Usage
- Paliperidone is prescribed for the acute and maintenance treatment of schizophrenia in adults and adolescents aged 12 years and older. It is also indicated for the acute treatment of schizoaffective disorder, both as monotherapy and adjunctive therapy with mood stabilizers or antidepressants.
- Pharmacological Classification: Atypical antipsychotic.
- Mechanism of Action: Paliperidone acts as an antagonist at serotonin 5-HT2A and dopamine D2 receptors. It also exhibits antagonism at alpha-1 adrenergic and H1 histaminic receptors. The precise mechanism of action in schizophrenia and schizoaffective disorder is unknown, but its therapeutic effects are likely mediated through its combined effects on these receptor systems.
Alternate Names
- 9-Hydroxyrisperidone (major active metabolite of risperidone)
- Brand Names: Invega, Invega Sustenna, Invega Trinza, Invega Hafyera, Erzofri
How It Works
- Pharmacodynamics: Paliperidone primarily exerts its antipsychotic effects through antagonism of dopamine D2 and serotonin 5-HT2A receptors in the brain. The antagonism of alpha-1 adrenergic receptors can lead to orthostatic hypotension and other cardiovascular effects. Histamine H1 receptor antagonism may contribute to sedation.
- Pharmacokinetics: Paliperidone is well absorbed after oral administration, reaching peak plasma concentration in approximately 24 hours for the extended-release tablets. It is extensively metabolized in the liver, primarily via CYP2D6 and to a lesser extent by CYP3A4. Elimination occurs mainly through renal excretion (approximately 62%) and to a lesser extent through fecal excretion.
- Mode of Action: Paliperidone acts by binding to and blocking dopamine D2 and serotonin 5-HT2A receptors, thus modulating dopaminergic and serotonergic neurotransmission in the brain.
- Receptor Binding, Enzyme Inhibition or Neurotransmitter Modulation: As mentioned above, paliperidone is an antagonist at serotonin 5-HT2A, dopamine D2, alpha-1 adrenergic, and H1 histaminic receptors. It does not significantly inhibit CYP450 enzymes.
- Elimination Pathways: Predominantly renal excretion (about 62%), with a smaller fraction eliminated in the feces.
Dosage
Standard Dosage
Adults (Schizophrenia and Schizoaffective Disorder):
- Oral: Initial: 6 mg once daily in the morning. Maintenance: 3-12 mg once daily, adjusted based on clinical response and tolerability. Dose adjustments should be made in increments of 3 mg/day at intervals of 5 days or more.
Adolescents (12-17 years) (Schizophrenia):
- Oral: Initial: 3 mg once daily in the morning. Maintenance: 3 to 12 mg/day
Children (Under 12 years):
Special Cases:
- Elderly Patients: Start with a lower dose (e.g., 3 mg/day) and titrate cautiously, considering potential renal impairment.
- Patients with Renal Impairment:
- Mild to moderate (CrCl 50-80 mL/min): Initial: 3 mg/day; Maximum: 6 mg/day.
- Moderate to severe (CrCl 10-50 mL/min): Initial: 1.5 mg/day; Maximum: 3 mg/day.
- Patients with Hepatic Dysfunction: No dose adjustment is necessary for mild to moderate hepatic impairment. Use with caution in severe hepatic impairment.
- Patients with Comorbid Conditions: Dosage adjustments may be needed based on specific comorbid conditions (e.g., cardiovascular disease, diabetes) and concomitant medications.
Clinical Use Cases (for Injectable Paliperidone Palmitate):
- Intubation/Surgical Procedures/Mechanical Ventilation/ICU Use/Emergency Situations: Paliperidone extended-release tablets or long-acting injectable formulations are not typically used in these acute settings. Rapid-acting antipsychotics are generally preferred for managing agitation or psychosis in these situations.
Dosage Adjustments:
Dosage modifications are based on patient-specific factors:
- Renal/Hepatic Dysfunction: As mentioned above.
- Metabolic Disorders or Genetic Polymorphisms: Consider dose adjustments for patients with conditions or genetic variations affecting drug metabolism.
Side Effects
Common Side Effects:
- Extrapyramidal symptoms (EPS), including parkinsonism, akathisia, dystonia.
- Tachycardia
- Insomnia
- Sedation/Somnolence
- Headache
- Weight gain
- Increased prolactin levels
Rare but Serious Side Effects:
- Neuroleptic malignant syndrome (NMS)
- Tardive dyskinesia
- QT prolongation
- Seizures
- Severe allergic reactions (e.g., anaphylaxis, angioedema)
Long-Term Effects:
- Tardive dyskinesia
- Metabolic syndrome (weight gain, dyslipidemia, hyperglycemia)
- Cardiovascular effects (e.g., hypertension, QTc prolongation)
Adverse Drug Reactions (ADR):
- Agranulocytosis
- Thromboembolic events
- Severe dyskinesias
Contraindications
- Hypersensitivity to paliperidone or risperidone.
- Dementia-related psychosis in elderly patients.
- Concomitant use with drugs known to prolong the QTc interval (e.g., Class IA and III antiarrhythmics).
Drug Interactions
Paliperidone has potential interactions with a large number of medications, including:
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CYP450 Inducers/Inhibitors: Strong CYP2D6 inhibitors (e.g., paroxetine, fluoxetine) may increase paliperidone concentrations. Strong CYP3A4 inducers (e.g., carbamazepine, rifampin) may decrease paliperidone concentrations.
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QT Prolonging Drugs: Avoid concomitant use with other drugs that prolong the QT interval.
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CNS Depressants: Additive sedative effects may occur with alcohol, benzodiazepines, and other CNS depressants.
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Antihypertensives: Paliperidone may enhance the hypotensive effects of antihypertensive medications.
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Dopamine Agonists: May decrease the efficacy of paliperidone.
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Medications metabolized by CYP2D6
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Medications affecting serotonin levels
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Medications affecting dopamine levels
Pregnancy and Breastfeeding
- Pregnancy Safety Category: C (Australia); Not assigned (US FDA).
- Fetal Risks: Limited data are available. Potential risks include extrapyramidal and/or withdrawal symptoms in neonates exposed during the third trimester.
- Breastfeeding: Paliperidone is excreted in breast milk. Breastfeeding is generally not recommended while taking paliperidone. Consider the risks and benefits for the mother and infant. If breastfeeding, monitor infants for potential adverse reactions, like excessive sedation, failure to thrive, jitteriness and extrapyramidal symptoms.
Drug Profile Summary
- Mechanism of Action: Dopamine D2 and serotonin 5-HT2A receptor antagonist.
- Side Effects: EPS, tachycardia, akathisia, sedation, weight gain, increased prolactin.
- Contraindications: Hypersensitivity, dementia-related psychosis in the elderly, concomitant use with QTc prolonging drugs.
- Drug Interactions: CYP2D6 and 3A4 inhibitors/inducers, QT prolonging drugs, CNS depressants.
- Pregnancy & Breastfeeding: Use with caution during pregnancy; breastfeeding not recommended.
- Dosage: Adults: 6 mg/day initially, 3-12 mg/day maintenance; Adolescents: 3mg/day initially, 3-12 mg/day maintenance; adjust for renal impairment.
- Monitoring Parameters: Weight, blood pressure, heart rate, ECG (for QTc prolongation), EPS, prolactin levels, signs of NMS.
Popular Combinations
Paliperidone is sometimes combined with other medications, including:
- Mood stabilizers
- Antidepressants
- Other Antipsychotics
Precautions
- Monitor weight, blood glucose, lipids and electrocardiogram periodically, especially in patients at risk for metabolic syndrome or QT prolongation.
- Avoid abrupt discontinuation.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Paliperidone?
A: Adults: Initial 6 mg once daily, adjustable to 3-12 mg/day. Adolescents: 3 mg once daily, adjustable to 3-12 mg/day. Adjust for renal impairment. Elderly patients should start with a lower dose.
Q2: What are the common side effects?
A: Common side effects include EPS, tachycardia, akathisia, sedation, and weight gain.
Q3: Is Paliperidone safe during pregnancy?
A: Use cautiously during pregnancy; it’s potentially associated with extrapyramidal and/or withdrawal symptoms in neonates exposed during the third trimester. Consult with a specialist to understand the risks and benefits
Q4: Can Paliperidone be used in patients with renal impairment?
A: Yes, but dose adjustments are necessary depending on the severity of impairment.
Q5: What is the mechanism of action of Paliperidone?
A: Paliperidone is a dopamine D2 and serotonin 5-HT2A receptor antagonist.
Q6: What are the serious side effects to watch out for?
A: NMS, tardive dyskinesia, QT prolongation, and seizures are rare but serious side effects.
Q7: What should I monitor in patients taking Paliperidone?
A: Weight, blood pressure, heart rate, ECG, EPS, and prolactin levels should be monitored.
Q8: Does Paliperidone interact with other medications?
A: Yes, Paliperidone can interact with numerous drugs, including CYP450 inducers/inhibitors, QTc prolonging drugs, and CNS depressants. A comprehensive medication review is recommended.
Q9: What patient education should be provided?
A: Patients should be educated about potential side effects, the importance of adherence, and the need to avoid abrupt discontinuation. They should also be advised to report any unusual symptoms to their healthcare provider.
