`
` CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`
`APPLICATION NUMBER:
`
`
` 018936Orig1s111
`
`
`
`
`
`
`
` PROZAC
`
`(fluoxetine hydrochloride)
`
`
`
` Trade Name:
`
`
`Generic or Proper
`
` Name:
`
` Sponsor:
`
`
`
`
`
`
`
` Approval Date:
`
`
`
`
` Indication:
`
`
`
`
`
`
` Eli Lilly and Company
`
` October 6, 2021
`
`PROZAC® is a selective serotonin reuptake inhibitor
`indicated for:
` • Acute and maintenance treatment of Major Depressive
`
` Disorder (MDD)
`• Acute and maintenance treatment of Obsessive-
`
` Compulsive Disorder (OCD)
` • Acute and maintenance treatment of Bulimia Nervosa
`
`
` • Acute treatment of Panic Disorder, with or without
` agoraphobia
`
` PROZAC and olanzapine in combination for treatment
`
` of:
`• Acute Depressive Episodes Associated with Bipolar I
` Disorder
`
` • Treatment Resistant Depression.
`
`
`
`
`
`
`
`
`
`
`
`

`

`
`
`
`
`
`
`
`
`
`
` CENTER FOR DRUG EVALUATION AND RESEARCH
`
` 018936Orig1s111
`
`
` CONTENTS
`
` Reviews / Information Included in this NDA Review.
`
`
`
`
`
` Approval Letter
`
` Other Action Letters
`
` Labeling
`
` REMS
` Summary Review
`
`
` Officer/Employee List
`
` Office Director Memo
`
` Cross Discipline Team Leader Review
`
`
` Clinical Review(s)
` Product Quality Review(s)
`
`
`
` Non-Clinical Review(s)
` Statistical Review(s)
`
`
` Clinical Microbiology / Virology Review(s)
` Clinical Pharmacology Review(s)
`
`
`
` Other Reviews
` Risk Assessment and Risk Mitigation Review(s)
`
` Proprietary Name Review(s)
` Administrative/Correspondence Document(s)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` X
`
`
` X
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`
`
`
`
`
`
`
`
`
`
`
`
`
` X
`
`
` X
`
`
`
`

`

`
`
`
`
`
`
`
`
`CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`
`
`
`APPLICATION NUMBER:
`
` 018936Orig1s111
`
`
`
`
`APPROVAL LETTER
`
`
`

`

`
`
` NDA 018936/S-111
`
`
`
`
`SUPPLEMENT APPROVAL
`
`
`
`
`
`Eli Lilly and Company
`
`
`Attention: Richard Hoffman, MS, RAC
`
`
`
`Advisor, Global Regulatory Affairs – US
`
`Lilly Corporate Center
`
`Indianapolis, IN 46285
`
`
`Dear Mr. Hoffman
`
`
`
`
`Please refer to your supplemental new drug application (sNDA) dated and received
`
`
`
`
`July 2, 2021, and your amendments, submitted under section 505(b) of the Federal
`
`
`
`
`
`Food, Drug, and Cosmetic Act (FDCA) for Prozac (fluoxetine) capsules.
`
`
`
`
`
`We also refer to our letter dated June 7, 2021, notifying you, under Section 505(o)(4) of
`
`
`the FDCA, of new safety information pertaining to the association between the use of
`
`selective serotonin reuptake inhibitors (SSRI)/serotonin and norepinephrine reuptake
`
`
`
`inhibitors (SNRI) and the occurrence of sexual dysfunction that we believe should be
`
`included in the labeling for all SSRI and SNRI.
`
`
`
`This supplemental new drug application provides for revisions to the labeling for Prozac
`
`
`
`
`consistent with our June 7, 2021, safety labeling change notification letter.
`
`
`APPROVAL & LABELING
`
`
`We have completed our review of this application, as amended. It is approved, effective
`
`
`
`on the date of this letter, for use as recommended in the enclosed agreed-upon
`
`labeling.
`
`
`
`
`
`WAIVER OF ½ PAGE LENGTH REQUIREMENT FOR HIGHLIGHTS
`
`
`
`Please note that we have previously granted a waiver of the requirements of 21 CFR
`
`201.57(d)(8) regarding the length of Highlights of Prescribing Information.
`
`
`
`CONTENT OF LABELING
`
`As soon as possible, but no later than 14 days from the date of this letter, submit the
`
`
`
`content of labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using
`
`
`the FDA automated drug registration and listing system (eLIST), as described at
`
`
`FDA.gov.1 Content of labeling must be identical to the enclosed labeling (text for the
`
` 1 http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm
`
`
`
`
`
`Reference ID: 4868533
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
` NDA 018936/S-111
`
` Page 2
`
`
` Prescribing Information and Medication Guide), with the addition of any labeling
`
`
` changes in pending “Changes Being Effected” (CBE) supplements, as well as annual
`
`reportable changes not included in the enclosed labeling.
`
` Information on submitting SPL files using eList may be found in the guidance for
`
`
` industry SPL Standard for Content of Labeling Technical Qs and As.2
`
`
`
`The SPL will be accessible from publicly available labeling repositories.
`
`
`Also within 14 days, amend all pending supplemental applications that include labeling
`
`
`changes for this NDA, including CBE supplements for which FDA has not yet issued an
`
`
`
`action letter, with the content of labeling [21 CFR 314.50(l)(1)(i)] in Microsoft Word
`
`
`format, that includes the changes approved in this supplemental application, as well as
`
`annual reportable changes. To facilitate review of your submission(s), provide a
`
`highlighted or marked-up copy that shows all changes, as well as a clean Microsoft
`Word version. The marked-up copy should provide appropriate annotations, including
`
`supplement number(s) and annual report date(s).
`
`REQUIRED PEDIATRIC ASSESSMENTS
`
`
`
`Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for
`
`
`new active ingredients (which includes new salts and new fixed combinations), new
`
`indications, new dosage forms, new dosing regimens, or new routes of administration
`
`
`are required to contain an assessment of the safety and effectiveness of the product for
`
`the claimed indication in pediatric patients unless this requirement is waived, deferred,
`
`or inapplicable.
`
`
`
`Because none of these criteria apply to your application, you are exempt from this
`
`requirement.
`
`
`PROMOTIONAL MATERIALS
`
`You may request advisory comments on proposed introductory advertising and
`promotional labeling. For information about submitting promotional materials, see the
`
`
`final guidance for industry Providing Regulatory Submissions in Electronic and Non-
`Electronic Format-Promotional Labeling and Advertising Materials for Human
`
`Prescription Drugs.3
`
`You must submit final promotional materials and Prescribing Information, accompanied
`
`
`by a Form FDA 2253, at the time of initial dissemination or publication
`
`
` 2 We update guidances periodically. For the most recent version of a guidance, check the FDA Guidance
`
`
`
`
`
`
`
`
`
`
`
` Documents Database https://www.fda.gov/RegulatoryInformation/Guidances/default.htm.
` 3 For the most recent version of a guidance, check the FDA guidance web page at
`
`
`
`
`
`
`
`
`
`
` https://www.fda.gov/media/128163/download.
`
`
`U.S. Food and Drug Administration
`
`
`
`
`
`Silver Spring, MD 20993
`
`www.fda.gov
`
`
`
`Reference ID: 4868533
`
`

`

`
`
`
`
`
`
`
`
` NDA 018936/S-111
`
` Page 3
`
`
` [21 CFR 314.81(b)(3)(i)]. Form FDA 2253 is available at FDA.gov.4 Information and
`
`
`
`
`
` Instructions for completing the form can be found at FDA.gov.5
`
`All promotional materials that include representations about your drug product must be
`
`promptly revised to be consistent with the labeling changes approved in this
`
`
`
`supplement, including any new safety information [21 CFR 314.70(a)(4)]. The revisions
`
`in your promotional materials should include prominent disclosure of the important new
`
`safety information that appears in the revised labeling. Within 7 days of receipt of this
`
`
`
`
`letter, submit your statement of intent to comply with 21 CFR 314.70(a)(4).
`
`
`REPORTING REQUIREMENTS
`
`
`We remind you that you must comply with reporting requirements for an approved NDA
`
`
`(21 CFR 314.80 and 314.81).
`
`
`
`
`
`If you have any questions, call Ermias Zerislassie, Safety Regulatory Project Manager,
`
`
`at 301-796-2770.
`
`
`
`Sincerely,
`
`
`{See appended electronic signature page}
`
`
`Marc Stone, M.D.
`
`Deputy Director for Safety
`
`Division of Psychiatry
`
`Office of Neuroscience Center for Drug
`
`Evaluation and Research
`
`
`
`ENCLOSURE(S):
`
`
`
`• Content of Labeling
`
`
`o Prescribing Information
`
`
`o Medication Guide
`
`
`
`
`
`
`
` 4 http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM083570.pdf
`5 http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM375154.pdf
`
`
`
`U.S. Food and Drug Administration
`
`
`
`
`
`Silver Spring, MD 20993
`
`www.fda.gov
`
`Reference ID: 4868533
`
`

`

`Signature Page 1 of 1
`--------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically. Following this are manifestations of any and all
`electronic signatures for this electronic record.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
`
`MARC B STONE
`10/06/2021 03:01:53 PM
`
`Reference ID: 4868533
`
`

`

`
`
`
`
`
` CENTER FOR DRUG EVALUATION AND
`
` RESEARCH
`
`
`
`APPLICATION NUMBER:
`
` 018936Orig1s111
`
`
` LABELING
`
`
`
`
`
`

`

`
`
`
`
`
`
` 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, Sexual Dysfunction (5.17)
`10/2021
`
`
`
`---------------------------- 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-----------------------
` Pediatric
`
`
`
` Indication
` Adult
`
` MDD (2.1)
` 20 mg/day in am (initial
` 10 to 20 mg/day
`
`
`
` (initial dose)
`
` dose)
` 20 mg/day in am (initial
` 10 mg/day (initial
`
`
`
` dose)
`
` dose)
` 60 mg/day in am
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`•
`
`
`•
`
`•
`
`
`
` OCD (2.2)
`
`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:
`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: 4868533
`
`
`•
`
`
`•
`
` 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 (including triptans, tricyclic antidepressants, fentanyl,
`
`lithium, tramadol, tryptophan, buspirone, amphetamines, 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)
`
`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)
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`

`

`
`•
`
`
`•
`
`
`•
`
`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)
`
`
`•
`
`
`•
`
`
`•
`
`•
`
`
`•
`
`
`•
`
`
`•
`
` 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: 10/2021
`
`
`2.6
`
`
`2.7
`
`2.8
`
`2.9
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`WARNING: SUICIDAL THOUGHTS AND BEHAVIORS
`
`
`INDICATIONS AND USAGE
`1
`
`
`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
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`4 CONTRAINDICATIONS
`
`
`Monoamine Oxidase Inhibitors (MAOIs)
`4.1
`
`
`
`4.2
`Other Contraindications
`
`
`5 WARNINGS AND PRECAUTIONS
`
`Suicidal Thoughts and Behaviors in Children,
`5.1
`
`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
`
`
`Abnormal 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
`
`
`Clinical Trials Experience
`6.1
`
`
`6.2
`Postmarketing Experience
`
`
`7 DRUG INTERACTIONS
`
`
`Monoamine Oxidase Inhibitors (MAOI)
`7.1
`
`
`5.2
`
`5.3
`
`5.4
`
`Reference ID: 4868533
`
`
`7.2
`
`7.3
`
`7.4
`
`
`CNS Acting Drugs
`
`Serotonergic Drugs
`Drugs that Interfere with Hemostasis (e.g., NSAIDS,
`
`Aspirin, Warfarin)
`
`
`Electroconvulsive Therapy (ECT)
`7.5
`
`
`Potential for Other Drugs to affect PROZAC
`7.6
`
`
`Potential for PROZAC to affect Other Drugs
`7.7
`
`
`Drugs that Prolong the QT Interval
`7.8
`
`
`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
`
`
`Dependence
`9.3
`
`
`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
`
`
`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.
`
`
`
`

`

`
`
` 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®.
`
`
`
`DOSAGE AND ADMINISTRATION
`2
`
`
`
`
`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)].
`
`
`
`
`
`
`Obsessive Compulsive Disorder
`2.2
`
`
`Initial Treatment
`
`
`
`Reference ID: 4868533
`
`

`

`
`
` 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.
`
`
`
`
` 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.
`
`
` 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.
`
`
`
`
`
`
`
`
` 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 fluoxe