FLUPHENAZINE HCL

Clinical safety rating: safe

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

How it works

Fluphenazine is a phenothiazine antipsychotic that blocks postsynaptic D2 dopamine receptors in the mesolimbic system. It also exhibits alpha-adrenergic blocking, anticholinergic, and antihistaminergic effects.

What the body does with it

Metabolism	Primarily hepatic via CYP2D6 and other pathways; undergoes N-oxidation, sulfoxidation, and glucuronidation. Active metabolite (7-hydroxyfluphenazine) exists.
Excretion	Primarily hepatic metabolism via CYP2D6; <1% excreted unchanged in urine. Biliary/fecal elimination accounts for ~20-30% of metabolites. Renal clearance is negligible.
Half-life	Terminal elimination half-life is 15-30 hours (mean 24 hours) after IM administration; up to 9-12 hours after oral dosing due to first-pass metabolism. Steady-state reached in 5-10 days.
Protein binding	99% bound to serum proteins, primarily albumin and alpha1-acid glycoprotein.
Volume of Distribution	Apparent Vd: 10-20 L/kg (large due to high lipophilicity and extensive tissue binding). Indicates deep compartment distribution including CNS.
Bioavailability	Oral: approximately 40-50% (extensive first-pass metabolism). IM (short-acting): 100% (no first-pass). Decanoate: 100% IM, with slow release from injection site.
Onset of Action	Oral: 1-2 hours; IM (short-acting): 30-60 minutes; Onset of antipsychotic effect may take days to weeks.
Duration of Action	Oral: 6-8 hours; IM (short-acting): 12-24 hours; Decanoate (long-acting): 2-4 weeks (single injection). Clinical effect persists beyond half-life due to active metabolites.

Classification & Brands

Dosing & administration

Oral: 2.5-10 mg/day in divided doses every 6-8 hours; maintenance: 1-5 mg/day. IM: 1.25-2.5 mg every 6-8 hours. Decanoate (long-acting): 12.5-25 mg IM every 2-4 weeks.

Dosage form	Injectable
Renal impairment	No specific guidelines; use with caution in severe impairment (CrCl <10 mL/min) due to anticholinergic effects. No dose adjustment typically required.
Liver impairment	Child-Pugh A: no adjustment; Child-Pugh B: reduce dose by 25-50%; Child-Pugh C: avoid use or use with extreme caution (maximum 50% of normal dose).
Pediatric use	6-12 years: Oral 0.75-5 mg/day in divided doses; IM 0.25-0.75 mg every 6-8 hours (max 10 mg/day). Decanoate: not recommended in children.
Geriatric use	Start with 25-50% of adult dose (oral: 1-2.5 mg/day); increase slowly; monitor for extrapyramidal symptoms and hypotension. Avoid decanoate if possible.

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.

FDA category	Animal
Breastfeeding	Fluphenazine is excreted in breast milk; M/P ratio unknown. Monitor infant for drowsiness, irritability, and feeding difficulties. Generally not recommended unless benefits outweigh risks; consider alternative agents with more safety data.
Teratogenic Risk	First trimester: Data insufficient to determine risk; antipsychotics generally not major teratogens but risk-benefit assessment required. Second and third trimester: Possible risk of extrapyramidal symptoms or withdrawal in neonate if used near term. Overall: FDA Pregnancy Category C (animal studies show adverse effects, no adequate human studies).

Warnings & precautions

■ FDA Black Box Warning

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Fluphenazine is not approved for the treatment of dementia-related psychosis.

Side Effect Profile

Common Effects	Extrapyramidal symptoms
Serious Effects

Absolute Contraindications

["Comatose states","CNS depression (e.g., from alcohol/barbiturates)","Blood dyscrasias","Hepatic disease (severe)","Subcortical brain damage","Hypersensitivity to fluphenazine or other phenothiazines"]

Clinical Precautions

Precautions

["Increased mortality in elderly with dementia-related psychosis","Tardive dyskinesia","Neuroleptic malignant syndrome (NMS)","QT prolongation and arrhythmias","Lower seizure threshold","Leukopenia/neutropenia/agranulocytosis","Anticholinergic effects (e.g., heatstroke, ileus)","Hepatic effects","Ocular changes"]

Clinical Tips & Counseling

Drug interactions

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FLUPHENAZINE HCL

Clinical safety rating: safe

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

How it works

What the body does with it

Metabolism	Primarily hepatic via CYP2D6 and other pathways; undergoes N-oxidation, sulfoxidation, and glucuronidation. Active metabolite (7-hydroxyfluphenazine) exists.
Excretion	Primarily hepatic metabolism via CYP2D6; <1% excreted unchanged in urine. Biliary/fecal elimination accounts for ~20-30% of metabolites. Renal clearance is negligible.
Half-life	Terminal elimination half-life is 15-30 hours (mean 24 hours) after IM administration; up to 9-12 hours after oral dosing due to first-pass metabolism. Steady-state reached in 5-10 days.
Protein binding	99% bound to serum proteins, primarily albumin and alpha1-acid glycoprotein.
Volume of Distribution	Apparent Vd: 10-20 L/kg (large due to high lipophilicity and extensive tissue binding). Indicates deep compartment distribution including CNS.
Bioavailability	Oral: approximately 40-50% (extensive first-pass metabolism). IM (short-acting): 100% (no first-pass). Decanoate: 100% IM, with slow release from injection site.
Onset of Action	Oral: 1-2 hours; IM (short-acting): 30-60 minutes; Onset of antipsychotic effect may take days to weeks.
Duration of Action	Oral: 6-8 hours; IM (short-acting): 12-24 hours; Decanoate (long-acting): 2-4 weeks (single injection). Clinical effect persists beyond half-life due to active metabolites.

Classification & Brands

Dosing & administration

Oral: 2.5-10 mg/day in divided doses every 6-8 hours; maintenance: 1-5 mg/day. IM: 1.25-2.5 mg every 6-8 hours. Decanoate (long-acting): 12.5-25 mg IM every 2-4 weeks.

Dosage form	Injectable
Renal impairment	No specific guidelines; use with caution in severe impairment (CrCl <10 mL/min) due to anticholinergic effects. No dose adjustment typically required.
Liver impairment	Child-Pugh A: no adjustment; Child-Pugh B: reduce dose by 25-50%; Child-Pugh C: avoid use or use with extreme caution (maximum 50% of normal dose).
Pediatric use	6-12 years: Oral 0.75-5 mg/day in divided doses; IM 0.25-0.75 mg every 6-8 hours (max 10 mg/day). Decanoate: not recommended in children.
Geriatric use	Start with 25-50% of adult dose (oral: 1-2.5 mg/day); increase slowly; monitor for extrapyramidal symptoms and hypotension. Avoid decanoate if possible.

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.

FDA category	Animal
Breastfeeding	Fluphenazine is excreted in breast milk; M/P ratio unknown. Monitor infant for drowsiness, irritability, and feeding difficulties. Generally not recommended unless benefits outweigh risks; consider alternative agents with more safety data.
Teratogenic Risk	First trimester: Data insufficient to determine risk; antipsychotics generally not major teratogens but risk-benefit assessment required. Second and third trimester: Possible risk of extrapyramidal symptoms or withdrawal in neonate if used near term. Overall: FDA Pregnancy Category C (animal studies show adverse effects, no adequate human studies).

Warnings & precautions

■ FDA Black Box Warning

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Fluphenazine is not approved for the treatment of dementia-related psychosis.

Side Effect Profile

Common Effects	Extrapyramidal symptoms
Serious Effects