Iloperidone (Fanapt)
SGA • Last reviewed 2025-09-26
General information
Iloperidone (Fanapt) is a second-generation antipsychotic approved for the treatment of schizophrenia in adults. Its high affinity for adrenergic α1 receptors necessitates a slow titration schedule to limit orthostatic hypotension and syncope.
Tablets range from 1 mg to 12 mg. Iloperidone shows relatively low extrapyramidal symptom (EPS) rates and modest metabolic burden compared with some SGAs, but carries a warning for QT prolongation.
Common adverse effects include dizziness, somnolence, tachycardia, weight gain, and nasal congestion.
Because of its orthostatic risk, iloperidone is often reserved for patients who have not tolerated other SGAs despite its favorable EPS profile.
Dosing & administration
Start 1 mg twice daily on day 1 and titrate to 6–12 mg twice daily by day 5, increasing in 1 mg BID increments.
Maintenance range: 12–24 mg/day divided twice daily. Dose reductions are required with poor CYP2D6 metabolizers or when co-administered with strong CYP2D6 or CYP3A4 inhibitors.
If therapy is interrupted for ≥3 days, re-initiate titration from 1 mg twice daily to avoid hypotension.
Dose adjustments
- Strong CYP2D6 inhibitors (fluoxetine, paroxetine)
- Reduce iloperidone dose by 50%; max 12 mg/day.
- Strong CYP3A4 inhibitors (ketoconazole, clarithromycin)
- Reduce dose by 50% and monitor QT.
- CYP3A4 inducers (carbamazepine, rifampin)
- Avoid combination due to loss of efficacy.
Mechanism of action
Iloperidone antagonizes dopamine D2/D3 and serotonin 5-HT2A receptors, contributing to antipsychotic efficacy with relatively low EPS risk.
Marked α1-adrenergic antagonism explains orthostatic hypotension. Additional 5-HT6/5-HT7 antagonism may support pro-cognitive effects.
- High affinity for α1 (Ki ~0.3 nM) and 5-HT2A (Ki ~1.5 nM) receptors.
- D2 antagonism (Ki ~4 nM) provides antipsychotic action.
- Minimal muscarinic affinity limits anticholinergic effects.
Metabolism & pharmacokinetics
Bioavailability is ~96%; Tmax occurs 2–4 hours post-dose. Two active metabolites (P88, P95) contribute to efficacy.
Metabolism occurs via CYP2D6 and CYP3A4. Half-life is ~18 hours in extensive metabolizers and ~23 hours in poor metabolizers, supporting twice-daily administration.
Elimination is roughly equal in urine and feces; protein binding ~95%.
Drug interactions
Strong CYP2D6 or CYP3A4 inhibitors increase exposure; reduce dose by 50%.
CYP3A4 inducers reduce efficacy; avoid combination.
Additive QT prolongation with antiarrhythmics (amiodarone) or other QT-prolonging psychotropics.
Antihypertensives may synergize hypotension.
| Mechanism | Agents / factors | Management |
|---|---|---|
| CYP2D6 inhibition | Fluoxetine, paroxetine | Halve dose; monitor sedation |
| CYP3A4 inhibition | Ketoconazole | Halve dose; monitor QT |
| QT prolongation | Amiodarone, methadone | Avoid or obtain ECG |
Monitoring & safety checks
Sitting/standing BP
Baseline and during titration • Orthostasis
ECG
Baseline and as indicated • QT prolongation
Weight, lipids, glucose
Baseline, 3 months, annually • Metabolic monitoring
EPS assessment
Each visit • Monitor for akathisia
Counsel patients about orthostatic precautions during initial week.
Monitor for nasal congestion and tachycardia, especially in rapid titration.
Discontinuation guidance
Taper gradually (1–2 weeks) to limit relapse or cholinergic rebound.
If therapy is interrupted ≥3 days, re-initiate titration when restarting.
Adverse effects
Common: dizziness, somnolence, tachycardia, dry mouth, weight gain.
Serious: orthostatic hypotension, QT prolongation, neuroleptic malignant syndrome.
References
- FANAPT (iloperidone) prescribing information — DailyMed (2024)
- Efficacy and safety of iloperidone in acute schizophrenia — Schizophrenia Research (2008) DOI: 10.1016/j.schres.2008.08.010
- Iloperidone in schizophrenia: clinical review — Therapeutic Advances in Chronic Disease (2014) DOI: 10.1177/2040622314551560
Educational use only — verify details in current prescribing information and authoritative clinical guidelines before making prescribing decisions.