NEFAZODONE HYDROCHLORIDE
Clinical safety rating: safe
Animal studies have demonstrated safety
Nefazodone hydrochloride is a serotonin antagonist and reuptake inhibitor (SARI). It antagonizes the 5-HT2A receptor and inhibits serotonin and norepinephrine reuptake, leading to increased serotonergic and noradrenergic neurotransmission.
| Metabolism | Extensively metabolized in the liver, primarily by CYP3A4, to active metabolites including hydroxynefazodone and meta-chlorophenylpiperazine (mCPP). |
| Excretion | Primarily hepatic metabolism; <1% excreted unchanged renally; 55-65% excreted in urine as metabolites, 20-30% in feces. |
| Half-life | Terminal elimination half-life is 18-20 hours (range 11-24 h). Clinical context: Once-daily dosing achieves steady state in 4-5 days; prolonged half-life supports QD dosing. |
| Protein binding | 99% bound, primarily to albumin and alpha-1-acid glycoprotein. |
| Volume of Distribution | Approximately 0.4-1.3 L/kg (mean 0.7 L/kg). Clinical meaning: Moderate distribution, primarily in plasma and well-perfused tissues; not extensively sequestered in peripheral tissues. |
| Bioavailability | Oral bioavailability is approximately 20% (range 15-25%) due to extensive first-pass metabolism. Administration with food may increase absorption. |
| Onset of Action | Oral: Clinical antidepressant effect typically begins after 2-4 weeks; sedation may occur within 1-2 hours of first dose. |
| Duration of Action | Dosing interval: 24 hours due to half-life. Clinical note: Steady-state achieved in 4-5 days; sustained effect with regular dosing. |
Initial: 200 mg orally twice daily; may increase by 200 mg/day every 1-2 weeks to a maximum of 600 mg/day (300 mg twice daily). Usual therapeutic dose: 400-600 mg/day (divided twice daily).
| Dosage form | TABLET |
| Renal impairment | No specific GFR-based dose adjustments are established. Use with caution in patients with severe renal impairment (CrCl <30 mL/min). |
| Liver impairment | Contraindicated in patients with active liver disease or elevated baseline serum transaminases >3 times upper limit of normal. For Child-Pugh Class A or B, reduce dose by 50% and monitor liver function; avoid use in Child-Pugh Class C. |
| Pediatric use | Not approved for use in pediatric patients. Safety and efficacy have not been established. |
| Geriatric use | Initial dose should be reduced to 100 mg twice daily; subsequent titration should be slower and more cautious. Lower therapeutic doses may be sufficient due to increased plasma concentrations and decreased clearance. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
MAOIs can cause serotonin syndrome and CYP3A4 inhibitors may increase levels Can cause rare but serious hepatotoxicity.
| Breastfeeding | Breastfeeding safety: Limited data; nefazodone and its active metabolite hydroxynefazodone are excreted into human milk. Milk-to-plasma (M/P) ratio not established. Potential for adverse effects in nursing infants (e.g., irritability, feeding problems). Weigh benefits of breastfeeding against potential risks; consider monitoring infant for sedation, poor feeding, and growth. |
| Teratogenic Risk | Pregnancy category C. First trimester: Data insufficient, but nefazodone is a serotonin antagonist reuptake inhibitor; potential risk of neural tube defects cannot be excluded. Second and third trimesters: Risk of persistent pulmonary hypertension of the newborn (PPHN) and serotonin withdrawal syndrome. Late third trimester exposure may cause neonatal adaptation syndrome including respiratory distress, feeding difficulties, and tremors. |
■ FDA Black Box Warning
Risk of hepatotoxicity: Nefazodone has been associated with rare but severe and sometimes fatal liver injury. Treatment should not be initiated in patients with active liver disease or elevated baseline serum transaminases.
| Common Effects | Sedation |
| Serious Effects |
["Active liver disease or elevated baseline transaminases","Concomitant use with MAOIs or within 14 days of MAOI discontinuation","Hypersensitivity to nefazodone or any component of the formulation","Concomitant use with pimozide or carbamazepine","Concomitant use with terfenadine, astemizole, cisapride (due to CYP3A4 inhibition)"]
| Precautions | ["Hepatotoxicity (black box warning)","Serotonin syndrome","Suicidal thoughts and behaviors in young adults","Orthostatic hypotension","Priapism","QT prolongation (with overdose)","Concomitant use of MAOIs or within 14 days of MAOI discontinuation","Use with caution in patients with recent myocardial infarction or unstable heart disease"] |
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| Fetal Monitoring | Monitor mothers for weight gain, mood changes, and suicidal ideation. Fetal monitoring: Consider serial growth scans (third trimester) due to potential risk of low birth weight. Neonatal monitoring: Observe for symptoms of serotonin withdrawal (e.g., irritability, feeding difficulties, respiratory distress) for at least 48 hours after delivery. Assess for PPHN with echocardiography if respiratory distress occurs. |
| Fertility Effects | Reproductive impact: Serotonin antagonists may affect hypothalamic-pituitary-gonadal axis; animal studies show reduced fertility at high doses. Human data limited; possible effects on libido and erectile function. No specific data on female fertility, but potential for menstrual irregularities. Reversibility upon discontinuation is likely. |