• 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)

• 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, 5.18, 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, 5.18, 7.7, 7.8)

• Neuroleptic Malignant Syndrome: Manage with immediate discontinuation and close monitoring (5.3)
• Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes including hyperglycemia, dyslipidemia, and weight gain (5.4)
  • 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. (5.4)
  • Dyslipidemia: Appropriate clinical monitoring is recommended, including fasting blood lipid testing before beginning, and periodically during, treatment (5.4)
  • Weight gain: Consider potential consequences of weight gain. Monitor weight regularly (5.4)
• 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 (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone and St. John's Wort). If such symptoms occur, discontinue SYMBYAX 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 (5.5).
• Angle-Closure Glaucoma: Angle-closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants (5.6)
• Allergic Reactions and Rash: Discontinue upon appearance of rash or allergic phenomena (5.7)
• Activation of Mania/Hypomania: Screen for Bipolar Disorder and monitor for activation of mania/hypomania (5.8)
• Tardive Dyskinesia: Discontinue if clinically appropriate (5.9)
• 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 (5.10)
• 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 (5.11)
• Seizures: Use cautiously in patients with a history of seizures or with conditions that lower the seizure threshold (5.13)
• Abnormal 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 (5.14)
• Hyponatremia: Can occur in association with syndrome of inappropriate antidiuretic hormone (SIADH). Consider discontinuing SYMBYAX if symptomatic hyponatremia occurs (SIADH) (5.15)
• Potential for Cognitive and Motor Impairment: Has potential to impair judgment, thinking, and motor skills. Caution patients about operating machinery (5.16)
• 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, 5.18, 7.7, 7.8, 8.4,10)
• Hyperprolactinemia: May elevate prolactin levels (5.20)
• Long Elimination Half-Life of Fluoxetine: Changes in dose will not be fully reflected in plasma for several weeks (5.22)

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

• Monoamine Oxidase Inhibitor (MAOI): (2.4, 2.5, 4.1, 5.5, 7.1)
• Drugs Metabolized by CYP2D6: Fluoxetine is a potent inhibitor of CYP2D6 enzyme pathway (7.7)
• Tricyclic Antidepressants (TCAs): Monitor TCA levels during coadministration with SYMBYAX or when SYMBYAX has been recently discontinued (5.5, 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, 5.5, 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)
• 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, 5.18, 7.7, 7.8)

• Pregnancy: SYMBYAX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus (8.1)
• Nursing Mothers: Breast feeding is not recommended (8.3)
• 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)