotherapy is not indicated for the treatment of depressive episodes associated with Bipolar I Disorder.
`
`PROZAC
`(mg/day)
`20
`20
`20
`40+10
`40+10
`
`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.
`Administer fluoxetine 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. Adjust dosage, if indicated, 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. Adjust dosage, if indicated, with the individual
`components according to efficacy and tolerability.
`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
`Geriatric — Consider a lower or less frequent dosage for the elderly [see Use in Specific Populations (8.5)].
`Hepatic Impairment — As with many other medications, use a lower or less frequent dosage 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 (5.12)].
`PROZAC and Olanzapine in Combination — Use a starting dose of oral olanzapine 2.5 to 5 mg with fluoxetine
`20 mg 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. Titrate slowly and
`adjust dosage as needed in patients who exhibit a combination of factors that may slow metabolism. 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 (5.16) 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 (5.15)].
`
`Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric
`2.9
`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
`
`Reference ID: 5229460
`
`

`

`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 healthcare provider should, nevertheless, be
`aware of the possibility of emergent symptoms of serotonin syndrome with such use [see Warnings and Precautions
`(5.2)].
`
`6
`
`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
`
`•
`
`•
`
`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 (5.11) and Drug Interactions (7.7, 7.8)]
`•
`Thioridazine [see Warnings and Precautions (5.11) and Drug Interactions (7.7, 7.8)]
`Pimozide and thioridazine prolong the QT interval. 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
`
`Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults
`Patients with Major Depressive Disorder (MDD), both adult and pediatric, may experience worsening of their
`depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether
`or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a
`known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest
`predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing
`worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled
`analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs
`increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) 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.
`
`
`
`Reference ID: 5229460
`
`

`

`Table 2: Suicidality per 1000 Patients Treated
`Age Range
`Drug-Placebo Difference in Number of Cases of
`Suicidality per 1000 Patients Treated
`Increases Compared to Placebo
`14 additional cases
`5 additional cases
`Decreases Compared to Placebo
`1 fewer case
`6 fewer cases
`
`
`<18
`18-24
`
`25-64
`≥65
`
`7
`
`
`No suicides occurred in any of the pediatric trials. There were suicides in the adult