Paliperidone

Approved Indications:

• Schizophrenia:
• Treatment of schizophrenia in adults and adolescents aged ≥12 years
• Long-acting injectable forms approved for maintenance treatment in adults with schizophrenia
• Schizoaffective Disorder:
• Monotherapy or adjunct to mood stabilizers or antidepressants in adults

Off-label or Investigational Uses:

• Bipolar disorder (adjunctive in treatment-resistant cases – limited evidence)
• Behavioral disturbances in dementia (not routinely recommended due to safety risks)
• Severe aggression or psychosis in autism spectrum disorder (under specialist use only)

Route:

• Oral: Extended-release tablets (once daily)
• Intramuscular (IM): Long-acting injectables

Oral Extended-Release Tablets:

• Adults:
• Initial dose: 6 mg once daily (adjust based on response/tolerability)
• Range: 3–12 mg once daily
• Adolescents (≥12 years):
• Initial: 3 mg once daily
• Titrate as needed up to 6–12 mg/day

Long-Acting Injectables (Paliperidone Palmitate):

• Invega Sustenna® (monthly):
• Day 1: 234 mg IM (deltoid)
• Day 8: 156 mg IM (deltoid)
• Maintenance: 39–234 mg IM every month (deltoid or gluteal)
• Invega Trinza® (every 3 months):
• Use only after ≥4 months of stable treatment with monthly injections
• Dose based on last monthly dose (e.g., 78 mg monthly → 273 mg every 3 months)
• Invega Hafyera® (every 6 months):
• For patients stabilized on Invega Trinza
• Doses: 1,092 mg or 1,560 mg IM every 6 months

Renal Impairment (for oral tablets):

• CrCl 50–80 mL/min: Start at 3 mg/day
• CrCl 10–50 mL/min: Start at 1.5 mg/day
• CrCl <10 mL/min: Not recommended

Hepatic Impairment:

• Mild to moderate: No dose adjustment needed
• Severe impairment: Use with caution

Elderly:

• Start at lower dose; monitor renal function and orthostatic hypotension

Paliperidone is the active metabolite of risperidone and acts as a second-generation (atypical) antipsychotic. It functions by antagonizing central dopamine D2 receptors and serotonin 5-HT2A receptors, reducing dopaminergic and serotonergic neurotransmission associated with psychosis and mood disturbances. The D2 blockade alleviates positive symptoms (e.g., hallucinations, delusions), while 5-HT2A antagonism helps reduce extrapyramidal symptoms and may improve negative symptoms and cognition. Paliperidone also has activity at alpha-1, alpha-2 adrenergic, and H1 histamine receptors, which contribute to its side effect profile.

• Absorption:
• Oral ER tablets: Peak concentration in 24 hours
• Bioavailability: ~28% (oral ER)
• Food increases Cmax and AUC by ~60%; take consistently with or without food
• Distribution:
• Volume of distribution: ~487 L
• Plasma protein binding: 74%
• Metabolism:
• Minimal hepatic metabolism (mostly renal excretion)
• Metabolized by CYP3A4 and CYP2D6 (minor pathways)
• Elimination:
• Primarily via urine (59% unchanged drug)
• Half-life:
• Oral ER: ~23 hours
• Long-acting injectables: ~25–50 days depending on formulation

• Pregnancy:
• No longer categorized (previously FDA Pregnancy Category C)
• Use only if potential benefit justifies potential fetal risk
• Neonates exposed in the third trimester may experience extrapyramidal and withdrawal symptoms
• Lactation:
• Excreted in human breast milk
• Effects on infants are unknown; avoid or use with caution
• Consider switching to an agent with more lactation data if breastfeeding

• Primary Class: Atypical (Second-generation) Antipsychotic
• Subclass: Dopamine D2 and Serotonin 5-HT2A receptor antagonist
• Formulation Types: Oral extended-release; long-acting injectable depot

• Known hypersensitivity to paliperidone, risperidone, or formulation components
• Severe renal impairment (CrCl <10 mL/min for oral)
• History of severe extrapyramidal reactions or neuroleptic malignant syndrome (relative contraindication)
• Use of injectable forms in patients with acute circulatory collapse

• Increased Mortality in Elderly Patients with Dementia-Related Psychosis
• Boxed warning; not approved for this population
• Neuroleptic Malignant Syndrome (NMS):
• Rare but life-threatening; discontinue immediately if suspected
• Extrapyramidal Symptoms (EPS) & Tardive Dyskinesia:
• Monitor especially in long-term use
• Hyperprolactinemia:
• Can cause menstrual disorders, galactorrhea, or sexual dysfunction
• QT Prolongation:
• Caution in patients with risk factors (e.g., electrolyte imbalances, co-administered QT-prolonging drugs)
• Orthostatic Hypotension & Syncope:
• Especially in elderly or those on antihypertensives
• Seizures:
• Use with caution in seizure-prone patients

Common (≥10%):

• CNS: Somnolence, insomnia, anxiety, headache
• Neurological: Extrapyramidal symptoms, tremor, akathisia
• Endocrine/Metabolic: Hyperprolactinemia, weight gain
• GI: Nausea, constipation
• Injection site: Pain (in injectable formulations)

Less Common:

• Dizziness, blurred vision, dry mouth, fatigue, increased salivation

Rare but Serious:

• Neuroleptic Malignant Syndrome
• Tardive dyskinesia
• QT prolongation and arrhythmias
• Seizures
• Severe allergic reactions (e.g., angioedema)

Onset: Many side effects occur within the first few weeks of therapy; movement disorders and endocrine effects may appear later

• CYP450 Involvement:
• Minor substrate of CYP3A4 and CYP2D6
• Fewer interactions than risperidone
• Major Interactions:
• QT-prolonging drugs: Additive risk (e.g., amiodarone, sotalol)
• CNS depressants: Enhanced sedation
• Levodopa and dopamine agonists: Antagonistic effect on therapeutic action
• Alcohol: Avoid due to CNS depressant effects
• Antihypertensives: Increased risk of hypotension when combined

• Updated schizophrenia treatment guidelines (NICE, APA, WHO):
• Paliperidone LAI is recommended as a maintenance option for non-adherent patients
• Invega Hafyera® (6-month formulation): Recently approved in select regions to improve long-term compliance
• EMA and FDA have reaffirmed safety concerns in elderly with dementia, recommending avoidance
• Increased post-marketing surveillance for extrapyramidal side effects in adolescents

• Oral Tablets (Extended-Release):
• Store at 20°C to 25°C (68°F to 77°F)
• Protect from moisture and light
• Do not crush or chew
• Injectable Suspensions:
• Refrigerate at 2°C to 8°C (36°F to 46°F)
• May be stored at room temperature (up to 25°C) for short periods if specified by brand
• Do not freeze
• Shake well before use
• Use immediately after opening