TRAZODONE HYDROCHLORIDE
Clinical safety rating: safe
Animal studies have demonstrated safety
Trazodone hydrochloride is a triazolopyridine derivative with antidepressant activity. Its mechanism of action is not fully understood, but it is believed to involve inhibition of serotonin reuptake and antagonism at 5-HT2A and 5-HT2C receptors, as well as antagonism at alpha1-adrenergic and histamine H1 receptors.
| Metabolism | Primarily hepatic via CYP3A4 to active metabolite meta-chlorophenylpiperazine (m-CPP). Also via CYP2D6 and CYP1A2. m-CPP is further metabolized by CYP2D6. Trazodone and m-CPP are also substrates for P-glycoprotein. |
| Excretion | Renal (70-75% as metabolites, <1% as parent drug); fecal (20-25%); biliary (minor) |
| Half-life | 5-9 hours (biphasic: alpha phase 3-6 min, beta phase 5-9 h); prolonged in elderly and hepatic impairment |
| Protein binding | 89-95% bound to albumin |
| Volume of Distribution | 0.8-1.5 L/kg (extensive distribution into tissues) |
| Bioavailability | Oral: ~65% (variable due to first-pass metabolism) |
| Onset of Action | Oral: 1-2 hours (sedative effect); antidepressant: 1-2 weeks |
| Duration of Action | Sedation: 4-6 hours; antidepressant: sustained with chronic dosing |
Initial 150 mg/day orally in divided doses, may increase by 50 mg/day every 3-4 days; usual range 150-400 mg/day; maximum 600 mg/day for inpatients.
| Dosage form | TABLET |
| Renal impairment | eGFR <30 mL/min: Use with caution; consider starting at 25-50 mg/day and titrate slowly. No specific dose reduction for mild-moderate impairment. |
| Liver impairment | Child-Pugh Class B or C: Reduce dose by 50% and titrate cautiously; contraindicated in severe hepatic impairment (Child-Pugh Class C) due to risk of hepatic encephalopathy. |
| Pediatric use | Not approved for use in children <18 years; limited data for depression: 1-2 mg/kg/day orally in divided doses, max 6 mg/kg/day or 400 mg/day. |
| Geriatric use | Initial dose 25-50 mg/day orally; increase slowly by 25-50 mg every 3-4 days; maximum 300 mg/day. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
CNS depressants may enhance sedative effects Can cause priapism a medical emergency.
| Breastfeeding | Enters breast milk in low levels. M/P ratio estimated at 0.1-0.2. Limited data suggest no adverse effects in infants but caution is advised. Monitor infant for drowsiness, poor feeding, and weight gain. |
| Teratogenic Risk | Pregnancy Category C. First trimester: Associated with a small increased risk of congenital malformations, particularly cardiac defects, based on some observational studies. Second and third trimesters: Risk of persistent pulmonary hypertension of the newborn (PPHN) and neonatal withdrawal syndrome including respiratory distress, jitteriness, and feeding difficulties if used near term. |
■ FDA Black Box Warning
WARNING: SUICIDAL THOUGHTS AND BEHAVIORS - Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. Closely monitor for worsening and emergence of suicidal thoughts and behaviors.
| Common Effects | insomnia |
| Serious Effects |
["Concomitant use of MAOIs or within 14 days of MAOI discontinuation","Concomitant use of linezolid or intravenous methylene blue","Hypersensitivity to trazodone or any component of the formulation","QT interval prolongation (congenital or acquired) or use with drugs that prolong QT interval"]
| Precautions | ["Suicidal thoughts and behaviors (monitor closely)","Serotonin syndrome (risk when co-administered with other serotonergic drugs)","Priapism (urgent intervention required)","Orthostatic hypotension and syncope (especially in patients with cardiovascular disease)","QT interval prolongation (risk increased with dose >300 mg/day or in patients with risk factors)","Activation of mania/hypomania (screen for bipolar disorder)","Angle-closure glaucoma (may cause mydriasis)","Hyponatremia (SIADH reported)","Use in patients with hepatic or renal impairment (caution advised)"] |
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| Fetal Monitoring | Monitor maternal blood pressure (risk of orthostatic hypotension), liver function tests (LFTs) periodically, and ECG (QTc prolongation risk). Fetal monitoring: Ultrasound for growth and development if used in first trimester; consider fetal echocardiography at 18-22 weeks gestation with early exposure. Monitor neonate for withdrawal symptoms after delivery. |
| Fertility Effects | In males, may cause erectile dysfunction, priapism (rare), and decreased libido, potentially impairing fertility. In females, hyperprolactinemia and galactorrhea have been reported, which may disrupt ovulation. Animal studies show no impairment of fertility at human therapeutic doses. |