Iloperidone Tablets (Fanapt™)
Pharmacology Update
Iloperidone Tablets (Fanapt™)
By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD. Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Elliott and Chan report no financial relationship to this field of study.
Iloperidone is the newest atypical antipsychotic agent to be approved by the FDA. It is chemically similar to risperidone and ziprasidone. Vanda Pharmaceuticals will market iloperidone as Fanapt™.
Indications
Iloperidone is indicated for the acute treatment of schizophrenia in adults.1
Dosage
The recommended target dose is 12-24 mg/day given twice daily. The titration schedule is 1 mg twice daily, increasing to 2 mg, 4 mg, 6 mg, 10 mg, and 12 mg twice daily on consecutive days to achieve the target dose. Iloperidone may be taken without regard to meals. It is not recommended for patients with hepatic dysfunction and the dose should be reduced in patients taking a strong inhibitor of CYP2D6 or CYP3A4, as iloperidone is metabolized by both CYP2D6 and CYP3A4.1
Iloperidone is available as 1 mg, 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, and 12 mg tablets.
Potential Advantages
Iloperidone appears to have minimal extrapyramidal symptoms and akathisia, and is associate with only minimal to modest elevation of prolactin levels.1,2
Potential Disadvantages
Orthostatic hypotension is common with iloperidone and occurs most frequently within the first week (19.5%).2 The titration schedule is intended to reduce this adverse event. Iloperidone prolongs QT interval to a similar degree as ziprasidone.3 Concomitant use of other drugs that may prolong QT interval or use in patients at risk for arrhythmias is not recommenced. One study suggests that iloperidone (20-24 mg/day) may be less effective than risperidone (4-8 mg/day).4 Most frequent adverse events (based on dose ranges of 10-16 mg and 20-24 mg) are dizziness (10-20%), dry mouth (8-10%), nausea (7-10%), and tachycardia (3-12%).1
Comments
Iloperidone is the latest addition to the atypical antipsychotic market. It acts primarily as a serotonin and dopamine antagonist (5-HT2A/D2). The iloperidone approval was based on 2 placebo- and active-controlled, short-term trials (4-6 weeks) in patients with schizophrenia or schizoaffective disorder. In the 6-week study (n = 706), iloperidone (12-16 mg/d or 20-24 mg/d) was compared to placebo and risperidone (4-8 mg/d).1,4 The primary endpoint was change from baseline on the 18-item Brief Psychiatric Rating Scale. Mean change from baseline based on intent-to-treat and last observation carried forward was -7.1 for the lower dose, -8.6 for the higher dose, -11.5 for risperidone, and -5.0 for placebo. The higher iloperidone dose range and risperidone arms were statistically different than placebo. Rates of study completion were 52%, 59%, 71%, and 54%, respectively.4
The second study was a 4-week study comparing iloperidone 24 mg/d to placebo and an active control (not specified in the labeling). Iloperidone was reported to be superior to placebo and similar to the active control.1 The primary endpoint in this study was the total Positive and Negative Syndrome Scale.
In a phase 3 study not used to support FDA approval, patients who completed the 6-week trial comparing iloperidone to haloperidol and placebo were randomized to a long-term study (46 weeks). Eligible patients had a 20% or greater improvement in positive and negative symptoms with iloperidone (4-16 mg/d) or haloperidol (5-20 mg). Similar rates of relapse (36.4%) and discontinuation (25.9% vs 29.8%) were observed.5
In a 4-week comparative study, the mean maximum change in the QTc interval was 16.2 msec for iloperidone (24 mg/day) compared to 12.3 msec for ziprasidone (160 mg/day).3 Clinically significant weight gain (> 7%) was similar between iloperidone and risperidone (12.3% vs 11.9%).2 Iloperidone shares the same boxed warning regarding increased mortality in elderly patients with dementia-related psychosis as other antipsychotics, as well as other warnings and precautions (e.g., cognitive impairment, suicide risk, hyperglycemia).
Clinical Implications
Iloperidone joins a crowded market and does not appear to offer any significant clinical advantages over existing atypical antipsychotics.
References
1. Fanapt Product Information. Rockville, MD: Vanda Pharmaceuticals, Inc.; May 2009.
2. Weiden PJ, et al. Safety profile of iloperidone: A pooled analysis of 6-week acute-phase pivotal trials. J Clin Psychopharmacol 2008;28(2 Suppl 1):S12-S19.
3. Cutler AJ, et al. Four-week, double-blind, placebo- and ziprasidone-controlled trial of iloperidone in patients with acute exacerbations of schizophrenia. J Clin Psychopharmacol 2008;28(2 Suppl 1):S20-S28.
4. Potkin SG, et al. Efficacy of iloperidone in the treatment of schizophrenia: Initial phase 3 studies. J Clin Psychopharmacol 2008;28(2 Suppl 1):S4-S11.
5. Kane JM, et al. Long-term efficacy and safety of iloperidone: Results from 3 clinical trials for the treatment of schizophrenia. J Clin Psychopharmacol 2008;28(2 Suppl 1):S29-S35.
Iloperidone is the newest atypical antipsychotic agent to be approved by the FDA. It is chemically similar to risperidone and ziprasidone. Vanda Pharmaceuticals will market iloperidone as Fanapt™.Subscribe Now for Access
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