Perphenazine (Trilafon)

FGA • Last reviewed 2025-09-26

General information

Perphenazine is a mid-potency phenothiazine antipsychotic indicated for schizophrenia and severe nausea/vomiting.

It offers balanced efficacy with moderate EPS and sedation; CATIE trial showed comparable outcomes to several SGAs at lower cost.

Available as tablets (2–16 mg), oral solution, and short-acting IM.

Perphenazine offers a cost-effective oral option when SGAs are ineffective or poorly tolerated, but requires vigilant monitoring for movement disorders.

Dosing & administration

Start 4–8 mg twice or three times daily; adjust to 16–64 mg/day divided.

Use lowest effective dose to limit side effects.

Elderly: begin 2–4 mg twice daily.

Typical dosing

Mild symptoms: 4 mg BID
Moderate symptoms: 8 mg TID
Maximum: 64 mg/day

Mechanism of action

Perphenazine antagonizes D2 receptors in mesolimbic pathways, reducing positive symptoms, while moderate anticholinergic activity reduces EPS compared with high-potency FGAs.

Histamine and α1 blockade produce sedation and orthostasis.

Metabolism & pharmacokinetics

Peak concentrations ~3–4 h post-dose. Extensive hepatic metabolism via CYP2D6/1A2/3A4.

Half-life ~9–12 h; adjust dosing in hepatic impairment.

Metabolites excreted in urine/bile; protein binding ~70%.

Tmax: 3–4 h
Half-life: 9–12 h
Metabolism: CYP2D6, CYP1A2, CYP3A4

Drug interactions

CYP2D6 inhibitors increase levels; reduce dose.

CNS depressants increase sedation.

Anticholinergics increase anticholinergic effects.

QT prolonging agents raise torsades risk.

Mechanism	Agents / factors	Management
CYP2D6 inhibition	Fluoxetine, paroxetine	Lower dose
CNS depression	Benzodiazepines, opioids	Monitor sedation
QT prolongation	Amiodarone	Avoid

Monitoring & safety checks

EPS/tardive dyskinesia
Each visit; AIMS q6 months • Moderate EPS risk
Weight/metabolic labs
Baseline, annually • Metabolic monitoring
Prolactin symptoms
Periodic • Hyperprolactinemia

Educate on EPS management (anticholinergics).

Discontinuation guidance

Taper gradually over weeks to avoid withdrawal dyskinesias and relapse.

Adverse effects

Common: EPS, sedation, anticholinergic symptoms.

Serious: tardive dyskinesia, neuroleptic malignant syndrome.

References

Perphenazine — Prescribing Information — FDA (2023)
CATIE trial — NEJM (2005) DOI: 10.1056/NEJMoa051688
The American Psychiatric Association Practice Guideline for the Treatment of Patients With Schizophrenia — American Psychiatric Association (2020)

Educational use only — verify details in current prescribing information and authoritative clinical guidelines before making prescribing decisions.