Paliperidone Palmitate

FDA-Approved Indications:

• Schizophrenia:
• For acute and maintenance treatment in adults with schizophrenia (all formulations)
• For adolescents aged 12–17 years (Invega Sustenna® only)
• Schizoaffective Disorder:
• As monotherapy or adjunct to mood stabilizers/antidepressants in adults (Invega Sustenna®)

Clinically Accepted (Off-label) Uses:

• Maintenance therapy in treatment-resistant bipolar disorder (investigational)
• Management of aggression in autism spectrum disorders or intellectual disabilities (specialist off-label use)

Route of Administration: Intramuscular (IM) only
Do not administer intravenously or subcutaneously

Invega Sustenna® (Once Monthly):

• Initiation:
• Day 1: 234 mg IM (deltoid)
• Day 8: 156 mg IM (deltoid)
• Maintenance (Monthly):
• 39 mg to 234 mg IM monthly into the deltoid or gluteal muscle
• Minimum interval: 35 days

Invega Trinza® (Every 3 Months):

• Initiate after ≥4 months of stable monthly dosing with Invega Sustenna®
• Dose conversion:
• 78 mg Sustenna → 273 mg Trinza
• 117 mg → 410 mg
• 156 mg → 546 mg
• 234 mg → 819 mg

Invega Hafyera® (Every 6 Months):

• Initiate after receiving ≥1 dose of Invega Trinza®
• Dose conversion:
• 546 mg Trinza → 1,092 mg Hafyera
• 819 mg Trinza → 1,560 mg Hafyera

Special Populations:

• Renal Impairment:
• CrCl 50–80 mL/min: Use lower starting doses
• CrCl <50 mL/min: Not recommended
• Hepatic Impairment:
• Mild to moderate: No adjustment required
• Severe: Use with caution
• Elderly:
• Start at the lower end of the dosing range
• Monitor for orthostatic hypotension and renal function
• Pediatrics:
• Invega Sustenna®: Approved for adolescents ≥12 years (schizophrenia)
• Trinza® and Hafyera®: Not approved in pediatric population

Paliperidone palmitate is a long-acting prodrug of paliperidone, the major active metabolite of risperidone. After intramuscular injection, paliperidone palmitate is slowly hydrolyzed to release paliperidone over time. Paliperidone acts by antagonizing dopamine D2 and serotonin 5-HT2A receptors in the central nervous system. D2 receptor blockade reduces positive psychotic symptoms (e.g., hallucinations, delusions), while 5-HT2A antagonism enhances dopaminergic transmission in certain pathways, improving negative symptoms and minimizing extrapyramidal side effects. Paliperidone also interacts with alpha-adrenergic and histaminergic receptors, which may contribute to orthostatic hypotension and sedation.

• Absorption:
• Prolonged release over 1–6 months depending on formulation
• Tmax:
• Invega Sustenna®: ~13 days
• Trinza®: ~30–33 days
• Hafyera®: ~30–33 days
• Distribution:
• Volume of distribution: ~1,960 L
• Plasma protein binding: ~74%
• Metabolism:
• Limited hepatic metabolism
• Minor involvement of CYP3A4 and CYP2D6 enzymes
• Excretion:
• 59% excreted unchanged in urine
• Terminal half-life:
• Sustenna®: 25–49 days
• Trinza®: 84–139 days
• Hafyera®: ~150 days

• Pregnancy:
• No assigned FDA pregnancy category under current labeling
• Animal studies show potential fetal harm; use only if benefits justify risks
• Neonates exposed in the third trimester may experience EPS or withdrawal symptoms
• Lactation:
• Paliperidone is excreted in breast milk
• Effects on breastfed infants are unknown; breastfeeding is not recommended during and for several months after treatment

• Class: Atypical (Second-Generation) Antipsychotic
• Subclass: Long-Acting Injectable Antipsychotic (LAI)
• Pharmacologic Category: Dopamine D2 and Serotonin 5-HT2A receptor antagonist

• Known hypersensitivity to paliperidone, risperidone, or formulation components
• Severe renal impairment (CrCl <50 mL/min for injectables)
• History of severe hypersensitivity reactions (e.g., anaphylaxis)
• Comatose states or CNS depression

• Boxed Warning: Increased mortality in elderly patients with dementia-related psychosis
• Not approved for use in dementia-related psychosis
• Neuroleptic Malignant Syndrome (NMS):
• Rare but life-threatening; discontinue immediately if suspected
• Tardive Dyskinesia:
• Risk increases with prolonged use, especially in elderly
• Hyperprolactinemia:
• Can lead to sexual dysfunction, galactorrhea, amenorrhea, gynecomastia
• QT Prolongation:
• Monitor in patients with risk factors or on QT-prolonging drugs
• Orthostatic Hypotension and Syncope:
• Especially in elderly or volume-depleted patients
• Seizures:
• Use with caution in seizure-prone individuals
• Injection-site reactions:
• Include pain, swelling, redness, and induration

Very Common (≥10%):

• Extrapyramidal symptoms (e.g., akathisia, tremor)
• Somnolence
• Injection site pain
• Hyperprolactinemia
• Weight gain
• Headache

Common (1–10%):

• Dizziness, fatigue
• Orthostatic hypotension
• Anxiety, insomnia
• GI disturbances: nausea, constipation
• Increased appetite

Serious/Rare:

• Neuroleptic malignant syndrome
• Tardive dyskinesia
• QT interval prolongation
• Severe hypersensitivity
• Suicidal ideation (especially in adolescents)

Onset:

• Most side effects occur during the first 1–2 months
• Extrapyramidal symptoms and prolactin-related effects may appear later

• Enzyme Involvement:
• Minor substrate of CYP3A4 and CYP2D6 (not clinically significant)

Major Interactions:

• QT-Prolonging Agents (e.g., amiodarone, moxifloxacin): Increased risk of arrhythmias
• CNS Depressants (e.g., opioids, benzodiazepines): Increased sedation
• Dopaminergic Drugs (e.g., levodopa): Antagonistic effect
• Alcohol: May enhance sedation and impair judgment

Food Interactions: Not significant (IM formulation bypasses GI absorption)

• Invega Hafyera® (6-month IM):
• Recently approved for stable schizophrenia patients after Invega Trinza®
• Improves adherence and long-term relapse prevention
• Updated Treatment Guidelines (APA, NICE, WHO):
• LAI antipsychotics recommended for patients with poor adherence to oral agents
• Paliperidone palmitate remains a first-line LAI option
• Label Updates:
• Enhanced monitoring for injection-site reactions
• Stronger warnings on QT prolongation and extrapyramidal effects

• Refrigeration: Store between 2°C and 8°C (36°F–46°F)
• Room Temperature: May be stored up to 25°C (77°F) for short periods as per manufacturer
• Protection: Do not freeze; protect from light
• Handling:
• Shake syringe vigorously for at least 10 seconds before administration
• Use immediately after opening
• For deep IM injection only—deltoid or gluteal, depending on dose/formulation
• Disposal: Follow hazardous drug handling and disposal procedures