TRIAVIL 4-25
Clinical safety rating: caution
Comprehensive clinical and safety monograph for TRIAVIL 4-25 (TRIAVIL 4-25).
TRIAVIL (amitriptyline/perphenazine) combines a tricyclic antidepressant (amitriptyline) that inhibits reuptake of norepinephrine and serotonin, and a phenothiazine antipsychotic (perphenazine) that blocks dopamine D2 receptors, serotonin 5-HT2 receptors, and alpha-adrenergic receptors, with additional anticholinergic, antihistaminergic, and antiemetic properties.
| Metabolism | Amitriptyline: primarily hepatic via CYP2C19, CYP2D6, CYP3A4; active metabolite nortriptyline. Perphenazine: hepatic metabolism via CYP2D6, CYP3A4, and CYP1A2. |
| Excretion | Renal: ~70% as metabolites (including amitriptyline and perphenazine metabolites) and <5% unchanged; fecal: ~30% via bile; enterohepatic recirculation occurs. |
| Half-life | Amitriptyline: 13–36 hours (mean ~21 hours); perphenazine: 8–21 hours (mean ~12 hours); steady-state achieved in 3–10 days. |
| Protein binding | Amitriptyline: 96% bound to albumin and alpha-1 acid glycoprotein; perphenazine: 90–95% bound to albumin. |
| Volume of Distribution | Amitriptyline: 12–18 L/kg (extensive tissue binding); perphenazine: 10–15 L/kg (large Vd due to lipophilicity). |
| Bioavailability | Oral: Amitriptyline ~50% (first-pass metabolism); perphenazine ~40% (extensive first-pass). |
| Onset of Action | Oral: Antidepressant effect 1–2 weeks, anxiolytic/antipsychotic effect 1–3 days. |
| Duration of Action | Oral: Amitriptyline effect persists 24–48 hours after single dose; perphenazine effect 6–12 hours; extended dosing maintains steady-state levels. |
One tablet (perphenazine 4 mg / amitriptyline 25 mg) orally 3 to 4 times daily. Maximum: 8 tablets daily.
| Dosage form | TABLET |
| Renal impairment | No specific dose adjustment guidelines; use with caution in severe renal impairment (CrCl <10 mL/min). Avoid if possible in ESRD. |
| 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 years: start with 1 tablet (2-10/25) orally 2-3 times daily; titrate to 4-25 strength as needed. Maximum 8 tablets daily. |
| Geriatric use | Start with 1 tablet (2-10/10 or 2-10/25) orally 1-2 times daily; titrate slowly. Reduce total daily dose by 50% compared to younger adults. Maximum 4 tablets daily. Monitor for anticholinergic effects, sedation, and orthostatic hypotension. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for TRIAVIL 4-25 (TRIAVIL 4-25).
| Breastfeeding | Amitriptyline and perphenazine are excreted into breast milk. M/P ratio for amitriptyline: approximately 0.8-1.5; for perphenazine: unknown. Relative infant doses are low for amitriptyline (around 1-2% of weight-adjusted maternal dose). Monitor infant for sedation, poor feeding, and extrapyramidal symptoms. Consider alternative therapy if high maternal doses or infant vulnerability. |
| Teratogenic Risk | First trimester: Use of amitriptyline/perphenazine (Triavil 4-25) is associated with a small increased risk of congenital malformations, particularly cardiovascular defects with tricyclic antidepressants. Perphenazine is a phenothiazine; first-trimester exposure may increase risk of neural tube defects and cardiac anomalies. Second and third trimesters: Chronic use may cause extrapyramidal symptoms, neonatal withdrawal (irritability, feeding difficulties), and anticholinergic effects in the neonate. Third-trimester use of amitriptyline may increase risk of persistent pulmonary hypertension of the newborn (PPHN). |
■ FDA Black Box Warning
WARNING: Increased mortality in elderly patients with dementia-related psychosis (perphenazine component). Antidepressants (amitriptyline) may increase risk of suicidal thoughts and behaviors in children, adolescents, and young adults. Not approved for use in pediatric patients.
| Serious Effects |
["Concomitant use with MAOIs (or within 14 days of MAOI therapy)","Recent myocardial infarction","Uncontrolled narrow-angle glaucoma","Urinary retention (e.g., due to prostatic hypertrophy)","Severe CNS depression or comatose states","Hypersensitivity to any component","Concurrent use of drugs that prolong QT interval or cause torsades de pointes"]
| Precautions | ["Anticholinergic effects (dry mouth, constipation, blurred vision, urinary retention, tachycardia)","Cardiovascular toxicity (QT prolongation, arrhythmias, orthostatic hypotension)","CNS depression (sedation, impaired motor function, risk of falls)","Neuroleptic malignant syndrome (NMS) with perphenazine","Tardive dyskinesia with prolonged perphenazine use","Seizure threshold lowering","Endocrine effects (hyperprolactinemia, gynecomastia, amenorrhea)","Hematologic toxicity (agranulocytosis)","Hepatic impairment","Serotonin syndrome with other serotonergic drugs"] |
Loading safety data…
| Fetal Monitoring | Maternal: monitor blood pressure, heart rate, liver function, complete blood count, and ECG (due to QT prolongation risk). Assess for extrapyramidal symptoms and anticholinergic effects. Fetal/neonatal: ultrasound for congenital anomalies if first-trimester exposure; monitor neonatal adaptation period for withdrawal, sedation, extrapyramidal signs, and feeding difficulties. |
| Fertility Effects | Hyperprolactinemia due to perphenazine (dopamine receptor antagonist) can cause menstrual irregularities, anovulation, and reduced fertility. Amitriptyline does not significantly affect fertility. Both drugs may affect sexual function. |