ETRAFON 2-10
Clinical safety rating: caution
Comprehensive clinical and safety monograph for ETRAFON 2-10 (ETRAFON 2-10).
ETRAFON 2-10 is a combination of the phenothiazine antipsychotic perphenazine and the tricyclic antidepressant amitriptyline. Perphenazine blocks dopamine D2 receptors, reducing dopaminergic neurotransmission in the mesolimbic pathway, while amitriptyline inhibits serotonin and norepinephrine reuptake, enhancing monoaminergic signaling.
| Metabolism | Perphenazine: hepatic via CYP2D6, CYP3A4, UGT. Amitriptyline: hepatic via CYP2C19, CYP2D6, and CYP3A4. |
| Excretion | Elimination is primarily renal (50-70% as metabolites, <5% unchanged) and biliary/fecal (30-50% as metabolites). |
| Half-life | The terminal elimination half-life is approximately 9-10 hours for perphenazine and 18-24 hours for amitriptyline; amitriptyline's active metabolite nortriptyline has a half-life of 18-44 hours, necessitating once-daily dosing for maintenance. |
| Protein binding | Perphenazine: 90% bound primarily to albumin; amitriptyline: 96% bound to albumin and alpha-1 acid glycoprotein. |
| Volume of Distribution | Perphenazine: Vd ~20 L/kg, indicating extensive tissue distribution; amitriptyline: Vd ~15 L/kg, reflecting high lipophilicity and extravascular sequestration. |
| Bioavailability | Oral bioavailability is 40-50% for perphenazine due to extensive first-pass metabolism; amitriptyline bioavailability is 30-45%, similarly affected by first-pass metabolism. |
| Onset of Action | Oral: 1-3 hours for antidepressant effect, with initial sedation within 1 hour; antipsychotic effect typically requires 2-4 weeks. |
| Duration of Action | Duration of antidepressant effect: 24-48 hours after single dose; antipsychotic effect persists 24 hours, with steady-state achieved in 7-10 days. |
1-2 tablets (perphenazine 2 mg / amitriptyline 10 mg) orally 3-4 times daily; max 8 tablets/day.
| Dosage form | TABLET |
| Renal impairment | GFR >50 mL/min: no adjustment; GFR 10-50 mL/min: reduce dose by 50%; GFR <10 mL/min: avoid use. |
| 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: 1 tablet (2-10) orally 2-3 times daily, max 6 tablets/day. |
| Geriatric use | Initial dose: 1 tablet (2-10) orally 1-2 times daily; increase slowly; monitor for anticholinergic effects, sedation, orthostatic hypotension; max 4 tablets/day. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for ETRAFON 2-10 (ETRAFON 2-10).
| Breastfeeding | Perphenazine: M/P ratio unknown; small amounts excreted in breast milk, theoretical risk of neonatal sedation and extrapyramidal effects. Amitriptyline: M/P ratio 1.0-1.4; relative infant dose ~2% of maternal weight-adjusted dose; case reports of drowsiness and constipation in breastfed infants. Breastfeeding not contraindicated but monitor for sedation, poor feeding, and motor development. |
| Teratogenic Risk | First trimester: Combination of perphenazine (Phenothiazine, FDA Category C) and amitriptyline (Tricyclic Antidepressant, FDA Category C). Perphenazine associated with limb malformations and CNS defects in retrospective studies; amitriptyline associated with cardiovascular defects in early pregnancy. Second trimester: Continued risk of CNS defects from perphenazine; amitriptyline may increase risk of preterm birth. Third trimester: Neonatal withdrawal syndromes (tachycardia, irritability, poor feeding) from both agents; extrapyramidal signs from perphenazine; persistent pulmonary hypertension from amitriptyline. |
■ FDA Black Box Warning
WARNING: Increased mortality in elderly patients with dementia-related psychosis; increased risk of suicidal thinking and behavior in children, adolescents, and young adults with antidepressants; neuroleptic malignant syndrome (NMS) with perphenazine; cardiotoxicity and QT prolongation with amitriptyline.
| Serious Effects |
Concomitant use with MAOIs, recent MI, QT prolongation, narrow-angle glaucoma, urinary retention, hypersensitivity to phenothiazines or TCAs, severe CNS depression.
| Precautions | CNS depression, orthostatic hypotension, anticholinergic effects (constipation, urinary retention), tardive dyskinesia, seizures, agranulocytosis, hepatic impairment, withdrawal symptoms, suicide risk. |
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| Fetal Monitoring | Maternal: Liver function tests, ECG for QTc prolongation, blood pressure, glucose, weight gain, and signs of extrapyramidal side effects. Fetal: Level 2 ultrasound at 18-20 weeks (cardiac and limb defects), fetal growth scans in third trimester, neonatal adaptation monitoring (withdrawal, respiratory depression, extrapyramidal signs). |
| Fertility Effects | Perphenazine: May elevate prolactin via dopamine blockade, leading to menstrual irregularities, anovulation, and galactorrhea; reversible. Amitriptycline: Minimal direct effect; SSRIs/TCAs may cause sexual dysfunction but fertility impact not established. Combined, possible reversible subfertility due to hyperprolactinemia. |