ࡱ>  bjbjVV e<< $PE9,fe#L#L###5%:o%% eeeeeeehke%1%1%%%e##4f6%0%0%0%F##e%0%e%0%0B]zb#}p(*_Jef<f8`B5l).5lzbzb&5lb<%%%0%%%%%ee--%%%f%%%%5l%%%%%%%%% : National Drug Monograph Iloperidone (Fanapt) November 2010 VA Pharmacy Benefits Management Services, Medical Advisory Panel, and VISN Pharmacist Executives The purpose of VA PBM Services drug monographs is to provide a comprehensive drug review for making formulary decisions. These documents will be updated when new clinical data warrant additional formulary discussion. Documents will be placed in the Archive section when the information is deemed to be no longer current. Executive Summary: Iloperidone is an oral, second-generation antipsychotic medication currently indicated by the FDA for the treatment of acute episodes of schizophrenia. The VA National Formulary currently contains the oral second generation antipsychotics risperidone, quetiapine, aripiprazole, ziprasidone, olanzapine, and clozapine, as well as numerous orally available first generation antipsychotics. The short-term efficacy of iloperidone was demonstrated in acute-phase studies. The first was a pooled analysis of three, six-week trials which compared iloperidone to placebo. One of the trials also compared iloperidone to the first generation antipsychotic haloperidol, while the other two trials used risperidone as an active comparator. The other published study was a four week trial comparing iloperidone to placebo, with ziprasidone as an active comparator. Data from one of these studies was analyzed based on genetic profiles of the patients. While the authors found that patients with 5 or 6 out of the 6 genes studied had a better response to iloperidone, and all of the genes individually were correlated with response, further study of this area may be needed. Genetic testing is not routinely performed in clinical practice. A third published trial demonstrated the long term efficacy of iloperidone for preventing relapse. Haloperidol was used as the comparator in this study. Times to relapse and relapse rates were similar between groups. However, iloperidone does not have labeling for this indication. The adverse effect profile of iloperidone is similar to risperidone with regards to metabolic side effects (weight gain, lipid and glycemic changes), but with less hyperprolactinemia. QTc prolongation was seen in rates similar to ziprasidone. A low rate of extrapyramidal symptoms was demonstrated in clinical trials. The recommended starting dose is 1mg twice daily, titrated daily to a usual target dose of 6-12mg twice daily. Dose titration is required due to the risk of orthostatic hypotension. Doses are titrated over the first week of treatment to effect and tolerability. Iloperidone is dosed twice daily. Doses of iloperidone should be reduced by one half in individuals who are CYP 2D6 poor metabolizers, as well as in those patients receiving concomitant inhibitors of CYP 3A4 and/or 2D6. Introduction1-3 Iloperidone is a second-generation antipsychotic approved by the FDA in 2009 for the treatment of acute schizophrenia in adults. The purposes of this monograph are to (1) evaluate the available evidence of safety, tolerability, efficacy, cost, and other pharmaceutical issues that would be relevant to evaluating iloperidone for possible addition to the VA National Formulary; (2) define its role in therapy; and (3) identify parameters for its rational use in the VA. Pharmacology/Pharmacokinetics1-4 The exact mechanism of action of iloperidone is not completely known. However, iloperidone is an antagonist of dopamine type 2 (D2) and serotonin type 2 (5-HT2) receptors and its effects in schizophrenia are believed to be mediated by these pharmacologic actions. In addition, affinity for noradrenergic alpha receptors (NE) of its metabolites may be responsible for the orthostatic hypotension that has been reported with iloperidone use. Iloperidone is metabolized hepatically to two metabolites, P88 and P95, via the cytochrome P450 isoenzymes 3A4 and 2D6, respectively. P88 is believed to have equal or decreased affinity for D2 and 5-HT2 receptors, while P95 has affinity only for 5-HT2A and noradrenergic receptors (NE1A, NE1B, NE1D, and NE2C). In CYP 2D6 fast metabolizers, the elimination half-lives for iloperidone, P88 and P95 are 18, 26, and 23 hours respectively, and in poor metabolizers the half-lives are 33, 37 and 31 hours, respectively. The table below briefly outlines the basic pharmacokinetic properties of iloperidone: Table 1 Basic pharmacokinetic properties of iloperidone ParameterIloperidoneRisperidoneZiprasidoneMetabolismHepatic via CYP 2D6 and 3A4Hepatic via CYP 2D6Hepatic via CYP 3A4EliminationLess than 1% excreted unchanged. Excretion of metabolites is 58.2% urine, 19.9% fecal70% renal (risperidone and 9-hydroxyrisperidone active metabolite); 14% fecal. Less than 1% unchangedHalf-life18 hours3 hours in extensive metabolizers, up to 20 hours in poor metabolizers. Metabolite: 21-30 hours. 4-5 hours (single dose) 9-10 hours (repeated dosing) Protein Binding95%90% (parent), 77% (metabolite)Greater than 99% Bioavailability96%70%60% FDA Approved Indication(s) and Off-label Uses1-3 Iloperidone is FDA approved for the acute treatment of schizophrenia in adults. Potential off-label uses for iloperidone include the treatment of conditions for which a second generation atypical antipsychotic would be appropriate, such as schizoaffective disorder, bipolar disorder, and chronic maintenance treatment of schizophrenia. One of the short term trials included schizoaffective disorder and approximately 25% of patients had this diagnosis across all groups. No specific data were published on the efficacy of iloperidone within this subset of patients. In addition, another trial showed similar efficacy to haloperidol in the chronic maintenance phase of schizophrenia in patients who had responded acutely. In this trial, 6.3% of all patients had a diagnosis of schizoaffective disorder. No data regarding iloperidone use in patients with Bipolar Disorder are available. Current VA National Formulary Alternatives The following second generation oral antipsychotics are alternatives to iloperidone on the VA National Formulary: Risperidone Quetiapine Ziprasidone Aripiprazole Olanzapine Clozapine In addition, there are a number of typical oral antipsychotics on the VA National Formulary that are alternatives to iloperidone. Dosage and Administration1-3 Due to concerns regarding orthostatic hypotension, a titration schedule has been recommended by the manufacturers of iloperidone: Day 1Day 2Day 3Day 4 Day 5Day 6 Day 7 and beyondDose1mg BID2mg BID4mg BID6mg BID8mg BID10mg BID12mg BID The manufacturer recommends titrating using the above schedule until efficacy is seen or the maximum dose is attained. The usual target effective range is 12-24 mg daily, given in two divided doses. The maximum labeled dose of iloperidone is 12 mg twice daily. Iloperidone may be dosed without regards to meals. Renal effects: Less than 1% of iloperidone is excreted unchanged; therefore no dosage adjustment is required in patients with renal impairment. Hepatic Effects: Due to its extensive hepatic metabolism and the lack of studies in this population, the use of iloperidone in patients with any degree of hepatic impairment is not recommended. Poor CYP 2D6 Metabolizers: Patients who are known poor metabolizers of CYP 2D6 should have their dose reduced by one-half. Patients receiving CYP 2D6 or 3A4 inhibitors: It is recommended that patients on concomitant therapy with drugs that inhibit CYP 3A4 and 2D6 have their iloperidone dose reduced by one-half. See "Drug Interactions" below for more information. Patients receiving CYP 2D6 and 3A4 inducers: No literature or guidance has been provided regarding use in patients receiving concomitant inducers of these enzymes. Efficacy5-10 Efficacy Measures The Positive and Negative Syndrome Scale (PANSS) is a scale commonly used to assess the severity of illness in patients with schizophrenia. As its name suggests, the PANSS assesses both positive and negative symptoms, as well as more general symptoms. There are 30 items total, which are rated 1-7 (with 7 being most severe). The PANSS is identified by several subscales. The PANSS-T is used to identify the total score, the PANSS-P is the positive symptom score, the PANSS-N is the negative symptoms score, and the PANSS-GP is the general psychopathology score, which includes items not considered in the positive or negative symptoms scales. The PANSS is one of the most commonly used and well validated scales in schizophrenia research. The Brief Psychiatric Rating Scale (BPRS) is another rating scale used to assess severity of illness in schizophrenia. The BPRS is derived from the PANSS, but only has 18 items, compared to the 30 of the PANSS. The BPRS is another very commonly used scale in both research and practice due to its validity and ease of administration. The Clinical Global Impressions is a 7 point Likert scale used commonly in psychiatric studies to assess overall patient functioning. Specific subscales used are the CGI-S (severity) and CGI-C or CGI-I (change or improvement). The higher the score, the worse the severity of the disease (severity scale) or a greater worsening of the disease. Summary of efficacy findings Articles in this section are referred to by study number. For more information on each trial, please refer to the appendix. Below is a summary of each trial. Studies ILP3000, ILP3004, and ILP3005: Data was published as a pooled analysis of 3 randomized control trials comparing iloperidone to placebo. Each study was a six week comparison of iloperidone to placebo with an active comparator group. Dosing of all study drugs was twice daily. A total of 1943 patients were evaluated in this analysis. Study ILP3000 took place at 45 centers in the United States, and compared iloperidone 4 mg, 8mg and 12 mg daily to placebo, with haloperidol 15 mg daily as an active comparator. The primary endpoint was the change in PANSS-T score for the combined 8 mg/day and 12 mg/day groups vs. placebo. Study ILP3004 evaluated two dosage ranges of iloperidone (4 mg, 6 mg, or 8 mg daily and 10 mg, 12 mg, or 16 mg daily) as well as risperidone (4 mg, 6 mg, or 8 mg daily) compared with placebo. This study was conducted at 65 sites worldwide. The primary endpoint was change in BPRS score, although it initially had been change in PANSS-T score and was changed midway through the study. Study ILP3005 evaluated two dosage ranges of iloperidone (12mg or 16mg daily and 20mg or 24mg daily) and risperidone 6 mg or 8 mg daily with placebo. This study also took place at 65 sites worldwide. The primary endpoint was change in BPRS score from baseline. Results: Study ILP3000: Only the iloperidone 12mg/day (given as 6mg twice a day) group and the haloperidol group showed a significant difference vs. placebo regarding change in PANSS-T score. However, the primary endpoint was the combined results of the 8mg/day and 12mg/day groups vs. placebo, which did not show a statistically significant difference. Study ILP3004: All 3 groups (iloperidone 4-8mg/day, iloperidone 10-16mg/day, and risperidone 4-8mg/day) showed a significant difference vs. placebo for the primary endpoint, change in BPRS score. However, when corrected for completer analysis, the iloperidone groups were no longer statistically different than the placebo group, while the risperidone group maintained superiority. Similarly, the iloperidone groups did not show superiority when patients with schizoaffective disorder were excluded, while risperidone continued to show superiority to placebo. Study ILP3005: Only the higher dose iloperidone group (20-24mg/day) and the risperidone group (6-8mg/day) showed a significant difference in the primary endpoint, change in BPRS score. These results held up even when patients with schizoaffective disorder were excluded. Pooled Analysis: All treatment groups showed a significant difference vs. placebo in change in BPRS score and change in PANSS-T score. Study ILP3101 (published): Study ILP3101 was a four-week, acute phase randomized controlled trial comparing iloperidone to placebo for the treatment of individuals with acute episodes of schizophrenia. The study was conducted at 35 sites in the United States and 9 sites in India. Patients were randomized to receive Iloperidone 24 mg daily, ziprasidone 160 mg daily or placebo in a 2:1:1 ratio. Both active medications were titrated over the course of Week 1. The primary endpoint was the change from baseline in the PANSS-T score. A total of 593 patients were evaluated in this study. Results: Both the iloperidone and ziprasidone showed a significant decrease in PANSS-T scores vs. placebo at the end of 28 days of treatment. This was the primary endpoint of the trial. Improvement of the secondary endpoints of BPRS, PANSS-P, and PANSS-N was also noted. No improvement was seen in PANSS-GP. More patients in the iloperidone group experienced improvement ( > 20% improvement in PANSS-P) than placebo (72% vs. 52%, p = 0.005). Pharmacogenomic analysis of study ILP3101: An analysis of patients from study ILP3101 was performed, evaluating presence of six genes associated with response to iloperidone. The Single Nucleotide Polymorphisms (SNPs) evaluated were NPAS3, XKR4, TNR, GRIA4, GFRA2 and NUDT9P1. All six of the genes individually were associated with a greater decrease in PANSS-T score compared with absence of the gene in patients who received iloperidone. In addition, 4 out of 6 of the genes were associated with greater decreases in PANSS-T score in iloperidone receiving patients compared with patients with the gene who received ziprasidone. Probability of response (defined as 20% or greater decrease in PANSS-T) was also increased among each of the individual genes compared with absence of each of the genes. Patients with 5 or 6 of the genes were more likely to respond than the general response rate in the study. Patients with 0 to 2 of the genes present were less likely to respond to iloperidone than the overall response rate in the study. The NNT for patients with 5 or 6 of the genes present was 3 vs. placebo. The individual NNTs for each of the genes ranged from 4 to 8 vs. placebo treated patients. Other antipsychotics (besides iloperidone and ziprasidone) were not studied and therefore it is unknown what the impact of these genes is on the efficacy of other agents. Studies ILP3001, ILP3002, and ILP3003 (published): These studies were designed to evaluate the long-term efficacy and safety of iloperidone compared to haloperidol, and were published as a pooled analysis of 3 randomized, placebo-controlled, flexible-dose, prospective multicenter trials (studies ILP3001, ILP3002 and ILP3003), which in total used 121 sites worldwide. In these three trials, patients received 6 weeks of iloperidone or haloperidol acutely, with responders (a 20% or greater decrease from baseline in the PANSS-T) in both groups progressing to a 46 week double-blind, long-term relapse prevention phase. A total of 1644 patients were randomized in this study, 1326 completed the 6-week phase, and 473 were included in the long term phase efficacy analysis (with 489 in the long term phase safety analysis). Of note, the FDA explicitly noted in its review of iloperidone that it did not consider these studies due to the lack of a placebo control arm. In the 6-week double-blind phase, 1644 patients were randomized to iloperidone (n = 1239) and haloperidol (n = 405), with 1014 patients (81.8%) completing in the iloperidone group, and 312 (77.0%) completing in the haloperidol group. Of the completers, 371 (36.6%) in the iloperidone group and 118 (37.8%) in the haloperidol group showed a treatment response and were eligible to be included in the 46 week double-blind maintenance phase. Relapse rates were similar between groups (iloperidone = 43.5%, haloperidol =41.2%), as was time to relapse (HR 1.030, 95% CI 0.743-1.428; P = 0.8596). Time to relapse was the primary endpoint. Relapse was defined as: Worsening of PANSS-T by > 25%, including a 10-point or greater change, from start of the extended phase. Discontinuation due to lack of efficacy Aggravated psychosis with hospitalization > 2-point increase in CGI-C, during the extended phase. Unpublished Trial (ILPB202)data from FDA review of Iloperidone This study was a randomized controlled trial over 11 sites in the United States. This study compared the efficacy of 4 mg and 8mg of iloperidone daily (dosed twice daily) vs. placebo, randomized in a 1:1:1 fashion. The primary outcome measure was the change in PANSS-T score. A total of 91 patients were included in this study. Results: No significant difference between any of the groups for the primary outcome (change in PANSS-T score) was seen in this study. Safety data for study ILPB202 is not available and is therefore not discussed. For further details on the efficacy results of the clinical trials, refer to  REF _Ref80503441 \h  \* MERGEFORMAT Appendix: Clinical Trials (page 13). Adverse Events (Safety Data).1, 5-10 Deaths and Other Serious Adverse Events Deaths: In studies ILP3000, ILP3004 and ILP3005, only 1 patient died, and that patient was in the risperidone group. Study ILP3101 reported no deaths in their study comparing iloperidone to ziprasidone. In studies ILP3001, ILP3002, and ILP3003, 4 deaths (0.3%) occurred among patients receiving iloperidone. In addition, 2 patients treated with iloperidone died either 3 days after the protocol ended or within 28 days after withdrawing from the study. One death was possibly related to the study drug. This is compared with 1 death (0.2%) in the haloperidol group. Among patients meeting criteria for the long-term phase, 3 died (2 in the iloperidone group, 1 in the haloperidol group. Serious Adverse Events (SAE): Studies ILP3000, ILP3004, and ILP3005: Across all iloperidone groups, 10 patients (1%) reported a total of 12 SAEs. In the haloperidol group, 3 patients (2.5%) reported a total of 13 SAEs In the risperidone group, 6 patients (2%) experienced a total of 8 SAEs. Treatment emergent SAEs reported in the iloperidone groups included agitation (2), dystonia (2), schizophrenia (2), CPK increase, delusion, general edema, hepatic enzyme increase, priapism, and psychotic disorder. Study ILP3101: A total of nine patients (2%) reported treatment-emergent serious adverse events (iloperidone 0.7%, ziprasidone 1%, placebo 3%). The most common SAEs were convulsion (placebo [n =2]) and psychotic disorder (iloperidone [n =1], ziprasidone [n =2]) Studies ILP3001, ILP3002 and ILP3003: In the 6-week phase, 7.6% of iloperidone patients and 7.7% of haloperidol patients reported at least one SAE. Psychiatric disorders were the most common SAE associated with discontinuation (iloperidone 5.3%, haloperidol 4.5%). In the 46 week extended phase, SAEs were reported by 18.1% in the iloperidone group and 16.1% in the haloperidol group. Psychiatric disorders were the most common (iloperidone 16.7%, haloperidol 11.0%), of these schizophrenia aggravated and psychosis aggravated being the most commonly reported. These were also the most common SAEs associated with discontinuation. Common Adverse Events Treatment Emergent Adverse Reactions in Short-Term, Fixed or Flexible Dose Placebo-Controlled Trials in Adult Patients (all values are percentages): EventPlacebo (n = 587)Iloperidone 10-16mg/day (n = 483)Iloperidone 20-24mg/day (n = 391)Arthralgia233Fatigue346Musculoskeletal Stiffness113Weight Increased119Tachycardia1312Vision Blurred231Nausea8710Dry Mouth1810Diarrhea457Abdominal Discomfort113Nasopharyngitis343Upper Respiratory Tract Infection123Dizziness71020Somnolence5915Extrapyramidal Disorder454Tremor233Lethargy131Ejaculation Failure< 122Nasal Congestion258Dyspnea< 122Rash232Orthostatic Hypotension136Hypotension< 1< 13Note that these are adverse events occurring in at least 2% of patient receiving iloperidone and in greater amounts that patients receiving placebo. Other Adverse Events Weight gain: In studies ILP3000, ILP3004 and ILP3005, weight gain after 6-weeks was similar between the iloperidone and risperidone groups and significantly greater than placebo. Clinically significant weight gain (> 7% from baseline) was seen in 12.3% of all iloperdone patients, was similar to the risperidone group, and appeared to be dose dependent. In study ILP3101, mean 4-week weight increased by 2.8kg in the iloperidone group, compared with 1.1 kg in the ziprasidone group and 0.5kg in the placebo group. Clinically significant weight gain (> 7% from baseline) was seen in 21% of the iloperidone group, 7% of the ziprasidone group, and 3% of the placebo group. In studies ILP3001, ILP3002, and ILP3003, weight increased at 6 weeks by 2.6 kg and 3.8 kg at endpoint (last observation). This was compared to 0.6 kg and 2.3 kg at the respective time points in the haloperidol group. Patients finishing all 52 weeks gained a mean 4.8 kg in the iloperidone group and 3.0 kg in the haloperidol group. The proportion of patients gaining clinically significant amounts of weight was not reported. Extrapyramidal Symptoms and Akathisia: In the short term trials of iloperidone, EPS as measured by the Extrapyramidal Symptom Rating Scale (ESRS) was generally improved from baseline. In comparison, haloperidol resulted in some worsening in subscales related to parkinsonism and dystonia and ziprasidone resulted in some worsening in akathisia. In the long term trials (ILP3001, ILP3002, and ILP3003), improvement in EPS was noted in 48.2% of patients receiving iloperidone compared to 37.4% of patients receiving haloperidol. Conversely, worsening was only noted by 13.5% of patients receiving iloperidone, compared with 36.4% of patients receiving haloperidol. Akathisia was improved in 24.3% of patients receiving iloperidone compared to 16.9% of patients receiving haloperidol, while worsening of akathisia was noted in only 9.2% of patients receiving iloperidone, compared to 23.7% of patients receiving haloperidol. Orthostatic Hypotension: Orthostatic hypotension was reported in 19.5% of iloperidone-receiving patients in reference #6, which appeared to be dose independent. However, only 2.4% these patients had sustained orthostasis, which appeared to be dose dependent. In the ILP 3101 study, 7% of patients had orthostatic hypotension. Data on orthostasis was not published in studies ILP3001, ILP3002 or ILP3003. Tolerability Iloperidone was relatively well tolerated in trials. Discontinuation rates due to adverse events were between 3.9% and 6.7% among iloperidone receiving patients. These discontinuation rates were similar to comparator groups. The most common adverse effect to lead to discontinuation was an increase in psychotic symptoms. For further details on the safety results of the clinical trials, refer to  REF _Ref80503441 \h  \* MERGEFORMAT Appendix: Clinical Trials (page  PAGEREF _Ref80503441 \h 13). Contraindications1 Contraindications include known sensitivity to iloperidone or any component of its formulation. Hypersensitivity reactions reported include urticaria and pruritus. . Warnings and Precautions1, 6-10 Risk of Mortality: Iloperidone, like all antipsychotics, contains the following box warning: Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. FANAPT is not approved for the treatment of patients with dementia-related psychosis. The explanation for this boxed warning is that a pooled-analysis of placebo-controlled trials showed an 1.6-1.7 times greater risk of death in elderly dementia patients receiving other atypical antipsychotics, with the most common causes of death being cardiovascular (e.g., heart failure, sudden death) and infectious (e.g., pneumonia). In addition, observational studies of have shown an increased risk with the use of conventional antipsychotics. Iloperidone also has a warning of an increased in cerebrovascular events, including stroke and transient ischemic attacks, in elderly with dementia. This recommendation is based on analysis of clinical trials with other atypical antipsychotics. QTc Prolongation: In trials, patients receiving iloperidone had similar increases in QTc interval to patients receiving ziprasidone and haloperidol. In trials, no patient had an increase in QTc interval from less than 500 msec to 500 msec or greater. Two iloperidone patients and one ziprasidone patient had an increase in QTc by 15% or greater in a comparison study. Changes in QTc interval among patients receiving iloperidone appeared dose dependent, with greater mean increases occurring in patients receiving higher doses of iloperidone. However, patients with congenital long QT syndrome, as well as medical conditions necessitating the use of medications which may prolong the QTc interval were not studied and therefore caution should be exercised in these populations. (See Drug Interactions) Orthostatic Hypotension was observed in patients receiving iloperidone in trials. While transient for most patients, some patients did have sustained orthostatic hypotension, which was dose related. Elderly patients, which may be more susceptible to orthostatic effects of medications, were not specifically studied; therefore caution must be used in this population. Metabolic Effects: Iloperidone was reported to have associated increases in weight gain compared with placebo and ziprasidone, and similar to risperidone. In addition, increases in blood glucose values were reported, although the significance of these specific values is not known. Lipid values remained fairly stable during trials of iloperidone. Hyperprolactinemia: Greater increases in prolactin concentrations were seen in patients receiving risperidone and haloperidol than iloperidone. However, small but significant increases in prolactin concentrations were seen in patients receiving iloperidone. Other adverse events that have been reported among antipsychotics and which may be of concern to patient receiving iloperidone: Neuroleptic Malignant Syndrome Tardive Dyskinesia Seizures Leukopenia, Neutropenia, and Agranulocytosis Body Temperature Dysregulation Dysphagia Suicidality Priapism Cognitive and Motor Impairment Pregnancy/Lactation: Iloperidone has not been studied in these populations in humans. In rats, iloperidone did cause fetal changes. Iloperidone is rated Pregnancy Category C, and as such should only be used if the benefits outweigh the risks. Iloperidone was excreted in the milk of rats and is believed to be excreted in human breast milk. Women receiving iloperidone should not breastfeed due to the unknown risks to infants. Postmarketing Safety Experience (Optional) No postmarketing safety reports have been published. Sentinel Events No Sentinel Event Data has been reported regarding iloperidone. Look-alike / Sound-alike (LA / SA) Error Risk Potential As part of a JCAHO standard, LASA names are assessed during the formulary selection of drugs. Based on clinical judgment and an evaluation of LASA information from four data sources (Lexi-Comp, USP Online LASA Finder, First Databank, and ISMP Confused Drug Name List), the following drug names may cause LASA confusion: LA/SA for generic name (iloperidone): Iloperidone-risperidone Iloperidone-paliperidone LA/SA for trade name (Fanapt): Fanapt-Xanax11 Drug Interactions1,2, 6-10 Drug-Drug Interactions Because iloperidone is metabolized by the CYP 3A4 and 2D6 systems, a dosage reduction by one half is recommended when administered with strong inhibitors of these enzymes. Specific agents include fluoxetine, paroxetine, clarithromycin, erythromycin, and azole antifungals (i.e. ketoconazole, itraconazole) and protease inhibitors (ritonovir, atazanavir, saquinivir, etc). There did not appear to be any additive effects on AUC when inhibitors of both enzyme systems (i.e. paroxetine and ketoconazole) were both co-administered with iloperidone. Because iloperidone was associated with small increases in the QTc interval in clinical trials, it is recommended to avoid giving concomitantly with other medications that may also increase QTc interval. Examples include class IA and III antiarrythmics (i.e. quinidine, procainamide; ibutilide, dofelitide, etc.), amiodarone, fluoroquinolones (levofloxacin, moxifloxacin), quinine, and thioridazine. In addition, individuals with preexisting cardiac arrhythmias should use caution when initiating iloperidone therapy. Iloperidone did not appear to have any effect on the concentrations of other drugs that are substrates of CYP 3A4 or 2D6. Drug-Lab Interactions No interactions between iloperidone and lab tests have been reported. Acquisition Costs Table 2 Acquisition Costs of Iloperidone Tablets DrugDose*Cost/Day/patient ($)*Cost/Year/patient ($)Iloperidone1 6 mg BID 6.50 (3.25/day if split) 2,372.50 (1,186.25 if split). Iloperidone8-12 mg BID6.502,372.50 *Costs as of October 2010 Note that iloperidone tablets are not scored. While no information exists specifically regarding splitting of tablets, splitting of unscored tablets may be more difficult for patients. Note that while 1 year figures are provided (assuming daily use), iloperidone is not FDA approved for maintenance therapy. Pharmacoeconomic Analysis No published pharmacoeconomic analyses are available for iloperidone at this time. Conclusions In a limited number of published studies published trials, iloperidone showed greater efficacy than placebo, but similar efficacy to comparator controls. In addition, treatment refractory patients were excluded from participation in trials, which would limit its use in that specific population. While iloperidone does have a favorable side effect profile in terms of extrapyramidal symptoms, its metabolic profile showed some weight gain, glycemic and lipid changes, which were similar to risperidone in trials. In addition, while QTc prolongation was small, it may be concerning to some patients, especially those with preexisting conduction abnormalities. A higher rate of orthostatic hypotension than other atypical antipsychotics and an extended titration schedule may make use in the veteran population complicated. One study did indicate that certain individuals would likely benefit more than others based on genetic profiling; more research in this area is needed before it can be recommended in routine practice. References: Fanapt (iloperidone) [package insert]. Rockville, MD. Vanda Pharmaceuticals; 2010. Marino J, Caballero J. Iloperidone for the treatment of schizophrenia. Ann Pharmacother 2010;44: 863-70. Iloperidone. In: Drugdex [database on the Internet]. Greenwood Village (CO): Thompson Micromedex; 1974-2010 [cited 4 Oct 2010]. Available from: www.micromedex.com. Subscription required to view. Sainati SM, Hubbard JW, Grasing K, et al. Safety, tolerability, and effect of food on the pharmacokinetics of iloperidone (HP 873), a potential atypical antipsychotic. J Clin Pharmacol 1995;35:713-20. Potkin SG, Litman RE, Torres R, et al. Efficacy of iloperidone in the treatment of schizophrenia: initial phase 3 studies. J Clin Psychopharmacol, 2008;28:S4-S11. Weiden PJ, Cutler AJ, Polmeropoulos MH, et al. Safety profile of iloperidone: a pooled analytsis of 6-week acute-phase pivotal trials. J Clin Psychopharmacol, 2008;28:S12-S19. Cutler AJ, Kalali AH, Weiden PJ, 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:S20-S28. Volpi S, Potkin SG, Malhotra AK, et al. Applicability of a genetic signature for enhanced iloperidone efficacy in the treatment of schizophrenia. J Clin Psychiatry, 2009;70(6):801-9. Kane JM, Lauriello J, Laska E, et al. Long-term efficacy and safety of iloperidone: results from 3 clinical trials for the treatment of schizophrenia. J Clin Psychopharmacol, 2008;28:S29-S35. Chuen MM. Iloperidone [Clinical Review]. United States Food and Drug Administration Center for Drug Evaluation and Research, Washington (DC): 2008. Available from:  HYPERLINK "http://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022192s000TOC.cfm" http://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022192s000TOC.cfm Sound-alike pair #2. In: ISMP medication safety alert, 2010 July 29,15(15):1-4. Prepared September October, 2010 Monograph author: Stephen Caruana, Pharm.D., PGY-2, Psychiatry; Contact person: Todd Semla, MS, Pharm.D., BCPS Appendix: Clinical Trials A literature search was performed on PubMed/Medline (1966 to September 2010) using the search terms iloperidone and Fanapt. The search was limited to studies performed in humans and published in English language. Reference lists of review articles and the manufacturers AMCP dossier were searched for relevant clinical trials. All randomized controlled trials published in peer-reviewed journals were included. Published Randomized, Placebo and Active controlled trials of Iloperidone. Citation Design Analysis type SettingEligibility CriteriaInterventionsPatient Population ProfileEfficacy Results Safety Results ILP3000, ILP3004 and ILP3005 (pooled analysis): Potkin et al. (Efficacy Analysis) Weiden et al. (Safety Analysis) Pooled analysis of three 6-week acute phase, double-blind, placebo controlled RCTs. Inclusion: Men and Women age 18-65 Acute or subacute exacerbation of Schizophrenia or Schizoaffective disorder PANSS > 60 at baseline Exclusion: Patients requiring other psychotropic drugs (including antidepressants and mood stabilizers). Clozapine use within 60 days. Failure to improve after sufficient exposure to any antipsychotic treatment in the last 2 years. Study 1: ILO 4mg/d ILO 8mg/d ILO 12mg/d HAL 15mg/d PLA Study 2: ILO 4-8mg/d ILO 10-16mg/d RIS 4-8mg/d PLA Study 3: ILO 12-16 mg/d ILO 20-24mg/d RIS 6-8mg/d PLA (All study drugs dosed BID) Medications for insomnia, agitation, and/or restlessness (zolpidem, chloral hydrate and lorazepam), were allowed but study assessments were not performed until at least 4 hours after administration. Anticholinergic medications for EPS were allowed as needed for treatment emergent effects, but only after assessment of EPS using the Extrapyramidal Symptom Rating Scale (ESRS). Mean Age (all groups): 38.7 years Male: 68% Female: 32% White: 59% Black: 33% Asian: 2% Other: 6% Schizophrenia: 75% Schizoaffective: 25% Baseline PANSS-T: 94.8 Baseline BPRS: 55.1  Study 1 (N =573) ILO 4mg/d ILO 8mg/d ILO 12mg/d HAL 15mg/d PLA Outcome N=113 N=114 N=115 N =114 N=117  in PANSS-T - 9.0 (p = 0.097) - 7.8 (p =0.227) - 9.9 (p = 0.047 -13.9 (p < 0.001) - 4.6 Study 2 N =590) IL 4 8 mg/d ILO 10-16 mg/d RIS 4-8 g/d PLA Outc me N=143 N=149 N =146 N=152  in BPRS - 6.2 (p = 0.012) - 7.2 (p =0.001) -10.3 (p < 0.001 2.5 Study 3 (N =671) ILO 12-16 mg/d ILO 20-24 m /d RIS 6-8 mg/d PLA Outcome N=230 N=141 N = 48 N=152  i BPRS - 7.1 (p = 0.09 ) - 8.6 p =0.010) -11.5 (p < 0.001) - 5.0 Pooled analysis of patients remaining in Studies 1, 2 and 3 for at least 2 weeks. Pooled (N =1553) ILO 4 8 mg/d ILO 10-16 mg/d ILO 20-24 mg/d HAL 15 mg/ RIS 4-8 mg/d PLA N = 316 417 118 87 265 350 Change in BPRS (all p < 0.05 vs, PLA) - 7.9 - 9.2 -10.0 -11.4 -11.9 - 2.5 Change in PANSS-T -11.6 -14.1 -16.5 -18.8 -18.9 -7.7 Change in PANSS-P -4.1 -5.1 -5.8 -6.3 -7.1 -3.0 Change in PANSS-N -1.9 -2.8 -3.6 -3.7 -3.6 -1.7 Change in PANSS-GP -5.6 -6.4 -7.3 -8.9 -8.4 -3.1 Change in CGI-S -0.7 -0.7 -0.7 N/A -0.9 -0.4 Pooled safety analysis: Pooled (N =1553) ILO 4-8 mg/d ILO 10-16 mg/d ILO 20-24 mg/d HAL 15 mg/d RIS 4-8 mg/d PLA Outcome N=463 N= 456 N = 125 N = 118 N = 306 N= 440 % pts with at least 1 AE 81.0 78.9 76.0 94.9 78.4 75.7 % of pts with at least one SAE 0.9 0.7 2.4 2.5 2.0 0.9 % of pts with at least 1 AE leading to discontinuation 5.4 3.9 3.6 7.6 6.2 4.8 Adverse Events appearing in at least 5% in any group: Pooled (N =1553) ILO 4-8 mg/d ILO 10-16 mg/d ILO 20-24 mg/d HAL 15 mg/d RIS 4-8 mg/d PLA AE (%) N= 463 N= 456 N = 125 N = 118 N = 306 N= 440 Akathisia 3.7 1.5 4.8 13.6 6.9 3.6 Dizziness 12.1 10.3 23.2 5.1 7.2 6.8 Dry Mouth 5.2 7.9 10.4 2.5 2.9 1.4 Dyspepsia 7.8 5.5 4.8 11.0 5.9 5.5 Dystonia 0.9 0.9 0.8 11.9 2.6 0.7 Extrapyramidlal disorder 5.4 4.8 4.0 20.3 9.5 4.8 Fatigue 4.3 4.6 6.4 7.6 1.6 2.7 Flatulence 1.9 1.3 1.6 5.1 2.3 1.1 Nasal congestion 4.8 5.0 5.6 1.7 2.6 2.3 Somnolence 5.0 5.7 8.0 6.8 5.9 2.7 Tremor 2.8 2.6 4.8 22.0 6.9 1.8 Metabolic changes: Pooled (N =1553) ILO 4-8 mg/d ILO 10-16 mg/d ILO 20-24 mg/d HAL 15 mg/d RIS 4-8 mg/d PLA Change in parameter N=463 N= 456 N = 125 N = 118 N = 306 N= 440 Glucose, mg/dl 7.2 9.0 16.2 10.8 3.6 -3.6 Total Cholesterol mg/dL 0.0 0.0 0.0 0.0 -3.9 -7.7 Triglycerides (mg/dl) -26.5 -26.5 -26.5 0.0 -26.5 -35.4 Prolactin (g/L) -38.0 -23.1 N/A 115.8 214.5 -57.4 ILP3101 Cutler et al. Four week, double-blind, placebo controlled trialMen and women age 18-65 Women had to be non lactating, non-pregnant and use adequate contraception BMI between 18 and 35. Diagnosis of schizophrenia CGI-S 3 scores of 4 or greater at baseline PANSS of 70 or greater at screening and baseline Score of 4 or greater on at least 2 of the following PANSS-P symptoms at screening and baseline: Delusions, conceptual disorganiszation, hallucinations, and suspiciousness/persecution Exclusion: met criteria for schizophreniform or schizoaffective disorder Other Axis I diagnosis that would interfere with protocol compliance Diagnosis or history of chemical dependence Toxic psychosis in past 6 months Clinical presentation possibly connected to drug/alcohol use Positive drug screen for amphetamines, cocaine, PCP or opiates. Major neurologic deficit or disorder Congenital long QT syndrome Clinically significant GI, hepatic or renal disease Psychosis failing to improve after exposure to 2 or more antipsychotic treatment s within the past 2 years Imminent harm to self or others Hospitalized for 14 or more days immediately before screening Significant medical illness within 4 weeks of screening or persistently abnormal lab finding. ILO 24mg/d ZIP 160mg/d PLA During week 1, titration occurred: ILO Day 1: 1mg BID Day 2: 2mg BID Day 3: 4mg BID Day 4: 6mg BID Day 5: 8mg BID Day 6: 10mg BID Day 7: 12 mg BID ZIP Day 1-2: 20mg BID Day 3-4: 40mg BID Day 5-6: 60mg BID Day 7: 80mg BID All doses were given with food. Zoplidem or similar medication allowed for insomnia, with 8 hours before any assessments. Lorazepam (or similar medication) for agitation or restlessness allowed with 4 hours before assessment Benztropine allowed for EPS after ESRS performed. Mean age: 39.9 years Males: 79.6% Females: 20.4% Race: White: 35.1% Black: 50.4% Asian: 8.8% Native American: 0.5% Pacific Islander: 0.3% Other: 4.9% Weight: 81.5kg Height: 173.1cm Schizophenia type: Disorganized 3.9% Paranoid 84.5% Undifferentiated 11.6%Rating Scale Changes at Day 28: Scale ILO 24mg/d (n = 283) ZIP 160mg/d (n = 144) PLA (N = 140) BPRS -7.39* -7.21* -4.62 PANSS-P -4.21*** -4.23** -2.22 PANSS-N -2.96* -3.06* -1.91 PANSS-GP -4.94 -5.24 -3.18 CGI-S -0.65** -0.67* -0.39 * P < 0.05, 2-tailed ** P < 0.01 2-tailed *** P< 0.001 2-tailedChanges In metabolic parameters at Day 28: Parameter ILO 24mg/d (n = 300) ZIP 160mg/d (n = 150) PLA (n = 147) Total Chol. (mg/dL) 8.1 4.1 -0.5 Triglycerides (mg/dL) 0.8 4.6 19.5 Glucose (mg/dL) 7.9 4.7 3.2 % glucose outside reference range 13.6% 11.3% 8.0% Prolactin (ng/ml) 2.6 1.9 -6.3 Treatment Emergent Adverse Effects [as number (%)]: AE ILO (n = 300) ZIP (n=150) PLA (n = 147) Any AE 255 (85) 130 (87) 108 (74) Dizziness 51 (17) 20 (13) 11 (8) Sedation 38 (13) 41 (27) 12 (8) Weight increased 34 (11) 7 (5) 3 (2) Dry mouth 26 (9) 11 (7) 1 (0.7) HR increased 24 (8) 9 (6) 1 (0.7) Nasal Congestion 25 (8) 5(3) 4 (3) Tachycardia 28 (9) 3 (2) 1 (0.7) EPS 10 (3) 14 (9) 3 (2) Agitation 10 (3) 10 (7) 4 (3) Orthostatic Hypotension 21 (7) 0 3 (2) Somnolence 12 (4) 9 (6) 2 (1) Restlessness 11 (4) 8 (5) 3 (2) Anxiety 9 (3) 8 (5) 1 (0.7) Akathisia 4 (1) 11 (7) 0 Volpi et al. Pharmacogenetic study of patients in the Cutler et al. Study. Participation was optional for study patients.  See above for broader study population. 409 samples total 80% male 20% female 36% white 50% black 8% asian 5% other Improvement of Schizophrenia Symptoms per Genotype Group in Patients treated with Iloperidone: SNP's present PANSS-T PANSS-P PANSS-N PANSS-GP 0-2 -2.4* 3.9* -1.3* -9.0* 3 12.2 16.0 7.4 10.3 4 23.6 26.7 20.4 21.6 5-6 36.3* + 42.2 * + 30.9 * + 34.1* + Overall 18.7 23.4 15.4 15.7 *p<0.01 vs. overall. +p < 0.01 vs. pooled average of other three groups Genotype effect of individual SNPs on Treatment Efficacy: SNP Change in PANSS-T, SNP present Change in PANSS-T, SNP absent P-value present vs. absent P-value Iloperidone effect vs. Ziprasidone NPAS3 -18.56 -8.37 0.000030 0.018 XKR4 -13.87 -3.17 0.000036 0.034 TNR -15.15 -5.51 0.000013 0.047 GRIA4 -13.94 -3.17 0.000024 0.10 GFRA2 -14.80 -6.78 0.00030 0.22 NUDT9P1 -17.30 -6.18 0.0000003 0.017 N/A ILP3001, ILP 3002, and ILP 3003 (pooled analysis) Kane et al. 6-week short term phase, 46 week long term phase Double-blind, flexible dose, parallel group trial  Inclusion: Men and women age 18-65 Diagnosis of schizophrenia or schizoaffective disorder PANSS-T > 60 Women not pregnant, using adequate contraception Exclusion: Recent significant physical Illness Medical condition that could influence assessments Clinically significant abnormal lab finding Another Axis I diagnosis Schizophreniform disorder Imminent suicide risk Chemical dependence Failure to improve after sufficient exposure to antipsychotic treatment within the past 2 years.  ILO 4-16 mg/d HAL 5-20 mg/d Titration was allowed during weeks 1-4 as below: Week 1: ILO 2-8mg/d HAL 2-10mg/d Weeks 2-4: ILO: 4-16mg/d HAL 5-20mg/d Did not mention whether other medications were allowed during the study.  Baseline characteristics of extended phase group Mean Age: 34.7 years Males: 63.4% Females: 36.6% Mean Weight: 65.1 kg Race: White: 45.6% Black: 1 % Asian: 38.9% Other: 14.5% Mean age at diagnosis: 24.7% Previous hospitalization for psychosis: 83.4% DSM-IV classification: Disorganized 11.7% Catatonic 1.2% Paranoid 56.6% Residual 9.0% Schizoaffective 6.3% Undifferentiated 15.1% Relapse rates: Relapse Type ILO (n = 359) HAL (n = 114) Increase in PANSS-T by > 25% including > 10 point increase 93 (25.9%) 34 (29.8%) Aggravated psychosis with hospitalization 27 (7.5%) 7 (6.1%) A > 2 point increase of CGI-C after week 6 36 (10.0%) 6 (5.3%) Total 156 (43.5%) 47 (41.2%)  Adverse events reported in at least 5% of patients in either treatment group during the initial 6-week phase, as number (%): Adverse event ILO (n = 1231) HAL (n = 403) Insomnia 260 (21.1) 101 (25.1) Headache 106 (8.6) 22 (5.5) Anxiety 100 (8.1) 39 (9.7) Dizziness 72 (5.8) 13 (3.2) Restlessness 57 (4.6) 37 (9.2) Muscle Rigidity 50 (4.1) 85 (21.1) Akathisia 43 (3.5) 75 (18.6) Tremor 41 (3.3) 89 (22.1) Bradykinesia 16(1.3) 24 (6.0) Dystonia 13 (1.1) 29 (7.2) EPS 7 (0.6) 31 (7.7) Adverse events reported in at least 5% of patients in either treatment group during the long term maintenance phase, as number (%): Adverse Event ILO (n = 371) HAL (n = 118) Insomnia 67 (18.1) 20 (16.9) Anxiety 40 (10.8) 13 (11.0) Schizophrenia aggravated 33 (8.9) 7 (5.9) Headache 23 (6.2) 5 (4.2) Agitation 21 (5.7) 6 (5.1) Psychosis aggravated 21 (5.7) 5 (4.2) Dizziness 19 (5.1) 5 (4.2) Tremor 18 (4.9) 15 (12.7) Muscle rigidity 15 (4.0) 15 (12.7) Akathisia 14 (3.8) 17 (14.4) Restlessness 13 (3.5) 8 (6.8) Constipation 8 (2.2) 6 (5.1) EPS 3 (0.8) 7 (5.9) ILPB202 (unpublished)Inclusion: Age 18 to 55 years Males and surgically sterilized females Acute or relapsing schizophrenia (DSM-III) Hospital admission due to above within 4 weeks. Score or 4 or more on at least 1 of the symptoms on the PANSS-P CGI-S of 4 or more Able to be maintained free of antipsychotics for a minimum of 4 days (washout period) No requirement for other routine psychotropic medication No requirement for a standard regimen of any other medication. Exclusions: Any evidence of chronic CNS disease Substance Use Disorder within past 12 months Treatment with clozapine within 90 days Treatment with a depot neuroleptic within 1 treatment cycle Treatment within the previous 4 weeks with any drug known to have well defined toxicity to a major organ. Treatment with an MAOI within 2 weeks Requirement for ECT or any routine psychotropic or other medication . Inability to abstain completely from alcohol durin g study period. ILO 2 mg BID ILO 4 mg BID Placebo BIDNot reportedChange in PANSS-T score from baseline, LOCF at day 43. ILO 2mg BID ILO 4 mg BID Placebo Change in PANSS-T -4.13 -18.2 -6.68 p value (vs. placebo) 0.621 0.077 N/ANR, Number randomized. EPS = Extrapyramidal Symptoms, ESRS = Extrapyramidal Symptom Rating Scale. HAL = haloperidol, ILO = Iloperidone, PLA = Placebo RIS = Risperidone, ZIP = Ziprasidone PANSS-T = Positive and Negative Symptom Scale, Total Score. PANSS-P = PANSS positive scale, PANSS = PANSS Negative Scale, PANSS-GP = PANSS General Psychopathology Scale, BPRS: Brief Psychiatric Rating Scale, CGI: Clinical Global Impressions, SNP: Single Nucleotide Polymorphism.     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