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. |
| Molecular Weight | 312.44 |
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 | Avoid unless benefit outweighs risk; associated with neural tube defects and cardiac malformations due to valproate component. |
| 2nd trimester | Avoid; use only if clearly needed; monitor for fetal growth restriction and preterm labor. |
| 3rd trimester | Avoid; neonatal withdrawal syndromes (irritability, feeding difficulties) and persistent pulmonary hypertension may occur. |
Clinical note
Comprehensive clinical and safety monograph for SYMBYAX (SYMBYAX).
| Placental transfer | Both components cross the placenta; fluoxetine and its active metabolite norfluoxetine achieve cord blood concentrations approximately 50-70% of maternal plasma levels; olanzapine cord blood levels are approximately 50% of maternal levels. |
| Breastfeeding | Both olanzapine and fluoxetine are excreted into breast milk; monitor infant for sedation, poor feeding, and weight gain. AAP classifies fluoxetine as a drug with possible adverse effects. Consider risk versus benefit. |
■ 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 |
Hypersensitivity to olanzapine or fluoxetineUse of MAOIs within 14 days (risk of serotonin syndrome)Use of pimozide or thioridazine (QT prolongation risk)Use of tryptophan or St. John's Wort
| 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…
| Lactation Rating | L3 - Moderately Safe |
| 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. |
| 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. |
| Food/Dietary | Avoid alcohol and grapefruit products. Grapefruit may increase olanzapine levels. Take with or without food; high-fat meals may delay absorption. |
| Clinical Pearls | Symbyax (olanzapine/fluoxetine) is a fixed-dose combination for depressive episodes in bipolar I disorder. Monitor for metabolic syndrome (weight gain, hyperglycemia, dyslipidemia) especially with olanzapine component. Risk of serotonin syndrome with other serotonergic drugs. Extrapyramidal symptoms and tardive dyskinesia possible. Neuroleptic malignant syndrome risk. Requires gradual dose titration and discontinuation. |
| Patient Advice | Take exactly as prescribed; do not change dose without consulting doctor. · May cause drowsiness; avoid driving or operating machinery until effects known. · Report symptoms of serotonin syndrome (agitation, hallucinations, rapid heart rate, fever, muscle stiffness). · Monitor weight and blood sugar regularly; report excessive thirst, hunger, or urination. · Avoid alcohol and other CNS depressants. · Do not stop suddenly; withdrawal symptoms may occur. |