Iloperidone for schizophrenia
New treatment option for patients who have not fully responded to or cannot tolerate other antipsychotics
The bottom line: reduce iloperidone dosage by 50% for patients who are taking a strong CYP2D6 and/or CYP3A4 inhibitor (see Dosing below).
Efficacy
In clinical trials, iloperidone was shown to be efficacious in treating positive and negative symptoms and general psychopathology in acute episodes of schizophrenia. It is important to consider the efficacy studies of iloperidone within the context of the history of its development plan.
Early clinical trials. Most of iloperidone’s phase II and III studies were conducted by Novartis between 1998 and 2002. Initial phase III studies included three 6-week, double-blind, placebo-controlled acute trials comparing a range of iloperidone doses with placebo and an active comparator:5,6
- The first trial compared iloperidone, 4, 8, or 12 mg/d, with placebo or haloperidol, 15 mg/d.
- The second compared iloperidone, 4 to 8 mg/d or 10 to 16 mg/d, with placebo and risperidone, 4 to 8 mg/d.
- The third compared iloperidone, 12 to 16 mg/d or 20 to 24 mg/d, with placebo or risperidone, 6 to 8 mg/d.
These studies totaled 1,066 patients in the iloperidone treatment arms, with target dosages for iloperidone ranging from 4 to 24 mg/d. Iloperidone was more efficacious than placebo for positive, negative, and overall total symptoms on the Positive and Negative Syndrome Scale (PANSS), albeit 4 mg/d and 8 mg/d dosages narrowly missed the .05 significance level.
The haloperidol and risperidone active controls appeared more effective than iloperidone in the original analyses, but these studies were not designed for analysis of comparative efficacy. The protocols for all of these studies used an up-titration schedule for the iloperidone groups that took 1 week to reach steady-state levels, whereas the haloperidol and risperidone groups had a briefer up-titration to target dose.
The interpretation of these studies is complex and a detailed discussion is beyond the scope of this article. However, a post-hoc analysis that included subjects who remained in the study after 2 weeks of double-blind medication showed that iloperidone performed comparably to risperidone7 and haloperidol.8
A new phase III trial. The question remained whether iloperidone was as efficacious as other first-line antipsychotics but had been “penalized” by its slower up-titration schedule and clinical trial design flaws. After acquiring the development rights to iloperidone from Novartis and reviewing prior study designs and results, Vanda Pharmaceuticals designed another phase III study comparing iloperidone with placebo and ziprasidone. Its purpose was to correct for possible design flaws in the previous studies.
Ziprasidone was selected as the active control because of its established efficacy, safety, and twice-daily dosing. In this trial, researchers attempted to match the 2 drugs’ up-titration schedules. Twice-daily doses were given with food as follows:
- iloperidone, 1, 2, 4, 6, 8, 10, and 12 mg (days 1 to 7, respectively)
- ziprasidone, 20 mg (days 1 to 2), 40 mg (days 3 to 4), 60 mg (days 5 to 6), and 80 mg (day 7).
By day 7, target dosages were reached: iloperidone, 24 mg/d, and ziprasidone, 160 mg/d.9
Patients receiving iloperidone showed significantly greater improvement in PANSS total scores at 4 weeks vs those receiving placebo (–12.0, iloperidone; –7.1, placebo; P < .01).9 Patients receiving ziprasidone also achieved significantly greater improvement vs those receiving placebo (–12.3; P < .05 vs placebo).
The iloperidone and ziprasidone groups showed significantly greater improvement from baseline vs placebo in PANSS positive (P) and negative (N) subscale scores. Significantly more patients receiving iloperidone (72%) than placebo (52%) experienced improvement (≥20% reduction from baseline) in PANSS-P scores (P = .005).
Patients receiving iloperidone had a significantly greater reduction in Clinical Global Impression-Severity scale score vs placebo (–0.65 and –0.39, respectively; P = .007), as did patients receiving ziprasidone (–0.67; P = .013).
Iloperidone met all predefined protocol criteria for efficacy vs placebo and had efficacy equal to the highest approved dose of ziprasidone. These results demonstrated that iloperidone has comparable efficacy to ziprasidone and support the validity of the re-analysis of earlier studies showing comparable efficacy between iloperidone and risperidone7 or haloperidol.8 In July 2008 the FDA issued a not approvable letter for iloperidone, requesting further clinical trials because of concerns about the drug’s efficacy compared with risperidone. The FDA approved iloperidone in May 2009 after the manufacturer provided additional data from existing trials that demonstrated comparable efficacy to risperidone.
Long-term efficacy. A double-blind extension study compared patients remaining on blinded iloperidone (4 to 16 mg/d) or haloperidol (5 to 20 mg/d) after completing a 6-week efficacy study.10 The drugs showed equivalent efficacy in preventing relapse over 46 weeks follow-up. Because this study included no placebo group, the FDA does not consider it to be an interpretable relapse prevention study.
