HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`SYMBYAX safely and effectively. See full prescribing information
`for SYMBYAX.
`
`SYMBYAX (olanzapine and fluoxetine) capsules for oral use
`Initial U.S. Approval: 2003
`
`WARNING: SUICIDAL THOUGHTS AND BEHAVIORS and
`INCREASED MORTALITY IN ELDERLY PATIENTS WITH
`DEMENTIA-RELATED PSYCHOSIS
`
`•
`
`•
`
`See full prescribing information for complete boxed warning.
`Increased risk of suicidal thinking and behavior in children,
`adolescents, and young adults taking antidepressants.
`SYMBYAX is not approved for use in children less than 10
`years of age. Monitor for worsening and emergence of
`suicidal thoughts and behaviors (5.1, 8.4).
`Elderly patients with dementia-related psychosis treated with
`antipsychotic drugs are at an increased risk of death.
`SYMBYAX is not approved for the treatment of patients with
`dementia-related psychosis (5.2).
`
` --------------------------- RECENT MAJOR CHANGES --------------------------
`
`Warnings and Precautions (5.6, 5.16) 8/2023
`
` ---------------------------- INDICATIONS AND USAGE ---------------------------
`SYMBYAX® combines olanzapine, an atypical antipsychotic and
`fluoxetine, a selective serotonin reuptake inhibitor, indicated for
`treatment of:
`•
`Acute Depressive Episodes Associated with Bipolar I Disorder (1)
`•
`Treatment Resistant Depression (1)
`
`•
`•
`
` ------------------------ DOSAGE AND ADMINISTRATION -----------------------
`•
`Adult Starting Dose: 6 mg olanzapine with 25 mg fluoxetine
`(6 mg/25 mg, once daily in the evening (2.1, 2.2)
`Adult Maximum Dose: 12 mg/50 mg once daily (2.1, 2.2).
`Pediatric Bipolar Depression Starting Dose: 3 mg/25 mg once
`daily (for ages 10 to 17 years) (2.1)
`Pediatric Bipolar Depression Maximum Dose: 12 mg/50 mg (2.1)
`Starting dose in patients predisposed to hypotensive reactions,
`hepatic impairment, or with potential for slowed metabolism:
`3 mg/25 mg to 6 mg/25 mg. Escalate dose cautiously (2.3)
`
`•
`•
`
` ----------------------DOSAGE FORMS AND STRENGTHS ---------------------
`•
`Capsules: 3 mg/25 mg, 6 mg/25 mg (mg olanzapine/mg
`equivalent fluoxetine) (3)
`
` ------------------------------- CONTRAINDICATIONS ------------------------------
`• Monoamine Oxidase Inhibitors (MAOI): Because of the risk of
`serotonin syndrome, do not use MAOIs intended to treat
`psychiatric disorders with SYMBYAX or within 5 weeks of
`stopping treatment with SYMBYAX. Do not use SYMBYAX within
`14 days of stopping an MAOI intended to treat psychiatric
`disorders. In addition, do not start SYMBYAX in a patient who is
`being treated with linezolid or intravenous methylene blue. (4.1)
`Pimozide: Do not use. Risk of QT interval prolongation (4.2, 5.20,
`7.7, 7.8)
`Thioridazine: Do not use. Risk of QT interval prolongation. Do not
`use thioridazine within 5 weeks of discontinuing SYMBYAX (4.2,
`5.20, 7.7, 7.8)
`
`•
`
`•
`
`•
`
` ------------------------ WARNINGS AND PRECAUTIONS -----------------------
`•
`Neuroleptic Malignant Syndrome: Manage with immediate
`discontinuation and close monitoring (5.3)
`Drug Reaction with Eosinophilia and Systemic Symptoms
`(DRESS): Discontinue if DRESS is suspected (5.4)
`• Metabolic Changes: Atypical antipsychotic drugs have been
`associated with metabolic changes including hyperglycemia,
`dyslipidemia, and weight gain (5.5)
`•
`Hyperglycemia and Diabetes Mellitus: In some cases
`extreme and associated with ketoacidosis or hyperosmolar
`coma or death. Monitor for symptoms of hyperglycemia.
`Perform fasting blood glucose testing before beginning, and
`periodically during treatment. (5.5)
`Dyslipidemia: Appropriate clinical monitoring is
`recommended, including fasting blood lipid testing before
`beginning, and periodically during, treatment (5.5)
`
`•
`
`1
`
`• Weight gain: Consider potential consequences of weight
`gain. Monitor weight regularly (5.5)
`Serotonin Syndrome: Serotonin syndrome has been reported with
`SSRIs and SNRIs, including SYMBYAX, both when taken alone,
`but especially when co-administered with other serotonergic
`agents. If such symptoms occur, discontinue SYMBYAX and
`serotonergic agents and initiate supportive treatment. If
`concomitant use of SYMBYAX 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 (5.6).
`Angle-Closure Glaucoma: Angle-closure glaucoma has occurred
`in patients with untreated anatomically narrow angles treated with
`antidepressants (5.7)
`Allergic Reactions and Rash: Discontinue upon appearance of
`rash or allergic phenomena (5.8)
`Activation of Mania/Hypomania: Screen for Bipolar Disorder and
`monitor for activation of mania/hypomania (5.9)
`Tardive Dyskinesia: Discontinue if clinically appropriate (5.10)
`Orthostatic Hypotension: Can be associated with bradycardia and
`syncope. Risk is increased during initial dose titration. Use
`caution in patients with cardiovascular disease or cerebrovascular
`disease, and those conditions that could affect hemodynamic
`responses (5.11)
`Leukopenia, Neutropenia, and Agranulocytosis: Has been
`reported with antipsychotics, including SYMBYAX. Patients with a
`history of a clinically significant low white blood cell count (WBC)
`or drug induced leukopenia/neutropenia should have their
`complete blood count (CBC) monitored frequently during the first
`few months of therapy. Consider discontinuing SYMBYAX at the
`first sign of a clinically significant decline in WBC in the absence
`of other causative factors (5.13)
`Seizures: Use cautiously in patients with a history of seizures or
`with conditions that lower the seizure threshold (5.15)
`Increased Risk of Bleeding: SSRIs increase the risk of bleeding.
`Use with NSAIDs, aspirin, warfarin, or other drugs that affect
`coagulation may potentiate the risk of gastrointestinal or other
`bleeding (5.16)
`Hyponatremia: Can occur in association with syndrome of
`inappropriate antidiuretic hormone (SIADH). Consider
`discontinuing SYMBYAX if symptomatic hyponatremia occurs
`(SIADH) (5.17)
`Potential for Cognitive and Motor Impairment: Has potential to
`impair judgment, thinking, and motor skills. Caution patients about
`operating machinery (5.18)
`QT Prolongation: QT prolongation and ventricular arrhythmia
`including Torsade de Pointes have been reported with fluoxetine.
`Use with caution in conditions that predispose to arrhythmias or
`increased fluoxetine exposure. Use cautiously in patients with risk
`factors for QT prolongation (4.2, 5.20)
`Anticholinergic (antimuscarinic) Effects: Use with caution with
`other anticholinergic drugs and in patients with urinary retention,
`prostatic hypertrophy, constipation, history of paralytic ileus or
`related conditions (5.21)
`Hyperprolactinemia: May elevate prolactin levels (5.22)
`Long Elimination Half-Life of Fluoxetine: Changes in dose will not
`be fully reflected in plasma for several weeks (5.24)
`Sexual Dysfunction: SYMBYAX use may cause symptoms of
`sexual dysfunction (5.26)
`
`•
`
`•
`
`•
`
`•
`
`•
`•
`
`•
`
`•
`
`•
`
`•
`
`•
`
`•
`
`•
`
`•
`•
`
`•
`
` ------------------------------- ADVERSE REACTIONS ------------------------------
`Most common adverse reactions (≥5% and at least twice that for
`placebo) in adults: sedation, weight increased, appetite increased, dry
`mouth, fatigue, edema, tremor, disturbance in attention, blurred vision.
`Children and adolescents: sedation, weight increased, appetite
`increased, tremor, triglyceride increased, hepatic enzymes increased
`(6.1)
`
`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 Inhibitor (MAOI): (2.4, 2.5, 4.1, 5.6, 7.1)
`•
`Drugs Metabolized by CYP2D6: Fluoxetine is a potent inhibitor of
`CYP2D6 enzyme pathway (7.7)
`
`Reference ID: 5229460
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

`•
`
`Drugs that Prolong the QT Interval: Do not use SYMBYAX in
`combination with thioridazine or pimozide. Use SYMBYAX with
`caution in combination with other drugs that prolong the QT
`interval (4.2, 5.20, 7.7, 7.8)
`
` ------------------------ USE IN SPECIFIC POPULATIONS -----------------------
`
`2
`
`Pregnancy: SSRI use, particularly later in pregnancy, may
`increase the risk for persistent pulmonary hypertension and
`symptoms of poor adaptation (respiratory distress, temperature
`instability, feeding difficulty, hypotonia, irritability, tremor) in the
`neonate. Olanzapine may cause extrapyramidal symptoms and/or
`withdrawal symptoms in neonates with third trimester exposure
`(8.1)
`Pediatric Use: Safety and efficacy of Symbyax for the treatment of
`bipolar I depression in patients under 10 years of age have not
`been established. Safety and efficacy of Symbyax for treatment
`resistant depression in patients under 18 years of age have not
`been established (8.4)
`Hepatic Impairment: Use a lower or less frequent dose in patients
`with cirrhosis (8.6)
`
`
`
` •
`
`•
`
`•
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`Guide.
`
`Revised: 8/2023
`
`5.26 Sexual Dysfunction
`
`6 ADVERSE REACTIONS
`6.1
`Clinical Trials Experience
`6.2
`Postmarketing Experience
`
`7 DRUG INTERACTIONS
`7.1
`Monoamine Oxidase Inhibitors (MAOIs)
`7.2
`CNS Acting Drugs
`7.3
`Other Serotonergic Drugs
`7.4
`Drugs that Interfere with Hemostasis (e.g., NSAIDs,
`Aspirin, Warfarin)
`Electroconvulsive Therapy (ECT)
`Potential for Other Drugs to Affect SYMBYAX
`Potential for SYMBYAX to Affect Other Drugs
`Drugs that Prolong the QT Interval
`
`7.5
`7.6
`7.7
`7.8
`
`8 USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`8.2
`Lactation
`8.3
`Females and Males of Reproductive Potential
`8.4
`Pediatric Use
`8.5
`Geriatric Use
`8.6
`Hepatic Impairment
`
`9 DRUG ABUSE AND DEPENDENCE
`9.3
`Dependence
`
`10 OVERDOSAGE
`10.1 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
`
`14 CLINICAL STUDIES
`14.1 Depressive Episodes Associated with Bipolar I Disorder
`14.2 Treatment Resistant Depression
`
`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.
`
`•
`
`•
`
`•
`•
`
`•
`
`•
`•
`•
`
`•
`
`•
`
`•
`•
`
`•
`
`•
`
`Tricyclic Antidepressants (TCAs): Monitor TCA levels during
`coadministration with SYMBYAX or when SYMBYAX has been
`recently discontinued (5.6, 7.7)
`CNS Acting Drugs: Caution is advised if the concomitant
`administration of SYMBYAX and other CNS-active drugs is
`required (7.2)
`Antihypertensive Agent: Enhanced antihypertensive effect (7.7)
`Levodopa and Dopamine Agonists: May antagonize
`levodopa/dopamine agonists (7.7)
`Benzodiazepines: May potentiate orthostatic hypotension and
`sedation (7.6, 7.7)
`Clozapine: May elevate clozapine levels (7.7)
`Haloperidol: Elevated haloperidol levels have been observed (7.7)
`Carbamazepine: Potential for elevated carbamazepine levels and
`clinical anticonvulsant toxicity (7.7)
`Phenytoin: Potential for elevated phenytoin levels and clinical
`anticonvulsant toxicity (7.7)
`Alcohol: May potentiate sedation and orthostatic hypotension
`(7.7)
`Serotonergic Drugs: (2.4, 2.5, 4.1, 5.6, 7.3)
`Fluvoxamine: May increase olanzapine levels; a lower dose of the
`olanzapine component of SYMBYAX should be considered (7.6)
`Drugs that Interfere with Hemostasis: (e.g., NSAIDs, Aspirin,
`Warfarin, etc.): May potentiate the risk of bleeding (7.4)
`Drugs Tightly Bound to Plasma Proteins: Fluoxetine may cause
`shift in plasma concentrations (7.7)
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`WARNING: SUICIDAL THOUGHTS AND BEHAVIORS and
`INCREASED MORTALITY IN ELDERLY PATIENTS WITH
`DEMENTIA-RELATED PSYCHOSIS
`
`1
`
`INDICATIONS AND USAGE
`
`2 DOSAGE AND ADMINISTRATION
`2.1
`Depressive Episodes Associated with Bipolar I Disorder
`2.2
`Treatment Resistant Depression
`2.3
`Specific Populations
`2.4
`Switching a Patient To or From a Monoamine Oxidase
`Inhibitor (MAOI) Intended to Treat Psychiatric Disorders
`Use of SYMBYAX with Other MAOIs such as Linezolid or
`Methylene Blue
`Discontinuation of Treatment with SYMBYAX
`
`2.5
`
`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
`Increased Mortality in Elderly Patients with Dementia-
`Related Psychosis
`Neuroleptic Malignant Syndrome (NMS)
`Drug Reaction with Eosinophilia and Systemic Symptoms
`(DRESS)
`Metabolic Changes
`5.5
`Serotonin Syndrome
`5.6
`Angle-Closure Glaucoma
`5.7
`Allergic Reactions and Rash
`5.8
`Activation of Mania/Hypomania
`5.9
`5.10 Tardive Dyskinesia
`5.11 Orthostatic Hypotension
`5.12 Falls
`5.13
`Leukopenia, Neutropenia, and Agranulocytosis
`5.14 Dysphagia
`5.15 Seizures
`5.16
`Increased Risk of Bleeding
`5.17 Hyponatremia
`5.18 Potential for Cognitive and Motor Impairment
`5.19 Body Temperature Dysregulation
`5.20 QT Prolongation
`5.21 Anticholinergic (antimuscarinic) Effects
`5.22 Hyperprolactinemia
`5.23 Concomitant Use of Olanzapine and Fluoxetine Products
`5.24
`Long Elimination Half-Life of Fluoxetine
`5.25 Discontinuation Adverse Reactions
`
`Reference ID: 5229460
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

`3
`
`
`
`FULL PRESCRIBING INFORMATION
`
`WARNING: SUICIDAL THOUGHTS AND BEHAVIORS and INCREASED MORTALITY IN ELDERLY
`PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS
`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.
`In patients of all ages who are started on antidepressant therapy, monitor closely for worsening and
`emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation
`and communication with the healthcare provider. SYMBYAX is not approved for use in children less than 10
`years of age [see Warnings and Precautions (5.1), Use in Specific Populations (8.4)].
`Increased Mortality in Elderly Patients with Dementia-Related Psychosis — Elderly patients with
`dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. SYMBYAX
`(olanzapine and fluoxetine) is not approved for the treatment of patients with dementia-related psychosis [see
`Warnings and Precautions (5.2)].
`
`INDICATIONS AND USAGE
`1
`SYMBYAX® is indicated for the treatment of:
`• Acute depressive episodes in Bipolar I Disorder [see Clinical Studies (14.1)].
`• Treatment resistant depression (Major Depressive Disorder in patient who do not respond to 2 separate trials of
`different antidepressants of adequate dose and duration in the current episode) [see Clinical Studies (14.2)].
`
`2
`
`DOSAGE AND ADMINISTRATION
`
`2.1
`
`Depressive Episodes Associated with Bipolar I Disorder
`Adults — Administer SYMBYAX once daily in the evening, generally beginning with the 6 mg/25 mg (mg
`olanzapine/mg equivalent fluoxetine) capsule. While food has no appreciable effect on the absorption of olanzapine and
`fluoxetine given individually, the effect of food on the absorption of SYMBYAX has not been studied. Make dosage
`adjustments, if indicated, according to efficacy and tolerability. Antidepressant efficacy was demonstrated with SYMBYAX
`in a dose range of olanzapine 6 mg to 12 mg and fluoxetine 25 mg to 50 mg [see Clinical Studies (14.1)]. The safety of
`doses above 18 mg of olanzapine and 75 mg of fluoxetine has not been evaluated in adult clinical studies. Periodically
`reexamine the need for continued pharmacotherapy.
`Children and Adolescents (10 to 17 years of age) — Administer SYMBYAX once daily in the evening, generally
`beginning with the 3 mg/25 mg capsule, without regard to meals, with a recommended target dose within the approved
`dosing range (6/25; 6/50; 12/50 mg) [see Clinical Studies (14.1)]. The safety of doses above 12 mg of olanzapine and
`50 mg of fluoxetine has not been evaluated in pediatric clinical studies. Periodically reexamine the need for continued
`pharmacotherapy.
`
`2.2
`
`Treatment Resistant Depression
`Administer SYMBYAX once daily in the evening, generally beginning with the 6 mg/25 mg capsule. While food
`has no appreciable effect on the absorption of olanzapine and fluoxetine given individually, the effect of food on the
`absorption of SYMBYAX has not been studied. Adjust dosage, if indicated, according to efficacy and tolerability.
`Antidepressant efficacy was demonstrated with SYMBYAX in a dose range of olanzapine 6 mg to 18 mg and fluoxetine
`25 mg to 50 mg [see Clinical Studies (14.2)]. The safety of doses above 18 mg/75 mg has not been evaluated in clinical
`studies. Periodically reexamine the need for continued pharmacotherapy.
`
`2.3
`
`Specific Populations
`Start SYMBYAX at 3 mg/25 mg or 6 mg/25 mg in 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 SYMBYAX
`(female gender, geriatric age, nonsmoking 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. SYMBYAX has not been systematically studied in patients >65 years of age or in patients <10 years of age
`[see Use in Specific Populations (8.5) and Clinical Pharmacology (12.3, 12.4)].
`
`Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric
`2.4
`Disorders
`At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and
`initiation of therapy with SYMBYAX. Conversely, at least 5 weeks should be allowed after stopping SYMBYAX before
`starting an MAOI intended to treat psychiatric disorders [see Contraindications (4.1)].
`
`2.5
`
`Use of SYMBYAX with Other MAOIs such as Linezolid or Methylene Blue
`
`Reference ID: 5229460
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

`4
`
`Do not start SYMBYAX 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 SYMBYAX 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 are judged to outweigh the risks of serotonin
`syndrome in a particular patient, SYMBYAX 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 SYMBYAX may be
`resumed 24 hours after the last dose of linezolid or intravenous methylene blue [see Warnings and Precautions (5.6)].
`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 SYMBYAX is unclear. The clinician should, nevertheless, be aware of
`the possibility of emergent symptoms of serotonin syndrome with such use [see Warnings and Precautions (5.6)].
`
`2.6
`
`Discontinuation of Treatment with SYMBYAX
`Symptoms associated with discontinuation of fluoxetine, a component of SYMBYAX, SNRIs, and SSRIs, have
`been reported [see Warnings and Precautions (5.25)].
`
`3
`
`DOSAGE FORMS AND STRENGTHS
`Capsules (mg olanzapine/mg equivalent fluoxetine):
`•
`3 mg/25 mg
`•
`6 mg/25 mg
`
`4
`
`CONTRAINDICATIONS
`
`4.1 Monoamine Oxidase Inhibitors (MAOIs)
`The use of MAOIs intended to treat psychiatric disorders with SYMBYAX or within 5 weeks of stopping treatment
`with SYMBYAX is contraindicated because of an increased risk of serotonin syndrome. The use of SYMBYAX within 14
`days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated [see Dosage and Administration
`(2.4) and Warnings and Precautions (5.6)].
`Starting SYMBYAX 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 (2.5) and
`Warnings and Precautions (5.6)].
`
`4.2
`
`Other Contraindications
`• Pimozide [see Warnings and Precautions (5.20) and Drug Interactions (7.7, 7.8)]
`• Thioridazine [see Warnings and Precautions (5.20) and Drug Interactions (7.7, 7.8)]
`Pimozide and thioridazine prolong the QT interval. SYMBYAX can increase the levels of pimozide and
`thioridazine through inhibition of CYP2D6. SYMBYAX can also prolong the QT interval.
`
`5
`
`WARNINGS AND PRECAUTIONS
`
`5.1
`
`Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults
`Patients with Major Depressive Disorder (MDD), both adult and pediatric, may experience worsening of their
`depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether
`or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a
`known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest
`predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing
`worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled
`analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs
`increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24)
`with Major Depressive Disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the
`risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with
`antidepressants compared to placebo in adults aged 65 and older.
`The pooled analyses of placebo-controlled trials in children and adolescents with MDD, Obsessive Compulsive
`Disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over
`4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included
`a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There
`was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients
`for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the
`highest incidence in MDD. The risk differences (drug versus placebo), however, were relatively stable within age strata
`and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000
`patients treated) are provided in Table 1.
`
`
`Table 1: Suicidality per 1000 Patients Treated
`
`Reference ID: 5229460
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

`Age Range
`
`
`<18
`18-24
`
`25-64
`≥65
`
`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
`
`5
`
`
`
`No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not
`sufficient to reach any conclusion about drug effect on suicide.
`It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there
`is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of
`antidepressants can delay the recurrence of depression.
`All patients being treated with antidepressants for any indication should be monitored appropriately and
`observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial
`few months of a course of drug therapy, or at times of dose changes, either increases or decreases.
`The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness,
`impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric
`patients being treated with antidepressants for Major Depressive Disorder as well as for other indications, both psychiatric
`and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of
`depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms
`may represent precursors to emerging suicidality.
`Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the
`medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms
`that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset,
`or were not part of the patient’s presenting symptoms.
`If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible,
`but with recognition that abrupt discontinuation can be associated with certain symptoms [see Warnings and Precautions
`(5.25)].
`
`Families and caregivers of patients being treated with antidepressants for Major Depressive Disorder or
`other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for
`the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above,
`as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such
`monitoring should include daily observation by families and caregivers. Prescriptions for SYMBYAX should be
`written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of
`overdose.
`It should be noted that SYMBYAX is not approved for use in treating any indications in patients less than 10 years
`of age [see Use in Specific Populations (8.4)].
`
`5.2
`
`Increased Mortality in Elderly Patients with Dementia-Related Psychosis
`Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk
`of death. SYMBYAX is not approved for the treatment of patients with dementia-related psychosis [see Boxed
`Warning and Use in Specific Populations (8.5)].
`In olanzapine placebo-controlled clinical trials of elderly patients with dementia-related psychosis, the incidence of
`death in olanzapine-treated patients was significantly greater than placebo-treated patients (3.5% vs 1.5%, respectively).
`Meta-Analysis of Antipsychotic Use in Dementia-Related Psychosis — Elderly patients with dementia-related
`psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of seventeen placebo-controlled
`trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-
`treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-
`week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the
`placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g.,
`heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to
`atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which
`the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to
`some characteristic(s) of the patients is not clear. SYMBYAX (olanzapine and fluoxetine) is not approved for the treatment
`of patients with dementia-related psychosis [see Use in Specific Populations (8.5)].
`Cerebrovascular Adverse Events (CVAE), Including Stroke — Cerebrovascular adverse events (e.g., stroke,
`transient ischemic attack), including fatalities, were reported in patients in trials of olanzapine in elderly patients with
`dementia-related psychosis. In placebo-controlled trials, there was a significantly higher incidence of cerebrovascular
`
`Reference ID: 5229460
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

`6
`adverse events in patients treated with olanzapine compared to patients treated with placebo. Olanzapine and SYMBYAX
`are not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning].
`
`5.3
`
`Neuroleptic Malignant Syndrome (NMS)
`A potentially fatal symptom complex sometimes referred to as NMS has been reported in association with
`administration of antipsychotic drugs, including olanzapine. Clinical manifestations of NMS are hyperpyrexia, muscle
`rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia,
`diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatinine phosphokinase, myoglobinuria
`(rhabdomyolysis), and acute renal failure.
`The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important
`to exclude cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic
`infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important
`considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary
`central nervous system pathology.
`The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs and other drugs not
`essential to concurrent therapy, 2) intensive symptomatic treatment and medical monitoring, and 3) treatment of any
`concomitant serious medical problems for which specific treatments are available. There is no general agreement about
`specific pharmacological treatment regimens for NMS.
`If after recovering from NMS, a patient requires treatment with an antipsychotic, the patient should be carefully
`monitored, since recurrences of NMS have been reported [see Warnings and Precautions (5.5)].
`
`5.4
`
`Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)
`Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported with olanzapine exposure.
`DRESS may present with a cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, and/or
`lymphadenopathy with systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and/or pericarditis.
`DRESS is sometimes fatal. Discontinue SYMBYAX if DRESS is suspected.
`
`5.5 Metabolic Changes
`Atypical antipsychotic drugs have been associated with metabolic changes including hyperglycemia, dyslipidemia,
`and weight gain. Metabolic changes may be associated with increased cardiovascular/cerebrovascular risk. Olanzapine’s
`specific metabolic pr