ETRAFON-A
Clinical safety rating: caution
Comprehensive clinical and safety monograph for ETRAFON-A (ETRAFON-A).
ETRAFON-A is a combination of perphenazine (a typical antipsychotic) and amitriptyline (a tricyclic antidepressant). Perphenazine blocks dopamine D2 receptors, while amitriptyline inhibits serotonin and norepinephrine reuptake.
| Metabolism | Perphenazine: primarily via CYP2D6, also CYP3A4 and CYP1A2. Amitriptyline: primarily via CYP2C19 and CYP2D6, also CYP3A4 and CYP1A2. |
| Excretion | Renal: 50-60% as unchanged drug and metabolites (primarily glucuronide conjugates); Biliary/Fecal: 30-40%; up to 10% excreted via sweat/saliva. |
| Half-life | Terminal elimination half-life: 18-36 hours (mean 24 h); context: in elderly or hepatic impairment may extend beyond 48 h, requiring dose adjustment. |
| Protein binding | 95-99% bound to albumin and alpha1-acid glycoprotein. |
| Volume of Distribution | Vd: 7-10 L/kg (range 5-15 L/kg); clinical meaning: extensive tissue binding, with high CNS penetration (brain:plasma ratio 20:1). |
| Bioavailability | Oral: 40-60% (first-pass metabolism); IM: 70-80%; IV: 100%. |
| Onset of Action | Oral: 1-3 hours; IM: 30-60 minutes; IV: 5-15 minutes (for antipsychotic effect). |
| Duration of Action | Oral: 12-24 hours (single dose); IM: 6-12 hours; IV: 4-8 hours; clinical notes: antidepressant effect may require 2-4 weeks, anxiolytic effect within first week. |
Etrafon-A (perphenazine 4 mg/amitriptyline 10 mg) is not FDA-approved; typical dosing per manufacturer: 1 tablet 3-4 times daily, up to 4 tablets/day. Route: oral.
| Dosage form | TABLET |
| Renal impairment | No specific guidelines; use with caution in severe renal impairment (GFR <30 mL/min). Avoid if CrCl <10 mL/min due to risk of tricyclic accumulation. |
| Liver impairment | Contraindicated in severe hepatic impairment (Child-Pugh Class C). For mild-moderate (Child-Pugh A/B): reduce dose by 50% and monitor. |
| Pediatric use | Not recommended for children <12 years. For adolescents >12 years: initiate at 1/2 tablet (2 mg/5 mg) 2-3 times daily; maximum 4 tablets/day. |
| Geriatric use | Start at 1/4 to 1/2 tablet (1-2 mg perphenazine/2.5-5 mg amitriptyline) 1-2 times daily; increase slowly. Maximum 2 tablets/day. Avoid in elderly with delirium or dementia. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for ETRAFON-A (ETRAFON-A).
| Breastfeeding | Both perphenazine and amitriptyline are excreted into breast milk. The M/P ratio for amitriptyline is approximately 0.8-1.3. Infant exposure is low (estimated relative infant dose <2% for amitriptyline and its metabolite), but sedation, apnea, and hypotonia have been reported. Breastfeeding is not recommended unless potential benefit outweighs risk. |
| Teratogenic Risk | Etrafon-A (perphenazine and amitriptyline) is associated with increased risk of congenital malformations when used in the first trimester, particularly cardiovascular defects and neural tube defects. Third trimester exposure may cause neonatal withdrawal symptoms, including respiratory distress, feeding difficulties, and extrapyramidal signs. Perphenazine, a phenothiazine, may cause fetal extrapyramidal effects; amitriptyline, a tricyclic antidepressant, has been linked to limb defects in case reports. |
■ FDA Black Box Warning
Increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants. Perphenazine is not approved for elderly patients with dementia-related psychosis due to increased risk of death.
| Serious Effects |
["Concomitant use with MAOIs or within 14 days of MAOI therapy","Recent myocardial infarction","Severe hepatic impairment","Narrow-angle glaucoma","Urinary retention","Blood dyscrasias","Hypersensitivity to perphenazine or amitriptyline"]
| Precautions | ["Suicidality in children and young adults","Neuroleptic malignant syndrome","Tardive dyskinesia","Cardiovascular effects (QT prolongation, orthostatic hypotension)","Anticholinergic effects","Seizures","Hepatic impairment"] |
| Food/Dietary | Avoid alcohol. Grapefruit juice may increase perphenazine levels; avoid excessive consumption. High-fat meals may delay absorption. Ensure adequate hydration to prevent constipation. |
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| Fetal Monitoring | Maternal: Monitor for extrapyramidal symptoms, sedation, anticholinergic effects, cardiac conduction abnormalities (ECG), and blood pressure. Fetal/neonatal: Ultrasound for fetal growth and anatomy in pregnancy; neonatal monitoring for jitteriness, hypotonia, respiratory depression, and feeding difficulties after delivery. |
| Fertility Effects | May impair fertility due to hyperprolactinemia (perphenazine) and sexual dysfunction (both components). Data on direct effects on spermatogenesis or oogenesis are limited. |
| Clinical Pearls | Etrafon-A is a fixed-dose combination of perphenazine (a typical antipsychotic) and amitriptyline (a tricyclic antidepressant). Use cautiously due to additive anticholinergic effects (e.g., urinary retention, constipation, blurred vision). Monitor for extrapyramidal symptoms (EPS) from perphenazine and cardiac arrhythmias (QT prolongation) from both components. Avoid abrupt discontinuation to prevent withdrawal or rebound psychosis/depression. Contraindicated with MAOIs due to risk of hypertensive crisis. Note that Etrafon-A is not recommended for first-line therapy of depression or psychosis as separate agents allow for more flexible dosing. |
| Patient Advice | Take exactly as prescribed; do not stop suddenly. · Avoid alcohol; may cause excessive drowsiness and dizziness. · Report signs of infection (fever, sore throat) as agranulocytosis can occur. · Use caution when driving or operating machinery due to sedation. · Rise slowly from sitting/lying to prevent fainting. · Do not take with other antidepressants or MAOIs within 14 days. · Inform doctor if you become pregnant or plan to breastfeed. |