What is Fanapt (iloperidone), including its mechanism of action, dosing regimen, side effects, contraindications, and monitoring recommendations?

What is Fanapt (Iloperidone)?

Fanapt (iloperidone) is an atypical antipsychotic medication approved by the FDA for the acute treatment of schizophrenia in adults, acting primarily through combined dopamine D2 and serotonin 5-HT2A receptor antagonism. 1

Mechanism of Action

Iloperidone functions as a high-affinity antagonist at multiple receptor sites, which explains both its therapeutic effects and side effect profile 1:

• Primary targets: Dopamine D2 (Ki = 6.3 nM), D3 (Ki = 7.1 nM), serotonin 5-HT2A (Ki = 5.6 nM), and norepinephrine α1 receptors (Ki = 0.36 nM) 1
• Moderate affinity: Dopamine D4, serotonin 5-HT6 and 5-HT7 receptors 1
• Low affinity: Serotonin 5-HT1A, dopamine D1, and histamine H1 receptors 1
• Minimal anticholinergic activity: No appreciable affinity for muscarinic receptors (Ki >1000 nM), which reduces cognitive side effects 1

The drug forms an active metabolite (P88) with a similar receptor binding profile to the parent compound 1.

Dosing Regimen

Initial Titration (Critical for Safety)

Iloperidone requires slow titration over 7 days to minimize orthostatic hypotension and dizziness 1, 2:

• Day 1: 1 mg twice daily
• Day 2: 2 mg twice daily
• Day 3: 4 mg twice daily
• Day 4: 6 mg twice daily
• Day 5: 8 mg twice daily
• Day 6: 10 mg twice daily
• Day 7: 12 mg twice daily (target dose)

Maintenance Dosing

• Target therapeutic range: 6–12 mg twice daily (12–24 mg/day total) 1, 3
• Administration: Can be taken without regard to meals 1
• Steady state: Achieved within 3–4 days of dosing 1

Dose Adjustments for Drug Interactions

When co-administered with strong CYP2D6 or CYP3A4 inhibitors, reduce the iloperidone dose by 50% 1. This is critical because:

• CYP2D6 poor metabolizers have a 33-hour half-life versus 18 hours in extensive metabolizers 1
• CYP3A4 inhibition significantly increases iloperidone exposure and QTc prolongation risk 2

Clinical Efficacy

Acute Treatment of Schizophrenia

In Phase III trials, iloperidone demonstrated efficacy comparable to other atypical antipsychotics 4, 5:

• PANSS total score reduction: Iloperidone 12 mg twice daily reduced scores by 12 points versus 7.1 points for placebo (P < 0.01) 3
• Comparison to active controls: Efficacy was equivalent to haloperidol and ziprasidone in post-hoc analyses 4, 5
• Long-term maintenance: In 52-week trials, iloperidone showed equivalent time to relapse compared to haloperidol 5

Pharmacogenomic Considerations

Single nucleotide polymorphisms (SNPs) have been identified that predict enhanced response to iloperidone during both acute and long-term treatment 5. This represents a potential future avenue for personalized medicine approaches.

Side Effects and Safety Profile

Common Adverse Events (≥5% incidence)

The most frequently reported side effects include 1, 3:

• Dizziness (5.1%–23.2%, dose-related)
• Dry mouth (5.2%–10.4%)
• Somnolence (4%–13%)
• Fatigue
• Nasal congestion
• Orthostatic hypotension (especially during first week)
• Tachycardia
• Weight gain (12% experienced clinically significant weight gain, primarily during initiation) 2

Favorable Safety Characteristics

Iloperidone has a notably favorable extrapyramidal symptom (EPS) profile compared to typical antipsychotics and some atypical agents 2, 5:

• Lower EPS rates than haloperidol and risperidone 2
• Rare akathisia 4, 6
• Minimal prolactin elevation 6
• No medically important changes in lipid and glucose parameters in short- and long-term studies 5, 6

Critical Safety Concerns

QTc Prolongation (Black Box Consideration)

Iloperidone prolongs the QTc interval by approximately 10 milliseconds, comparable to ziprasidone and haloperidol 1, 2, 4:

• Avoid combination with other QTc-prolonging drugs (e.g., quinidine, procainamide, disopyramide) 1
• Monitor serum potassium and magnesium in patients at risk for electrolyte disturbances 1
• QTc prolongation is heightened under CYP2D6 and CYP3A4 inhibition 2
• Obtain baseline ECG before initiating therapy in patients with cardiovascular disease 1

Orthostatic Hypotension

Orthostatic hypotension is common during the first week of treatment due to potent norepinephrine α1 receptor antagonism 1, 6:

• The slow 7-day titration schedule is specifically designed to mitigate this risk 2, 3
• Monitor heart rate and blood pressure, especially in patients with cardiovascular disease, cerebrovascular disease, or risk of dehydration 1

Neuroleptic Malignant Syndrome (NMS)

Manage NMS with immediate discontinuation of iloperidone and close monitoring 1. Signs include hyperpyrexia, muscle rigidity, altered mental status, and autonomic instability.

Tardive Dyskinesia

Discontinue iloperidone if clinically appropriate when tardive dyskinesia develops 1. The risk appears lower than with typical antipsychotics but remains a concern with all dopamine antagonists.

Metabolic Changes

Monitor for hyperglycemia/diabetes mellitus, dyslipidemia, and weight gain, though metabolic changes are modest compared to olanzapine or clozapine 1, 2.

Hematologic Effects

Leukopenia, neutropenia, and agranulocytosis have been reported with antipsychotics 1:

• Perform complete blood counts (CBC) in patients with pre-existing low WBC or history of drug-induced leukopenia/neutropenia 1
• Consider discontinuing iloperidone if clinically significant WBC decline occurs without other causative factors 1

Priapism

Cases of priapism have been reported; severe priapism may require surgical intervention 1.

Contraindications

Iloperidone is contraindicated in patients with known hypersensitivity to iloperidone or any formulation components 1.

Special Populations and Warnings

Elderly Patients with Dementia-Related Psychosis

BLACK BOX WARNING: Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at increased risk of death. Iloperidone is NOT approved for use in patients with dementia-related psychosis 1.

Additionally, there is an increased incidence of cerebrovascular adverse reactions (stroke, TIA) in this population 1.

Pregnancy and Lactation

• Pregnancy: May cause extrapyramidal and/or withdrawal symptoms in neonates with third-trimester exposure 1
• Lactation: Advise patients not to breastfeed while taking iloperidone 1

Pediatric Use

Safety and effectiveness have not been established in children and adolescents 1.

Hepatic Impairment

Iloperidone is not recommended for patients with severe hepatic impairment 1.

Monitoring Recommendations

Baseline Assessment

Before initiating iloperidone 1:

• ECG (especially in patients with cardiovascular risk factors)
• Electrolytes (potassium, magnesium)
• Complete blood count (if risk factors for leukopenia)
• Fasting glucose and lipid panel
• Blood pressure (orthostatic measurements)

Ongoing Monitoring

• First week: Monitor blood pressure and heart rate closely for orthostatic hypotension 1
• Metabolic parameters: Periodic monitoring of weight, glucose, and lipids 1
• CBC: In patients with pre-existing low WBC or history of drug-induced blood dyscrasias 1
• ECG: Consider periodic monitoring in patients at risk for QTc prolongation 1

Common Pitfalls and Clinical Considerations

Acute Setting Limitations

The slow 7-day titration schedule required to minimize orthostatic hypotension limits the utility of iloperidone in acute psychiatric emergencies 2. For patients requiring rapid symptom control, other antipsychotics with faster titration schedules may be more appropriate.

Drug Interactions

Always check for CYP2D6 and CYP3A4 inhibitors before prescribing iloperidone 1, 2:

• Strong CYP2D6 inhibitors: fluoxetine, paroxetine, quinidine
• Strong CYP3A4 inhibitors: ketoconazole, clarithromycin, ritonavir

Intraoperative Floppy Iris Syndrome (IFIS)

IFIS may occur during cataract surgery in patients taking iloperidone, requiring modifications to surgical technique 1. Inform ophthalmologists of iloperidone use prior to surgery.

Cognitive and Motor Impairment

Use caution when operating machinery or driving, as iloperidone may cause somnolence and dizziness 1.

Overdose Management

In case of overdose 1:

• No specific antidote exists
• Establish and maintain airway; ensure adequate oxygenation
• Consider gastric lavage (after intubation if unconscious) and activated charcoal with laxative
• Commence continuous ECG monitoring
• Avoid disopyramide, procainamide, and quinidine (additive QTc effects)
• Avoid epinephrine and dopamine for hypotension (may worsen hypotension due to α-blockade)
• Use intravenous fluids or alternative sympathomimetic agents for circulatory collapse
• Contact Poison Help Line (1-800-222-1222) for additional guidance

Place in Therapy

Iloperidone represents an effective treatment option for schizophrenia with a particularly favorable EPS and akathisia profile, making it attractive for patients whose compliance is limited by these effects 2, 5. However, its role is tempered by:

• The need for slow titration (limiting acute use)
• Twice-daily dosing requirement
• QTc prolongation concerns
• Lack of superiority data versus other atypical antipsychotics

The drug is best suited for maintenance treatment in stable outpatients who have experienced intolerable EPS or akathisia with other antipsychotics 2, 6.