ETRAFON 2-25
Clinical safety rating: caution
Comprehensive clinical and safety monograph for ETRAFON 2-25 (ETRAFON 2-25).
Combination of perphenazine (a typical antipsychotic) and amitriptyline (a tricyclic antidepressant). Perphenazine blocks postsynaptic dopamine D2 receptors in the mesolimbic system, also antagonizes alpha-adrenergic, histaminergic, and muscarinic receptors. Amitriptyline inhibits reuptake of serotonin and norepinephrine at the presynaptic neuronal membrane, enhancing serotonergic and noradrenergic neurotransmission.
| Metabolism | Amitriptyline is primarily metabolized by CYP2C19, CYP2D6, and CYP3A4. Perphenazine is metabolized by CYP2D6. |
| Excretion | Renal: approximately 25-50% as metabolites and unchanged drug; biliary/fecal: 10-25% as metabolites; the remainder is extensively metabolized via hepatic pathways. |
| Half-life | Perphenazine: 8-12 hours (terminal); amitriptyline: 15-24 hours (terminal), with nortriptyline active metabolite half-life 18-44 hours. Steady-state achieved in 4-7 days. |
| Protein binding | Perphenazine: 90-97% bound to albumin and alpha1-acid glycoprotein; amitriptyline: 82-96% bound to albumin. |
| Volume of Distribution | Perphenazine: 10-20 L/kg; amitriptyline: 8-18 L/kg. Large Vd indicates extensive tissue distribution, including CNS. |
| Bioavailability | Oral: perphenazine 40-60% due to first-pass metabolism; amitriptyline 30-60%. Intramuscular (if applicable) not available for this fixed combination. |
| Onset of Action | Oral: 1-3 hours for antidepressant effect; antipsychotic effects may take days to weeks. |
| Duration of Action | Oral: 12-24 hours for amitriptyline; perphenazine requires dosing 2-4 times daily due to shorter half-life. Clinical effects persist for days after discontinuation. |
One tablet (2 mg perphenazine, 25 mg amitriptyline) orally three or four times daily. Maintenance: 2-4 tablets daily.
| Dosage form | TABLET |
| Renal impairment | No specific guidelines; use with caution. GFR <10 mL/min: avoid due to anticholinergic accumulation. |
| Liver impairment | Child-Pugh A: no adjustment. Child-Pugh B: reduce dose by 50%. Child-Pugh C: contraindicated. |
| Pediatric use | Not recommended for children <12 years. For adolescents 12-18 years: start with 0.5-1 tablet (2-25) two or three times daily; maximum 6 tablets daily. |
| Geriatric use | Initial dose: 1 tablet (2-25) once or twice daily; increase slowly. Maximum 4 tablets daily. Avoid in elderly with dementia. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for ETRAFON 2-25 (ETRAFON 2-25).
| Breastfeeding | Perphenazine and amitriptyline are excreted in breast milk; M/P ratio not established. Likely low levels but may cause drowsiness, irritability, or impaired development in nursing infants. Consider alternative agents; if used, monitor infant for sedation and feeding issues. |
| Teratogenic Risk | First trimester: Case reports suggest increased risk of congenital malformations (limb deformities, CNS defects) based on limited data; perphenazine crosses placenta. Second trimester: Possible risk of extrapyramidal symptoms in neonate. Third trimester: Risk of neonatal withdrawal (tremors, hypertonia) and extrapyramidal signs; use near term may cause neonatal respiratory depression. Overall, avoid use unless benefits outweigh risks. |
■ FDA Black Box Warning
WARNING: Suicidality and Antidepressant Drugs. Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children, adolescents, and young adults with major depressive disorder and other psychiatric disorders. Anyone considering the use of Etrafon or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber.
| Serious Effects |
["Concomitant use with MAOIs or within 14 days of MAOI therapy","Recent myocardial infarction","Uncontrolled narrow-angle glaucoma","Urinary retention","Hypersensitivity to perphenazine, amitriptyline, or any component","Concomitant use with agents that prolong QT interval","Severe bone marrow depression","CNS depression from alcohol or other depressants"]
| Precautions |
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| Fetal Monitoring | Maternal serum levels of amitriptyline (therapeutic range 100-250 ng/mL) and perphenazine (therapeutic range 0.5-2 ng/mL) may be monitored if toxicity concerns. Fetal ultrasound for limb defects and CNS anomalies if first-trimester exposure. Neonatal monitoring for extrapyramidal symptoms, withdrawal, respiratory depression, and ECG changes. |
| Fertility Effects | May cause hyperprolactinemia (via perphenazine D2 blockade) leading to menstrual irregularities, anovulation, and galactorrhea, potentially impairing fertility. Amitriptyline may also elevate prolactin. Effects are reversible upon discontinuation. |
| ["Increased risk of suicidal thinking and behavior in children, adolescents, and young adults","Neuroleptic malignant syndrome (NMS)","Tardive dyskinesia","Cardiovascular effects (QT prolongation, orthostatic hypotension, tachycardia)","Anticholinergic effects (urinary retention, constipation, blurred vision)","Seizure threshold lowering","Hematologic toxicity (agranulocytosis)","Hepatic impairment","Endocrine effects (hyperprolactinemia, gynecomastia)","Withdrawal symptoms if abruptly discontinued"] |