Iloperidonesee

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

• 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.^{1 22 23}

  
  


• 
  

  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.^{1 23}

  
  


• 
  

  Most fatalities appeared to result from cardiovascular-related events (e.g., heart failure, sudden death) or infections (mostly pneumonia).^{1 23}

  
  


• 
  

  Observational studies suggest that conventional or first-generation antipsychotic agents also may increase mortality in such patients.^{1 22}

  
  


• 
  

  Antipsychotic agents, including iloperidone, are not approved for the treatment of dementia-related psychosis.^{1 22 23}

  
  

Introduction

Piperidinyl-benzisoxazole derivative; atypical or second-generation antipsychotic agent.^{1 3 4 6 7 8 9 10 11 12 13 14 15 87}

Uses for Iloperidonesee

Schizophrenia

Acute treatment of schizophrenia in adults.^{1 2 4 5}

American Psychiatric Association (APA) considers most atypical antipsychotic agents first-line drugs for the management of the acute phase of schizophrenia (including first psychotic episodes).¹⁶

Patients who do not respond to or tolerate one drug may be successfully treated with an agent from a different class or with a different adverse effect profile.^{16 17 18 19}

When deciding among treatment alternatives, consider that iloperidone may prolong the QT interval.¹ 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.¹ In many cases, other drugs should be tried first.¹ (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.¹ (See Dosage under Dosage and Administration.) Keep this delay in mind when selecting an agent for acute treatment of schizophrenia.¹

Iloperidonesee Dosage and Administration

General

• 
  

  When switching from other antipsychotic agents to iloperidone, abrupt discontinuance of previous agent may be acceptable for some patients with schizophrenia, but gradual discontinuance may be most appropriate for others.¹ In all cases, minimize period of overlapping antipsychotic administration.¹

  
  

Administration

Oral Administration

Administer tablets orally twice daily without regard to meals.¹ However, administration with food may minimize adverse effects.⁸

Dosage

Must titrate slowly from a low initial dosage to avoid orthostatic hypotension;^{1 87} therefore, symptom control may be delayed during first 1–2 weeks of therapy.¹ (See Orthostatic Hypotension and Syncope under Cautions and see Schizophrenia under Uses.)

Follow initial titration schedule if treatment has been interrupted for >3 days.¹

Some of the drug’s adverse effects are dose related.¹

Adults

Schizophrenia

Oral

For acute treatment, initial dosage is 1 mg twice daily.^{1 87} Dosage increases to reach the recommended target dosage range of 6–12 mg twice daily may be made with daily dosage adjustments to 2, 4, 6, 8, 10, and 12 mg twice daily on days 2, 3, 4, 5, 6, and 7, respectively.^{1 87}

Optimum duration of therapy is not known, but maintenance therapy with antipsychotics is well established.^{1 16} In responsive patients, continue drug therapy beyond the acute response and as long as clinically necessary and tolerated; periodically reassess need for continued therapy.^{1 16}

In patients with remitted first or multiple episodes, APA recommends either indefinite maintenance therapy or gradual discontinuance of the antipsychotic with close follow-up and a plan to reinstitute treatment upon symptom recurrence.¹⁶ Consider antipsychotic therapy discontinuance only after ≥1 year of symptom remission or optimal response while receiving the drug.¹⁶ Indefinite maintenance antipsychotic treatment is recommended if patient has experienced multiple previous psychotic episodes or 2 episodes within 5 years.¹⁶

Prescribing Limits

Adults

Schizophrenia

Oral

Maximum 12 mg twice daily.¹

Special Populations

Hepatic Impairment

Use not recommended in patients with any degree of hepatic impairment.^{1 15} (See Special Populations under Pharmacokinetics.)

Renal Impairment

Routine dosage adjustment not required.¹ (See Renal Impairment under Cautions and see Special Populations under Pharmacokinetics.)

Geriatric Patients

Routine dosage adjustment not required.¹

Gender or Race

No dosage adjustment necessary based on gender or race.¹

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).¹ May resume previous iloperidone dosage upon discontinuance of the potent CYP2D6 or CYP3A4 inhibitor.¹

Also reduce iloperidone dosage by 50% when given in combination with both a CYP2D6 and CYP3A4 inhibitor.¹ (See Interactions.)

Poor Metabolizers of CYP2D6

Reduce dosage by 50%;¹ exposure to iloperidone is higher in poor metabolizers of CYP2D6 than in extensive metabolizers.^{1 10} Laboratory tests are available to identify poor CYP2D6 metabolizers.¹ (See Special Populations and also see Elimination under Pharmacokinetics.)

Cautions for Iloperidonesee

Contraindications

• 
  

  Known hypersensitivity (e.g., pruritus, urticaria) to iloperidone or to any ingredient in the formulation.¹

  
  

Warnings/Precautions

Warnings

Increased Mortality in Geriatric Patients with Dementia-related Psychosis

Increased risk of death with use of either conventional (first-generation) or atypical (second-generation) antipsychotics in geriatric patients with dementia-related psychosis.^{1 22 23 25}

Antipsychotic agents, including iloperidone, are not approved for the treatment of dementia-related psychosis.^{1 22 23} (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis in Boxed Warning, see Cerebrovascular Events in Geriatric Patients with Dementia-related Psychosis under Cautions, and see Dysphagia 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.¹ Iloperidone is not approved for the treatment of dementia-related psychosis.¹ (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis in Boxed Warning.)

Prolongation of QT Interval

Corrected QT (QT_c) interval prolonged by 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} CYP2D6 or CYP3A4 inhibition increases this effect; under conditions of both CYP2D6 and CYP3A4 inhibition, mean QT_c interval (corrected using Fridericia’s formula) was prolonged by about 19 msec at dosage of 12 mg twice daily.¹ No cases of torsades de pointes or other severe cardiac arrhythmias reported during premarketing clinical trials.¹

Factors that may increase the risk of torsades de pointes and/or sudden death in association with drugs that prolong the QT_c interval include 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 MI, and/or uncompensated heart failure.¹

Avoid concomitant use of other drugs known to prolong the QT_c interval (see Interactions).¹ Also avoid use in patients with congenital QT-interval prolongation or a history of cardiac arrhythmias.¹

Use with caution in patients concurrently receiving drugs that inhibit iloperidone’s metabolism and in patients with reduced CYP2D6 activity (see Special Populations under Dosage and Administration and see Interactions).¹

Hypokalemia and/or hypomagnesemia may increase the risk of QT prolongation and cardiac arrhythmias.¹ Manufacturer recommends baseline and periodic monitoring of serum potassium and magnesium in patients at risk for disturbances of these electrolytes.¹

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).¹

Discontinue iloperidone therapy in patients with persistent QT_c interval measurements >500 msec.¹ Further evaluation, including cardiac monitoring, is recommended in patients with symptoms suggestive of cardiac arrhythmias (e.g., dizziness, palpitations, syncope).¹

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.¹

Immediately discontinue therapy and initiate supportive and symptomatic therapy if NMS occurs.¹ Careful monitoring recommended if therapy is reinstituted following recovery; the risk that NMS can recur must be considered.¹

Tardive Dyskinesia

Tardive dyskinesia, a syndrome of potentially irreversible, involuntary, dyskinetic movements, reported with use of antipsychotic agents.¹

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.¹ In patients requiring chronic treatment, use smallest dosage and shortest duration of treatment producing a satisfactory clinical response; periodically reassess need for continued therapy.¹

APA recommends assessing patients receiving atypical antipsychotic agents for abnormal involuntary movements every 12 months; for patients at increased risk for tardive dyskinesia, assess every 6 months.¹⁶ Consider discontinuance of iloperidone if signs and symptoms of tardive dyskinesia appear.¹ However, some patients may require treatment despite presence of the syndrome.¹

Hyperglycemia and Diabetes Mellitus

Hyperglycemia, sometimes severe and associated with ketoacidosis, hyperosmolar coma, or death, reported in patients receiving atypical antipsychotic agents, including iloperidone.^{1 26 27 28 29 30 31 32 33 34 35 36 39 52 53 54 58 77} Clinically important differences between iloperidone and placebo in mean change from baseline to end point in serum glucose concentrations not observed in short-term clinical trials.¹

Closely monitor patients with preexisting 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).^{1 26 27 28 29 30 31 32 33 34 35 36 37} If manifestations of hyperglycemia occur in any iloperidone-treated patient, perform fasting blood glucose testing.^{1 26 27 28 29 30 31 32 33 34 35 36 37}

Some patients who developed hyperglycemia while receiving an atypical antipsychotic have required continuance of antidiabetic treatment despite discontinuance of the suspect drug; in other patients, hyperglycemia resolved with discontinuance of the antipsychotic.^{1 26 27 28 29 30 31 32 33 34 35 36 37 58}

Weight Gain

Mean weight gain of 2 kg reported during short-term studies; weight gain was ≥7% of baseline body weight in 12 or 18% of patients receiving iloperidone 10–16 or 20–24 mg daily, respectively.¹ (See Hyperglycemia and Diabetes Mellitus under Cautions.)

Seizures

Seizures occurred in 0.1% of iloperidone-treated patients compared with 0.3% of placebo recipients in short-term clinical trials.¹

Use with caution in patients with a history of seizures or with conditions that may lower the seizure threshold (e.g., dementia of the Alzheimer’s type); conditions that lower the seizure threshold may be more prevalent in patients ≥65 years of age.¹

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.^{1 5}

Syncope reported in 0.4% of iloperidone-treated patients when dosage was increased slowly as recommended in short-term clinical trials.¹ Orthostatic hypotension reported in 3 or 5% of patients receiving iloperidone 10–16 or 20–24 mg daily, respectively.¹ Increased incidence of orthostatic hypotension and syncope would be expected with more rapid dosage titration.^{1 14} (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).¹ Consider monitoring orthostatic vital signs in patients who are susceptible to hypotension.¹

Hematologic Effects

Leukopenia and neutropenia temporally related to antipsychotic agents.^{1 78} Agranulocytosis (including fatal cases) also reported with antipsychotic agents.¹

Possible risk factors for leukopenia and neutropenia include preexisting low WBC count and a history of drug-induced leukopenia or neutropenia.^{1 78} Monitor CBC frequently during the first few months of therapy in patients with such risk factors.¹ Discontinue iloperidone at the first sign of a decline in WBC count in the absence of other causative factors.¹

Carefully monitor patients with clinically important neutropenia for signs and symptoms of infection (e.g., fever) and treat promptly if they occur.¹ Discontinue iloperidone if severe neutropenia (ANC <1000/mm³) occurs; monitor WBC until recovery occurs.¹

Hyperprolactinemia

May cause elevated serum prolactin concentrations, which may persist during chronic administration and cause clinical disturbances (e.g., galactorrhea, amenorrhea, gynecomastia, impotence).^{1 10 16} Chronic hyperprolactinemia associated with hypogonadism may lead to decreased bone density in both females and males.^{1 16}

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 16}

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.^{1 16}

Body Temperature Regulation

Antipsychotic agents may disrupt ability to regulate core body temperature.¹

Use appropriate caution in patients subjected to 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 associated with the use of antipsychotic agents.¹

Aspiration pneumonia is a common cause of morbidity and mortality in geriatric patients, particularly those with advanced Alzheimer’s dementia.¹ Use with caution in patients at risk for aspiration pneumonia.¹ Iloperidone is not approved for the treatment of patients with dementia-related psychosis.¹ (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis in Boxed Warning.)

Suicide

Attendant risk with psychotic illnesses; closely supervise high-risk patients.¹ Prescribe in the smallest quantity consistent with good patient management to reduce the risk of overdosage.¹

Priapism

Priapism reported in patients receiving drugs with α-adrenergic blocking activity, including iloperidone.¹ Severe priapism may require surgical intervention.¹

Cognitive and Motor Impairment

Judgment, thinking, or motor skills may be impaired.¹ Somnolence (including sedation) reported in about 12% of patients receiving iloperidone dosages ≥10 mg daily.¹ (See Advice to Patients.)

Specific Populations

Pregnancy

Category C.¹

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; monitor neonates exhibiting such symptoms.^{1 88 89 90} Symptoms were self-limiting in some neonates but varied in severity; some infants required intensive support and prolonged hospitalization.^{1 88 89 90}

Lactation

Iloperidone distributes into milk in rats; not known whether iloperidone and/or its metabolites distribute into human milk.¹ Women receiving iloperidone should not breast-feed.¹

Pediatric Use

Safety and efficacy not established in pediatric and adolescent patients.¹

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether they respond differently than younger adults.¹

Geriatric patients with dementia-related psychosis treated with either conventional or atypical antipsychotic agents are at an increased risk of death;^{1 22 23} increased incidence of cerebrovascular events also observed with certain atypical antipsychotic agents.¹ Iloperidone is not approved for the treatment of dementia-related psychosis.¹ (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

Use not recommended in patients with any degree of hepatic impairment.^{1 15} (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).^{1 15} (See Special Populations under Pharmacokinetics.) Routine dosage adjustment is not necessary.¹

Common Adverse Effects

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} weight gain.^{1 2}

Interactions for Iloperidonesee

Primarily metabolized by CYP2D6 and CYP3A4.^{1 8 9 10} Iloperidone is not a substrate for CYP isoenzymes 1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, or 2E1 and does not induce isoenzymes 1A2, 2C8, 2C9, 2C19, 3A4, or 3A5 in vitro.¹

Drugs Affecting Hepatic Microsomal Enzymes

CYP3A4 and CYP2D6 inhibitors: Potential pharmacokinetic interaction (inhibition of iloperidone clearance resulting in increased plasma concentrations).¹ 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.¹ Also reduce iloperidone dosage by 50% when given in combination with both a CYP2D6 and CYP3A4 inhibitor.¹

Drug interaction studies have evaluated effects of certain potent CYP3A4 or CYP2D6 inhibitors on iloperidone pharmacokinetics (see Specific Drugs under Interactions).¹ Concomitant administration with weaker CYP3A4 inhibitors not studied.¹ Effects of other potent CYP2D6 inhibitors expected to be similar to those of fluoxetine or paroxetine.¹

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

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.¹ (See Specific Drugs under Interactions.)

Iloperidone does not substantially inhibit the metabolism of drugs metabolized by CYP isoenzymes 1A1, 1A2, 2A6, 2B6, 2C8, 2C9, or 2E1 in vitro.¹

Drugs that Prolong QT Interval

Potential additive effect on QT-interval prolongation; avoid concomitant use of other drugs known to prolong the QT_c interval.^{1 42 81 82 83 87} (See Prolongation of QT Interval under Cautions and see Specific Drugs under Interactions.)

Specific Drugs

Drug	Interaction	Comments
Alcohol	Possible additive CNS effects1	Avoid concomitant use1
Antiarrhythmics, class IA and III (e.g., amiodarone, procainamide, quinidine, sotalol)	Increased risk of QT-interval prolongation1	Avoid concomitant use1
Anticholinergic agents	Possible disruption of body temperature regulation1	Use with caution1
Antipsychotic agents that prolong QT interval (e.g., asenapine, chlorpromazine, haloperidol, olanzapine, paliperidone, pimozide, quetiapine, thioridazine, ziprasidone)	Increased risk of QT-interval prolongation1 42 81	Avoid concomitant use1
Clarithromycin	Possible increase in AUCs of iloperidone and its P88 and P95 metabolites during concurrent administration1	Use with caution and reduce iloperidone dosage by about 50% during concurrent administration; resume previous iloperidone dosage upon discontinuance of clarithromycin1 Reduce iloperidone dosage by about 50% if given concurrently with both clarithromycin (a CYP3A4 inhibitor) and a CYP2D6 inhibitor1
CNS agents	Possible additive CNS effects1	Use with caution1
Dextromethorphan	17% increase in total exposure and 26% increase in peak plasma concentrations of dextromethorphan during concurrent administration1
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 extensive CYP2D6 metabolizers1 Single dose of iloperidone did not affect fluoxetine pharmacokinetics1	Use with caution and reduce iloperidone dosage by 50% during concurrent administration; resume previous iloperidone dosage upon discontinuance of fluoxetine1 Reduce iloperidone dosage by about 50% if given concurrently with both fluoxetine (a CYP2D6 inhibitor) and a CYP3A4 inhibitor1
Gatifloxacin	Increased risk of QT-interval prolongation1	Avoid concomitant use1
Hypotensive agents	Possible additive hypotensive effects; may result in orthostatic hypotension and syncope1	Use with caution; consider monitoring orthostatic vital signs and reducing iloperidone dosage if hypotension develops1
Itraconazole and ketoconazole	Concomitant administration of ketoconazole and iloperidone increased AUCs of iloperidone and its P88 and P95 metabolites by 57, 55, and 35%, respectively1	Use with caution and reduce iloperidone dosage by about 50% during concurrent administration; resume previous iloperidone dosage upon discontinuance of itraconazole or ketoconazole1 Reduce iloperidone dosage by about 50% if given concurrently with both a CYP2D6 inhibitor and either itraconazole or ketoconazole (CYP3A4 inhibitors)1
Levomethadyl acetate (no longer commercially available in US)	Increased risk of QT-interval prolongation1	Avoid concomitant use1
Methadone	Increased risk of QT-interval prolongation1	Avoid concomitant use1
Moxifloxacin	Increased risk of QT-interval prolongation1	Avoid concomitant use1
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 administration1	Use with caution and reduce iloperidone dosage by 50% during concurrent administration; resume previous iloperidone dosage upon discontinuance of paroxetine1 Reduce iloperidone dosage by about 50% if given concurrently with both paroxetine (a CYP2D6 inhibitor) and a CYP3A4 inhibitor1
Pentamidine	Increased risk of QT-interval prolongation1	Avoid concomitant use1
Smoking	Pharmacokinetic interaction unlikely1
Tetrabenazine	Increased risk of QT-interval prolongation1 83	Avoid concomitant use1 83

Iloperidonesee Pharmacokinetics

Absorption

Bioavailability

Well absorbed following oral administration; peak plasma concentrations achieved within 2–4 hours.^{1 10 12 15} Steady-state concentrations of iloperidone and its 2 main metabolites, P88 and P95, attained within 3–4 days.^{1 10}

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.^{1 7 9 10 15}

Special Populations

In patients with mild or moderate hepatic impairment, the pharmacokinetic profiles of iloperidone and P88 were not substantially altered in a single-dose study; however, exposure to P88 was substantially increased compared with healthy individuals.^{13 15}

Renal impairment (Cl_cr <30 mL/minute) minimally affected peak plasma concentrations of iloperidone, P88, and P95 in a single-dose study.¹ AUCs increased by 24% for iloperidone, decreased by 6% for P88, and increased by 52% for P95.¹

Poor metabolizers of CYP2D6 have higher exposure to iloperidone compared with extensive metabolizers.^{1 10}

Distribution

Extent

Iloperidone distributes into milk in rats; not known whether iloperidone and its metabolites distribute into human milk.¹

Plasma Protein Binding

Iloperidone and its metabolites: Approximately 93–95%.^{1 8 12 13}

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.^{1 8 9 10} (See Actions.)

Elimination Route

Radiolabeled drug is mostly eliminated in urine (about 58 and 45% in extensive and poor metabolizers of CYP2D6, respectively),¹ with feces accounting for about 20% (extensive metabolizers) to 22% (poor metabolizers).¹

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.^{1 10 15}

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C); protect from light and moisture.¹

ActionsActions

• 
  

  Exact mechanism of action of iloperidone and other antipsychotic agents 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.^{1 2 3 4 6 15}

  
  


• 
  

  Exhibits high affinity for 5-HT_2A and D₂ and D₃ receptors; moderate affinity for D₄, 5-HT₆ and 5-HT₇, and α₁-adrenergic 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 15} Possesses no appreciable affinity for muscarinic cholinergic receptors.^{1 7 11 15}

  
  


• 
  

  Functions as an antagonist at D₂ and D₃, 5-HT_1A, and α₁- and α_2C-adrenergic receptors.¹

  
  


• 
  

  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-HT_2A and α_1A-, α_1B-, α_1D-, and α_2C-adrenergic receptors.^{1 8 10 13 15}

  
  

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 22 23} Importance of informing patients and caregivers 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 Importance of instructing patients to inform clinicians that they are taking iloperidone before they take any new drug.¹

  
  


• 
  

  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, and confusion.¹

  
  


• 
  

  Risk of orthostatic hypotension, especially when initiating or reinitiating treatment or increasing the dosage.¹

  
  


• 
  

  Importance of informing patients in whom chronic iloperidone use is contemplated about the risk of tardive dyskinesia.¹ Importance of informing patients to report any muscle movements that cannot be stopped to a healthcare professional.¹

  
  


• 
  

  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.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, as well as 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 (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.)

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Iloperidone

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets	1 mg	Fanapt	Novartis
		2 mg	Fanapt	Novartis
		4 mg	Fanapt	Novartis
		6 mg	Fanapt	Novartis
		8 mg	Fanapt	Novartis
		10 mg	Fanapt	Novartis
		12 mg	Fanapt	Novartis
	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	Novartis

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions