Paliperidone

Paliperidone is the active metabolite of risperidone (9-hydroxyrisperidone), a second-generation antipsychotic used for schizophrenia and schizoaffective disorder. It comes as an oral extended-release tablet and as monthly and 3-monthly long-acting injections. It is cleared mainly by the kidney, so kidney function sets the dose.

Classification. Second-generation antipsychotic, benzisoxazole derivative.

Mechanism. Potent antagonism of 5-HT2A and dopamine D2 receptors, with alpha-1 and histamine H1 blockade.

Pharmacokinetics. Oral extended-release bioavailability about 28%; peak at 24 hours. Little hepatic metabolism; about 59% is excreted unchanged in urine. Half-life about 23 hours orally and 25 to 49 days after the palmitate injection. A P-glycoprotein substrate.

Schizophrenia and schizoaffective disorder, adults (oral extended-release).

• Start 6 mg once daily in the morning (3 mg if cautious).
• Titration: increase in 3 mg steps at intervals of at least 5 days.
• Usual 3 to 12 mg daily. Maximum 12 mg daily.

Adolescents aged 12 to 17 years with schizophrenia. Under 51 kg: start 3 mg, maximum 6 mg daily. 51 kg or more: start 3 mg, maximum 12 mg daily.

Maintenance monthly depot (palmitate, intramuscular).

• Confirm oral tolerance with paliperidone or risperidone first.
• Day 1: 234 mg deltoid; day 8: 156 mg deltoid.
• Then monthly 39 to 234 mg (usual 117 mg), in deltoid or gluteal muscle. Maximum 234 mg monthly.

Maintenance 3-monthly depot. Use only after at least 4 months of stable monthly treatment. Give 3.5 times the last monthly dose (78 mg becomes 273 mg; 117 mg becomes 410 mg; 156 mg becomes 546 mg; 234 mg becomes 819 mg) every 3 months.

Dose limits. Creatinine clearance 50 to under 80 mL/min: oral start 3 mg, maximum 6 mg daily; monthly depot 156 mg on day 1 and 117 mg on day 8, then 78 mg monthly. Creatinine clearance 10 to under 50 mL/min: oral start 1.5 mg, maximum 3 mg daily; depot not advised. Under 10 mL/min: not advised. Mild to moderate liver impairment: no adjustment.

Contraindications. Hypersensitivity to paliperidone or risperidone. Boxed-warning-level increase in mortality in older adults with dementia-related psychosis. Caution in Parkinson disease, Lewy body dementia, cardiac disease, QT risk and gastrointestinal narrowing (for the oral tablet).

Serious adverse effects. Neuroleptic malignant syndrome, tardive dyskinesia, QT prolongation, orthostatic hypotension, hyperglycaemia and diabetes, marked hyperprolactinaemia, priapism, seizures, neutropenia (rare), stroke in older adults with dementia, venous thromboembolism.

Common adverse effects. Extrapyramidal symptoms, akathisia, weight gain, tachycardia, headache, sedation, raised prolactin, injection site pain.

Interactions. Carbamazepine and rifampicin lower levels (P-glycoprotein induction); increase the dose if needed. Valproate raises levels modestly. Antihypertensives add hypotension. Levodopa is antagonised. QT-prolonging drugs add risk. Drugs that reduce kidney function raise levels.

Common prescribing errors. Not adjusting for kidney function; skipping the day 8 loading injection; using the 3-monthly form before stabilisation; crushing or chewing the tablet.

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 monitor the infant for sedation and extrapyramidal symptoms.
• Children: oral use from 12 years only.
• Older adults: use kidney function to set the dose; stroke and mortality risk in dementia.
• Kidney impairment: when creatinine clearance is 50 to under 80 mL/min the oral maximum is 6 mg daily; when 10 to under 50 mL/min the oral maximum is 3 mg daily; avoid the depot in moderate to severe impairment.
• Liver impairment: no adjustment for mild to moderate.

Formulations. Extended-release tablets 1.5 mg, 3 mg, 6 mg and 9 mg; palmitate injection 39 mg to 234 mg (monthly), 273 mg to 819 mg (3-monthly). Swallow tablets whole with or without food, consistently; the tablet shell may appear in the stool. Give the first two monthly injections in the deltoid.

Baseline. Weight, BMI, waist, blood pressure, creatinine clearance, fasting glucose or HbA1c, lipids, prolactin if symptomatic, ECG if cardiac risk, 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 creatinine clearance at least annually and when illness reduces kidney function. Measure prolactin if symptoms occur.

Stopping. Reduce gradually; the depot has a long tail, so relapse may appear weeks to months after the last injection.

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