Fanapt (Iloperidone) Dosing, Titration, and Monitoring in Adult Schizophrenia
Initial Dosing and Titration Schedule
Fanapt requires a mandatory 7-day titration to minimize orthostatic hypotension and dizziness, which are the primary limiting factors for dose escalation. 1
Standard Titration Protocol
- 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 1
Target therapeutic dosage: 6–12 mg twice daily (12–24 mg/day total) 1, 2
Administer with or without food. 1
Pharmacokinetic Considerations
Time to peak plasma concentration occurs in 2–4 hours, but the elimination half-life is 18 hours for extensive CYP2D6 metabolizers and 33 hours for poor CYP2D6 metabolizers. 3 This pharmacokinetic profile supports twice-daily dosing. 3
Special Population Dosing
CYP2D6 Poor Metabolizers
Reduce the dose by one-half for patients who are CYP2D6 poor metabolizers. 1
Modified titration schedule:
- 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 5–7: Titration complete 1
Target dosage: 3–6 mg twice daily 1
Hepatic Impairment
- Mild hepatic impairment: No dose adjustment needed 1
- Moderate hepatic impairment: May require dose reduction if clinically indicated 1
- Severe hepatic impairment: Not recommended 1
Drug Interaction Dose Modifications
Strong CYP2D6 Inhibitors (e.g., fluoxetine, paroxetine)
Reduce iloperidone dose by one-half when co-administered with strong CYP2D6 inhibitors. 1 When the inhibitor is withdrawn, increase iloperidone back to the previous dose. 1
Strong CYP3A4 Inhibitors (e.g., ketoconazole, clarithromycin)
Reduce iloperidone dose by one-half when co-administered with strong CYP3A4 inhibitors. 1 When the inhibitor is withdrawn, increase iloperidone back to the previous dose. 1
Combined CYP2D6 and CYP3A4 Inhibition
Reduce iloperidone dose by approximately one-half when both CYP2D6 and CYP3A4 inhibitors are used concomitantly. 1 When both inhibitors are withdrawn, increase iloperidone back to the previous dose. 1
Efficacy Assessment Timeline
Antipsychotic therapy should be implemented for a period of no less than 4–6 weeks using adequate dosages before determining efficacy of the medication choice. 4 Any immediate effects are more likely due to sedation, with antipsychotic effects becoming more apparent after the first 1–2 weeks. 4
If no results are apparent after 4–6 weeks, or if side effects are not manageable, a trial of a different antipsychotic should be undertaken. 4
In Phase III trials, iloperidone 12 mg twice daily significantly lowered PANSS total scores compared to placebo (−12 vs −7.1; P < 0.01) at 4 weeks. 2
Monitoring Requirements
Cardiovascular Monitoring
Monitor heart rate and blood pressure at baseline and during titration, particularly in patients with known cardiovascular or cerebrovascular disease. 1 Iloperidone can cause orthostatic hypotension and syncope, especially during initial dose titration. 1
Iloperidone prolongs the QTc interval. 1, 3, 5 Avoid use in combination with other drugs known to prolong QTc. 1 Monitor serum potassium and magnesium in patients at risk for electrolyte disturbances. 1
Metabolic Monitoring
Baseline assessment should include:
- Body mass index (BMI) and waist circumference
- Blood pressure
- Fasting glucose
- Fasting lipid panel 4
Follow-up monitoring:
- BMI monthly for 3 months, then quarterly
- Blood pressure, fasting glucose, and lipids at 3 months, then annually 4
Iloperidone demonstrates modest weight gain with no medically important changes in lipid and glucose parameters. 3, 5
Hematologic Monitoring
Perform complete blood counts in patients with pre-existing low white blood cell count or history of leukopenia/neutropenia. 1 Consider discontinuing iloperidone if clinically significant decline in WBC occurs in the absence of other causative factors. 1
Extrapyramidal Symptoms
Monitor for extrapyramidal symptoms at each visit, though iloperidone has minimal EPS, akathisia, and prolactin elevation. 3, 5, 6
Clinical Symptom Monitoring
During the acute psychotic phase, either frequent outpatient visits or hospitalization is needed to address the degree of psychosis and potential danger to self and/or others. 4 Once stabilized, monitoring should occur at least weekly initially, with frequency decreasing as clinically indicated. 4
Physician contact should be maintained on at least a monthly basis to adequately monitor symptom course, side effects, and compliance. 4
Reinitiation After Treatment Gap
If patients have had an interval off iloperidone of more than 3 days, follow the full initiation titration schedule upon restarting. 1
Common Adverse Events
The most common adverse events (incidence ≥5% and 2-fold greater than placebo) include:
- Dizziness (5.1%–23.2%)
- Dry mouth (5.2%–10.4%)
- Somnolence (4%–13%)
- Nasal congestion
- Orthostatic hypotension
- Tachycardia
- Weight gain
- Fatigue
- Dyspepsia (4.8%–7.8%) 1, 2
Adverse events appear dose-related. 2
Critical Pitfalls to Avoid
Never skip or accelerate the 7-day titration schedule. Instituting large dosages during early treatment does not hasten recovery and more often results in unnecessarily excessive doses and side effects, particularly orthostatic hypotension and dizziness. 4, 1, 3
Do not use iloperidone in combination with other QTc-prolonging drugs without careful consideration. 1
Avoid use in patients with dementia-related psychosis. Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at increased risk of death. 1
Monitor for priapism. Cases have been reported with iloperidone; severe priapism may require surgical intervention. 1
Be aware of Intraoperative Floppy Iris Syndrome (IFIS) risk during cataract surgery. 1
Maintenance Therapy
Most patients with schizophrenia need long-term antipsychotic medication therapy. 4 In the recovery/residual phase, antipsychotic therapy has well-documented efficacy in preventing relapse, with approximately 65% of adult patients receiving placebo relapsing within 1 year compared to 30% receiving antipsychotics. 4
The medication dosage should be periodically reassessed to ensure the lowest effective dose is being used. 4 Many clinicians wait 1–6 months between medication adjustments unless worsening symptoms or adverse effects warrant more immediate action. 4
Place in Therapy
Iloperidone would be an attractive option in patients who are particularly prone to extrapyramidal symptoms or who are showing prominent negative symptoms and cognitive deficits. 6 Its favorable profile regarding EPS, akathisia, prolactin elevation, and modest metabolic effects makes it suitable for patients who have not tolerated other second-generation antipsychotics. 3, 5, 6
Iloperidone is best suited for patients with good medication adherence due to its oral-only formulation and twice-daily dosing requirement. 6 Use with caution in patients prone to side effects related to alpha-adrenergic blockade (orthostatic hypotension, dizziness). 6
Efficacy appears similar to ziprasidone and haloperidol, though iloperidone may be inferior in efficacy to risperidone. 3