Iloperidone

Pronunciation: ilo-PER-i-done
Class: Antipsychotic

Trade Names

Fanapt
- Tablets, oral 1 mg
- Tablets, oral 2 mg
- Tablets, oral 4 mg
- Tablets, oral 6 mg
- Tablets, oral 8 mg
- Tablets, oral 10 mg
- Tablets, oral 12 mg
- Titration Pack contains two 1 mg, two 2 mg, two 4 mg, and two 6 mg oral tablets (total of 8 tablets)

Pharmacology

Exact mechanism of antipsychotic action is unknown. It is proposed that efficacy is caused by dopamine type 2 and serotonin type 2 antagonisms.

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Pharmacokinetics

Absorption

Relative bioavailability is 96% compared with oral solution. T max is 2 to 4 h. Steady state is attained within 3 to 4 days. Administration with a high-fat meal delayed T max by 1 h.

Distribution

Vd is 1,340 to 2,800 L. Protein binding is approximately 95%.

Metabolism

Primarily metabolized in the liver by carbonyl reduction, CYP2D6, and CYP3A4 to metabolites P95 and P88.

Elimination

Elimination mainly through hepatic metabolism by CYP2D6 and CYP3A4. Mean elimination half-lives for iloperidone, P88, and P95 in CYP2D6 extensive metabolizers are 18, 26, and 23 h, respectively, and in poor metabolizers are 33, 37, and 31 h, respectively.

Special Populations

Renal Function Impairment

Unlikely to have impact on the pharmacokinetics.

Hepatic Function Impairment

Pharmacokinetic studies have not been conducted.

Elderly

No dosage adjustment recommended.

Gender

No dosage adjustment recommended.

Race

No dosage adjustment recommended.

Smoking

No effect on pharmacokinetics.

Indications and Usage

Treatment of adults with schizophrenia.

Contraindications

Hypersensitivity to iloperidone or any component of the product.

Dosage and Administration

Schizophrenia
Adults

PO Starting dosage is 1 mg twice daily. Increases to reach target dosage range of 6 to 12 mg twice daily may be made with adjustments to 2 mg twice daily, 4 mg twice daily, 6 mg twice daily, 8 mg twice daily, 10 mg twice daily, and 12 mg twice daily on days 2, 3, 4, 5, 6, and 7, respectively. Max is 12 mg twice daily (24 mg/day).

Dosage adjustments CYP2D6 and CYP3A4 inhibitors

Reduce dose by 50% when administered with CYP2D6 (eg, fluoxetine, paroxetine) and CYP3A4 inhibitors (eg, clarithromycin, ketoconazole). When inhibitor is withdrawn, dose may be increased.

CYP2D6 poor metabolizers

Reduce dose by 50% for poor metabolizers of CYP2D6.

General Advice

  • Administer without regard to meals.
  • Must be titrated slowly from a low starting dose to avoid orthostatic hypotension.
  • It is recommended that the initiation titration schedule be followed whenever patients are off iloperidone for more than 3 days.

Storage/Stability

Store between 59° and 86°F. Protect from light and moisture.

Drug Interactions

Abiraterone

Abiraterone plasma concentrations may be elevated, increasing the pharmacologic effects and risk of adverse reactions. Avoid coadministration.

Alcohol, CNS depressants

May cause additive CNS depressant effects. Use with caution. Avoid concurrent use of alcohol.

Antihypertensives

May enhance hypotensive effects of some antihypertensives. Monitor orthostatic vital signs.

CYP2D6 inhibitors (eg, fluoxetine, paroxetine)

May increase iloperidone plasma concentrations. During coadministration, reduce iloperidone dose by 50%. When the CYP2D6 inhibitor is discontinued, increase the dose of iloperidone to the previous level.

CYP3A4 inhibitors (eg, clarithromycin, ketoconazole)

May increase iloperidone plasma concentrations. During coadministration, reduce iloperidone dose by 50%. When the CYP2D6 inhibitor is discontinued, increase the dose of iloperidone to the previous level.

Dextromethorphan

Coadministration may increase the C max and AUC of dextromethorphan. The interaction is not likely to be clinically important.

Metoclopramide

Coadministration may increase the risk of extrapyramidal reactions. Coadministration is contraindicated.

QT interval–prolonging drugs (eg, antiarrhythmic agents [eg, amiodarone, bretylium, disopyramide, dofetilide, procainamide, propafenone, quinidine, sotalol], arsenic trioxide, chlorpromazine, cisapride, dasatinib, dolasetron, droperidol, lapatinib, mefloquine, mesoridazine, methadone, moxifloxacin, nilotinib, pentamidine, pimozide, romidepsin, tacrolimus, thioridazine, vandetanib, ziprasidone)

The risk of life-threatening cardiac arrhythmias, including torsades de pointes, may be increased. Iloperidone should not be administered with any other drug that prolongs the QT interval.

Adverse Reactions

Cardiovascular

Tachycardia (12%); orthostatic hypotension (5%); hypotension (3%); palpitations (at least 1%).

CNS

Dizziness (20%); somnolence (15%); fatigue (6%); extrapyramidal disorder (5%); lethargy, tremor (3%); akathisia, dyskinesia (2%); aggression, delusion, restlessness (at least 1%); bradykinesia, dystonia (1%).

Dermatologic

Rash (3%).

GI

Dry mouth, nausea (10%); diarrhea (7%); abdominal discomfort (3%).

Genitourinary

Ejaculation failure (2%); erectile dysfunction, urinary incontinence (at least 1%).

Lab Tests

Hematocrit low (1%).

Metabolic-Nutritional

Weight increased (9%); weight decreased (at least 1%).

Musculoskeletal

Arthralgia, musculoskeletal stiffness (3%); muscle spasms, myalgia (at least 1%).

Ophthalmic

Vision blurred (3%); conjunctivitis (including allergic) (at least 1%).

Respiratory

Nasal congestion (8%); nasopharyngitis (4%); upper respiratory tract infection (3%); dyspnea (2%).

Precautions

Warnings

Increased mortality in elderly patients with dementia-related psychosis

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. During the course of a typical 10-week trial, the rate of death in drug-treated patients was approximately 4.5% compared with a rate of approximately 2.6% in the placebo group. Although the causes of death varied, most of the deaths appeared to be CV (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature. Iloperidone is not approved for the treatment of patients with dementia-related psychosis.


Monitor

Monitor serum potassium and magnesium in patients at risk for electrolyte disturbances. Monitor orthostatic vital signs in patients who are vulnerable to hypotension. Periodically reassess patients to determine the need for continued treatment. Suicide attempt is inherent in psychotic illnesses; closely monitor high-risk patients during drug therapy. Monitor for signs and symptoms of NMS.

Frequently monitor CBC during the first few months of therapy in patients with a history of clinically significant low WBC or drug-induced leukopenia/neutropenia. Carefully monitor patients with neutropenia for signs and symptoms of infection.

Monitor diabetic patients regularly for worsening of glucose control. Monitor all patients for symptoms of hyperglycemia, including polydipsia, polyuria, polyphagia, and weakness. Ensure that patients with risk factors for diabetes mellitus (eg, obesity, family history of diabetes) who are starting atypical antipsychotic therapy undergo fasting blood glucose testing at the beginning of treatment and periodically thereafter.


Pregnancy

Category C . Neonates exposed to antipsychotics during the third trimester of pregnancy are at risk of extrapyramidal and/or withdrawal symptoms.

Lactation

Unknown.

Children

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

Elderly

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death compared with placebo. Cerebrovascular events (eg, cerebrovascular accidents, transient ischemic attack), including fatalities, have been seen in elderly patients with dementia-related psychoses.

Hypersensitivity

Reactions have included pruritus and urticaria.

Hepatic Function

Not recommended for patients with hepatic impairment.

Hazardous Tasks

Judgment, thinking, or motor skills may be impaired.

Body temperature regulation

Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents.

Dysphagia

Esophageal dysmotility and aspiration have been associated with antipsychotic drugs. Use iloperidone cautiously in patients at risk for aspiration pneumonia.

Hematologic effects

Leukopenia/neutropenia and agranulocytosis have been reported.

Hyperglycemia and diabetes mellitus

Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported.

Hyperprolactinemia

Prolactin levels may be elevated.

NMS

Has occurred and is potentially fatal. Signs and symptoms include altered mental status, diaphoresis, hyperpyrexia, irregular BP, irregular pulse, muscle rigidity, and tachycardia.

Orthostatic hypotension

May induce orthostatic hypotension associated with dizziness, tachycardia, and syncope.

Priapism

May occur; severe priapism may require surgical intervention.

QT prolongation

Because QTc prolongation may occur, avoid use in patients receiving other drugs that prolong the QTc interval and in patients with congenital long QT syndrome or history of cardiac arrhythmias. Use with caution in patients with known CV disease (eg, heart failure, history of MI). Hypokalemia and/or hypomagnesemia may increase risk of QT prolongation.

Seizures

Use with caution in patients with a history of seizures or with conditions that potentially lower seizure threshold.

Suicide

Possible suicide attempts are inherent in psychotic illness. Closely supervise high-risk patients. Prescribe the smallest quantity consistent with good patient management.

Tardive dyskinesia

Syndrome of potentially irreversible involuntary dyskinetic movements may develop. Prevalence is higher in elderly patients, especially women. Use lowest effective dose for shortest period of time needed.

Weight gain

Weight gain of 7% or more of body weight may occur.

Overdosage

Symptoms

Drowsiness, extrapyramidal symptoms, hypotension, QT prolongation, sedation, tachycardia.

Patient Information

  • Instruct patients to take the dose twice daily as prescribed, without regard to meals.
  • Advise patients to consult their health care provider immediately if they feel faint, lose consciousness, or have heart palpitations. Counsel patients not to take iloperidone with other drugs that cause QT interval prolongation. Tell patients to inform all of their health care providers that they are taking iloperidone before any new drug is taken.
  • Counsel patients and caregivers that a potentially fatal symptom complex, sometimes referred to as NMS, has been reported in association with administration of antipsychotic drugs. Signs and symptoms of NMS include altered mental status, evidence of autonomic instability (eg, cardiac dysrhythmia, diaphoresis, irregular pulse or blood pressure, tachycardia), hyperpyrexia, and muscle rigidity.
  • Advise patients of the risk of orthostatic hypotension, particularly at the time of initiating treatment, reinitiating treatment, or increasing the dose.
  • Because iloperidone may have the potential to impair judgment, thinking, or motor skills, caution patients about operating hazardous machinery, including automobiles, until they are reasonably certain that iloperidone therapy does not affect them adversely.
  • Advise patients to notify their health care provider if they become pregnant or intend to become pregnant during therapy with iloperidone.
  • Advise patients not to breast-feed an infant if they are taking iloperidone.
  • Advise patients to inform their health care provider if they are taking or planning to take any prescription or OTC drugs because there is a potential for interactions.
  • Inform patients to avoid alcohol while taking iloperidone.
  • Advise patients regarding appropriate care in avoiding overheating and dehydration.

Copyright © 2009 Wolters Kluwer Health.

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