Iloperidone

Pronunciation: (ilo-PER-i-done)
Class: Piperidinyl-benzisoxazole antipsychotic

Trade Names

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

Pharmacology

Has antipsychotic effect; exact mechanism of action is unknown. Proposed efficacy caused by dopamine type 2 and serotonin type 2 antagonisms.

Pharmacokinetics

Absorption

Relative bioavailability is 96% compared with oral solution. T _max is 2 to 4 h. Steady state within 3 to 4 days.

Distribution

Vd is 1,340 to 2,800 L. Protein binding is about 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

Not recommend for patients with hepatic impairment

Elderly

No dosage adjustment recommended.

Gender

No dosage adjustment recommended.

Race

No dosage adjustment recommended.

Indications and Usage

Acute treatment of adults with schizophrenia.

Contraindications

Standard considerations.

Dosage and Administration

Schizophrenia
Adults

PO Starting dose is 1 mg twice daily. Increases to reach target dose 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). Efficacy was demonstrated with a dosage range of 6 to 12 mg twice daily. Effectiveness for more than 6 wk has not been evaluated.

Dosage adjustments CYP2D6 and CYP3A4 inhibitors

Reduce dose by 50% when administered with CYP2D6 and CYP3A4 inhibitors. When inhibitor is withdrawn, dose may be increased.

CYP2D6 poor metabolizers

Consider dosing adjustment in poor metabolizers of CYP2D6.

General Advice

Can be administered without regard to meals.
Recommended that the initiation titration schedule be followed whenever patients are off iloperidone for more than 3 days.

Storage/Stability

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

Drug Interactions

Alcohol, CNS depressants

May cause additive CNS depressant effects.

Antihypertensives

May enhance hypotensive effects of some antihypertensives.

CYP2D6 inhibitors (eg, fluoxetine, paroxetine)

May increase iloperidone plasma concentrations. During coadministration, reduce iloperidone dose by 50%.

CYP3A4 inhibitors (eg, clarithromycin, ketoconazole)

May increase iloperidone plasma concentrations. During coadministration, reduce iloperidone dose by 50%.

QT interval–prolonging drugs (eg, bretylium, disopyramide, procainamide, quinidine)

The additive effect of iloperidone with other drugs that prolong the QT interval cannot be excluded.

Laboratory Test Interactions

None well documented.

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, dystonia (2%).

GI

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

Genitourinary

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

Miscellaneous

Rash (3%); hematocrit low (1%).

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 about 4.5% compared with a rate of about 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.

Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. 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.

Monitor patients for symptoms of hyperglycemia.

Monitor CBC in patients with preexisting low WBC or a history of drug-induced leukopenia/neutropenia, and discontinue iloperidone at first sign of decline of WBC in the absence of other causative factors.

Pregnancy

Category C .

Lactation

Unknown.

Children

Safety and effectiveness in children 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.

Hepatic Function

Iloperidone is not recommended for patients with hepatic impairment.

Body temperature regulation

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

Cerebrovascular events

In placebo-controlled trials with risperidone, aripiprazole, and olanzapine in elderly patients with dementia, there was a higher incidence of cerebrovascular adverse reactions, including fatalities compared with placebo-treated patients.

Electrolyte disturbances

Hypokalemia and/or hypomagnesemia may increase risk of QT prolongation.

Orthostatic hypotension

Iloperidone can induce orthostatic hypotension associated with dizziness, tachycardia, and syncope.

QT prolongation

Iloperidone is associated with prolongation of the QTc interval. Avoid use of iloperidone in combination with other drugs that are known to prolong QTc interval.

Cognitive motor impairment

Judgment, thinking, or motor skills may be impaired.

Dysphagia

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

Hematologic effects

In clinical trials and postmarketing experience, events of 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 in patients treated with atypical antipsychotics, including iloperidone.

Hyperprolactinemia

Iloperidone elevates prolactin levels.

NMS

Has been reported in association with administration of antipsychotic drugs. Clinical manifestations may include hyperpyrexia, muscle rigidity, altered mental status, evidence of autonomic instability, elevated creatine phosphokinase, myoglobinuria, and acute renal failure. Immediately discontinue antipsychotic drug if NMS is diagnosed.

Priapism

Drugs with alpha-adrenergic properties have been reported to cause priapism. Iloperidone shares this pharmacologic activity and 3 cases were reported in the premarketing iloperidone program.

Seizures

As with other antipsychotics, use iloperidone 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

Tardive dyskinesia may develop in patients treated with antipsychotic drugs. Prevalence appears to be highest among elderly patients, especially elderly women. The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and total cumulative dose of antipsychotic administered increase.

Weight gain

Weight gain of 7% or more of body weight was 13% for iloperidone patients versus 4% for placebo patients.

Overdosage

Symptoms

Reported signs and symptoms resulted from an exaggeration of the known pharmacological effects (eg, drowsiness and sedation, QT prolongation, tachycardia and hypotension) of iloperidone.

Patient Information

Instruct patient to take 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 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 hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia).
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 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 plan 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.