FLUPHENAZINE HYDROCHLORIDE
Clinical safety rating: safe
CNS depressants may enhance sedative effects Can cause extrapyramidal symptoms and neuroleptic malignant syndrome.
Antipsychotic that blocks postsynaptic dopamine D2 receptors in the mesolimbic system; also exhibits anticholinergic, alpha-adrenergic blocking, and extrapyramidal effects.
| 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). |
| Molecular Weight | 510.44 |
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. |
| 1st trimester | Associated with risk of congenital malformations, particularly during first trimester; use only if benefit outweighs risk. |
| 2nd trimester | May cause extrapyramidal symptoms and jaundice in neonate; use with caution. |
| 3rd trimester | Risk of neonatal extrapyramidal symptoms, withdrawal syndrome, and jaundice; avoid use near term 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; detectable in cord blood and amniotic fluid. |
| Breastfeeding |
■ FDA Black Box Warning
Increased mortality in elderly patients with dementia-related psychosis. Fluphenazine is not approved for the treatment of dementia-related psychosis.
| Common Effects | Extrapyramidal symptoms |
| Serious Effects |
Comatose statesCNS depressionSubcortical brain damageBlood dyscrasiasPheochromocytomaKnown hypersensitivity to fluphenazine or other phenothiazines
| 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. |
| Food/Dietary | Avoid alcohol due to additive CNS depression. Grapefruit juice may increase fluphenazine levels; avoid concurrent use. Limit caffeine as it may exacerbate restlessness or insomnia. No specific food restrictions otherwise. |
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| Fluphenazine is excreted into breast milk in low levels; monitor infant for drowsiness, extrapyramidal symptoms, and developmental delay. Discuss with patient the benefits of breastfeeding versus potential risks. |
| Lactation Rating | L2 – Limited data, probably compatible |
| Teratogenic Risk | Fluphenazine crosses the placenta. First trimester: limited human data, animal studies show increased risk of congenital anomalies (e.g., neural tube defects) at high doses. Avoid unless benefit outweighs risk. Second/third trimester: risk of extrapyramidal symptoms and withdrawal in neonates (e.g., agitation, hypertonia, tremor). Case reports of neonatal jaundice and prolonged QT interval. Use lowest effective dose. |
| Fetal Monitoring | Monitor maternal blood pressure, heart rate, QT interval (ECG), and extrapyramidal symptoms. Fetal monitoring: serial ultrasounds for growth, consider third-trimester fetal heart rate monitoring to assess for QT prolongation. Neonatal monitoring: assess for extrapyramidal symptoms, sedation, and jaundice after birth. |
| Fertility Effects | Fluphenazine may elevate prolactin levels via dopamine D2 receptor blockade, leading to galactorrhea, anovulation, and menstrual irregularities. These effects are reversible upon discontinuation. No known direct effect on sperm or ova fertility, but hyperprolactinemia can impair fertility. Consider monitoring prolactin in women of childbearing age. |
| Clinical Pearls | Fluphenazine is a high-potency first-generation antipsychotic with a lower incidence of sedation and orthostatic hypotension but higher risk of extrapyramidal symptoms (EPS). Use the lowest effective dose; start with 2.5-10 mg/day orally in divided doses. Depot formulations (enanthate/decanoate) are available for long-term maintenance. Monitor for tardive dyskinesia with prolonged use. Avoid in patients with blood dyscrasias, hepatic disease, or comatose states. ECG monitoring recommended due to QTc prolongation risk. |
| Patient Advice | Take exactly as prescribed; do not stop abruptly without consulting your doctor. · You may experience drowsiness, dizziness, or blurred vision initially. Avoid driving until you know how the medication affects you. · Report any involuntary muscle movements, especially of the face or tongue, to your doctor promptly. · Avoid alcohol and limit caffeine intake. · Notify your doctor if you develop fever, sore throat, or jaundice. · Store medication at room temperature, away from light and moisture. |