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. |
| Molecular Weight | 403.97 Da (perphenazine 403.97; amitriptyline 277.4; combination product) |
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 | Avoid unless clearly needed. Associated with congenital malformations (limb defects, CNS malformations) in first trimester exposure. Limited data but risk cannot be excluded. |
| 2nd trimester | Use only if potential benefit justifies risk. Possible effects on fetal growth and development; monitor for neonatal adverse effects if used near term. |
| 3rd trimester | Avoid in third trimester due to risk of neonatal withdrawal (irritability, hypertonia, tremor, feeding difficulties) and extrapyramidal symptoms. Also risk of maternal hypotension and sedation. |
Clinical note
Comprehensive clinical and safety monograph for ETRAFON 2-25 (ETRAFON 2-25).
| Placental transfer | Both perphenazine and amitriptyline cross the placenta. Perphenazine is highly bound to plasma proteins, limiting transfer, but fetal concentrations can be significant. Amitriptyline and its metabolite nortriptyline cross readily. |
| Breastfeeding |
■ 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 |
Hypersensitivity to perphenazine, amitriptyline, or any componentConcomitant use with monoamine oxidase inhibitors (MAOIs) or within 14 days of MAOI therapySevere CNS depression (e.g., coma, barbiturate intoxication)Angle-closure glaucomaUrinary retention (notably due to prostatic hypertrophy)Pyloric stenosis or paralytic ileusConcurrent use of drugs causing QT prolongation (e.g., certain antiarrhythmics, antipsychotics) due to additive risk of torsades de pointes
Loading safety data…
| Perphenazine and amitriptyline are excreted into breast milk in small amounts. Monitor infant for sedation, irritability, and feeding problems. American Academy of Pediatrics recommends caution; consider risk-benefit. If used, observe infant for adverse effects. |
| Lactation Rating | L3 (Moderately Safe) |
| 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. |
| 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. |
| Precautions |
| 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 |
| Food/Dietary | Avoid tyramine-rich foods (aged cheese, cured meats, fermented foods) due to possible hypertensive crisis with amitriptyline. Limit alcohol and caffeine. Grapefruit juice may alter drug metabolism; avoid large quantities. |
| Clinical Pearls | ETRAFON 2-25 is a fixed-dose combination of perphenazine 2 mg and amitriptyline 25 mg. Use with caution in elderly patients due to increased risk of anticholinergic effects, sedation, and orthostatic hypotension. Monitor for extrapyramidal symptoms from perphenazine. Avoid concurrent use with MAOIs; allow a 14-day washout. ECG monitoring recommended due to QT prolongation risk from amitriptyline. |
| Patient Advice | Take exactly as prescribed; do not increase dose or stop suddenly. · May cause drowsiness; avoid driving or operating heavy machinery until you know how this medication affects you. · Rise slowly from sitting or lying to prevent dizziness. · Avoid alcohol and other CNS depressants. · Report any involuntary muscle movements, shuffling walk, or tremor to your doctor. · Do not take with MAO inhibitors (e.g., for depression) within 14 days. · Seek emergency care if you experience fast/irregular heartbeat, fainting, or signs of allergic reaction (rash, hives, swelling). · Use caution in hot weather; may affect body temperature regulation. · Store at room temperature away from moisture and heat. |