Iloperidone

Approved Indication (FDA):

• Schizophrenia in adults: Iloperidone is indicated for the acute treatment of schizophrenia. It helps manage both the positive symptoms (hallucinations, delusions) and negative symptoms (social withdrawal, apathy).

Off-label/clinically accepted uses:

• Bipolar disorder (adjunctive treatment) – occasionally used when first-line antipsychotics are not tolerated.
• Schizoaffective disorder – as part of combination therapy under specialist care.
• Aggression and agitation in psychiatric conditions – limited use based on clinical experience.

Adults:

• Starting dose: 1 mg orally twice daily.
• Titration: Increase dose gradually over 4–7 days to reduce orthostatic hypotension risk.
• Target dose: 12–24 mg/day (divided into two doses).
• Maximum dose: 24 mg/day.
• Minimum effective dose: 6–12 mg/day.

Pediatrics:

• Not approved for use in individuals under 18 years of age.

Elderly:

• Increased sensitivity to side effects like hypotension or QT prolongation; start at the lowest possible dose and titrate cautiously.

Renal Impairment:

• Mild to moderate: No adjustment needed.
• Severe: Use with caution; insufficient data.

Hepatic Impairment:

• Mild to moderate: Use with caution.
• Severe: Not recommended due to lack of safety data.

Administration:

• Administer orally with or without food.
• Tablets should be swallowed whole with water and not chewed or crushed.

Iloperidone is an atypical (second-generation) antipsychotic. Its primary action is antagonism at central dopamine D2 and serotonin 5-HT2A receptors, leading to reduced dopaminergic and serotonergic neurotransmission in the brain. It also blocks alpha-1 adrenergic receptors, which contributes to its antihypertensive and orthostatic hypotension effects. The modulation of these neurotransmitters helps to reduce psychotic symptoms, including delusions, hallucinations, and disorganized thinking, while also improving mood and affect.

• Absorption: Rapid oral absorption; peak plasma levels in 2–4 hours.
• Bioavailability: ~96% (oral).
• Distribution: Extensive; ~95% protein bound.
• Metabolism: Extensively metabolized in the liver via CYP2D6 and CYP3A4 enzymes.
• Elimination half-life:
• 18 hours in extensive metabolizers
• 33 hours in poor metabolizers
• Excretion: Primarily through urine (~45%) and feces (~50%) as metabolites.

Pregnancy:

• Category C (FDA) – Animal studies showed adverse fetal effects, but no adequate human data.
• Use only if clearly needed and if benefits outweigh risks.
• Neonates exposed in third trimester may experience extrapyramidal or withdrawal symptoms.

Lactation:

• Unknown if excreted in human milk.
• Due to potential adverse effects in infants, breastfeeding is not recommended during treatment and for some time after the last dose.

• Class: Atypical Antipsychotic
• Subclass: Second-generation antipsychotic (SGA), serotonin-dopamine antagonist

• Hypersensitivity to iloperidone or any formulation component
• History of QT prolongation or congenital long QT syndrome
• Concurrent use with other QT-prolonging drugs (e.g., antiarrhythmics)
• Recent myocardial infarction or unstable cardiac arrhythmia

• QT prolongation: Dose-dependent risk. Avoid in patients with known QT disorders or with other QT-prolonging drugs.
• Orthostatic hypotension: Most common during initiation and titration; titrate slowly.
• Neuroleptic Malignant Syndrome (NMS): Rare but life-threatening. Discontinue immediately if suspected.
• Tardive Dyskinesia: Can occur with long-term use; monitor regularly.
• Metabolic changes: Weight gain, hyperlipidemia, and glucose dysregulation possible.
• Leukopenia/neutropenia: Monitor CBC during therapy if clinical symptoms appear.
• Seizures: Use cautiously in patients with seizure history.
• Cognitive/motor impairment: May affect mental alertness; avoid driving or machinery initially.

Very Common (≥10%):

• Dizziness
• Somnolence
• Orthostatic hypotension
• Dry mouth
• Nasal congestion

Common (1–10%):

• Weight gain
• Tachycardia
• Fatigue
• Tremor
• Extrapyramidal symptoms (EPS)

Uncommon but Serious:

• QT interval prolongation
• Tardive dyskinesia
• Neuroleptic malignant syndrome
• Hyperprolactinemia
• Seizures
• Severe neutropenia

Timing:

• Dizziness and hypotension most common during early titration.
• Weight gain and metabolic effects typically develop over weeks to months.

• CYP2D6 and CYP3A4 inhibitors (e.g., paroxetine, fluoxetine, ketoconazole): Increase plasma concentration of iloperidone; dosage adjustment required.
• QT-prolonging drugs (e.g., quinidine, amiodarone, sotalol): Increased risk of life-threatening arrhythmias.
• CNS depressants (e.g., alcohol, opioids, sedatives): Additive sedative effects.
• Antihypertensives: Enhanced risk of hypotension.
• Enzyme inducers (e.g., rifampin, carbamazepine): May reduce efficacy by increasing clearance.

• Labeling now emphasizes mandatory slow titration due to hypotension and QT risk.
• Regular ECG monitoring recommended for patients with cardiovascular risks or on QT-prolonging drugs.
• Metabolic monitoring (weight, glucose, lipids) is now standard during long-term therapy.
• Pediatric use remains unapproved pending further research.

• Storage temperature: 20°C to 25°C (68°F to 77°F)
• Permissible excursion range: 15°C to 30°C (59°F to 86°F)
• Humidity/light protection: Store in original packaging, away from moisture and direct light
• Reconstitution: Not applicable
• Precautions: Keep out of reach of children. No refrigeration required.