SYMBYAX
Clinical safety rating: caution
Comprehensive clinical and safety monograph for SYMBYAX (SYMBYAX).
Symbyax is a combination of olanzapine (an atypical antipsychotic) and fluoxetine (a selective serotonin reuptake inhibitor). Olanzapine antagonizes dopamine D2, serotonin 5-HT2A, and other CNS receptors; fluoxetine inhibits serotonin reuptake. Synergy targets depressive and manic symptoms via dopaminergic and serotonergic modulation.
| Metabolism | Olanzapine is primarily metabolized by CYP1A2 and to a lesser extent by CYP2D6; fluoxetine is metabolized by CYP2D6 and CYP2C9, with fluoxetine being a potent inhibitor of CYP2D6. |
| Excretion | Olanzapine: ~57% renal (7% unchanged, rest as metabolites; 30% fecal as metabolites from biliary excretion). Fluoxetine: ~60% renal (primarily as metabolites; <10% unchanged) and ~40% fecal (via biliary excretion of metabolites). |
| Half-life | Olanzapine: 21-54 h (mean 30 h in adults; longer in elderly and hepatic impairment). Fluoxetine: 4-6 days (norfluoxetine 4-16 days). Extensive accumulation with chronic dosing; steady-state reached in 2-4 weeks for fluoxetine. |
| Protein binding | Olanzapine: 93% (albumin and α1-acid glycoprotein). Fluoxetine: 94.5% (albumin and α1-acid glycoprotein); norfluoxetine: 92-95%. |
| Volume of Distribution | Olanzapine: ~14-27 L/kg (large; extensive tissue distribution). Fluoxetine: ~20-45 L/kg (very large; extensive tissue binding, including brain). |
| Bioavailability | Olanzapine: 100% oral (well-absorbed; minimal first-pass metabolism). Fluoxetine: 72-90% oral (first-pass metabolism reduces bioavailability; food decreases rate but not extent). |
| Onset of Action | Oral: Antipsychotic effect (olanzapine): 1-2 weeks (full effect 4-6 weeks). Antidepressant effect (fluoxetine): 2-4 weeks (full effect 6-8 weeks). No parenteral formulation. |
| Duration of Action | Olanzapine: 24 h (once daily dosing). Fluoxetine: 2-3 days after single dose; prolonged due to norfluoxetine (5-7 days). Clinical effect persists for weeks after discontinuation due to long half-lives. |
6 mg/25 mg to 12 mg/50 mg orally once daily; maximum 12 mg/50 mg per day.
| Dosage form | CAPSULE |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment. Not recommended for severe renal impairment (CrCl <30 mL/min) due to lack of data. |
| Liver impairment | Child-Pugh Class A or B: No adjustment. Child-Pugh Class C: Not recommended due to lack of data. |
| Pediatric use | Not approved for use in pediatric patients (safety and efficacy not established). |
| Geriatric use | Initiate at 6 mg/25 mg daily; use caution due to increased sensitivity and risk of hypotension, sedation, and extrapyramidal symptoms. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for SYMBYAX (SYMBYAX).
| Breastfeeding | Both olanzapine and valproate are excreted into breast milk. Olanzapine M/P ratio approximately 0.2-0.5; valproate M/P ratio approximately 0.05-0.07. Limited data suggest low infant exposure, but monitor for sedation, poor feeding, and thrombocytopenia or hepatotoxicity due to valproate. Use caution, especially with high doses. Consider risk-benefit. |
| Teratogenic Risk | First trimester: Increased risk of major congenital malformations, particularly cardiovascular and neural tube defects, due to valproate component. Avoid use unless no alternative. Second and third trimesters: Fetal growth restriction, neonatal withdrawal syndrome (irritability, feeding difficulties, respiratory distress), and persistent pulmonary hypertension of the newborn (PPHN) with olanzapine component. Valproate increases risk of neurodevelopmental delay. Use lowest effective dose if unavoidable. |
■ FDA Black Box Warning
WARNING: SUICIDALITY AND ANTIDEPRESSANT DRUGS. Antidepressants increased the risk of suicidal thinking and behavior in short-term studies in children, adolescents, and young adults with major depressive disorder and other psychiatric disorders. Monitor closely for clinical worsening, suicidality, or unusual changes in behavior. Family and caregivers should be advised to observe for these signs. Symbyax is not approved for use in pediatric patients.
| Serious Effects |
["Concomitant use of MAOIs (monoamine oxidase inhibitors) or within 14 days of discontinuing an MAOI.","Concomitant use of pimozide or thioridazine due to QT prolongation risk.","Use in patients with uncontrolled narrow-angle glaucoma.","Hypersensitivity to olanzapine, fluoxetine, or any component of the formulation."]
| Precautions | ["Elderly patients with dementia-related psychosis treated with antipsychotics are at increased risk of death; Symbyax is not approved for this condition.","Increased risk of suicidal thinking and behavior in young adults, children, and adolescents.","Neuroleptic Malignant Syndrome (NMS): potentially fatal, requires immediate discontinuation.","Hyperglycemia and diabetes mellitus: monitor glucose in patients with risk factors.","Dyslipidemia: monitor lipid profiles.","Weight gain: significant weight gain may occur.","Tardive dyskinesia: discontinue if signs/symptoms appear.","Seizures: use cautiously in patients with history of seizures.","Serotonin syndrome: risk particularly with concomitant use of serotonergic drugs.","Angle-closure glaucoma: may cause mydriasis; avoid in patients with untreated narrow-angle glaucoma.","QT prolongation: caution in patients at risk for ventricular arrhythmias.","Hepatic impairment: caution in patients with hepatic disease.","Neutropenia/leukopenia: monitor CBC baseline and periodically.","Activation of mania/hypomania: screen for bipolar disorder prior to treatment."] |
Loading safety data…
| Fetal Monitoring | Preconception: Folate supplementation 5 mg daily. Pregnancy: Maternal serum valproate levels (target lowest effective), liver function tests, and platelet count every 1-2 months. Fetal monitoring: Detailed anatomy ultrasound at 18-20 weeks; consider fetal echocardiogram. Third trimester: Nonstress tests and biophysical profiles for IUGR. Neonatal: Monitor for withdrawal symptoms, PPHN, and coagulopathy. |
| Fertility Effects | Valproate may cause polycystic ovary syndrome (PCOS) and menstrual irregularities, reducing fertility. Olanzapine may cause hyperprolactinemia, leading to ovulatory dysfunction and decreased libido. Both components can contribute to anovulation. Effects are reversible upon dose reduction or discontinuation. |