Fluphenazine

Indications

• FDA-approved for the management of manifestations of psychotic disorders in adults, principally schizophrenia and schizoaffective disorder.
• The decanoate depot is FDA-approved for patients who require prolonged parenteral antipsychotic therapy, including those with poor oral adherence.
• Off-label use in acute mania and in psychotic depression as an adjunct, though second-generation agents now hold the guideline recommendations.
• Off-label control of severe chronic tics and Tourette syndrome when higher-potency dopamine blockade is needed and pimozide is unsuitable.
• Off-label management of chorea and behavioral dyscontrol in Huntington disease, generally after VMAT2 inhibitors have been considered.
• Not indicated for dementia-related psychosis, delirium prophylaxis, or nonpsychotic anxiety, where risk clearly exceeds benefit.

Mechanism of action

• High-affinity postsynaptic dopamine D2 antagonism in the mesolimbic pathway underlies antipsychotic efficacy at low milligram doses.
• Nigrostriatal D2 blockade at the same doses gives one of the highest extrapyramidal symptom rates among available antipsychotics.
• Tuberoinfundibular blockade produces marked, sustained hyperprolactinemia with amenorrhea, galactorrhea, and reduced bone mineral density.
• Weak muscarinic and histaminic affinity means less sedation and dry mouth than chlorpromazine but no intrinsic protection against dystonia.
• Modest alpha-1 antagonism gives intermediate orthostatic risk, and 5-HT2A blockade is minor compared with second-generation agents.

Pharmacokinetics

• Oral bioavailability is low and variable at roughly 20-50 percent because of substantial first-pass hepatic metabolism.
• The hydrochloride salt has a half-life near 15 hours, while the decanoate ester behaves as a depot with an apparent half-life of about 14 days.
• Decanoate is hydrolyzed in muscle to free fluphenazine, peaking at 24-72 hours and reaching steady state after roughly 4 to 6 injections.
• CYP2D6 is the principal metabolizing enzyme, so poor metabolizers and patients on 2D6 inhibitors accumulate drug and extrapyramidal effects.
• Protein binding exceeds 90 percent and the drug is highly lipophilic, with negligible renal elimination of unchanged fluphenazine.

Dosing

• Oral therapy starts at 2.5-10 mg/day divided every 6 to 8 hours; most patients stabilize on a maintenance dose of 1-5 mg/day.
• Increase gradually by 2.5 mg steps; doses above 20 mg/day are rarely more effective and the labeled ceiling is 40 mg/day.
• Decanoate is usually initiated at 12.5-25 mg intramuscularly or subcutaneously every 2 to 3 weeks, adjusted in 12.5 mg increments.
• A common conversion is a decanoate dose in milligrams roughly equal to 1.2 times the stabilized oral daily dose given every 2 weeks.
• No renal adjustment is defined; reduce doses and extend intervals in hepatic impairment because clearance is entirely hepatic.
• Taper oral therapy over weeks; when stopping a depot, remember drug persists for 6 to 8 weeks after the final injection.

Adverse effects

• Extrapyramidal symptoms dominate, with akathisia, parkinsonism, and acute dystonia reported in a third or more of treated patients.
• Tardive dyskinesia risk is high with chronic exposure, on the order of 5 percent per year in adults and considerably more in older patients.
• Hyperprolactinemia is nearly universal at therapeutic doses, causing menstrual disruption, galactorrhea, and sexual dysfunction.
• Neuroleptic malignant syndrome, though rare, is well described with high-potency phenothiazines and can occur weeks after a depot injection.
• Sedation, orthostatic hypotension, and anticholinergic effects are milder than with chlorpromazine but still limit dosing in frail patients.
• Rare but serious effects include agranulocytosis, cholestatic jaundice, QT prolongation, seizures, and photosensitivity reactions.

Monitoring

• Baseline and semiannual AIMS assessment, with a directed extrapyramidal exam at every visit during titration and after each depot change.
• Baseline CBC and liver enzymes, repeated if fever, sore throat, jaundice, or unexplained malaise develops during therapy.
• ECG at baseline in patients with cardiac disease, electrolyte disturbance, or concurrent QT-prolonging drugs, and after dose escalation.
• Prolactin level when amenorrhea, galactorrhea, or sexual dysfunction appears, with bone density review for long-term elevated levels.
• Weight, fasting glucose, and lipids at baseline and annually, plus creatine kinase whenever rigidity or unexplained fever emerges.

Interactions

• CYP2D6 inhibitors such as fluoxetine, paroxetine, bupropion, and duloxetine raise fluphenazine levels and markedly increase extrapyramidal risk.
• Enzyme inducers including carbamazepine, phenytoin, and rifampin lower concentrations and can cause loss of psychotic symptom control.
• Additive QT prolongation with methadone, ondansetron, macrolides, and class III antiarrhythmics; correct hypokalemia before combining.
• Additive sedation and respiratory depression with opioids, benzodiazepines, and alcohol, and additive hypotension with antihypertensives.
• Contraindicated in comatose states, severe CNS depression, subcortical brain damage, blood dyscrasias, liver disease, and phenothiazine allergy.

Special populations

• Pregnancy exposure lacks a clear teratogenic signal, but third-trimester use risks neonatal extrapyramidal signs and withdrawal symptoms.
• Fluphenazine passes into breast milk in small amounts; monitor the infant for sedation and abnormal movements if nursing continues.
• Safety and efficacy in children have not been established, so pediatric use is off-label and should be reserved for specialist settings.
• In older adults start at the lowest effective dose given heightened tardive dyskinesia risk and the boxed dementia mortality warning.
• Hepatic impairment is a labeled contraindication in significant liver disease; renal impairment requires no specific dose adjustment.

Clinical pearls

• Depot drug lingers 6-8 weeks after the last dose, so new movement problems can start late.
• Test tolerability with oral fluphenazine before committing a patient to the decanoate depot.
• Prophylactic benztropine is often needed given the very high acute dystonia rate in young men.