Fluphenazine

Fluphenazine is a high-potency piperazine phenothiazine antipsychotic, used orally and as a long-acting decanoate depot for schizophrenia and other psychoses. It causes frequent extrapyramidal symptoms but little sedation, hypotension or anticholinergic effect, and it can worsen depressive symptoms.

Classification. First-generation (typical) antipsychotic, piperazine phenothiazine.

Mechanism. Potent dopamine D2 antagonism, with weak antimuscarinic, antihistamine and alpha-1 effects.

Pharmacokinetics. Oral bioavailability about 2 to 3% because of first-pass metabolism. Metabolised by CYP2D6. Oral half-life about 15 hours; decanoate half-life 7 to 10 days after repeated injections, with steady state in about 2 to 3 months.

Schizophrenia, adults (oral).

• Start 2.5 mg two to three times daily.
• Titration: increase by 2.5 to 5 mg daily every few days based on response and extrapyramidal effects.
• Usual 5 to 10 mg daily in divided doses. Maximum 20 mg daily (some labels permit 40 mg).
• Duration: at least 12 months after a first episode.

Maintenance depot (decanoate, deep intramuscular or subcutaneous).

• Test dose: 12.5 mg (6.25 mg in older adults). Observe for 4 to 7 days.
• Then 12.5 to 100 mg every 2 to 5 weeks (usually 14 to 35 days), adjusted to response. Maximum 100 mg each injection; avoid shorter intervals than 14 days.
• Continue oral cover for the first weeks and stop it as depot levels build.

Older adults. Oral start 1 mg daily to 2.5 mg daily; depot test dose 6.25 mg.

Contraindications. Coma or severe CNS depression, bone marrow suppression, liver impairment, phaeochromocytoma, subcortical brain damage, known QT prolongation, marked depression, hypersensitivity. Boxed-warning-level increase in mortality in older adults with dementia-related psychosis.

Serious adverse effects. Neuroleptic malignant syndrome, acute dystonia, parkinsonism, akathisia, tardive dyskinesia (a higher risk with long-term depot use), torsades de pointes, seizures, agranulocytosis (rare), cholestatic jaundice (rare), depression.

Common adverse effects. Extrapyramidal symptoms, restlessness, dry mouth, constipation, sexual dysfunction, galactorrhoea, injection site pain, mild sedation.

Interactions. Fluoxetine, paroxetine and bupropion raise levels. Carbamazepine and rifampicin lower levels. QT-prolonging drugs (macrolides, quinolones, quinine, artemether-lumefantrine, chloroquine, ondansetron) add risk. Anticholinergics, alcohol and sedatives add effects. Levodopa is antagonised. Lithium can increase neurotoxicity.

Common prescribing errors. Skipping the test dose; using intervals shorter than 14 days; escalating the depot dose before steady state is reached; not prescribing an anticholinergic for dystonia.

Special groups.

• Pregnancy: use only if benefit outweighs risk; third-trimester exposure can cause neonatal extrapyramidal symptoms and withdrawal.
• Breastfeeding: excreted in milk; avoid or use with infant monitoring.
• Children: not advised.
• Older adults: lower doses; high risk of parkinsonism and falls; mortality in dementia.
• Kidney impairment: start low.
• Liver impairment: contraindicated.

Formulations. Tablets 1 mg, 2.5 mg, 5 mg and 10 mg; decanoate injection 25 mg/mL in oil. Inject into the gluteal muscle with a wide-bore needle; rotate sites; maximum volume 2 mL each site.

Baseline. ECG, potassium and magnesium, weight, blood pressure, fasting glucose or HbA1c, lipids, prolactin if symptomatic, full blood count, liver tests, and a baseline rating of extrapyramidal symptoms.

Monitoring. Weight and waist at baseline, 4, 8 and 12 weeks, then annually; fasting glucose or HbA1c and lipids at baseline, 12 weeks, then annually. Check extrapyramidal symptoms at each review and rate abnormal movements every 6 to 12 months. Repeat the ECG after dose increases; stop or reduce if QTc is over 500 ms. Review for depression at each visit. For acute dystonia give procyclidine 5 to 10 mg by intramuscular or slow intravenous injection.

Stopping. Stop depot injections gradually; relapse may take weeks to appear because of the long half-life.

Referral and escalation. Refer to psychiatry for first-episode psychosis, treatment resistance, or persistent extrapyramidal symptoms. Fever with rigidity, syncope or QTc over 500 ms needs emergency care.