ILOPERIDONE
Clinical safety rating: safe
Animal studies have demonstrated safety
Iloperidone is an atypical antipsychotic with high affinity for serotonin 5-HT2A and dopamine D2 receptors; also moderate affinity for D3, D4, 5-HT6, 5-HT7, and α1-adrenergic receptors; low affinity for H1, 5-HT1A, and α2-adrenergic receptors; no affinity for M1 muscarinic receptors.
| Metabolism | Primarily metabolized by CYP3A4 and CYP2D6 to two major metabolites (P88 and P95); also a minor substrate of CYP1A2, CYP2C8, CYP2C9, CYP2C19, and CYP2E1. |
| Excretion | Primarily hepatic metabolism via CYP3A4 and CYP2D6; approximately 7% excreted unchanged in urine and 18% in feces; total renal elimination of metabolites ~25%, fecal ~60%. |
| Half-life | Terminal elimination half-life 18 hours in extensive CYP2D6 metabolizers, 33 hours in poor metabolizers; clinical context: steady-state reached in ~5-7 days. |
| Protein binding | ~95% bound to serum proteins, primarily albumin and alpha-1-acid glycoprotein. |
| Volume of Distribution | Vd/F ~20 L/kg (oral); large distribution indicates extensive tissue binding. |
| Bioavailability | Oral bioavailability is approximately 96% relative to oral solution; food does not significantly affect absorption. |
| Onset of Action | Oral: peak plasma concentration at 2-4 hours; clinical antipsychotic effect may be seen within 1-2 weeks. |
| Duration of Action | Duration of effect is approximately 24 hours with once-daily dosing; steady-state maintained with regular administration. |
| Molecular Weight | 426.48 |
1-2 mg orally twice daily; target dose 6-12 mg/day; maximum 12 mg/day
| Dosage form | TABLET |
| Renal impairment | GFR 30-59 mL/min: reduce dose by 50%; GFR 15-29 mL/min: reduce by 75%; GFR <15 mL/min: not recommended |
| Liver impairment | Child-Pugh class B: reduce dose by 50%; Child-Pugh class C: contraindicated |
| Pediatric use | Not established; safety and efficacy not evaluated in patients <18 years |
| Geriatric use | Initiate at 1 mg twice daily; increase slowly; monitor for orthostatic hypotension and anticholinergic effects |
| 1st trimester | Limited data; avoid unless benefit outweighs risk. Antipsychotic use may be associated with congenital malformations, but risk appears low. Consider risk of untreated maternal psychiatric illness. |
| 2nd trimester | Limited data; avoid unless necessary. Monitor for excessive weight gain and gestational diabetes. Use lowest effective dose. |
| 3rd trimester | Avoid during third trimester due to risk of extrapyramidal symptoms and/or withdrawal in neonates. Consider non-pharmacologic options. |
Clinical note
Strong CYP2D6 or CYP3A4 inhibitors require dose adjustment Can cause orthostatic hypotension and QT prolongation.
| Placental transfer | Iloperidone crosses the placenta; molecular weight (426.48 Da) suggests passive diffusion. Data on placental transfer is limited but consistent with other atypical antipsychotics. |
| Breastfeeding | Iloperidone is excreted into breast milk in low amounts; relative infant dose estimated <10%. Monitor infant for sedation, irritability, and feeding problems. Consider benefits of breastfeeding vs. risk of infant exposure. Alternative antipsychotics with more data may be preferred. |
■ FDA Black Box Warning
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Iloperidone is not approved for the treatment of patients with dementia-related psychosis.
| Common Effects | Dizziness |
| Serious Effects |
Hypersensitivity to iloperidone or any component of the formulationConcurrent use with strong CYP3A4 inducers (e.g., carbamazepine, rifampin) results in subtherapeutic levels and is not recommendedUse in patients with history of long QT syndrome or with QTc >500 msec (due to dose-related QTc prolongation)
| Precautions | Increased mortality in elderly patients with dementia-related psychosis, QT interval prolongation (particularly with concomitant use of drugs that prolong QT or in patients with risk factors), Neuroleptic malignant syndrome (NMS), Tardive dyskinesia, Metabolic changes (hyperglycemia, dyslipidemia, weight gain), Orthostatic hypotension (particularly during initial dose titration), Seizures, Leukopenia, neutropenia, and agranulocytosis, Body temperature regulation impairment, Dysphagia, Cognitive and motor impairment |
Loading safety data…
| Lactation Rating | L3 (Moderately Safe) |
| Teratogenic Risk | First trimester: Limited human data; animal studies show increased fetal resorption and developmental delays at doses similar to human exposure. Second and third trimesters: May cause extrapyramidal symptoms and/or withdrawal symptoms in neonates (e.g., agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, feeding disorder). |
| Fetal Monitoring | Monitor mother for adverse effects (e.g., QTc prolongation, hypotension, extrapyramidal symptoms). Fetal monitoring: assess growth (ultrasound) and neonatal behavior for withdrawal or extrapyramidal symptoms postpartum. |
| Fertility Effects | Hyperprolactinemia may occur, potentially leading to menstrual irregularities, anovulation, and reduced libido, which may impair female fertility. In males, hyperprolactinemia may cause erectile dysfunction and reduced sperm production. |
| Food/Dietary | Grapefruit juice may inhibit CYP3A4 metabolism, increasing iloperidone concentrations; avoid concurrent use. High-fat meals may slightly reduce absorption; take consistency. |
| Clinical Pearls | Iloperidone is an atypical antipsychotic with a low propensity for extrapyramidal symptoms but significant QTc prolongation risk; obtain baseline ECG and monitor electrolytes. Titrate slowly to mitigate orthostatic hypotension due to alpha-1 blockade. Dosing adjustments required in CYP2D6 poor metabolizers (reduce dose by 50%). Avoid concomitant use with QT-prolonging drugs or CYP3A4/2D6 inhibitors/inducers. |
| Patient Advice | Do not drive or operate machinery until you know how iloperidone affects you, as it may cause dizziness, drowsiness, or blurred vision. · Rise slowly from sitting or lying positions to prevent falls due to low blood pressure. · Report any fast, pounding, or irregular heartbeat, especially with lightheadedness or fainting. · Avoid alcohol and grapefruit juice as they may increase side effects or drug levels. · If you experience muscle stiffness, fever, confusion, or sweating, seek emergency help immediately, as these may be signs of neuroleptic malignant syndrome. |