Iloperidone is considered an atypical antipsychotic agent.1, 4, 7, 8, 10, 11, 12, 13, 14, 15, 87
Iloperidone is used for the treatment of schizophrenia in adults.1
Short-term efficacy of iloperidone in the acute management of schizophrenia was supported by 2 placebo- and active comparator-controlled clinical studies of 4 and 6 weeks' duration in adults who met DSM-III/IV criteria for schizophrenia.1, 2, 4, 5 The studies primarily used the Positive and Negative Syndrome Scale (PANSS) or the Brief Psychiatric Rating Scale (BPRS) to assess the effects of drug treatment in improving the clinical manifestations of schizophrenia.1, 2, 4 Patients enrolled in the 6-week study were randomized to receive one of two iloperidone dosage ranges (12-16 or 20-24 mg daily) with an initial 1-week titration period, the active control risperidone (6-8 mg daily), or placebo.1, 4 At study end point, both dosage ranges of iloperidone were found to be superior to placebo as assessed by the change from baseline in the BPRS total score.1, 4 Risperidone appeared to be superior to iloperidone within the first 2 weeks of this study, which may be due at least in part to the drug's more rapid dosage titration.1 Patients enrolled in the 4-week study were randomized to receive iloperidone (24 mg daily), ziprasidone (160 mg daily), or placebo for 3 weeks following a 1-week titration period.1, 2 At study end point, iloperidone 24 mg daily was found to be superior to placebo as assessed by the change from baseline in the PANSS total score.1, 2 Iloperidone appeared to have similar efficacy as the active control drug, ziprasidone, which also needed a slow titration period to reach the target dosage.1, 2
In a longer-term study, iloperidone was found to be effective in delaying the time to relapse in adults who met DSM-IV criteria for schizophrenia and who had been stabilized on iloperidone dosages of up to 24 mg daily.1, 91 In this study, 303 outpatients with schizophrenia who remained stable following 12 weeks of open-label treatment with flexible dosages of iloperidone (8-24 mg daily given as twice-daily doses) entered a double-blind, relapse prevention phase in which they were randomized to receive placebo or to continue receiving their current iloperidone dosage for up to 26 weeks.1, 91 Based on results from an interim analysis that demonstrated maintenance efficacy of iloperidone, the study was stopped early.1, 91 These interim results, which were later confirmed by the final analysis, showed that iloperidone-treated patients (modal dosage of 12 mg daily) experienced a substantially longer time to relapse or impending relapse than those receiving placebo (mean time to relapse of 139 and 71 days, respectively).1, 91 Approximately 20% of the iloperidone-treated patients experienced a relapse compared with about 63% of those receiving placebo.91 In addition, a pooled analysis of three 1-year studies in patients with schizophrenia or schizoaffective disorder has shown iloperidone (4-16 mg daily) to be effective for up to 1 year (with similar efficacy as haloperidol) in preventing relapse and to be generally well tolerated in such patients.6, 15
The American Psychiatric Association (APA) recommends that patients with schizophrenia be treated with an antipsychotic agent.107 The APA states that, with the possible exception of clozapine, there currently is no definitive evidence that one atypical antipsychotic agent will have superior efficacy compared with another agent in the class, although meaningful differences in response may be observed in individual patients.107 The choice of an antipsychotic agent should be individualized, considering patient preference, past response to therapy, concurrent medical conditions, and medication-specific factors (e.g., adverse effect profile, available formulations, potential drug interactions, receptor binding profiles, pharmacokinetic considerations).107 Patients whose symptoms improve on an antipsychotic agent should continue treatment with an antipsychotic agent long-term; in most patients, it is appropriate to continue the same antipsychotic medication rather than switch to another antipsychotic medication for maintenance therapy.107
Guidelines from the Department of Veterans Affairs and Department of Defense similarly recommend the use of antipsychotic medication for acute and maintenance treatment of schizophrenia.108 Choice of antipsychotic medication should be based on patient-specific factors and the side effect profiles of the different antipsychotic medications.108 Clozapine should generally be reserved for individuals with treatment-resistant schizophrenia.108
Iloperidone is used for the acute treatment of manic or mixed episodes associated with bipolar I disorder in adults.1
The efficacy of iloperidone for the acute treatment of manic or mixed episodes associated with bipolar I disorder was established in a multicenter, randomized, double-blind, placebo-controlled study enrolling patients who met DSM-V criteria for bipolar I disorder (manic or mixed type).1, 94 In this 4-week trial, patients were randomized to received a fixed dosage of iloperidone (24 mg/day administered as 12 mg twice daily) or placebo.1, 94 Manic symptoms were assessed using the Young Mania Rating Scale (Y-MRS); the primary endpoint was the change in Y-MRS total score from baseline to day 28.1, 94 The 24 mg/day dosage of iloperidone was superior to placebo, as assessed by the change in Y-MRS total score from baseline.1, 94 Subgroup analyses did not reveal clear evidence of differential responsiveness based on age, sex, or race.1
Legacy practice guidelines from APA recommend lithium plus an antipsychotic or valproate plus an antipsychotic for first-line treatment of patients with severe manic or mixed episodes associated with bipolar I disorder; patients with less severe symptoms may be treated with lithium, valproate, or antipsychotic monotherapy.109 Selection of a specific treatment should be based on clinical factors such as illness severity, associated features (e.g., rapid cycling, psychosis), and patient preference, with particular attention to side effect profiles.109 Manic or mixed episodes with psychotic features usually require treatment with an antipsychotic.109 Atypical antipsychotics are generally preferred over typical antipsychotics because of their more benign side effect profile.109 Following remission of an acute episode, maintenance pharmacologic treatment is recommended; first-line options for maintenance therapy include lithium and valproate.109 The guideline states that, for patients treated with an antipsychotic medication during the acute episode, the need for ongoing antipsychotic therapy should be reassessed upon entering the maintenance phase; antipsychotics should generally be discontinued, unless they are required to control persistent psychosis or prevent recurrence.109 The role of iloperidone is not specifically addressed.109
Guidelines from the Department of Veterans Affairs and Department of Defense suggest lithium or quetiapine monotherapy for the treatment of acute mania in patients with bipolar disorder.110 If lithium or quetiapine is not selected based on patient preference or characteristics, olanzapine, paliperidone, or risperidone are recommended as alternative treatments.110 If none of these therapies are considered suitable based on patient preference or characteristics, other suggested options include aripiprazole, asenapine, carbamazepine, cariprazine, haloperidol, valproate, or ziprasidone.110 For patients who experience breakthrough episodes of mania or unsatisfactory response to initial treatment, lithium or valproate in combination with an antipsychotic (haloperidol, asenapine, quetiapine, olanzapine, or risperidone) is recommended.110 For prevention of mania recurrence, lithium or quetiapine is recommended; alternatives include olanzapine, paliperidone, or risperidone.110
Dispensing and Administration Precautions
Iloperidone is commercially available as tablets, which are administered orally twice daily without regard to meals.1
Store iloperidone tablets at 25°C (excursions permitted between 15-30°C); protect the tablets from exposure to light and moisture.1
For the management of schizophrenia in adults, the manufacturer recommends an initial iloperidone dosage of 1 mg given orally twice daily.1, 87 Dosage increases to reach the recommended target dosage range of 6-12 mg given twice daily (total dosage of 12-24 mg daily) may then be made with daily dosage adjustments not to exceed 2 mg twice daily (4 mg daily) (e.g., 2, 4, 6, 8, 10, and 12 mg twice daily on days 2, 3, 4, 5, 6, and 7, respectively).1 The maximum recommended iloperidone dosage is 12 mg given twice daily (total dosage of 24 mg daily).1
For the acute treatment of manic or mixed episodes associated with bipolar I disorder in adults, the manufacturer recommends an initial iloperidone dosage of 1 mg given orally twice daily.1 Dosage increases to reach the recommended target dosage of 12 mg given twice daily (total dosage of 24 mg daily) may then be made with daily dosage adjustments not to exceed 3 mg twice daily (6 mg daily) (e.g., 3, 6, 9, and 12 mg twice daily on days 2, 3, 4, and 5, respectively).1 The maximum recommended iloperidone dosage is 12 mg given twice daily (total dosage of 24 mg daily).1, 1
Dosage Modifications for Drug Interactions
If iloperidone is used concomitantly with a strong cytochrome P-450 (CYP) 2D6 inhibitor (e.g., fluoxetine, paroxetine), reduce the dosage of iloperidone by 50%.1 If the strong CYP2D6 inhibitor is discontinued, increase the dosage of iloperidone to the previous dosage.1
If iloperidone is used concomitantly with a strong CYP3A4 inhibitor (e.g., ketoconazole, clarithromycin), reduce the dosage of iloperidone by 50%.1 If the strong CYP3A4 inhibitor is discontinued, increase the dosage of iloperidone to the previous dosage.1
If iloperidone is used concomitantly with strong CYP2D6 and strong CYP3A4 inhibitors, reduce the dosage of iloperidone by 50%.1 If both CYP2D6 and CYP3A4 inhibitors are discontinued, increase the dosage of iloperidone to the previous dosage.1
Dosage adjustment of iloperidone is not necessary in patients with mild hepatic impairment.1 Dosage reduction may be required in patients with moderate hepatic impairment if clinically indicated.1 Iloperidone is not recommended in patients with severe hepatic impairment.1
The manufacturer makes no specific dosage recommendations for patients with renal impairment.1
The manufacturer makes no specific dosage recommendations for geriatric patients.1
Pharmacogenomic Considerations in Dosing
The manufacturer states that iloperidone dosage should be reduced by 50% in CYP2D6 poor metabolizers.1
For patients with schizophrenia, iloperidone should be initiated at 1 mg orally twice daily; the dosage may be titrated up to 2, 4, and 6 mg twice daily on days 2, 3, and 4 of therapy, respectively.1 The recommended dosage range is 3-6 mg twice daily.1
For patients with bipolar disorder, iloperidone should be initiated at 1 mg orally twice daily; the dosage may be titrated up to 3 and 6 mg twice daily on days 2 and 3 of therapy, respectively.1 The recommended dosage is 6 mg twice daily.1
Increased Mortality in Geriatric Patients with Dementia-related Psychosis
The prescribing information for iloperidone contains a boxed warning about the risk of increased mortality in geriatric patients with dementia-related psychosis.1 Antipsychotic agents increase the all-cause risk of death in geriatric patients with dementia-related psychosis.1 Analyses of 17 dementia-related psychosis placebo-controlled trials (modal duration of 10 weeks) revealed an approximate 1.6- to 1.7-fold increase in mortality among geriatric patients receiving mainly atypical antipsychotic agents compared with that observed in patients receiving placebo.1 Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5% compared with a rate of about 2.6% in the placebo group.1 Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature.1 The manufacturer states that iloperidone is not approved for the treatment of patients with dementia-related psychosis.1
Other Warnings and Precautions
Cerebrovascular Adverse Reactions, including Stroke, in Geriatric Patients with Dementia-related Psychosis
An increased incidence of adverse cerebrovascular events (cerebrovascular accidents and transient ischemic attacks), including fatalities, has been observed in geriatric patients with dementia-related psychosis treated with certain atypical antipsychotic agents (aripiprazole, olanzapine, risperidone) in placebo-controlled studies.1 The manufacturer states that iloperidone is not approved for the treatment of patients with dementia-related psychosis.1
In patients with schizophrenia or schizoaffective disorder, iloperidone was associated with corrected QT (QTc)-interval prolongation of 9 msec at a total daily dosage of 24 mg.1, 5, 14 The effect of iloperidone on the QT interval was increased by the presence of cytochrome P-450 (CYP) isoenzyme 2D6 inhibition (paroxetine) or CYP3A4 inhibition (ketoconazole); under conditions of both CYP2D6 and CYP3A4 inhibition, iloperidone 12 mg twice daily was associated with a mean QTc (Fridericia's formula) increase from baseline of about 19 msec.1 No cases of torsades de pointes or other severe cardiac arrhythmias were observed during the premarketing clinical trial program.1
The manufacturer states that iloperidone should be avoided in patients concurrently receiving other drugs known to prolong the QTc interval; these include class IA antiarrhythmics (e.g., quinidine, procainamide), class III antiarrhythmics (e.g., amiodarone, sotalol), antipsychotic medications (e.g., chlorpromazine, thioridazine), certain antibiotics (e.g., moxifloxacin), pentamidine, and methadone.1 The manufacturer also states that iloperidone should be avoided in patients with a known genetic susceptibility to congenital QT-interval prolongation and in those with a history of cardiac arrhythmias.1
Certain circumstances may increase the risk of torsades de pointes and/or sudden death in association with drugs that prolong the QTc interval, including bradycardia, hypokalemia or hypomagnesemia, concomitant use of other drugs that prolong the QTc interval, presence of congenital prolongation of the QT interval, recent acute myocardial infarction, and/or uncompensated heart failure.1
The manufacturer advises caution when using iloperidone concurrently with drugs that inhibit iloperidone's metabolism and in patients with reduced activity of CYP2D6.1
The manufacturer recommends that patients being considered for iloperidone therapy who are at risk for substantial electrolyte (i.e., potassium, magnesium) disturbances have baseline serum potassium and magnesium measurements with periodic monitoring.1 Hypokalemia and/or hypomagnesemia may increase the risk of QT-interval prolongation and cardiac arrhythmias.1 Iloperidone should be avoided in patients with a history of substantial cardiovascular illness (e.g., QT-interval prolongation, recent acute myocardial infarction, uncompensated heart failure, cardiac arrhythmia).1 Iloperidone therapy should be discontinued in patients with persistent QTc interval measurements exceeding 500 msec.1 Further evaluation, including cardiac monitoring, is recommended during iloperidone therapy in patients who experience symptoms that could indicate the occurrence of cardiac arrhythmias (e.g., dizziness, palpitations, syncope).1
Neuroleptic Malignant Syndrome
Neuroleptic malignant syndrome (NMS), a potentially fatal syndrome, has been reported in patients receiving antipsychotic agents, including iloperidone.1 Clinical manifestations of NMS include hyperpyrexia, muscle rigidity, altered mental status (including catatonic signs), and evidence of autonomic instability (e.g., irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia); other signs may include elevated creatine phosphokinase, myoglobinuria, and acute renal failure.1
If NMS is suspected, immediately discontinue iloperidone and provide intensive symptomatic treatment and monitoring.1
Use of antipsychotic agents may be associated with tardive dyskinesia (a syndrome of potentially irreversible, involuntary, dyskinetic movements).1 The risk of tardive dyskinesia appears highest among geriatric patients, especially women, but it is impossible to predict which patients will develop the syndrome.1 It is unknown whether antipsychotic drugs differ in their potential to cause tardive dyskinesia.1 The risk of developing tardive dyskinesia and the likelihood that it will become irreversible increase with the duration of treatment and the cumulative dose; however, the syndrome may develop after relatively brief treatment periods at low doses.1 It may also occur after treatment discontinuation.1
Tardive dyskinesia may remit, partially or completely, if antipsychotic treatment is discontinued.1 Antipsychotic treatment itself may suppress or partially suppress the signs and symptoms of tardive dyskinesia, possibly masking the underlying process.1 The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.1
Iloperidone should be prescribed in a manner that is most likely to minimize the occurrence of this syndrome.1 Chronic antipsychotic treatment generally should be reserved for patients who suffer from a chronic illness that is known to respond to antipsychotic agents, and for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate.1 In patients who do require chronic treatment, the smallest dosage and the shortest duration of treatment producing a satisfactory clinical response should be sought, and the need for continued treatment should be reassessed periodically.1
If signs and symptoms of tardive dyskinesia appear in an iloperidone-treated patient, iloperidone discontinuance should be considered; however, some patients may require continued treatment with the drug despite the presence of the syndrome.1
Atypical antipsychotic agents have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk, including hyperglycemia and diabetes mellitus, dyslipidemia, and body weight gain.1 While all of these drugs produce some metabolic changes, each drug has its own specific risk profile.1
Hyperglycemia, sometimes severe and associated with ketoacidosis, hyperosmolar coma, or death, has been reported in patients receiving atypical antipsychotic agents, including iloperidone.1 In a short-term controlled trial in patients with schizophrenia, 10.7% of iloperidone-treated patients and 2.5% of those receiving placebo experienced a shift from normal to high fasting glucose concentrations.1 In pooled analyses from clinical studies in adults with schizophrenia, patients who remained on iloperidone 10-16 mg/day demonstrated average blood glucose increases of 1.8, 5.4, and 5.4 mg/dL at 3-6 months, 6-12 months, and >12 months, respectively.1 In a smaller group of patients remaining on iloperidone 20-24 mg/day for schizophrenia, glucose decreased by 3.6 mg/dL at 3-6 months, by 9 mg/dL at 6-12 months, and by 18 mg/dL at >12 months.1 In a short-term controlled trial of adults with bipolar mania, mean changes from baseline in serum glucose and the proportion of patients with shifts in fasting glucose from normal to high were similar between patients receiving iloperidone and placebo.1 Assess fasting plasma glucose before or soon after initiation of antipsychotic therapy, and monitor periodically during long-term treatment.1
Undesirable changes in lipid parameters have been observed in patients treated with atypical antipsychotic agents.1 In a short-term study in adults with schizophrenia, patients receiving iloperidone had a mean increase from baseline in fasting lipid concentrations of approximately 8.2 mg/dL in total cholesterol, 9 mg/dL in low-density lipoprotein (LDL)-cholesterol, and a mean decrease of 0.8 mg/dL in fasting triglycerides.1 The proportion of patients with shifts from normal to high fasting total cholesterol, LDL cholesterol, and triglycerides were similar for iloperidone and placebo.1 The proportion of patients with shifts in fasting high-density lipoprotein (HDL)-cholesterol from normal to low was greater among patients receiving placebo (23.8% versus 12.1% among iloperidone-treated patients).1 In a pooled analysis of clinical studies in adults with schizophrenia, cholesterol and triglycerides decreased on average from baseline for patients remaining on treatment at 3-6 months, 6-12 months, and >12 months.1 In a short-term study in adults with bipolar mania, the mean changes from baseline in fasting total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides were similar between iloperidone and placebo.1 The proportion of patients with shifts in fasting total cholesterol from normal to high was greater among iloperidone-treated patients (10.7% versus 7.2% with placebo).1 Shifts from normal to high LDL and triglycerides and from normal to low HDL occurred at similar rates in the iloperidone and placebo groups.1 Obtain a fasting lipid profile before or soon after initiating iloperidone, and monitor periodically during iloperidone treatment.1
Weight gain has been observed with use of atypical antipsychotics, including iloperidone.1 Based on pooled data from short-term clinical studies in adults with schizophrenia, the proportion of patients experiencing a weight gain of 7% or more of their baseline body weight was 12% for iloperidone 10-16 mg daily and 18% for iloperidone 20-24 mg daily compared with 4% for placebo recipients.1 In all short- and long-term studies in adults with schizophrenia, the overall mean weight gain in iloperidone-treated patients was 2.1 kg.1 In a short-term clinical study of iloperidone 24 mg/day in adults with bipolar mania, the proportion of patients experiencing a weight gain of 7% or more of their baseline body weight was 35% among patients treated with iloperidone, compared to 14% among placebo-treated patients.1 The overall mean weight gain in iloperidone-treated patients was 4.6 kg, compared to 1.6 kg among placebo-treated patients.1 Monitor weight at baseline and frequently thereafter in patients treated with iloperidone.1
Orthostatic Hypertension and Syncope
Orthostatic hypotension associated with dizziness, tachycardia, and syncope may occur during iloperidone therapy; this reflects its α1-adrenergic blocking activity.1 In short-term clinical trials in patients with schizophrenia where the dosage was increased slowly as recommended, syncope was reported in 0.4% of patients receiving iloperidone compared with 0.2% of placebo recipients.1 Orthostatic hypotension was reported in 5% of patients receiving 20-24 mg of iloperidone daily, 3% of patients receiving 10-16 mg of iloperidone daily, and 1% of patients given placebo.1 In a short-term clinical trial in patients with bipolar mania, syncope was reported in 0.5% of patients treated with iloperidone, compared to 0% of patients treated with placebo.1 Orthostatic hypotension was reported in 4% of iloperidone-treated patients and 2% of placebo-treated patients.1 More rapid dosage titration would be expected to increase the incidence of orthostatic hypotension and syncope.1
Monitor orthostatic vital signs in patients who are vulnerable to hypotension (e.g., elderly patients, patients with dehydration or hypovolemia, patients taking concomitant antihypertensive medications), patients with known cardiovascular disease (e.g., history of myocardial infarction, ischemic heart disease, heart failure, or conduction abnormalities), and patients with cerebrovascular disease.1
Iloperidone therapy may cause somnolence, postural hypotension, and motor and sensory instability, which may lead to falls; as a consequence, fractures or other injuries may occur.1 For patients with diseases, conditions, or medications that could exacerbate these effects, fall risk assessments should be completed when initiating antipsychotic treatment and repeated periodically during long-term antipsychotic therapy.1
Like other antipsychotic agents, iloperidone may cause seizures; the risk is greatest among patients with a history of seizures or with conditions that lower the seizure threshold (these may be more prevalent in older patients).1
Leukopenia, Neutropenia, and Agranulocytosis
In clinical trial and/or postmarketing experience, leukopenia and neutropenia have been temporally related to antipsychotic agents.1 Agranulocytosis (including fatal cases) also has been reported.1
Possible risk factors for leukopenia and neutropenia include preexisting low leukocyte count and a history of drug-induced leukopenia or neutropenia.1 Patients with a preexisting low leukocyte count or a history of drug-induced leukopenia or neutropenia should have their CBC monitored frequently during the first few months of therapy.1 Iloperidone should be discontinued at the first sign of a decline in leukocyte count in the absence of other causative factors.1
Patients with neutropenia should be carefully monitored for fever or other signs or symptoms of infection and promptly treated if such signs and symptoms occur.1 In patients with severe neutropenia (absolute neutrophil count [ANC] less than 1000/mm3), iloperidone should be discontinued and the leukocyte count monitored until recovery occurs.1
Similar to other antipsychotic agents and drugs with dopamine D2 antagonistic activity, iloperidone can elevate plasma prolactin concentrations.1 In a short-term (4-week) trial in patients with schizophrenia, plasma prolactin concentrations increased an average of 2.6 ng/mL from baseline to study end point in iloperidone-treated patients (24 mg daily) compared with a decrease of 6.3 ng/mL in the placebo group; elevated prolactin concentrations were observed in 26% of patients receiving iloperidone compared with 12% of patients receiving placebo in this study.1 In short-term trials in schizophrenia, iloperidone was associated with relatively modest elevations in prolactin concentrations compared with some other antipsychotic agents.1, 10 In a short-term (4-week) trial in patients with bipolar mania, plasma prolactin concentrations increased an average of 15.66 ng/mL from baseline to study end point in iloperidone-treated patients compared with a decrease of 0.58 ng/mL in the placebo group; elevated prolactin concentrations were observed in 35% of patients receiving iloperidone compared with 1% of patients receiving placebo in this study.1
Clinical disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been associated with prolactin-elevating drugs.1 In a pooled analysis of iloperidone clinical trials, including longer-term trials, gynecomastia was reported in 2 males (0.1% of iloperidone-treated patients) compared with 0% of those receiving placebo, and galactorrhea was reported in 8 females (0.2% of iloperidone-treated patients) compared with 3 females (0.5%) receiving placebo.1 In addition, chronic hyperprolactinemia associated with hypogonadism may lead to decreased bone density in both female and male patients.1
If iloperidone therapy is considered for a patient with previously detected breast cancer, clinicians should consider that approximately one-third of human breast cancers are prolactin-dependent in vitro.1
Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents.1 The manufacturer recommends appropriate caution when iloperidone is used in patients who will be experiencing conditions that may contribute to an elevation in core body temperature (e.g., strenuous exercise, extreme heat, concomitant use of agents with anticholinergic activity, dehydration).1
Esophageal dysmotility and aspiration have been associated with the use of antipsychotic agents.1 Aspiration pneumonia is a common cause of morbidity and mortality in geriatric patients.1 Iloperidone and other antipsychotic agents should be used with caution in patients at risk for aspiration.1
Priapism may occur with iloperidone therapy; 4 cases of priapism were reported in the premarketing program (3 in patients with schizophrenia and 1 in patients with bipolar disorder).1 Drugs with α-adrenergic blocking activity have been reported to cause priapism, and iloperidone shares this pharmacologic activity.1 Severe priapism may require surgical intervention.1
Cognitive and Motor Impairment
Like other antipsychotic agents, iloperidone potentially may cause somnolence and impair judgment, thinking, or motor skills.1 In short-term, placebo-controlled clinical trials in patients with schizophrenia, somnolence (including sedation) was reported in 12% of adults receiving iloperidone dosages of at least 10 mg daily compared with 5.3% of those receiving placebo.1 In a short-term, placebo-controlled trial of bipolar mania, somnolence (including sedation) was reported in 8% of patients receiving iloperidone versus 3% treated with placebo.1
Caution patients about operating hazardous machinery, including motor vehicles, until they are reasonably certain that therapy with iloperidone does not affect them adversely.1
Intraoperative Floppy Iris Syndrome
Intraoperative floppy iris syndrome (IFIS) has been observed during cataract surgery in some patients on or previously treated with α11 -adrenergic blockers.1 IFIS is characterized by the combination of a flaccid iris that billows in response to intraoperative irrigation currents, progressive intraoperative miosis despite preoperative dilation with standard mydriatic drugs, and potential prolapse of the iris toward the phacoemulsification incisions.1 The patient's surgeon should be prepared for possible modifications to their surgical technique, such as utilization of iris hooks, iris dilator rings, or viscoelastic substances. Stopping α1-adrenergic blocker therapy prior to cataract surgery does not appear to provide benefit.1 Initiation of iloperidone in patients for whom cataract or glaucoma surgery is scheduled is not recommended.1
A pregnancy exposure registry has been established to monitor pregnancy outcomes in women exposed to iloperidone during pregnancy.1 For more information, clinicians may contact the National Pregnancy Registry for Atypical Antipsychotics at 866-961-2388 or visit [Web].1
Limited data are available regarding use of iloperidone in pregnant women and are not sufficient to inform a drug-associated risk for major birth defects and miscarriage.1 The drug was not teratogenic when administered orally to pregnant rats during organogenesis at dosages up to 26 times the maximum recommended human dosage (MRHD) of 24 mg daily on a mg/m2 basis.1 However, iloperidone prolonged the duration of pregnancy and parturition, increased still births and early intrauterine deaths, increased the incidence of developmental delays, and decreased postpartum pup survival.1 Iloperidone was not teratogenic when administered orally to pregnant rabbits during organogenesis at dosages up to 20 times the MRHD on a mg/m2 basis.1 However, the drug increased early intrauterine deaths and decreased fetal viability at term at the highest dosage, which also was a maternally toxic dosage.1
Neonates exposed to antipsychotic agents during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery.1 Symptoms reported to date have included agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder.1 The symptoms have varied in severity; some neonates recovered within hours to days without specific treatment while others have required prolonged hospitalization.1 Neonates should be monitored for extrapyramidal and/or withdrawal symptoms and managed appropriately if symptoms occur.1
Iloperidone is distributed into milk in rats.1 It is not known whether iloperidone and/or its metabolites distribute into milk in humans.1 The effects of the drug on breastfed infants or on milk production also are not known.1 Because of the potential for serious adverse reactions in breastfed infants, the manufacturer recommends that women receiving iloperidone not breast-feed.1
Safety and effectiveness of iloperidone in pediatric patients have not been established.1
Clinical trial experience with iloperidone in patients with schizophrenia who are 65 years of age or older is insufficient to determine whether they respond differently than younger adults.1 In premarketing clinical studies in patients with schizophrenia, 0.5% of 3210 iloperidone-treated patients were 65 years of age or older and no patients were 75 years of age or older.1 Of the 206 patients with bipolar mania treated with iloperidone in a clinical trial, 2 patients (0.1%) were 65 years of age and there were no patients older than 65 years of age.1
Geriatric patients with dementia-related psychosis treated with iloperidone are at an increased risk of death compared with those receiving placebo.1 In addition, an increased incidence of adverse cerebrovascular events (cerebrovascular accidents and transient ischemic attacks), including fatalities, has been observed in geriatric patients with dementia-related psychosis treated with certain atypical antipsychotic agents (aripiprazole, olanzapine, risperidone) in placebo-controlled studies.1 The manufacturer states that iloperidone is not approved for the treatment of patients with dementia-related psychosis.1
In patients with mild hepatic impairment (Child Pugh class A), the pharmacokinetic profiles of iloperidone and its P88 and P95 metabolites (total or unbound) were not substantially altered; no dosage adjustment is required in such patients.1 However, in subjects with moderate hepatic impairment (Child Pugh class B), exposure to the P88 metabolite was substantially higher (by 2-fold) and more variable compared with healthy individuals.1 Exposure to iloperidone and the P95 metabolite was generally similar between patients with moderate hepatic impairment and healthy controls.1 Dosage reduction may be required for patients with moderate hepatic impairment.1
Iloperidone has not been studied in patients with severe hepatic impairment, and use of the drug in such patients is not recommended.1
Following a single 3-mg dose, renal impairment (creatinine clearance <30 mL/minute) had minimal effect on peak plasma concentrations of iloperidone and its P88 and P95 metabolites.1 Area under the plasma concentration-time curve (AUC) was increased by 24% for iloperidone, decreased by 6% for P88, and increased by 52% for P95 in individuals with renal impairment.1
Pharmacogenomic Considerations
In pharmacokinetic studies, systemic exposure of iloperidone and its P88 metabolite were increased by 47 and 85%, respectively, in CYP2D6 poor metabolizers compared to normal metabolizers.1 Systemic exposure of the P95 metabolite was decreased by 85% in poor CYP2D6 metabolizers compared to normal metabolizers.1 Approximately 7% of white populations, 2% of Asian populations, and 2% of Black populations are poor CYP2D6 metabolizers.1
Adverse effects occurring in clinical trials in 5% or more of patients receiving short-term iloperidone therapy for schizophrenia and at a frequency at least twice that reported among patients receiving placebo include dizziness, fatigue, dry mouth, nasal congestion, tachycardia, orthostatic hypotension, somnolence, and weight gain.1
Adverse effects occurring in clinical trials in 5% or more of patients receiving short-term iloperidone therapy for bipolar mania and at a frequency at least twice that reported among patients receiving placebo include tachycardia, dizziness, dry mouth, increased hepatic enzymes, nasal congestion, weight gain, hypotension, and somnolence.1
Iloperidone is metabolized principally by cytochrome P-450 (CYP) isoenzymes 3A4 and 2D6.1
Iloperidone is not a substrate or inhibitor of CYP isoenzymes 1A1, 1A2, 2A6, 2B6, 2C8, 2C9, or 2E1; it is also not a substrate of CYP2C19, and not an inducer of CYP isoenzymes 1A2, 2C8, 2C9, 2C19, 3A4, or 3A5.1
Iloperidone and its active metabolite P88 are not substrates of P-glycoprotein (P-gp).1 Iloperidone is a weak P-gp inhibitor.1
Drugs Affecting Hepatic Microsomal Enzymes
CYP2D6 Inhibitors
Concomitant administration of fluoxetine (20 mg twice daily for 21 days), a strong inhibitor of CYP2D6, with a single 3-mg dose of iloperidone in healthy individuals classified as CYP2D6 extensive metabolizers increased the AUC of iloperidone and its P88 metabolite by approximately 2- to 3-fold and decreased the AUC of iloperidone's P95 metabolite by 50%.1 A single 3-mg dose of iloperidone had no effect on the pharmacokinetics of fluoxetine (20 mg twice daily).1
Concomitant administration of paroxetine (20 mg daily for 5-8 days), a strong inhibitor of CYP2D6, with multiple doses of iloperidone (8 or 12 mg twice daily) in patients with schizophrenia increased mean steady-state peak plasma concentrations of iloperidone and its P88 metabolite by about 1.6-fold and decreased mean steady-state peak concentrations of its P95 metabolite by 50%.1
The manufacturer advises caution and states that the dosage of iloperidone should be reduced by 50% when given in combination with strong CYP2D6 inhibitors.1 When a strong CYP2D6 inhibitor is withdrawn from combined therapy, the iloperidone dosage should be returned to the previous dosage.1
CYP3A4 Inhibitors
Concomitant administration of ketoconazole (200 mg twice daily for 4 days), a strong CYP3A4 inhibitor, with a single 3-mg iloperidone dose in healthy individuals increased the AUC of iloperidone and its P88 and P95 metabolites by 57, 55, and 35%, respectively.1
The manufacturer advises caution and states that the dosage of iloperidone should be reduced by 50% when given in combination with strong CYP3A4 inhibitors.1 When a strong CYP3A4 inhibitor is withdrawn from combined therapy, the iloperidone dosage should be returned to the previous dosage.1
Concomitant administration of iloperidone with weaker CYP3A4 inhibitors (e.g., erythromycin, grapefruit juice) has not been studied.1
Concomitant CYP2D6 and CYP3A4 Inhibitors
Concomitant administration of both paroxetine (20 mg once daily for 10 days) and ketoconazole (200 mg twice daily) with iloperidone (8 or 12 mg twice daily) in patients with schizophrenia increased steady-state plasma iloperidone and P88 concentrations by 1.4-fold and decreased steady-state P95 concentrations by 1.4-fold.1 Therefore, concurrent administration of iloperidone with inhibitors of both of its metabolic pathways did not add to the effect observed when either inhibitor was given alone.1
The effect of iloperidone on the corrected QT (QTc) interval is augmented by CYP2D6 and CYP3A4 inhibition.1 Concomitant administration of paroxetine (20 mg daily) and ketoconazole (200 mg twice daily) with iloperidone (12 mg twice daily) resulted in a mean increase in QTc interval of about 19 msec compared with baseline.1
The manufacturer advises caution and states that the dosage of iloperidone should be reduced by 50% when given in combination with both a CYP3A4 inhibitor and a CYP2D6 inhibitor.1 When both the CYP3A4 inhibitor and the CYP2D6 inhibitor are withdrawn from combined therapy, the iloperidone dosage should be returned to the previous dosage.1
Drugs Metabolized by Hepatic Microsomal Enzymes
CYP2D6 Substrates
Concomitant single-dose administration of iloperidone (3 mg) with dextromethorphan (80 mg), a CYP2D6 substrate, resulted in a 17% increase in total exposure and a 26% increase in peak plasma concentration of dextromethorphan in healthy individuals.1 The manufacturer states that an interaction between iloperidone and other CYP2D6 substrates is unlikely.1
CYP3A4 Substrates
In patients with schizophrenia, concomitant administration of iloperidone (up to 10 mg twice daily for 14 days) and midazolam, a CYP3A4 substrate, resulted in a less than 50% increase in total exposure of midazolam at iloperidone steady state and had no effect on peak plasma concentrations of midazolam.1 The manufacturer therefore states that interactions between iloperidone and other CYP3A4 substrates are unlikely.1
Because disruption of body temperature regulation is possible, iloperidone should be used with caution in patients concurrently receiving drugs with anticholinergic activity.1
Drugs that Prolong QT Interval
Because of additive effects on QT-interval prolongation, concomitant use of iloperidone with other drugs known to prolong the QTc interval should be avoided; these include class IA antiarrhythmics (e.g., quinidine, procainamide), class III antiarrhythmics (e.g., amiodarone, sotalol), antipsychotic medications (e.g., chlorpromazine, thioridazine), certain antibiotics (e.g., moxifloxacin), pentamidine, and methadone.1
Concomitant use of iloperidone with alcohol should be avoided.1
Concomitant use of iloperidone and antihypertensive agents may cause symptomatic hypotension.1 The manufacturer recommends avoiding concomitant use of iloperidone with α1-adrenergic blockers, and adjusting the dosage of medications that affect blood pressure as needed.1
Iloperidone is not a substrate for CYP1A2 in vitro; therefore, smoking should not alter the pharmacokinetics of the drug.1
Iloperidone is a piperidinyl-benzisoxazole derivative; the drug has been referred to as an atypical antipsychotic agent.1 Although the exact mechanism of action of iloperidone is unknown, it has been suggested that the efficacy of iloperidone is mediated through a combination of antagonist activity at central dopamine type 2 (D2) and serotonin type 2 (5-hydroxytryptamine [5-HT2]) receptors.1
Iloperidone acts as an antagonist with high binding affinity for 5-HT2A, D2 and D3, and α1-adrenergic receptors.1 The drug has moderate affinity for D4, 5-HT6, and 5-HT7 receptors and low affinity for 5-HT1A, D1, and histamine H1 receptors.1 Iloperidone possesses no appreciable affinity for muscarinic cholinergic receptors.1 Iloperidone has 2 main metabolites, P88 and P95; the affinity of the P88 metabolite is generally equal to or less than that of the parent compound while the P95 metabolite demonstrates affinity for 5-HT2A and α1A-, α1B-, α1D-, and α2C-adrenergic receptors.1
Iloperidone is well absorbed following oral administration of the tablets, with peak plasma concentrations occurring within 2-4 hours.1 Steady-state plasma concentrations of iloperidone and its two main metabolites, P88 and P95, are reached within 3-4 days.1 Administration with a high-fat meal did not significantly impact maximum plasma concentrations or AUC of iloperidone or its metabolites; time to maximum concentration was delayed by 1, 2, and 6 hours for iloperidone, P88, and P95, respectively.1 At therapeutic concentrations, iloperidone and its metabolites (P88 and P95) are approximately 97 and 92% bound to plasma proteins, respectively.1 Iloperidone is primarily metabolized by carbonyl reduction, cytochrome P-450 (CYP) isoenzyme 2D6-mediated hydroxylation, and CYP3A4-mediated O-demethylation; P88 and P95 undergo further oxidation and/or conjugation with glucuronic acid.1, 8, 9, 10 The P88 metabolite penetrates the CNS and is thought to contribute to the drug's antipsychotic activity whereas the P95 metabolite does not readily penetrate the CNS and primarily contributes to the adverse effect profile of the drug.8, 10, 13, 15 The mean elimination half-lives of iloperidone, P88, and P95 are 18, 26, and 23 hours, respectively, in extensive metabolizers of CYP2D6 and 33, 37, and 31 hours, respectively, in poor metabolizers of CYP2D6.1 The majority of radiolabeled iloperidone was recovered in the urine (mean of 58.2 and 45.1% in extensive and poor metabolizers of CYP2D6, respectively), with feces accounting for 19.9% (extensive metabolizers) and 22.1% (poor metabolizers) of the radiolabeled dose.1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets | 1 mg | ||
2 mg | Fanapt® | Vanda | ||
4 mg | Fanapt® | Vanda | ||
6 mg | Fanapt® | Vanda | ||
8 mg | Fanapt® | Vanda | ||
10 mg | Fanapt® | Vanda | ||
12 mg | Fanapt® | Vanda | ||
Titration Pack | 2 Tablets, Iloperidone 1 mg (Fanapt®) 2 Tablets, Iloperidone 2 mg (Fanapt®) 2 Tablets, Iloperidone 4 mg (Fanapt®) 2 Tablets, Iloperidone 6 mg (Fanapt®) | Fanapt® Titration Pack | Vanda |
AHFS® Drug Information. © Copyright, 1959-2025, Selected Revisions May 10, 2025. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
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