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. |
| Molecular Weight | High molecular weight (perflutren microspheres ~1-10 µm); exact MW not applicable. |
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 | Avoid. Perflutren is not indicated for use in pregnancy. No adequate human data; animal studies not available. Potential fetal harm from microsphere components. |
| 2nd trimester | Avoid. Same as first trimester; no safety data. |
| 3rd trimester | Avoid. Same as first trimester; no safety data. |
Clinical note
Comprehensive clinical and safety monograph for ETRAFON 2-10 (ETRAFON 2-10).
| Placental transfer | Unlikely due to large molecular size and rapid clearance; but not studied. |
| Breastfeeding | Not recommended. No data on excretion into human milk; risk of adverse effects in infant (e.g., hypersensitivity). |
| Lactation Rating |
■ 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 |
Hypersensitivity to perflutren or any componentKnown right-to-left shuntsSevere pulmonary hypertensionUnstable cardiopulmonary status
| Precautions | CNS depression, orthostatic hypotension, anticholinergic effects (constipation, urinary retention), tardive dyskinesia, seizures, agranulocytosis, hepatic impairment, withdrawal symptoms, suicide risk. |
| Food/Dietary | Avoid tyramine-rich foods (aged cheeses, cured meats, fermented products) due to potential hypertensive crisis with amitriptyline. Grapefruit juice may increase plasma levels of both components. Limit caffeine intake as it may worsen anxiety. |
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| L5 |
| 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. |
| 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. |
| Clinical Pearls | ETRAFON 2-10 is a fixed-dose combination of perphenazine 2 mg and amitriptyline 10 mg. It is primarily used for depression with anxiety or agitation. Monitor for anticholinergic effects (amitriptyline) and extrapyramidal symptoms (perphenazine). Avoid in patients with narrow-angle glaucoma, urinary retention, or recent MAOI use. Taper gradually to avoid withdrawal. |
| Patient Advice | Take exactly as prescribed. Do not stop abruptly. · May cause drowsiness; avoid driving or operating machinery until effects are known. · Avoid alcohol and other CNS depressants. · Report any muscle stiffness, tremors, or restlessness (possible extrapyramidal symptoms). · May cause dry mouth; use sugar-free gum or candy. · Do not take with MAOIs or within 14 days of stopping them. · Store at room temperature away from moisture and heat. |