AHFS Class:

• Atypical Antipsychotics 28:16.08.04

Generic Name(s):

• Iloperidone

Chemical Name:

• 4'-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)piperidino]propoxy]-3'-methoxyacetophenone

Molecular Formula:

• C₂₄H₂₇FN₂O₄

Iloperidone is considered an atypical or second-generation antipsychotic agent.1,4,7,8,10,11,12,13,14,15,87

Schizophrenia

Iloperidone is used for the treatment of schizophrenia.1,2,4,5,91 Schizophrenia is a chronic major psychotic disorder that frequently has devastating effects on various aspects of the patient's life and is associated with an increased risk of suicide and increased overall mortality.28,30,69 The principal manifestations of schizophrenia usually are described in terms of positive, negative, and cognitive symptoms.28,33,34 Positive (i.e., psychotic) symptoms include hallucinations and delusions, while negative symptoms include decreases in emotional expression, initiation of goal-directed behavior (avolition), speech productivity (alogia), ability to experience pleasure from external stimuli (anhedonia), and apparent interest in social interactions (asociality).28,30,34 Cognitive symptoms include impairments in attention, concentration, and memory.30,33,34 Diagnostic criteria for schizophrenia also may include disorganized speech (e.g., frequent derailment or incoherence) or grossly disorganized or catatonic behavior.69

Short-term efficacy of oral 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 manufacturer states that the need for continued therapy with iloperidone should be reassessed periodically.1 (See Dosage under Dosage and Administration.)

When deciding among the alternative treatments available for schizophrenia, the manufacturer states that the clinician should consider that iloperidone is associated with prolongation of the corrected QT (QT_c) interval.1 (See Prolongation of QT Interval under Cautions.) Prolongation of the QT_c interval with some other drugs has been associated with the ability to cause torsades de pointes-type arrhythmia (a potentially fatal polymorphic ventricular tachycardia that can result in sudden death).1 In many cases, consideration of this risk would lead to the conclusion that other drugs should be tried first.1 It is not yet known whether iloperidone will cause torsades de pointes or increase the rate of sudden death.1

Because iloperidone must be titrated to achieve an effective dosage, symptom control may be more delayed during the first 1-2 weeks of therapy compared with some other antipsychotic agents that do not require a similar titration period.1 (See Dosage under Dosage and Administration.) Clinicians should keep this delay in mind when selecting an antipsychotic agent for the acute treatment of schizophrenia.1

Preliminary evidence suggests that several genetic markers may help to predict the clinical response and tolerability of iloperidone in patients with schizophrenia; additional pharmacogenetic studies are under way to further investigate the potential use of such markers to optimize individualized antipsychotic therapy.2,15,84,85,86

Antipsychotic therapy is integral to the management of patients with schizophrenia,28,29,31 both for management of acute psychotic symptoms and for maintenance treatment to prevent symptom recurrence.28,29,30,31,32 The American Psychiatric Association (APA) and other experts consider antipsychotic agents (i.e., first- and second-generation antipsychotic agents) to be first-line drugs for the management of schizophrenia (including first psychotic episodes).28,29,31,32 The APA states that, with the possible exception of clozapine for the management of treatment-resistant symptoms, there currently is no definitive evidence that one antipsychotic agent will have superior efficacy compared with another agent, although meaningful differences in response may be observed in individual patients.28 Therefore, initial choice of an antipsychotic agent should be individualized, and generally be made in the context of shared decision-making, taking into consideration multiple patient- and drug-related factors, including adverse effect profiles, concurrent medical conditions or risk factors, potential for drug interactions, and potential pharmacogenomic considerations, as well as the patient's preferences, prior responses to treatment, available formulations, and cost.28,29,30,31,32 Patient response and tolerance to antipsychotic agents are variable, and patients who do not respond to or tolerate one drug may be successfully treated with another drug with different receptor binding or adverse effect profile.28,70,71,72

The APA recommends that patients with schizophrenia whose symptoms have improved with an antipsychotic agent continue to receive such therapy.28 The APA also suggests that patients whose symptoms have improved with an antipsychotic agent continue to be treated with the same antipsychotic agent; however, some circumstances (e.g., patient preferences, drug availability, adverse effects) may necessitate a change in antipsychotic agent.28 Drug therapy should be used as part of a comprehensive, patient-centered treatment plan that includes evidence-based nonpharmacologic and pharmacologic treatments for schizophrenia.28,30 Clinicians may consult APA's Practice Guideline for the Treatment of Patients with Schizophrenia (available at [Web]) for additional information on the treatment of schizophrenia.28

For additional information on the symptomatic management of schizophrenia, including treatment recommendations, see Schizophrenia and Other Psychotic Disorders under Uses: Psychotic Disorders, in the Phenothiazines General Statement 28:16.08.24.

Administration

Iloperidone is commercially available as tablets, which are administered orally twice daily without regard to meals.1 However, adverse effects may be minimized when the drug is taken with food.8 A parenteral formulation of iloperidone currently is not commercially available.1,8

Dosage

Schizophrenia

Iloperidone must be titrated slowly from a low initial dosage to avoid orthostatic hypotension due to its α₁-adrenergic blocking activity.1,87 (See Orthostatic Hypotension and Syncope under Cautions.)

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 In short-term clinical studies, iloperidone's efficacy was demonstrated in a dosage range of 6-12 mg given twice daily.1,2,4 The maximum recommended iloperidone dosage is 12 mg given twice daily (total dosage of 24 mg daily); dosages exceeding 24 mg daily have not been systematically evaluated in clinical trials.1

Clinicians should be aware that patients need to be titrated to an effective dosage of iloperidone; therefore, symptom control may be delayed during the first 1-2 weeks of therapy compared with some other antipsychotic agents that do not require similar titration.1 Clinicians should also be aware that some adverse effects associated with iloperidone are dose related.1

In a longer-term clinical study, maintenance therapy with iloperidone (in total dosages of up to 24 mg daily) has been shown to be effective in delaying time to relapse in adults who were stabilized on the drug.1,91 In addition, in a pooled analysis of 3 long-term (one-year) studies, iloperidone (4-16 mg daily) was found to be effective in preventing relapse in patients with schizophrenia or schizoaffective disorder and was generally well tolerated.6,15 The manufacturer states that the need for continued therapy should be reassessed periodically.1

In patients with schizophrenia whose symptoms have improved with an antipsychotic agent, continued treatment (i.e., maintenance therapy) with an antipsychotic agent is recommended to reduce the risk of relapse.28,29,30,31 The APA suggests that such patients continue to be treated with the same antipsychotic agent that was effective during acute treatment.28 Some experts have recommended maintenance antipsychotic therapy for at least 1-2 years after the first psychotic episode29,30,31 and for 2-5 years or longer following recurrent episodes.30,31,32 Indefinite maintenance antipsychotic treatment may be necessary in many cases; however, the benefits and risks of continued antipsychotic therapy should be assessed periodically in the context of shared decision-making, taking into consideration each patient's risk of relapse, drug-associated adverse effects, course of disease, and the specific goals and needs of each patient.28,29,30,32

Although there are no data to specifically address reinitiation of iloperidone therapy following a treatment interruption, the manufacturer recommends that the usual titration schedule be followed whenever patients have had a period off therapy of more than 3 days.1

Special Populations

Routine dosage adjustment of iloperidone is not necessary in patients with renal impairment.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 (See Hepatic Impairment under Cautions.)

Routine dosage adjustment is not necessary in geriatric patients.1 Dosage adjustment also is not necessary based on gender or race.1

Pharmacogenomics and CYP2D6 Poor Metabolizer Phenotype

Iloperidone dosage should be reduced by 50% in cytochrome P-450 (CYP) isoenzyme 2D6 poor metabolizers,1 since CYP2D6 poor metabolizers have a higher exposure to iloperidone than extensive metabolizers (see Description).1,10 Laboratory tests are available to identify CYP2D6 poor metabolizers.1

Drugs Affecting Hepatic Microsomal Enzymes

Iloperidone dosage should be reduced by 50% when administered concurrently with potent CYP2D6 inhibitors (e.g., fluoxetine, paroxetine) or potent CYP3A4 inhibitors (e.g., clarithromycin, itraconazole, ketoconazole).1 When the CYP2D6 or CYP3A4 inhibitor is withdrawn from combined therapy, the previous iloperidone dosage may be resumed.1 Iloperidone dosage should also be reduced by about 50% when given in combination with both a CYP2D6 and CYP3A4 inhibitor.1 (See Drug Interactions.)

Contraindications

Iloperidone is contraindicated in patients with known hypersensitivity to iloperidone or any components in the formulation.1 Anaphylaxis, angioedema, and other hypersensitivity reactions (including throat tightness; oropharyngeal swelling; swelling of the face, lips, mouth, and tongue; urticaria; rash; and pruritus) have been reported in patients receiving iloperidone.1

Warnings/Precautions

Warnings

Increased Mortality in Geriatric Patients with Dementia-related Psychosis

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 (i.e., aripiprazole, olanzapine, quetiapine, risperidone) 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 (See Adverse Cerebrovascular Events, including Stroke, in Geriatric Patients with Dementia-related Psychosis and also see Geriatric Use under Cautions.)

Other Warnings and Precautions

Adverse Cerebrovascular Events, 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 (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis and also see Geriatric Use under Cautions.)

Prolongation of QT Interval

In patients with schizophrenia or schizoaffective disorder, iloperidone was associated with corrected QT (QT_c)-interval prolongation of 2.9, 3.9, and 9.1 msec at total daily dosages of 4-8, 10-16, and 20-24 mg, respectively.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 QT_c (Fridericia's formula) increase from baseline of about 19 msec.1 (See Ketoconazole, Itraconazole, and Other CYP3A4 Inhibitors and also see Paroxetine under Drug Interactions.) 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 QT_c interval (see Drugs that Prolong QT Interval under Drug Interactions).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 QT_c interval, including bradycardia, hypokalemia or hypomagnesemia, concomitant use of other drugs that prolong the QT_c 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 (see Pharmacogenomics and CYP2D6 Poor Metabolizer Phenotype under Dosage and Administration, see Drug Interactions, and also see Description).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 QT_c 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 requiring immediate discontinuance of the drug and intensive symptomatic treatment, has been reported in patients receiving antipsychotic agents, including iloperidone.1 (See Advice to Patients.) For additional information on NMS, see Neuroleptic Malignant Syndrome under Cautions: Nervous System Effects, in the Phenothiazines General Statement 28:16.08.24.

Tardive Dyskinesia

Because use of antipsychotic agents may be associated with tardive dyskinesia (a syndrome of potentially irreversible, involuntary, dyskinetic movements), 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

The American Psychiatric Association (APA) currently recommends that patients with schizophrenia who are receiving antipsychotic agents be assessed clinically for abnormal involuntary movements at baseline and at each follow-up visit and that assessment with a structured instrument (e.g., the Abnormal Involuntary Movement Scale [AIMS], Dyskinesia Identification System: Condensed User Scale [DISCUS]) occur at least every 6 months in patients considered at high risk for tardive dyskinesia (including patients older than 55 years of a women; individuals with a mood disorder, substance use disorder, intellectual disability, or CNS injury; individuals with high cumulative exposure to antipsychotic medications, particularly high-potency dopamine type 2 (D₂) receptor antagonists; and patients who experience acute dystonic reactions, clinically significant parkinsonism, or akathisia) or at least every 12 months in other patients as well as if a new onset or exacerbation of preexisting movements is observed at any follow-up visit.28 In some jurisdictions, the frequency of monitoring for involuntary movements in individuals receiving antipsychotic agents may also be subject to local regulations.28

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

APA recommends that patients who have moderate to severe or disabling tardive dyskinesia associated with antipsychotic therapy be treated with a vesicular monoamine transporter 2 (VMAT2) inhibitor (e.g., deutetrabenazine, valbenazine, tetrabenazine); such treatment may also be considered for patients with mild tardive dyskinesia based on factors such as patient preference, associated impairment, and effect on psychosocial functioning.28 (See Deutetrabenazine 28:56, Tetrabenazine 28:56, and Valbenazine 28:56.)

For additional information on tardive dyskinesia, see Tardive Dyskinesia under Cautions: Nervous System Effects, in the Phenothiazines General Statement 28:16.08.24.

Metabolic Changes

Atypical antipsychotic agents have been associated with metabolic changes, 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 (See Hyperglycemia and Diabetes Mellitus, see Dyslipidemia, and also see Weight Gain under Cautions.)

Hyperglycemia and Diabetes Mellitus

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 While confounding factors such as an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population make it difficult to establish with certainty the relationship between use of agents in this drug class and glucose abnormalities, epidemiologic studies (which did not include iloperidone) suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotic agents included in the studies (e.g., clozapine, olanzapine, quetiapine, risperidone).1,38,39,40,41,76

Patients with preexisting diabetes mellitus in whom therapy with an atypical antipsychotic is initiated should be periodically monitored for worsening of glucose control; those with risk factors for diabetes (e.g., obesity, family history of diabetes) should undergo fasting blood glucose testing upon therapy initiation and periodically throughout treatment.1 All patients treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia (including polydipsia, polyuria, polyphagia, and weakness) during therapy, and any patient who develops such symptoms should undergo fasting blood glucose testing.1 (See Advice to Patients.) In some cases, patients who developed hyperglycemia while receiving an atypical antipsychotic have required continuance of antidiabetic treatment despite discontinuance of the atypical antipsychotic; in other cases, hyperglycemia resolved with discontinuance of the antipsychotic.1

For further information on managing the risk of hyperglycemia and diabetes mellitus associated with atypical antipsychotic agents, see Hyperglycemia and Diabetes Mellitus under Cautions: Precautions and Contraindications, in Clozapine 28:16.08.04.

Dyslipidemia

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 in a fixed dosage of 24 mg daily 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 0.55 mg/dL in high-density lipoprotein (HDL)-cholesterol and a mean decrease of 0.83 mg/dL in fasting triglycerides.1

Weight Gain

Weight gain has been observed with use of atypical antipsychotics, including iloperidone.1 Based on pooled data from short-term clinical studies, 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, the overall mean weight gain in iloperidone-treated patients was 2.1 kg.1

Clinical monitoring of weight is recommended in patients receiving iloperidone.1

Seizures

In short-term clinical trials, seizures occurred in 0.1% of patients treated with iloperidone compared with 0.3% of patients receiving placebo.1 As with other antipsychotic agents, iloperidone should be used with caution in patients with a history of seizures or with conditions that may lower the seizure threshold; conditions that lower the seizure threshold may be more prevalent in patients 65 years of age or older.1

Orthostatic Hypotension and Syncope

Orthostatic hypotension associated with dizziness, tachycardia, and syncope may occur during iloperidone therapy, particularly when treatment with the drug is initiated or reinitiated or the dosage is increased, because of the drug's α₁-adrenergic blocking activity.1,5 In short-term clinical trials 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 More rapid dosage titration would be expected to increase the incidence of orthostatic hypotension and syncope.1,14 (See Dosage under Dosage and Administration.)

Iloperidone should be used with caution in patients with known cardiovascular disease (e.g., heart failure, history of myocardial infarction, ischemic heart disease, conduction abnormalities), cerebrovascular disease, or conditions that would predispose patients to hypotension (e.g., dehydration, hypovolemia, concomitant antihypertensive therapy).1 Consideration should be given to monitoring orthostatic vital signs in iloperidone-treated patients who are susceptible to hypotension.1

Falls

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 or conditions or those receiving other drugs that could exacerbate these effects, fall risk assessments should be completed when initiating antipsychotic treatment and repeated periodically during long-term antipsychotic therapy.1

Leukopenia, Neutropenia, and Agranulocytosis

In clinical trial and/or postmarketing experience, leukopenia and neutropenia have been temporally related to antipsychotic agents.1,78 Agranulocytosis (including fatal cases) also has been reported with other antipsychotic agents.1

Possible risk factors for leukopenia and neutropenia include preexisting low leukocyte count and a history of drug-induced leukopenia or neutropenia.1,78 Patients with a preexisting low leukocyte count or a history of drug-induced leukopenia or neutropenia should have their complete blood count 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 Lithium has reportedly been used successfully in the treatment of several cases of leukopenia associated with aripiprazole, clozapine, and some other drugs; however, further clinical experience is needed to confirm these anecdotal findings.78

Hyperprolactinemia

Similar to other antipsychotic agents and drugs with dopamine D₂ antagonistic activity, iloperidone can elevate plasma prolactin concentrations, which may persist during chronic use of the drug.1,10 In a short-term (4-week) trial, 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, iloperidone was associated with relatively modest elevations in prolactin concentrations compared with some other antipsychotic agents (e.g., first-generation antipsychotics including haloperidol, risperidone).1,10

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

Body Temperature Regulation

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

Dysphagia

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 pneumonia.1

Suicide

There is an attendant risk of suicide in patients with psychotic illnesses; high-risk patients should be closely supervised.1 Iloperidone should be prescribed in the smallest quantity consistent with good patient management to reduce the risk of overdosage.1

Priapism

Priapism may occur with iloperidone therapy;1,93 3 cases of priapism were reported in the premarketing program.1 Drugs with α-adrenergic blocking activity have been reported to cause priapism, and iloperidone shares this pharmacologic activity.1,93 Severe priapism may require surgical intervention.1

Cognitive and Motor Impairment

Like other antipsychotic agents, iloperidone potentially may impair judgment, thinking, or motor skills.1 In short-term, placebo-controlled clinical trials, somnolence (including sedation) was reported in 11.9% of adults receiving iloperidone dosages of at least 10 mg daily compared with 5.3% of those receiving placebo.1 (See Advice to Patients.)

Specific Populations

Pregnancy

Pregnancy registry: 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

Risk summary: 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 The background risk of major birth defects and miscarriage for the indicated population is unknown.1 In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.1

Fetal/Neonatal adverse reactions: Neonates exposed to antipsychotic agents during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery.1,88,89,90 Symptoms reported to date have included agitation, hypertonia, hypotonia, tardive dyskinetic-like symptoms, tremor, somnolence, respiratory distress, and feeding disorder.1,88,89,90 The symptoms have varied in severity; some neonates recovered within hours to days without specific treatment while others have required prolonged hospitalization.1,88,89,90 Neonates should be monitored for extrapyramidal and/or withdrawal symptoms and managed appropriately if symptoms occur.1

Lactation

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

Pediatric Use

Safety and effectiveness of iloperidone in pediatric and adolescent patients have not been established.1

Geriatric Use

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, 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

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 the safety and efficacy of iloperidone in the treatment of dementia-related psychosis have not been established and that the drug is not approved for the treatment of patients with dementia-related psychosis.1 (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis and Cerebrovascular Adverse Events, including Stroke, in Geriatric Patients with Dementia-related Psychosis under Cautions).1 For additional information on the use of antipsychotic agents in the management of dementia-related psychosis, see Geriatric Considerations under Uses: Psychotic Disorders, in the Phenothiazines General Statement 28:16.08.24.1

Hepatic Impairment

In a single-dose study evaluating the pharmacokinetics of iloperidone in patients with mild hepatic impairment, the pharmacokinetic profiles of iloperidone and its P88 and P95 metabolites (total or unbound) were not substantially altered.1,13,15 However, in subjects with moderate hepatic impairment, exposure to the P88 metabolite (unbound) was substantially higher (by twofold) and more variable compared with healthy individuals.1,13,15 (See Special Populations under Dosage and Administration.)

Iloperidone has not been studied in patients with severe hepatic impairment, and use of the drug in such patients is not recommended.1

Renal Impairment

Because iloperidone is highly metabolized with less than 1% of the drug excreted unchanged, renal impairment is unlikely to substantially alter the pharmacokinetics of the drug.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_0-∞) was increased by 24% for iloperidone, decreased by 6% for P88, and increased by 52% for P95 in individuals with renal impairment.1 Routine dosage adjustment is not necessary in patients with renal impairment.1

Common Adverse Effects

Adverse effects occurring in clinical trials in 5% or more of patients receiving short-term iloperidone therapy for schizophrenia (for at least one iloperidone dosage studied) and at a frequency at least twice that reported among patients receiving placebo include dizziness,1,2,5 somnolence or sedation,1,2,5 fatigue,1,5 dry mouth,1,2,5 nasal congestion,1,2,5 tachycardia,1,2 orthostatic hypotension,1,2 and weight gain.1,2

Iloperidone is metabolized principally by cytochrome P-450 (CYP) isoenzymes 3A4 and 2D6.1,8,9,10

Iloperidone is not a substrate for CYP isoenzymes 1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, or 2E1.1

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

Inhibitors of CYP3A4 (e.g., clarithromycin, itraconazole, ketoconazole) or CYP2D6 (e.g., fluoxetine, paroxetine) may reduce clearance of iloperidone resulting in increased plasma concentrations of the drug.1 (See Drugs Affecting Hepatic Microsomal Enzymes under Dosage and Administration and see also Fluoxetine and Other CYP2D6 Inhibitors; Ketoconazole, Itraconazole, and Other CYP3A4 Inhibitors; and Paroxetine under Drug Interactions.)

Pharmacokinetic interactions with inhibitors or inducers of CYP isoenzymes 1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, or 2E1 are unlikely since iloperidone is not a substrate for these isoenzymes.1

Drugs Metabolized by Hepatic Microsomal Enzymes

Clinically important pharmacokinetic interactions with substrates of CYP isoenzymes 1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2E1, 3A4, or 3A5 are considered unlikely.1

Pharmacokinetic interactions with substrates of CYP2D6 also are unlikely.1 (See Dextromethorphan and Other CYP2D6 Substrates under Drug Interactions.)

Anticholinergic Agents

Because disruption of body temperature regulation is possible, iloperidone should be used with caution in patients concurrently receiving drugs with anticholinergic activity.1 (See Body Temperature Regulation under Cautions.)

Drugs that Prolong QT Interval

Because of additive effects on QT-interval prolongation, concomitant use of iloperidone with other drugs known to prolong the corrected QT (QT_c) interval, including class IA antiarrhythmics (e.g., procainamide, quinidine), class III antiarrhythmics (e.g., amiodarone, sotalol), some antipsychotic agents (e.g., chlorpromazine, thioridazine, haloperidol, olanzapine, pimozide, quetiapine, ziprasidone), some anti-infective agents (e.g., gatifloxacin, moxifloxacin), and other drugs (e.g., levomethadyl acetate [no longer commercially available in the US], methadone, pentamidine, tetrabenazine), should be avoided.1,82,83,87 (See Prolongation of QT Interval under Cautions.)

Other CNS Agents or Alcohol

Concomitant use of iloperidone with other CNS agents or alcohol may produce additive CNS effects.1 Caution is advised when iloperidone and other CNS agents are used concomitantly; use of alcohol during iloperidone therapy should be avoided.1

Hypotensive Agents

Because of its α₁-adrenergic blocking activity and potential to cause orthostatic hypotension and syncope, the manufacturer recommends that iloperidone be used with caution in patients receiving antihypertensive agents and other drugs that can cause hypotension; monitoring of orthostatic vital signs should be considered in such patients.1 (See Orthostatic Hypotension and Syncope under Cautions and also see Advice to Patients.)

Dextromethorphan and Other 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

Fluoxetine and Other CYP2D6 Inhibitors

Concomitant administration of fluoxetine (20 mg twice daily for 21 days), a potent inhibitor of CYP2D6, with a single 3-mg dose of iloperidone in healthy individuals classified as CYP2D6 extensive metabolizers increased the area under the concentration-time curve (AUC) of iloperidone and its P88 metabolite by approximately twofold to threefold 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 The manufacturer advises caution and states that the dosage of iloperidone should be reduced by 50% when given in combination with fluoxetine.1 When fluoxetine is withdrawn from combined therapy, the iloperidone dosage should be returned to the previous dosage.1 (See Drugs Affecting Hepatic Microsomal Enzymes under Dosage and Administration.)

The manufacturer states that other potent CYP2D6 inhibitors would be expected to have similar effects as fluoxetine and therefore advises caution and appropriate iloperidone dosage reduction.1 When the CYP2D6 inhibitor is withdrawn from combined therapy, the iloperidone dosage may then be returned to the previous level.1 (See Paroxetine under Drug Interactions.)

Ketoconazole, Itraconazole, and Other CYP3A4 Inhibitors

Concomitant administration of ketoconazole (200 mg twice daily for 4 days), a potent 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 therefore advises caution and recommends that the iloperidone dosage be reduced by about 50% when concurrently administered with itraconazole, ketoconazole, or other potent inhibitors of CYP3A4 (e.g., clarithromycin).1 When the CYP3A4 inhibitor is withdrawn from combined therapy, the iloperidone dosage should be increased to the previous dosage.1 (See Drugs Affecting Hepatic Microsomal Enzymes under Dosage and Administration.)

Concomitant administration of iloperidone with weaker CYP3A4 inhibitors (e.g., erythromycin, grapefruit juice) has not been studied.1

Concomitant administration of both ketoconazole (200 mg twice daily) and paroxetine (20 mg once daily for 10 days) 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 plasma 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 manufacturer advises caution and states that iloperidone dosage should be reduced by about 50% when given in combination with both a CYP2D6 and CYP3A4 inhibitor.1 (See Drugs Affecting Hepatic Microsomal Enzymes under Dosage and Administration.)

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 corrected QT (QT_c) interval of about 19 msec compared with baseline.1 (See Prolongation of QT Interval under Cautions.)

Midazolam and other 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

Paroxetine

Concomitant administration of paroxetine (20 mg daily for 5-8 days), a potent 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 recommends that the iloperidone dosage be reduced by 50% when given concurrently with paroxetine.1 When paroxetine is withdrawn from combined therapy, the iloperidone dosage should be returned to the previous dosage.1 (See Drugs Affecting Hepatic Microsomal Enzymes under Dosage and Administration.) A similar effect is expected to occur with concomitant administration of other potent CYP2D6 inhibitors.1

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 manufacturer advises caution and states that the iloperidone dosage should be reduced by about 50% when given in combination with both a CYP2D6 and CYP3A4 inhibitor.1 (See Drugs Affecting Hepatic Microsomal Enzymes under Dosage and Administration.)

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 corrected QT (QT_c) interval of about 19 msec compared with baseline.1 (See Prolongation of QT Interval under Cautions.)

Smoking

Iloperidone is not a substrate for CYP1A2 in vitro; therefore, smoking should not alter the pharmacokinetics of the drug.1

Description

Iloperidone is a piperidinyl-benzisoxazole derivative structurally related to risperidone; the drug has been referred to as an atypical or second-generation antipsychotic agent.1,3,4,6,7,8,9,10,11,12,13,14,15,87 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.1,2,3,4,6,15

Iloperidone acts as an antagonist with high binding affinity for 5-HT_2A, 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-HT_1A, D₁, and histamine H₁ receptors.1,2,3,4,6,7,8,10,11,12,13,14 Iloperidone possesses no appreciable affinity for muscarinic cholinergic receptors.1,7,11,15 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-HT_2A and α_1A-, α_1B-, α_1D-, and α_2C-adrenergic receptors.1,8,10,15

Iloperidone is well absorbed following oral administration of the tablets, with peak plasma concentrations occurring within 2-4 hours.1,8,10,12,15 Steady-state plasma concentrations of iloperidone and its two main metabolites, P88 and P95, are reached within 3-4 days.1,10 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; the drug's two principal metabolites, 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 CYP2D6.1,10,15 (See Pharmacogenomics and CYP2D6 Poor Metabolizer Phenotype under Dosage and Administration.) 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

Advice to Patients

Importance of advising patients and caregivers that geriatric patients with dementia-related psychosis treated with antipsychotic agents are at an increased risk of death.1 Patients and caregivers also should be informed that iloperidone is not approved for treating geriatric patients with dementia-related psychosis.1

Importance of patients immediately informing their clinician if they feel faint, lose consciousness, or have heart palpitations.1 Importance of counseling patients not to take iloperidone with other drugs that prolong the QT interval.1 Patients should be instructed to inform clinicians that they are taking iloperidone before any new drug is taken.1 (See Prolongation of QT Interval under Cautions and also see Drugs that Prolong QT Interval under Drug Interactions.)

Importance of informing patients and caregivers about the risk of neuroleptic malignant syndrome (NMS), a rare but potentially life-threatening syndrome that can cause high fever, muscle stiffness, sweating, fast or irregular heart beat, change in blood pressure, confusion, and kidney damage.1

Importance of informing patients about the risk of metabolic changes (e.g., hyperglycemia and diabetes mellitus, weight gain) with iloperidone and the need for specific monitoring for such changes during therapy.1 Importance of patients being aware of the symptoms of hyperglycemia (e.g., increased thirst, increased urination, increased appetite, weakness).1 Importance of informing patients who are diagnosed with diabetes or those with risk factors for diabetes (e.g., obesity, family history of diabetes) that they should have their blood glucose monitored at the beginning of and periodically during iloperidone therapy.1 Importance of informing patients that clinical monitoring of weight is recommended during iloperidone therapy1

Importance of informing patients about the risk of orthostatic hypotension, especially when initiating or reinitiating treatment or increasing the dosage.1

Because somnolence and impairment of judgment, thinking, or motor skills may be associated with iloperidone, patients should be cautioned about performing activities requiring mental alertness, such as driving or operating hazardous machinery, while taking iloperidone until they gain experience with the drug's effects.1

Importance of avoiding alcohol during iloperidone therapy.1

Importance of avoiding overheating or dehydration.1

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, dietary supplements, and/or herbal products, since there is a potential for adverse drug interactions (see Drug Interactions).1 Importance of also informing clinicians about any concomitant illnesses (e.g., cardiovascular disease, diabetes mellitus, seizures).1

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1,90 Importance of clinicians informing patients about the benefits and risks of taking antipsychotics during pregnancy, including that third trimester use of iloperidone may cause extrapyramidal and/or withdrawal symptoms in neonates, and about the pregnancy exposure registry (see Pregnancy under Cautions).1,90 Importance of advising patients not to stop taking iloperidone if they become pregnant without consulting their clinician; abruptly stopping antipsychotic agents may cause complications.90 Importance of advising patients not to breast-feed during iloperidone therapy.1

Importance of informing patients of other important precautionary information.1 (See Cautions.)

Additional Information

Overview^® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

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