Usage
Iloperidone is an atypical antipsychotic medication primarily prescribed for the treatment of schizophrenia in adults. It is also used for the acute treatment of manic or mixed episodes associated with bipolar I disorder in adults. It is classified as a serotonin-dopamine antagonist and exerts its therapeutic effects through a combination of dopamine D2 and serotonin 5-HT2A receptor antagonism.
Alternate Names
Iloperidone is marketed under the brand name Fanapt. There are no widely used alternate names or regional variations.
How It Works
Pharmacodynamics: Iloperidone primarily acts as an antagonist at dopamine D2 and serotonin 5-HT2A receptors. It also exhibits affinity for other receptors, including serotonin 5-HT1A, dopamine D3, alpha-1 adrenergic, and alpha-2C adrenergic receptors. The combined effects on these receptors contribute to its antipsychotic and mood-stabilizing properties.
Pharmacokinetics:
- Absorption: Iloperidone is well-absorbed after oral administration, with peak plasma concentrations occurring within 1 to 2 hours. Food does not significantly affect absorption.
- Metabolism: Iloperidone undergoes extensive hepatic metabolism, primarily by CYP2D6 and CYP3A4 enzymes, resulting in two major active metabolites, P88 and P95. These metabolites contribute significantly to the overall clinical effect.
- Elimination: Iloperidone and its metabolites are eliminated through both renal and hepatic routes, with a half-life of approximately 18 hours. Less than 1% of the dose is excreted unchanged.
Mode of Action: Iloperidone’s antipsychotic effects are primarily mediated through its antagonism of D2 receptors in the mesolimbic pathway, reducing dopaminergic hyperactivity associated with positive symptoms of schizophrenia. The 5-HT2A receptor antagonism likely contributes to the improvement of negative symptoms and cognitive function, and may reduce the risk of extrapyramidal side effects (EPS).
Dosage
Standard Dosage
Adults:
- Schizophrenia: The recommended starting dose is 1 mg twice daily, titrated gradually to a target dose of 6-12 mg twice daily in increments of 2 mg per day.
- Bipolar I Disorder (Manic or Mixed Episodes): The recommended starting dose is 1 mg twice daily, titrated to a target dose of 12 mg twice daily, following a specific titration schedule.
- Maximum dose: The maximum recommended dose is 24 mg/day for both indications.
Children:
The safety and efficacy of iloperidone have not been established in children.
Special Cases:
- Elderly Patients: Use with caution due to increased risk of adverse effects, including orthostatic hypotension and cerebrovascular events. Start with a lower dose and titrate carefully. Not approved for dementia-related psychosis in elderly patients.
- Patients with Renal Impairment: No dosage adjustment is necessary for patients with renal impairment.
- Patients with Hepatic Dysfunction: No dosage adjustment is necessary in mild hepatic impairment. Dose reduction may be considered in moderate hepatic impairment. Iloperidone is not recommended in severe hepatic impairment.
- Patients with Comorbid Conditions: Careful monitoring and dose adjustments may be needed in patients with cardiovascular disease or other conditions that predispose them to orthostatic hypotension.
Clinical Use Cases
Iloperidone is not indicated for intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations.
Dosage Adjustments
- CYP2D6 Poor Metabolizers: Reduce the dose by 50%.
- Strong CYP2D6 or CYP3A4 Inhibitors: Reduce the dose by 50% when co-administered with these inhibitors (e.g., fluoxetine, paroxetine, ketoconazole, clarithromycin). Increase to previous dose upon discontinuation of the inhibitor.
Side Effects
Common Side Effects:
Dizziness, drowsiness, dry mouth, fatigue, nasal congestion, weight gain, orthostatic hypotension, tachycardia, syncope.
Rare but Serious Side Effects:
QTc prolongation, Neuroleptic Malignant Syndrome (NMS), tardive dyskinesia, seizures, agranulocytosis, leukopenia, priapism, hypersensitivity reactions (e.g., anaphylaxis, angioedema).
Long-Term Effects:
Tardive dyskinesia (potentially irreversible movement disorder), metabolic changes (weight gain, dyslipidemia, hyperglycemia).
Adverse Drug Reactions (ADR):
Any of the rare but serious side effects listed above.
Contraindications
- Hypersensitivity to iloperidone or any of its components.
- Congenital long QT syndrome.
- History of cardiac arrhythmias.
- Recent myocardial infarction.
- Uncompensated heart failure.
- Concomitant use with other QTc-prolonging drugs.
Drug Interactions
Iloperidone interacts with numerous medications, including:
- QTc Prolonging Drugs: Avoid concomitant use (e.g., class IA and III antiarrhythmics, certain antipsychotics, some antibiotics).
- CYP2D6 and CYP3A4 Inhibitors: Reduce iloperidone dose (e.g., fluoxetine, paroxetine, ketoconazole, clarithromycin).
- CYP2D6 Inducers: May decrease iloperidone levels (e.g., rifampin).
- Antihypertensives: Enhanced hypotensive effects.
- CNS Depressants: Additive sedative effects.
Pregnancy and Breastfeeding
- Pregnancy: Pregnancy Category C. No adequate and well-controlled studies in humans. Use only if the potential benefit justifies the potential risk to the fetus. Neonates exposed to antipsychotics during the third trimester are at risk for extrapyramidal and/or withdrawal symptoms.
- Breastfeeding: It is unknown if iloperidone is excreted in human milk. Due to potential risk to the infant, breastfeeding while taking iloperidone is not recommended.
Drug Profile Summary
- Mechanism of Action: Dopamine D2 and serotonin 5-HT2A receptor antagonist.
- Side Effects: Dizziness, drowsiness, dry mouth, weight gain, orthostatic hypotension, QTc prolongation, tardive dyskinesia.
- Contraindications: Hypersensitivity, congenital long QT syndrome, history of cardiac arrhythmias, recent MI, uncompensated heart failure, concomitant QTc prolonging drugs.
- Drug Interactions: Numerous drug interactions, especially with QTc prolonging drugs and CYP2D6/3A4 inhibitors/inducers.
- Pregnancy & Breastfeeding: Use with caution during pregnancy, not recommended while breastfeeding.
- Dosage: Adults: Start 1 mg BID, titrate to 6-12 mg BID for schizophrenia, 12 mg BID for bipolar I disorder. Maximum: 24 mg/day.
- Monitoring Parameters: ECG (QTc interval), weight, blood glucose, lipids, extrapyramidal symptoms, complete blood count, liver function tests.
Popular Combinations
No specific popular combinations are typically used with iloperidone due to its potential for drug interactions. Combination therapy should be used cautiously, with appropriate monitoring.
Precautions
- General Precautions: Monitor for orthostatic hypotension, QTc prolongation, extrapyramidal symptoms, and metabolic changes. Screen for cardiovascular risk factors.
- Specific Populations: Not recommended for use in patients with severe hepatic impairment or dementia-related psychosis in the elderly.
- Lifestyle Considerations: Limit alcohol intake. Avoid activities requiring alertness until drug effects are known.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Iloperidone?
A: Adults: Start with 1 mg BID, titrated to 6-12 mg BID for schizophrenia, 12 mg BID for bipolar I disorder. Maximum dose is 24 mg/day.
Q2: How should Iloperidone be titrated to minimize orthostatic hypotension?
A: Titrate slowly in increments of no more than 2 mg/day to the target dose.
Q3: What are the most common side effects of Iloperidone?
A: Dizziness, drowsiness, dry mouth, fatigue, nasal congestion, and weight gain.
A: QTc prolongation, neuroleptic malignant syndrome, tardive dyskinesia, seizures, and severe orthostatic hypotension.
Q5: What are the contraindications to using Iloperidone?
A: Hypersensitivity to iloperidone, congenital long QT syndrome, history of cardiac arrhythmias, recent myocardial infarction, uncompensated heart failure, and concomitant use with QTc prolonging drugs.
Q6: Does Iloperidone interact with other medications?
A: Yes, Iloperidone interacts with many medications. Notably, QTc prolonging drugs, CYP2D6 and CYP3A4 inhibitors and inducers, antihypertensives, and CNS depressants.
Q7: Can Iloperidone be used during pregnancy and breastfeeding?
A: Iloperidone is a Pregnancy Category C drug and should be used during pregnancy only if the potential benefit outweighs the risk. It’s not recommended during breastfeeding due to potential risks to the infant.
Q8: What monitoring parameters are important for patients taking Iloperidone?
A: Monitor ECG (for QTc prolongation), weight, blood glucose, lipids, extrapyramidal symptoms, and perform periodic complete blood counts and liver function tests.
Q9: What is the mechanism of action of Iloperidone?
A: Iloperidone primarily acts as a dopamine D2 and serotonin 5-HT2A receptor antagonist.
Q10: What patient education should be provided when prescribing Iloperidone?
A: Counsel patients on potential side effects, including orthostatic hypotension management (slow position changes), the importance of adherence to the titration schedule, and to report any concerning symptoms promptly. Emphasize the risk of tardive dyskinesia and the importance of regular monitoring. Advise patients to avoid alcohol and activities requiring alertness until drug effects are known. Provide information about drug interactions and the importance of informing the healthcare provider about all concomitant medications.
