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Iloperidone

Class: Atypical Antipsychotics
VA Class: CN709
Chemical Name: 4′-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)piperidino]propoxy]-3′-methoxyacetophenone
Molecular Formula: C24H27FN2O4
CAS Number: 133454-47-4
Brands: Fanapt

Medically reviewed by Drugs.com on Dec 21, 2021. Written by ASHP.

Warning

    Increased Mortality in Geriatric Patients with Dementia-related Psychosis
  • Geriatric patients with dementia-related psychosis treated with antipsychotic agents are at an increased risk of death.

  • Antipsychotic agents, including iloperidone, are not approved for the treatment of patients with dementia-related psychosis. (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis under Cautions.)

Introduction

Piperidinyl-benzisoxazole derivative; atypical or second-generation antipsychotic agent.

Uses for Iloperidone

Schizophrenia

Treatment of schizophrenia.

American Psychiatric Association (APA) recommends that patients with schizophrenia be treated with an antipsychotic agent and that patients whose symptoms have improved with an antipsychotic agent continue to receive such therapy. APA also suggests that patients whose symptoms have improved with an antipsychotic agent should 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.

APA and other experts consider antipsychotic agents (i.e., first- and second-generation antipsychotic agents) first-line drugs for management of schizophrenia (including first psychotic episodes). 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 (e.g., adverse effect profiles, concurrent medical conditions or risk factors, potential for drug interactions, potential pharmacogenomic considerations, patient preferences, prior responses to treatment, available formulations, cost).

Patients who do not respond to or tolerate one antipsychotic agent may be successfully treated with another drug with different receptor binding or adverse effect profile.

Drug therapy should be used as part of a comprehensive, patient-centered treatment plan that includes evidence-based nonpharmacologic and pharmacologic treatments for schizophrenia. Consult APA’s Practice Guideline for the Treatment of Patients with Schizophrenia (at [Web]) for additional information on treatment of schizophrenia.

When deciding among treatment alternatives, consider that iloperidone may prolong the QT interval. Some other drugs that prolong the QT interval cause torsades de pointes-type arrhythmia; it is not yet known whether iloperidone causes torsades de pointes or increases the rate of sudden death. In many cases, other drugs should be tried first. (See Prolongation of QT Interval under Cautions.)

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

Iloperidone Dosage and Administration

Administration

Oral Administration

Administer tablets orally twice daily without regard to meals. However, administration with food may minimize adverse effects.

Dosage

Must titrate slowly from a low initial dosage to avoid orthostatic hypotension; therefore, symptom control may be delayed during first 1–2 weeks of therapy. (See Orthostatic Hypotension and Syncope under Cautions and see Schizophrenia under Uses.)

Follow initial titration schedule if treatment has been interrupted for >3 days.

Some of the drug’s adverse effects are dose related.

Adults

Schizophrenia
Oral

Initial dosage is 1 mg twice daily. May titrate to recommended target dosage range of 6–12 mg twice daily with dosage adjustments not exceeding 2 mg twice daily (e.g., 2, 4, 6, 8, 10, and 12 mg twice daily on days 2, 3, 4, 5, 6, and 7, respectively).

Maintenance therapy with iloperidone is well established in adults. Periodically reassess need for continued therapy.

In patients whose symptoms have improved, continued treatment (i.e., maintenance therapy) with an antipsychotic agent is recommended to reduce the risk of relapse. Some experts generally recommend maintenance antipsychotic therapy for at least 1–2 years after the first psychotic episode and for 2–5 years or longer following recurrent episodes. Indefinite maintenance treatment may be necessary; however, periodically assess the benefits and risks of continued antipsychotic therapy in the context of shared decision-making, taking into consideration each patient's risk of relapse, drug-associated adverse effects, course of disease, and specific goals and needs.

Prescribing Limits

Adults

Schizophrenia
Oral

Maximum 12 mg twice daily.

Special Populations

Hepatic Impairment

Mild hepatic impairment: Dosage adjustment not necessary.

Moderate hepatic impairment: Dosage reduction may be required, if clinically indicated.

Severe hepatic impairment: Not studied; use not recommended. (See Special Populations under Pharmacokinetics.)

Renal Impairment

Routine dosage adjustment not required. (See Renal Impairment under Cautions and see Special Populations under Pharmacokinetics.)

Geriatric Patients

Routine dosage adjustment not required.

Gender or Race

No dosage adjustment necessary based on gender or race.

Concomitant Use with CYP2D6 and/or CYP3A4 Inhibitors

Reduce iloperidone dosage by 50% if administered concomitantly with potent CYP2D6 inhibitors (e.g., fluoxetine, paroxetine) or potent CYP3A4 inhibitors (e.g., clarithromycin, itraconazole, ketoconazole). May resume previous iloperidone dosage upon discontinuance of the potent CYP2D6 or CYP3A4 inhibitor.

Also reduce iloperidone dosage by 50% when given in combination with both a CYP2D6 and CYP3A4 inhibitor. (See Interactions.)

Pharmacogenomics and CYP2D6 Poor Metabolizer Phenotype

Reduce dosage by 50%; exposure to iloperidone is higher in poor metabolizers of CYP2D6 than in extensive metabolizers. Laboratory tests are available to identify CYP2D6 poor metabolizers. (See Special Populations and also see Elimination under Pharmacokinetics.)

Cautions for Iloperidone

Contraindications

  • Known hypersensitivity to iloperidone or any ingredient in the formulation. Anaphylaxis, angioedema, and other hypersensitivity reactions (e.g., throat tightness; oropharyngeal swelling; swelling of the face, lips, mouth, and tongue; urticaria; rash; pruritus) reported.

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.

Analyses of 17 placebo-controlled trials in geriatric patients mainly receiving atypical antipsychotic agents revealed an approximate 1.6- to 1.7-fold increase in mortality compared with that in patients receiving placebo.

Most fatalities appeared to result from cardiovascular-related events (e.g., heart failure, sudden death) or infections (mostly pneumonia).

Antipsychotic agents, including iloperidone, are not approved for the treatment of dementia-related psychosis. (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis in Boxed Warning, and also see Cerebrovascular Events in Geriatric Patients with Dementia-related Psychosis under Cautions.)

Other Warnings and Precautions

Cerebrovascular Events in Geriatric Patients with Dementia-related Psychosis

Increased incidence of adverse cerebrovascular events (cerebrovascular accidents and TIAs), including fatalities, observed in geriatric patients with dementia-related psychosis treated with certain atypical antipsychotic agents (aripiprazole, olanzapine, risperidone) in placebo-controlled studies. Iloperidone is not approved for the treatment of patients with dementia-related psychosis. (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis in Boxed Warning.)

Prolongation of QT Interval

Corrected QT (QTc) interval prolonged by 2.9, 3.9, and 9.1 msec at total iloperidone daily dosages of 4–8, 10–16, and 20–24 mg, respectively. CYP2D6 or CYP3A4 inhibition increases this effect; under conditions of both CYP2D6 and CYP3A4 inhibition, mean QTc interval (corrected using Fridericia’s formula) was prolonged by about 19 msec at a dosage of 12 mg twice daily. No cases of torsades de pointes or other severe cardiac arrhythmias reported during premarketing clinical trials.

Factors that may increase the risk of torsades de pointes and/or sudden death in association with drugs that prolong the QTc interval include bradycardia, hypokalemia or hypomagnesemia, concomitant use of other drugs that prolong the QTc interval, presence of congenital prolongation of the QT interval, recent acute MI, and/or uncompensated heart failure.

Avoid concomitant use of other drugs known to prolong the QTc interval (see Interactions). Also avoid use in patients with a known genetic susceptibility to congenital QT-interval prolongation or a history of cardiac arrhythmias.

Use with caution in patients concurrently receiving drugs that inhibit iloperidone’s metabolism and in patients with reduced CYP2D6 activity (see Pharmacogenomics and CYP2D6 Poor Metabolizer Phenotype under Dosage and Administration and also see Interactions).

Hypokalemia and/or hypomagnesemia may increase the risk of QT-interval prolongation and cardiac arrhythmias. Manufacturer recommends baseline and periodic monitoring of serum potassium and magnesium in patients at risk for disturbances of these electrolytes.

Avoid use of iloperidone in patients with a history of clinically important cardiovascular illness (e.g., QT-interval prolongation, recent acute MI, uncompensated heart failure, cardiac arrhythmia).

Discontinue iloperidone therapy in patients with persistent QTc interval measurements >500 msec. Further evaluation, including cardiac monitoring, is recommended in patients with symptoms suggestive of cardiac arrhythmias (e.g., dizziness, palpitations, syncope).

Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS), a potentially fatal syndrome characterized by hyperpyrexia, muscle rigidity, altered mental status, and autonomic instability, reported with antipsychotic agents, including iloperidone.

Immediately discontinue therapy and initiate supportive and symptomatic therapy if NMS occurs. Careful monitoring recommended if therapy is reinstituted following recovery; the risk that NMS can recur must be considered.

Tardive Dyskinesia

Tardive dyskinesia, a syndrome of potentially irreversible, involuntary, dyskinetic movements, reported with use of antipsychotic agents.

Reserve long-term antipsychotic treatment for patients with chronic illness known to respond to antipsychotic agents, and for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients requiring chronic treatment, use smallest dosage and shortest duration of treatment producing a satisfactory clinical response; periodically reassess need for continued therapy.

APA recommends clinically assessing patients receiving antipsychotic agents for abnormal involuntary movements at baseline and at each follow-up visit and assessing such patients using a structured instrument (e.g., the Abnormal Involuntary Movement Scale [AIMS], Dyskinesia Identification System: Condensed User Scale [DISCUS]) at least every 6 months in patients considered at high risk for tardive dyskinesia (e.g., patients ≥55 years of age; 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 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. In some jurisdictions, the frequency of monitoring for involuntary movements in individuals receiving antipsychotic therapy may be subject to local regulations.

Consider discontinuance of iloperidone if signs and symptoms of tardive dyskinesia appear. However, some patients may require treatment despite presence of the syndrome.

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); may also consider VMAT2 inhibitor therapy in patients with mild tardive dyskinesia based on factors such as patient preference, associated impairment, and effect on psychosocial functioning.

Metabolic Changes

Atypical antipsychotic agents are associated with metabolic changes, including hyperglycemia and diabetes mellitus, dyslipidemia, and weight gain. While all atypical antipsychotics produce some metabolic changes, each drug has its own specific risk profile. (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, reported in patients receiving atypical antipsychotic agents, including iloperidone. In a short-term controlled trial in patients with schizophrenia, 10.7% of iloperidone-treated patients experienced a shift from normal to high fasting glucose concentrations.

Periodically monitor patients with an established diagnosis of diabetes mellitus for worsening of glucose control and perform fasting blood glucose testing at baseline and periodically in patients with risk factors for diabetes (e.g., obesity, family history of diabetes). If manifestations of hyperglycemia occur in any iloperidone-treated patient, perform fasting blood glucose testing.

Some patients who developed hyperglycemia while receiving an atypical antipsychotic have required continuance of antidiabetic treatment despite discontinuance of the atypical antipsychotic; in other patients, hyperglycemia resolved with discontinuance of the antipsychotic.

Dyslipidemia

Undesirable changes in lipid parameters observed in patients treated with atypical antipsychotics. In a short-term study, patients receiving iloperidone (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 LDL, and 0.55 mg/dL in HDL and a mean decrease of about 0.8 mg/dL in fasting triglycerides.

Weight Gain

Weight gain observed with atypical antipsychotic therapy, including iloperidone. Mean weight gain of 2.1 kg reported during short- and long-term studies with iloperidone.

Manufacturer recommends clinical monitoring of weight during therapy.

Seizures

Seizures occurred in 0.1% of iloperidone-treated patients compared with 0.3% of placebo recipients in short-term clinical trials.

Use 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.

Orthostatic Hypotension and Syncope

Risk of orthostatic hypotension associated with dizziness, tachycardia, and syncope, particularly when initiating or reinitiating therapy or increasing the dosage, because of iloperidone’s α1-adrenergic blocking activity.

Syncope reported in 0.4% of iloperidone-treated patients when dosage was increased slowly as recommended in short-term clinical trials. Orthostatic hypotension reported in 3 or 5% of patients receiving iloperidone 10–16 or 20–24 mg daily, respectively. Increased incidence of orthostatic hypotension and syncope would be expected with more rapid dosage titration. (See Dosage under Dosage and Administration.)

Use with caution in patients with known cardiovascular disease (e.g., heart failure, history of MI, ischemic heart disease, conduction abnormalities), cerebrovascular disease, or conditions that would predispose patients to hypotension (e.g., dehydration, hypovolemia, concomitant antihypertensive therapy). Consider monitoring orthostatic vital signs in patients who are susceptible to hypotension.

Falls

May cause somnolence, postural hypotension, and motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries.

In patients with diseases, conditions or other drugs that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic therapy and repeat such testing periodically during long-term therapy.

Leukopenia, Neutropenia, and Agranulocytosis

Leukopenia and neutropenia temporally related to antipsychotic agents reported during clinical trial and/or postmarketing experience. Agranulocytosis (including fatal cases) also reported with other antipsychotic agents.

Possible risk factors for leukopenia and neutropenia include preexisting low WBC count and a history of drug-induced leukopenia or neutropenia. Monitor CBC frequently during the first few months of therapy in patients with such risk factors. Discontinue iloperidone at the first sign of a decline in WBC count in the absence of other causative factors.

Carefully monitor patients with neutropenia for signs and symptoms of infection (e.g., fever) and treat promptly if they occur. Discontinue iloperidone if severe neutropenia (ANC <1000/mm3) occurs; monitor WBC until recovery occurs.

Hyperprolactinemia

May cause elevated serum prolactin concentrations, which may persist during chronic administration and cause clinical disturbances (e.g., galactorrhea, amenorrhea, gynecomastia, impotence). Chronic hyperprolactinemia associated with hypogonadism may lead to decreased bone density in both females and males.

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).

If contemplating iloperidone therapy in a patient with previously detected breast cancer, consider that approximately one-third of human breast cancers are prolactin-dependent in vitro.

Body Temperature Regulation

Antipsychotic agents may disrupt ability to regulate core body temperature.

Use appropriate caution 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).

Dysphagia

Esophageal dysmotility and aspiration associated with the use of antipsychotic agents.

Aspiration pneumonia is a common cause of morbidity and mortality in geriatric patients. Use with caution in patients at risk for aspiration pneumonia.

Suicide

Attendant risk with psychotic illnesses; closely supervise high-risk patients. Prescribe in the smallest quantity consistent with good patient management to reduce the risk of overdosage.

Priapism

Priapism reported in patients receiving drugs with α-adrenergic blocking activity, including iloperidone. Severe priapism may require surgical intervention.

Cognitive and Motor Impairment

Judgment, thinking, or motor skills may be impaired. Somnolence (including sedation) reported in about 12% of patients receiving iloperidone dosages ≥10 mg daily. (See Advice to Patients.)

Specific Populations

Pregnancy

Limited available data with iloperidone in pregnant women not sufficient to inform a drug-associated risk for major birth defects and miscarriage. The drug was not teratogenic in animal studies; however, other adverse effects (e.g., prolonged duration of pregnancy and parturition; increased still births and early intrauterine deaths; developmental delays; decreased postpartum pup survival) were observed in some animal studies.

Risk for extrapyramidal and/or withdrawal symptoms (e.g., agitation, hypertonia, hypotonia, tardive dyskinetic-like symptoms, tremor, somnolence, respiratory distress, feeding disorder) in neonates exposed to antipsychotic agents during the third trimester. Symptoms have varied in severity; some infants recovered within hours to days without specific treatment while others required prolonged hospitalization. Monitor neonates for extrapyramidal and/or withdrawal symptoms; if such symptoms occur, manage appropriately.

National Pregnancy Registry for Atypical Antipsychotics: 866-961-2388 and [Web].

Lactation

Iloperidone distributes into milk in rats; not known whether iloperidone and/or its metabolites distribute into human milk. Effects of the drug on nursing infants and on milk production also not known.

Women receiving iloperidone should not breast-feed because of the potential for serious adverse reactions in breastfed infants.

Pediatric Use

Safety and efficacy not established in pediatric and adolescent patients.

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether they respond differently than younger adults.

Geriatric patients with dementia-related psychosis treated with iloperidone are at an increased risk of death; increased incidence of cerebrovascular events also observed with certain atypical antipsychotic agents. Iloperidone is not approved for the treatment of patients with dementia-related psychosis. (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis in Boxed Warning and see Cerebrovascular Events in Geriatric Patients with Dementia-related Psychosis under Cautions.)

Hepatic Impairment

Dosage adjustment not necessary in patients with mild hepatic impairment. Dosage adjustment may be necessary in patients with moderate hepatic impairment, if clinically indicated.

Not studied in patients with severe hepatic impairment; use not recommended. (See Special Populations under Pharmacokinetics.)

Renal Impairment

Renal impairment is unlikely to substantially alter the pharmacokinetics of iloperidone; the drug is highly metabolized (<1% excreted unchanged). (See Special Populations under Pharmacokinetics.) Routine dosage adjustment is not necessary.

Common Adverse Effects

Dizziness, somnolence or sedation, fatigue, dry mouth, nasal congestion, tachycardia, orthostatic hypotension, weight gain.

Interactions for Iloperidone

Metabolized principally by CYP3A4 and CYP2D6.

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

Iloperidone and its active metabolite P88 are not substrates of P-glycoprotein (P-gp). Iloperidone is a weak P-gp inhibitor.

Drugs Affecting Hepatic Microsomal Enzymes

CYP3A4 and CYP2D6 inhibitors: Potential pharmacokinetic interaction (inhibition of iloperidone clearance resulting in increased plasma concentrations). Reduce iloperidone dosage by 50% if used concomitantly with a potent inhibitor of CYP2D6 or CYP3A4; may resume previous iloperidone dosage upon discontinuance of the CYP2D6 or CYP3A4 inhibitor. Also reduce iloperidone dosage by about 50% when given in combination with both a CYP2D6 and CYP3A4 inhibitor.

Drug interaction studies have evaluated effects of certain potent CYP3A4 or CYP2D6 inhibitors on iloperidone pharmacokinetics (see Specific Drugs under Interactions). Concomitant administration with weaker CYP3A4 inhibitors not studied. Effects of other potent CYP2D6 inhibitors expected to be similar to those of fluoxetine or paroxetine.

Inhibitors or inducers of CYP isoenzymes 1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, or 2E1: Pharmacokinetic interactions are unlikely.

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP isoenzymes 1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4, or 3A5: Pharmacokinetic interactions are unlikely. (See Specific Drugs under Interactions.)

Drugs that Prolong QT Interval

Potential additive effect on QT-interval prolongation; avoid concomitant use of other drugs known to prolong the QTc interval. (See Prolongation of QT Interval under Cautions and also see Specific Drugs under Interactions.)

Specific Drugs

Drug

Interaction

Comments

Alcohol

Possible additive CNS effects

Avoid concomitant use

Antiarrhythmics, class IA and III (e.g., amiodarone, procainamide, quinidine, sotalol)

Increased risk of QT-interval prolongation

Avoid concomitant use

Anticholinergic agents

Possible disruption of body temperature regulation

Use with caution

Antipsychotic agents that prolong QT interval (e.g., chlorpromazine, haloperidol, olanzapine, pimozide, quetiapine, thioridazine, ziprasidone)

Increased risk of QT-interval prolongation

Avoid concomitant use

Clarithromycin

Possible increase in AUC of iloperidone and its P88 and P95 metabolites during concurrent administration

Use with caution and reduce iloperidone dosage by 50% during concurrent administration; resume previous iloperidone dosage upon discontinuance of clarithromycin

Reduce iloperidone dosage by about 50% if given concurrently with both clarithromycin (a CYP3A4 inhibitor) and a CYP2D6 inhibitor

CNS agents

Possible additive CNS effects

Use with caution

Dextromethorphan

17% increase in total exposure and 26% increase in peak plasma concentrations of dextromethorphan during concurrent administration

Fluoxetine

Approximate twofold to threefold increase in AUC of iloperidone and its P88 metabolite and 50% decrease in AUC of its P95 metabolite during concurrent administration in CYP2D6 extensive metabolizers

Single dose of iloperidone did not affect fluoxetine pharmacokinetics

Use with caution and reduce iloperidone dosage by 50% during concurrent administration; resume previous iloperidone dosage upon discontinuance of fluoxetine

Reduce iloperidone dosage by about 50% if given concurrently with both fluoxetine (a CYP2D6 inhibitor) and a CYP3A4 inhibitor

Gatifloxacin

Increased risk of QT-interval prolongation

Avoid concomitant use

Hypotensive agents

Possible additive hypotensive effects; may result in orthostatic hypotension and syncope

Use with caution; consider monitoring orthostatic vital signs

Itraconazole and ketoconazole

Concomitant administration of ketoconazole and iloperidone increased AUC of iloperidone and its P88 and P95 metabolites by 57, 55, and 35%, respectively

Use with caution and reduce iloperidone dosage by 50% during concurrent administration; resume previous iloperidone dosage upon discontinuance of itraconazole or ketoconazole

Reduce iloperidone dosage by about 50% if given concurrently with both a CYP2D6 inhibitor and either itraconazole or ketoconazole (CYP3A4 inhibitors)

Levomethadyl acetate (no longer commercially available in US)

Increased risk of QT-interval prolongation

Avoid concomitant use

Methadone

Increased risk of QT-interval prolongation

Avoid concomitant use

Midazolam

Steady-state iloperidone increased total exposure of midazolam by <50%; peak midazolam concentrations not affected

Moxifloxacin

Increased risk of QT-interval prolongation

Avoid concomitant use

Paroxetine

Approximate 1.6-fold increase in mean steady-state peak plasma concentrations of iloperidone and its P88 metabolite and 50% decrease in mean steady-state peak plasma concentrations of its P95 metabolite during concurrent administration

Use with caution and reduce iloperidone dosage by 50% during concurrent administration; resume previous iloperidone dosage upon discontinuance of paroxetine

Reduce iloperidone dosage by about 50% if given concurrently with both paroxetine (a CYP2D6 inhibitor) and a CYP3A4 inhibitor

Pentamidine

Increased risk of QT-interval prolongation

Avoid concomitant use

Smoking

Pharmacokinetic interaction unlikely

Tetrabenazine

Increased risk of QT-interval prolongation

Avoid concomitant use

Iloperidone Pharmacokinetics

Absorption

Bioavailability

Well absorbed following oral administration; peak plasma concentrations achieved within 2–4 hours. Steady-state concentrations of iloperidone and its 2 main metabolites, P88 and P95, attained within 3–4 days.

Food

Standard high-fat meal did not substantially affect peak plasma concentrations or AUCs of iloperidone, P88, or P95; however, time to reach peak plasma concentrations was delayed by 1, 2, and 6 hours, respectively.

Special Populations

In patients with mild hepatic impairment, the pharmacokinetic profiles of iloperidone, P88, and P95 (total or unbound) were not substantially altered in a single-dose study; however, exposure to P88 (unbound) was increased twofold and more variable in patients with moderate hepatic impairment compared with healthy individuals. Not studied in patients with severe hepatic impairment.

Renal impairment (Clcr <30 mL/minute) minimally affected peak plasma concentrations of iloperidone, P88, and P95 in a single-dose study. AUCs increased by 24% for iloperidone, decreased by 6% for P88, and increased by 52% for P95.

CYP2D6 poor metabolizers have higher exposure to iloperidone compared with extensive metabolizers.

Distribution

Extent

Iloperidone distributes into milk in rats; not known whether iloperidone and its metabolites distribute into human milk.

Plasma Protein Binding

Iloperidone and its metabolites are approximately 97 and 92% protein bound, respectively.

Elimination

Metabolism

Metabolized mainly by carbonyl reduction, hydroxylation (mediated by CYP2D6), and O-demethylation (mediated by CYP3A4) to 2 main metabolites, P95 and P88; these metabolites undergo further oxidation and/or conjugation with glucuronic acid. (See Actions.)

Elimination Route

Radiolabeled drug is mostly eliminated in urine (about 58 and 45% in extensive and poor metabolizers of CYP2D6, respectively), with feces accounting for about 20% (extensive metabolizers) to 22% (poor metabolizers).

Half-life

Mean elimination half-lives for 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.

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C); protect from light and moisture.

Actions

  • Exact mechanism of action of iloperidone in schizophrenia is unknown; efficacy may be mediated through a combination of antagonist activity at central dopamine type 2 (D2) and serotonin type 2 (5-hydroxytryptamine [5-HT2]) receptors.

  • Functions as an antagonist and exhibits high affinity for 5-HT2A, D2 and D3, and α1-adrenergic receptors. Demonstrates moderate affinity for D4 and 5-HT6 and 5-HT7 receptors and low affinity for 5-HT1A, D1, and histamine H1 receptors. Possesses no appreciable affinity for muscarinic cholinergic receptors.

  • Iloperidone has 2 main metabolites, P88 and P95; the affinity of P88 is generally equal to or less than that of iloperidone while P95 only demonstrates affinity for 5-HT2A and α1A-, α1B-, α1D-, and α2C-adrenergic receptors.

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. Inform patients and caregivers that iloperidone is not approved for treating geriatric patients with dementia-related psychosis.

  • Importance of patients immediately informing their clinician if they feel faint, lose consciousness, or have heart palpitations. Importance of counseling patients not to take iloperidone with other drugs that prolong the QT interval. Importance of instructing patients to inform clinicians that they are taking iloperidone before they take any new drug.

  • Importance of informing patients and caregivers about the risk of NMS, which can cause high fever, stiff muscles, sweating, fast or irregular heart beat, change in BP, confusion, and kidney damage.

  • 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. Importance of patients being aware of the symptoms of hyperglycemia (e.g., increased thirst, increased urination, increased appetite, weakness). Importance of informing patients 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; patients who develop symptoms of hyperglycemia during therapy should have their blood glucose assessed.

  • Risk of orthostatic hypotension, especially when initiating or reinitiating treatment or increasing the dosage.

  • Risk of somnolence (i.e., sleepiness, drowsiness) and impaired judgment, thinking, or motor skills; importance of advising patients to exercise caution when performing activities requiring mental alertness (e.g., driving, operating hazardous machinery) until they gain experience with the drug’s effects.

  • Importance of avoiding alcohol during iloperidone therapy.

  • Importance of avoiding overheating or dehydration.

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, dietary supplements, and/or herbal products, as well as any concomitant illnesses (e.g., cardiovascular disease, diabetes mellitus, seizures).

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed. 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). Importance of advising patients not to stop taking iloperidone if they become pregnant without consulting their clinician; abruptly stopping antipsychotic agents may cause complications. Importance of advising patients not to breast-feed during iloperidone therapy.

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

Preparations

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.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Iloperidone

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

1 mg*

Fanapt

Vanda

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 DI Essentials™. © Copyright 2022, Selected Revisions December 21, 2021. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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