FLUPHENAZINE

Clinical safety rating: safe

Animal studies have demonstrated safety

How it works

Antipsychotic that blocks postsynaptic dopamine D2 receptors in the mesolimbic system, with high potency and additional antagonism at alpha-adrenergic, muscarinic, and histaminergic receptors.

What the body does with it

Metabolism	Primarily hepatic via CYP2D6 and CYP1A2; undergoes conjugation and oxidation to inactive metabolites.
Excretion	Primarily hepatic metabolism with biliary excretion. Less than 1% excreted unchanged in urine; fecal elimination accounts for approximately 20-30% of metabolites.
Half-life	Terminal elimination half-life is 15-30 hours, but may extend to 40-50 hours after chronic use; clinical context: dosing interval is typically 12-24 hours, and steady-state is reached within 3-5 days.
Protein binding	>99% bound to albumin and alpha-1 acid glycoprotein.
Volume of Distribution	10-35 L/kg (mean ~20 L/kg), indicating extensive tissue distribution and accumulation in brain and lung.
Bioavailability	Oral: about 40-50% due to first-pass metabolism; IM: 100%.
Onset of Action	Oral: 0.5-1 hour; intramuscular (IM): 20-30 minutes; intravenous (IV): 5-10 minutes.
Duration of Action	Oral: 6-8 hours; IM: 6-8 hours; IV: 4-6 hours. Note: Duration may be longer with high doses or hepatic impairment; decanoate ester (depot) provides 2-4 weeks of effect.

Classification & Brands

Dosing & administration

Fluphenazine decanoate (long-acting): 12.5-25 mg IM every 2 weeks; Fluphenazine hydrochloride (oral): 2.5-10 mg daily in divided doses; initial titration 2.5-10 mg/day, maintenance 1-5 mg/day. Maximum oral dose 20 mg/day.

Dosage form	Injectable
Renal impairment	Caution in severe renal impairment (CrCl <10 mL/min). No specific dose adjustment guidelines; use with monitoring. For decanoate, consider reducing dose or extending interval.
Liver impairment	Contraindicated in severe hepatic disease (Child-Pugh class C). In mild-to-moderate impairment (Child-Pugh A or B), reduce dose by 25-50% and titrate slowly; monitor for adverse effects.
Pediatric use	Oral: Initial 0.25-0.75 mg/day (1-2 divided doses); increase by 0.25-0.5 mg every 1-2 weeks to maximum of 10 mg/day for children 6-12 years. IM decanoate: not recommended in children <12 years.
Geriatric use	Initial oral dose: 1-2.5 mg daily; increase slowly by 1-2.5 mg every 4-7 days; typical maintenance 1-5 mg/day. Decanoate: reduced dose 6.25-12.5 mg every 2-4 weeks; monitor for extrapyramidal symptoms.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

CNS depressants may enhance sedative effects Can cause extrapyramidal symptoms and neuroleptic malignant syndrome.

Breastfeeding	Small amounts excreted in breast milk; M/P ratio approximately 0.5-1.0. Use with caution; monitor infant for sedation, hypotonia, and poor feeding.
Teratogenic Risk	First trimester: Limited data suggest possible low risk of congenital malformations; avoid if possible. Second and third trimesters: Risk of extrapyramidal symptoms, jaundice, and hyperbilirubinemia in neonates following late exposure. No definite major teratogen.
Fetal Monitoring

Warnings & precautions

■ FDA Black Box Warning

Increased mortality in elderly patients with dementia-related psychosis.

Side Effect Profile

Common Effects	Extrapyramidal symptoms
Serious Effects

Absolute Contraindications

["Comatose states","CNS depression from alcohol or other drugs","Known hypersensitivity to fluphenazine or phenothiazines","Blood dyscrasias (agranulocytosis)","Hepatic failure"]

Clinical Precautions

Precautions

["Tardive dyskinesia may develop","Neuroleptic malignant syndrome (NMS) risk","QT prolongation risk","Hepatic impairment caution","Blood dyscrasias (leukopenia/neutropenia) risk","Antiemetic effect may mask toxicity of other drugs"]

Clinical Tips & Counseling

Drug interactions

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