ILOPERIDONE

Clinical safety rating: safe

Animal studies have demonstrated safety

How it works

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.

What the body does with it

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.

Classification & Brands

Dosing & administration

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

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Strong CYP2D6 or CYP3A4 inhibitors require dose adjustment Can cause orthostatic hypotension and QT prolongation.

Breastfeeding	Iloperidone is excreted into human milk. M/P ratio: unknown. Use caution; consider benefits of breastfeeding vs. risk of infant exposure. Monitor infant for sedation, poor feeding, extrapyramidal symptoms.
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).

Warnings & precautions

■ 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.

Side Effect Profile

Common Effects	Dizziness
Serious Effects

Absolute Contraindications

["Known hypersensitivity to iloperidone or any component of the formulation"]

Clinical Precautions

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"]

Clinical Tips & Counseling

Drug interactions

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