FLUPHENAZINE HYDROCHLORIDE

Clinical safety rating: safe

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

How it works

Antipsychotic that blocks postsynaptic dopamine D2 receptors in the mesolimbic system; also exhibits anticholinergic, alpha-adrenergic blocking, and extrapyramidal effects.

What the body does with it

Metabolism	Hepatic via CYP2D6; metabolites include 7-hydroxyfluphenazine and N-oxide fluphenazine; undergoes first-pass metabolism.
Excretion	Primarily renal (approximately 50-60% as metabolites, <1% unchanged); fecal (30-40% via biliary elimination); small amount excreted in breast milk.
Half-life	Terminal elimination half-life 14-24 hours after oral administration; may be longer (up to 48 hours) with chronic use due to accumulation in deep tissues. Clinically, steady state is achieved in 4-7 days.
Protein binding	99% bound to albumin and alpha-1 acid glycoprotein.
Volume of Distribution	20-30 L/kg (extensive tissue binding, high penetration into brain and adipose tissue). Clinically indicates large extravascular distribution.
Bioavailability	Oral: 2.5-5% (extensive first-pass metabolism); IM: 100% (fluphenazine hydrochloride injection); decanoate: slow absorption with peak at 24-48 hours.
Onset of Action	Oral: 0.5-1 hour; IM: 0.25-0.5 hour; IV: 5-10 minutes.
Duration of Action	Oral: 6-8 hours; IM: 6-12 hours; IV: 4-6 hours. Note: Antipsychotic effects may require 2-3 weeks for full therapeutic response; decanoate ester formulations have prolonged duration (2-4 weeks).

Classification & Brands

Dosing & administration

2.5-10 mg orally divided every 6-8 hours initially; maintenance 1-5 mg orally daily. For severe psychoses, 2.5-10 mg intramuscularly every 6-8 hours. Maximum oral dose 40 mg/day.

Dosage form	TABLET
Renal impairment	No specific dose adjustment required for GFR >10 mL/min. For GFR <10 mL/min, use with caution and reduce dose by 50%.
Liver impairment	Child-Pugh Class A: No adjustment. Child-Pugh Class B: Reduce dose by 50%. Child-Pugh Class C: Use contraindicated.
Pediatric use	Children >12 years: 0.25-3.5 mg orally daily in divided doses; maximum 10 mg/day. For younger children, not recommended due to lack of data.
Geriatric use	Initial dose 1-2.5 mg orally daily; increase slowly. Use lower doses due to increased sensitivity and risk of 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.

FDA category	Animal
Breastfeeding	Fluphenazine is excreted into breast milk in small amounts. Reported M/P ratio approximately 0.2-0.5. Infant exposure estimated <1% of maternal weight-adjusted dose. No reports of adverse effects in breastfed infants, but monitor for sedation, poor feeding, and extrapyramidal symptoms. Benefits of breastfeeding generally outweigh risks, but use with caution, especially in premature or neurologically compromised infants.
Teratogenic Risk

Warnings & precautions

■ FDA Black Box Warning

Increased mortality in elderly patients with dementia-related psychosis. Fluphenazine is not approved for the treatment of dementia-related psychosis.

Side Effect Profile

Common Effects	Extrapyramidal symptoms
Serious Effects

Absolute Contraindications

Coma, CNS depression, bone marrow depression, pheochromocytoma, hypersensitivity to fluphenazine or phenothiazines, concurrent use with high doses of CNS depressants (e.g., alcohol, barbiturates).

Clinical Precautions

Precautions

Tardive dyskinesia (risk increases with cumulative dose/duration), neuroleptic malignant syndrome (hyperthermia, rigidity, autonomic instability), QT prolongation, hypotension, cholestatic jaundice, agranulocytosis (rare), seizures, impaired core body temperature regulation.

Clinical Tips & Counseling

Drug interactions

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FLUPHENAZINE HYDROCHLORIDE

Clinical safety rating: safe

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

How it works

Antipsychotic that blocks postsynaptic dopamine D2 receptors in the mesolimbic system; also exhibits anticholinergic, alpha-adrenergic blocking, and extrapyramidal effects.

What the body does with it

Metabolism	Hepatic via CYP2D6; metabolites include 7-hydroxyfluphenazine and N-oxide fluphenazine; undergoes first-pass metabolism.
Excretion	Primarily renal (approximately 50-60% as metabolites, <1% unchanged); fecal (30-40% via biliary elimination); small amount excreted in breast milk.
Half-life	Terminal elimination half-life 14-24 hours after oral administration; may be longer (up to 48 hours) with chronic use due to accumulation in deep tissues. Clinically, steady state is achieved in 4-7 days.
Protein binding	99% bound to albumin and alpha-1 acid glycoprotein.
Volume of Distribution	20-30 L/kg (extensive tissue binding, high penetration into brain and adipose tissue). Clinically indicates large extravascular distribution.
Bioavailability	Oral: 2.5-5% (extensive first-pass metabolism); IM: 100% (fluphenazine hydrochloride injection); decanoate: slow absorption with peak at 24-48 hours.
Onset of Action	Oral: 0.5-1 hour; IM: 0.25-0.5 hour; IV: 5-10 minutes.
Duration of Action	Oral: 6-8 hours; IM: 6-12 hours; IV: 4-6 hours. Note: Antipsychotic effects may require 2-3 weeks for full therapeutic response; decanoate ester formulations have prolonged duration (2-4 weeks).

Classification & Brands

Dosing & administration

2.5-10 mg orally divided every 6-8 hours initially; maintenance 1-5 mg orally daily. For severe psychoses, 2.5-10 mg intramuscularly every 6-8 hours. Maximum oral dose 40 mg/day.

Dosage form	TABLET
Renal impairment	No specific dose adjustment required for GFR >10 mL/min. For GFR <10 mL/min, use with caution and reduce dose by 50%.
Liver impairment	Child-Pugh Class A: No adjustment. Child-Pugh Class B: Reduce dose by 50%. Child-Pugh Class C: Use contraindicated.
Pediatric use	Children >12 years: 0.25-3.5 mg orally daily in divided doses; maximum 10 mg/day. For younger children, not recommended due to lack of data.
Geriatric use	Initial dose 1-2.5 mg orally daily; increase slowly. Use lower doses due to increased sensitivity and risk of 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.

FDA category	Animal
Breastfeeding	Fluphenazine is excreted into breast milk in small amounts. Reported M/P ratio approximately 0.2-0.5. Infant exposure estimated <1% of maternal weight-adjusted dose. No reports of adverse effects in breastfed infants, but monitor for sedation, poor feeding, and extrapyramidal symptoms. Benefits of breastfeeding generally outweigh risks, but use with caution, especially in premature or neurologically compromised infants.
Teratogenic Risk

Warnings & precautions

■ FDA Black Box Warning

Increased mortality in elderly patients with dementia-related psychosis. Fluphenazine is not approved for the treatment of dementia-related psychosis.

Side Effect Profile

Common Effects	Extrapyramidal symptoms
Serious Effects

Absolute Contraindications

Coma, CNS depression, bone marrow depression, pheochromocytoma, hypersensitivity to fluphenazine or phenothiazines, concurrent use with high doses of CNS depressants (e.g., alcohol, barbiturates).