Paliperidone

Indications

• Schizophrenia in adults and in adolescents ages 12-17 with the oral extended-release tablet, and in adults with the injectable formulations.
• Schizoaffective disorder in adults as monotherapy or as an adjunct to mood stabilizers or antidepressants, an indication unique in this class.
• Invega Sustenna is given monthly for schizophrenia and schizoaffective disorder, including after an inadequate response to oral treatment.
• Invega Trinza is given every 3 months only after at least 4 months of adequately dosed monthly Sustenna treatment.
• Invega Hafyera is given every 6 months after at least 4 months of Sustenna or one cycle of Trinza, the longest interval available in psychiatry.

Mechanism of action

• Paliperidone is 9-hydroxyrisperidone, the active metabolite of risperidone, so its receptor profile is essentially that of its parent drug.
• Potent antagonism at dopamine D2 and serotonin 5-HT2A receptors provides antipsychotic efficacy with dose-related extrapyramidal risk.
• Alpha-1 and alpha-2 adrenergic blockade produces orthostatic hypotension and reflex tachycardia, most evident during oral titration.
• Tuberoinfundibular D2 blockade raises prolactin more than any other agent in the class, a frequent reason for switching.
• Histamine H1 affinity is moderate, giving some sedation and appetite effect but less than olanzapine or quetiapine.

Pharmacokinetics

• The oral tablet uses an osmotic push-pull system giving about 28 percent bioavailability and a flat concentration curve over 24 hours.
• Metabolism is minimal, with roughly 59 percent excreted unchanged in urine, so CYP-mediated drug interactions are largely avoided.
• Oral half-life is about 23 hours; the injectable forms have apparent half-lives of 25-49 days and take months to reach steady state.
• Food increases oral exposure, so instruct patients to take the tablet the same way each day, either always with or always without breakfast.
• Renal clearance dominates, so exposure rises sharply as creatinine clearance falls and dose caps apply below 80 mL/min.

Dosing

• Oral schizophrenia and schizoaffective disorder: 6 mg once daily in the morning, with a usual range of 3-12 mg/day and no titration required.
• Adolescents under 51 kg have a maximum of 6 mg/day and those at or above 51 kg a maximum of 12 mg/day.
• Invega Sustenna initiation is 234 mg IM in the deltoid on day 1 and 156 mg IM on day 8, then 39-234 mg monthly in deltoid or gluteal muscle.
• Invega Trinza is 3.5 times the stabilized monthly dose, giving 273-819 mg IM every 3 months, and Hafyera is 1092 or 1560 mg every 6 months.
• Renal dose caps: maximum 6 mg/day oral when creatinine clearance is 50-79 mL/min and 3 mg/day when 10-49 mL/min; avoid below 10 mL/min.
• Injectables are not recommended when creatinine clearance is under 50 mL/min, and mild impairment requires a reduced initiation regimen.

Adverse effects

• Hyperprolactinemia is the most characteristic effect, producing amenorrhea, galactorrhea, gynecomastia, and sexual dysfunction.
• Dose-related extrapyramidal symptoms including akathisia, parkinsonism, and dystonia become common above 6 mg/day oral equivalent.
• Tachycardia, orthostatic hypotension, and dizziness occur early, and injection-site pain and induration are common with the injectables.
• Weight gain is moderate, generally intermediate in the class, with modest effects on lipids and fasting glucose.
• Tardive dyskinesia, neuroleptic malignant syndrome, and rare gastrointestinal obstruction with the nondeformable oral shell are the serious risks.

Monitoring

• Baseline and periodic weight, BMI, blood pressure, fasting glucose or A1c, and lipids, at 12 weeks and then annually.
• Serum creatinine and estimated creatinine clearance before starting and periodically, because dosing is entirely renally driven.
• Prolactin level whenever menstrual change, galactorrhea, gynecomastia, or sexual dysfunction is reported, and consider bone density if prolonged.
• AIMS at baseline and every 6-12 months, with closer attention in older patients and at higher dose equivalents.
• For injectables, confirm the correct needle length and injection site and document the interval, since a missed window requires a reinitiation algorithm.

Interactions

• Because metabolism is minimal, CYP interactions are few, which makes paliperidone attractive in patients on complex medication regimens.
• Strong inducers such as carbamazepine and rifampin still reduce exposure by about 35 percent through P-glycoprotein and mixed pathways.
• Additive orthostatic hypotension with antihypertensives and additive sedation with opioids, benzodiazepines, and alcohol.
• Additive QT effect with Class IA and III antiarrhythmics, methadone, and macrolides, though intrinsic QT risk is modest.
• Paliperidone antagonizes levodopa and dopamine agonists, so avoid it in Parkinson disease psychosis.

Special populations

• Third-trimester exposure risks neonatal extrapyramidal and withdrawal symptoms, and long-acting forms cannot be withdrawn quickly if needed.
• Lactation data are limited but modeled infant exposure is low; monitor breastfed infants for sedation and feeding problems.
• Oral use is approved from age 12 for schizophrenia, with weight-based dose caps and greater prolactin sensitivity than in adults.
• In older adults dose by renal function rather than age alone, and start at 3 mg/day oral when clearance is reduced.
• No specific adjustment is needed in mild to moderate hepatic impairment; severe impairment has not been studied.

Clinical pearls

• Choose paliperidone over risperidone when CYP2D6 interactions or variable metabolism are the problem.
• Dose is set by creatinine clearance, so recheck renal function before every dose increase.
• Trinza and Hafyera require prior stabilization on Sustenna; they are not starting formulations.