FLUPHENAZINE HCL
Clinical safety rating: safe
CNS depressants may enhance sedative effects Can cause extrapyramidal symptoms and neuroleptic malignant syndrome.
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.
| 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. |
| Molecular Weight | 437.52 |
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. |
| 1st trimester | Limited human data; animal studies not available or inadequate. Risk cannot be ruled out. Use only if potential benefit justifies risk. |
| 2nd trimester | Risk of extrapyramidal symptoms in newborn if used near term. Use only if clearly needed. |
| 3rd trimester | May cause neonatal withdrawal symptoms, agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, feeding disorder. Avoid in third trimester if possible. |
Clinical note
CNS depressants may enhance sedative effects Can cause extrapyramidal symptoms and neuroleptic malignant syndrome.
| FDA category | Animal |
| Placental transfer | Fluphenazine crosses the placenta; measurable concentrations in cord blood. Degree of transfer is moderate. |
| Breastfeeding |
■ 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.
| Common Effects | Extrapyramidal symptoms |
| Serious Effects |
Hypersensitivity to fluphenazine or any phenothiazineComatose statesCNS depression due to alcohol or other depressantsBlood dyscrasiasPheochromocytomaSevere hypotensionSubcortical brain damage
| 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 |
| Food/Dietary |
Loading safety data…
| Fluphenazine is excreted into human breast milk in small amounts. Monitor infant for drowsiness, extrapyramidal symptoms, and developmental delay. AAP recommends caution. |
| Lactation Rating | L3 - Moderately Safe |
| 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). |
| Fetal Monitoring | Monitor maternal blood pressure, weight gain, blood glucose, and extrapyramidal symptoms. Fetal monitoring for growth and neonatal adaptation at delivery. |
| Fertility Effects | May cause hyperprolactinemia leading to menstrual irregularities, anovulation, and decreased libido; reversible upon discontinuation. |
| Avoid excessive caffeine and alcohol. No specific food restrictions; however, consume with food if gastrointestinal upset occurs. Grapefruit juice may increase fluphenazine levels; caution concurrent use. |
| Clinical Pearls | Fluphenazine HCl is a high-potency first-generation antipsychotic with a lower incidence of sedation and orthostatic hypotension but higher risk of extrapyramidal symptoms (EPS) including acute dystonia, parkinsonism, and tardive dyskinesia. Use a test dose of 1.25-2.5 mg to assess EPS risk. For acute dystonia, treat promptly with benztropine or diphenhydramine. Avoid in patients with narrow-angle glaucoma, pheochromocytoma, or CNS depression. Monitor for neuroleptic malignant syndrome (NMS) and QT prolongation. Depot formulation (fluphenazine decanoate) requires strict adherence to injection schedule to avoid relapse. |
| Patient Advice | Take exactly as prescribed; do not stop abruptly without consulting your doctor. · Avoid alcohol and other CNS depressants (e.g., benzodiazepines, opioids) as they may increase sedation. · Report any involuntary muscle movements, stiffness, or restlessness immediately. · Rise slowly from sitting or lying to minimize dizziness from low blood pressure. · May cause drowsiness; avoid driving or operating heavy machinery until you know how it affects you. · Use sunscreen and protective clothing as this medication may increase sun sensitivity. · Do not use over-the-counter cold or allergy medications without approval from your doctor. · If you miss a dose, take it as soon as you remember unless it is close to the next dose; do not double doses. · Keep all appointments for blood tests and follow-up evaluations. · Contact your doctor if you experience fever, confusion, muscle rigidity, or rapid heart rate – these could be signs of neuroleptic malignant syndrome. |