Iloperidone: A Comprehensive Overview

Overview

Iloperidone is an atypical antipsychotic drug indicated for the acute treatment of manic (elevated or excitable mood) or mixed episodes associated with bipolar disorder (episodes of mood swings, unusual shifts in energy levels, and concentration) in adults. The drug was approved by the United States Food and Drug Administration in April 2024 for bipolar 1 disorder. Earlier, the drug was indicated only for treating schizophrenia, a condition that affects how a person thinks, behaves, and feels. Therefore, the article discusses Iloperidone, its indications, side effects, contraindications, drug dosage and administration, and precautions.

Indications

The drug is indicated for the following conditions:

• Manic or mixed episodes associated with bipolar 1 disorder.

• Schizophrenia (mental illness affecting how one behaves, thinks, and feels).

Dose Form, Route, and Strength

The drug is available in tablet form to be taken orally or through mouth.

Strengths: 1 mg (milligrams), 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, and 12 mg.

For Patients:

What Is Bipolar I Disorder?

Bipolar 1 disorder is a condition characterized by maniac episodes lasting for at least seven days. The maniac symptoms are present almost every day and throughout the day. A person suffering from bipolar 1 disorder usually experiences extreme mood changes (feeling irritated or extremely happy) and an increase in energy. The condition is often accompanied by depressive episodes that may last for more than two weeks.

What Is Iloperidone Prescribed For?

Iloperidone is prescribed for the acute treatment of manic or mixed episodes associated with bipolar 1 disorder in adults.

How Should Iloperidone Be Used?

The medication is available in tablet form to be taken orally (or through mouth) twice daily, with or without meals. The drug should be taken daily at the same time. One must follow the prescription label for directions to use the drug or may contact a doctor or pharmacist in case any part of the label instructions is not clearly understood. Also, the drug should be taken exactly as the doctor prescribes; the dosage, frequency, and duration should not be altered without consulting the doctor.

Healthcare providers usually start with a lower dose of Iloperidone and then gradually increase the dosage (not more than once a day for an initial seven days). If a person does not take the drug for three days at any time during the treatment course, the doctor starts again from a low drug dosage.

The drug usually cures the symptoms but cannot treat the condition. It takes a long time (more than two weeks) to control the symptoms after one starts taking Iloperidone. Therefore, one should continue taking the drug even if they start feeling better. One should not stop taking the drug without consulting the doctor.

What Are the Precautions to Be Followed Before Taking Iloperidone?

• If one has a history of allergic reactions to the drug, any of its ingredients, or any other drug, inform the doctor.

• The doctor should also be informed about all the prescription and non-prescription drugs that one is taking, including herbal products, nutritional supplements, and vitamins.

• A person should also inform the doctor if they have any history of medical conditions, such as diabetes (high blood glucose), prolonged QT interval, seizures (uncontrolled electrical activity in the brain cells), heart disease, liver and kidney disease, swallowing difficulty, breast cancer, or high cholesterol levels.

• The doctor should also be informed if one is pregnant, planning to get pregnant, or getting pregnant while taking Iloperidone. The drug can affect the newborn post-delivery or after taking the drug due to the last few months of pregnancy.

• The drug causes dizziness and affects the ability to judge, think, and move. Therefore, operating heavy machinery should be avoided while taking Iloperidone.

• Also, one should get out of bed slowly or from a lying position, as the drug can cause lightheadedness, fainting, and a fast heartbeat.

• Alcohol can also add to the effects of dizziness; therefore, one must ask the doctor about alcohol consumption during the treatment course with Iloperidone.

• People exposed to high temperatures or vigorous exercise must also ask the doctor, as the drug is known to increase body temperature and take longer to cool down.

• The drug also causes increased blood sugar levels; therefore, if one is already diabetic, one must inform the doctor beforehand. One may feel frequent urination, thirst, blurred vision, hunger, and weakness.

What Are the Side Effects of Iloperidone?

Common Side Effects:

• Diarrhea (watery or loose stool).

• Nausea.

• Stomach pain.

• Dry mouth.

• Weight gain.

• Joint pain.

• Sleepiness.

• Breast enlargement.

• Breast discharge.

• Decreased sexual ability in males.

• Missed menstrual periods.

• Dizziness, or feeling unsteady, and having issues with maintaining balance.

Serious Side Effects:

• Itching.

• Rash.

• Seizures.

• Hives.

• Confusion.

• Falling.

• Muscle stiffness.

• Sweating.

• Breathing and swallowing problems.

• Swollen face, lips, tongue, throat, feet, and hands.

• Dizziness, fainting, or irregular heartbeats.

• Involuntary face and body movements.

• Chills, fever, sore throat, and other signs of infection.

• Prolonged, painful erection.

Drug Dosage and Administration

Iloperidone needs to be titrated slowly, starting from a low dose, to avoid orthostatic hypotension due to its alpha-adrenergic blocking properties. The recommended initial drug dose for Iloperidone tablets is one milligram (mg) twice a day. The drug dosage is increased gradually to reach the target range of six to 12 mg twice a day (12 to 24 mg/day or milligrams per day) with daily dosage adjustments not to exceed two mg (milligrams) twice a day (four milligrams a day).

The maximum recommended dosage of Iloperidone is 12 mg (milligrams) twice daily (24 mg/day). Iloperidone doses above 24 mg/day have yet to be systematically evaluated in clinical trials. The drug’s efficacy was demonstrated in a dose range of six to 12 milligrams twice daily. Therefore, doctors should remember that individuals must be titrated to an effective dose of Iloperidone.

Control of symptoms can get delayed during the initial one to two weeks of treatment compared to some other antipsychotic drugs that do not require similar titration. Additionally, doctors should also be aware that some dose-related adverse effects are also associated with Iloperidone use. Also, the drug can be administered with or without meals.

Missed Dose

The missed dose should be taken as soon as one remembers it; however, if it is already time for the next scheduled dose, then the missed dose should be skipped, and the regularly scheduled dose should be taken. One should not take double the drug dosage to compensate for the missed one. Also, the best practice is to consult the healthcare provider for better guidance and understanding.

Overdose

In case of an overdose from Iloperidone, the poison control department must be contacted; however, if the victim collapses or has trouble breathing, and collapses, emergency services must be called immediately for timely intervention.

Management of Overdose:

There is no specific antidote for Iloperidone; therefore, the patient should be provided with immediate supportive measures, such as establishing an airway and ensuring adequate ventilation and oxygen supply. In the case of unconscious and intubated patients, gastric lavage or administration of activated charcoal can also be considered. Cardiovascular monitoring should also be done continuously, followed by antiarrhythmic therapy (NOTE: drugs that prolong the QT interval should not be included in the therapy).

Drug Storage and Disposal

The drug should be stored away from heat and moisture. Iloperidone is stored at a controlled temperature, 25 degrees Celsius or 77 degrees Fahrenheit, and excursion is permitted to 15 to 30 degrees Celsius or 59 to 86 degrees Fahrenheit. Expired and unneeded medication should be discarded safely to avoid accidental use by children or pets. The drug can be discarded by contacting the nearest or local garbage or recycling department or pharmacist to dispose of the medication through a take-back program. However, one does not have access to the take-back program. In that case, by visiting the website, they can discard the drug by following FDA (Food and Drug Administration) guidelines and protocols for safe drug disposal.

For Doctors:

Clinical Pharmacology:

Mechanism of Action

The mechanism of action of Iloperidone for bipolar 1 disorder is not known. However, it is known that the efficacy of Iloperidone is primarily mediated by serotonin type 2 (5-HT2) antagonisms and dopamine type 2 (D2).

Pharmacodynamics

The drug has a high affinity for dopamine D2 and D3 receptors, serotonin 5-HT2A, and norepinephrine NEα1 receptors, thus acting as an antagonist. It also has moderate affinity for serotonin 5-HT6, dopamine D4, and 5-HT7 receptors and almost low affinity for dopamine D1, serotonin 5-HT1A, and histamine H1 receptors. For cholinergic muscarinic receptors, the drug shows no affinity at all.

Pharmacokinetics

Absorption

The drug is well absorbed after oral (tablet) administration, with peak plasma concentration occurring within two to four hours. The tablet formulation's bioavailability over oral solution is almost 96 percent.

Distribution

Iloperidone's distribution volume is 1340 to 2800 liters (45,316 to 94,643 ounces). The plasma concentration of the drug and its metabolites (P88 and P95) is approximately three percent and eight percent, respectively.

Metabolism

The drug is metabolized via three biotransformation pathways: hydroxylation (mediated by CYP2D6), carbonyl reduction, and O-demethylation (mediated by CYP3A4).

The drug has two predominant metabolites, P95 and P88. The active metabolite accounts for around 13.5 percent of extensive metabolizers (EM) and 34 percent of poor metabolizers (PM), whereas P95 accounts for 47.9 percent of extensive metabolizers (EM) and 25 percent of poor metabolizers (PM).

Elimination

The drug is excreted via hepatic (kidney) metabolism or route. The radioactive materials can be recovered in urine, which is 58.2 percent extensive metabolizer and 45.1 percent poor metabolizer, and feces, which accounts for almost 19.9 percent and 21.1 percent EM and PM, respectively.

Ingredients

Active Ingredient: Iloperidone.

Inactive Ingredients: Lactose monohydrate, Crospovidone, microcrystalline cellulose, magnesium stearate, hydroxypropyl methylcellulose, colloidal silicon dioxide, and purified water (removed during processing).

Contraindications

• The drug is contraindicated in patients with a known history of allergic or hypersensitivity reactions.

Drug Warnings and Precautions:

QT prolongation

The drug is known to prolong the QT interval and is also associated with irregular heartbeat (arrhythmia) and sudden death. Therefore, healthcare providers must consider treating the patient with other antipsychotics first. Additionally, Iloperidone should be avoided in combination with other drugs that prolong QTc and inhibit Iloperidone metabolism. Patients at risk of electrolyte disturbances should be monitored for serum potassium and magnesium.

Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis

The drug is not approved for treating patients with dementia-related psychosis. This is because, in placebo-controlled trials, elderly subjects with dementia and individuals randomized to Aripiprazole, Risperidone, and Olanzapine had a higher incidence of transient ischemic attack and stroke, including fatal stroke.

Neuroleptic Malignant Syndrome (NMS)

Post antipsychotic drug administration, NMS, a potentially fatal symptom complex has been reported, including Iloperidone. Clinical symptoms of the condition include hyperpyrexia, muscle rigidity, altered mental status (including catatonic signs), and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia).

Elevated creatine phosphokinase, acute renal failure, and myoglobinuria (rhabdomyolysis) may also occur. Therefore, if neuroleptic malignant syndrome is suspected, the doctor must discontinue Iloperidone immediately and start symptomatic treatment and monitoring.

Increased Mortality in Elderly Patients with Dementia-Related Psychosis

Elderly patients with dementia-related psychosis, when treated with antipsychotic drugs, such as Iloperidone, are at an increased risk of death. However, placebo-controlled trials on patients with dementia-related psychosis did not reveal the actual causes of death. Still, most of the deaths appeared to be either infectious (such as pneumonia, an infection of the lungs) or cardiovascular (such as heart failure or sudden death). Thus, the drug is not approved for the treatment of patients with dementia-related psychosis.

Metabolic Changes

Atypical antipsychotic drugs or Iloperidone have also been associated with metabolic changes, such as dyslipidemia (elevated lipids or cholesterol), hyperglycemia (elevated blood glucose levels), and body weight gain, which may increase cardiovascular or cerebrovascular risk. All atypical antipsychotic drugs are known to produce metabolic changes; however, the specific risk profiles may vary for each drug in this class.

Tardive dyskinesia

It is a syndrome consisting of potentially involuntary, irreversible, dyskinetic movements that may develop in individuals treated with antipsychotic drugs. Elderly people, especially women, are at a high risk of developing tardive dyskinesia. However, it is challenging to predict which patients will develop the syndrome and also which antipsychotic drug will cause tardive dyskinesia. Therefore, the drug should be cautiously prescribed to an individual and in a way that helps reduce the risk of the syndrome. Also, in case the symptoms of the syndrome occur while the patient is taking the drug, it should be discontinued immediately. However, in some cases, the patient is given the antipsychotic drug despite the presence of symptoms.

Dysphagia

Antipsychotic drugs are also known to cause aspiration and esophageal dysmotility. Morbidity and mortality in elderly patients are usually caused due to aspiration pneumonia. Therefore, Iloperidone should be cautiously prescribed in patients at risk for aspiration.

Orthostatic Hypotension and Syncope

The drug can induce orthostatic hypotension in association with tachycardia, dizziness, and syncope. Thus, more rapid titration is advised to increase the orthostatic hypotension and syncope rate. Therefore, orthostatic vital signs should be carefully monitored in patients vulnerable to hypotension, including elderly patients, patients with known cardiovascular disease, such as history of ischemia heart disease, myocardial infarction, heart failure, or conduction abnormalities, patients with hypovolemia, dehydration, and concomitant treatment with antihypertensive medications, and patients with cerebrovascular disease.

Seizures

Iloperidone is known to cause seizures like any other antipsychotic drug. The risk of developing seizures is high in patients with pre-existing seizures or with any conditions that lower the seizure threshold. Also, conditions that lower the seizure threshold are usually more prevalent in older patients.

Body Temperature Regulation

Atypical antipsychotics often reduce core body temperature. Exposure to extreme heat, strenuous exercise, dehydration, and anticholinergic medications may increase core body temperature. Therefore, the drug should be cautiously used in patients who have dysregulated body temperature problems.

Falls

Antipsychotics, such as Iloperidone, may cause postural hypotension, somnolence, and motor and sensory instability, leading to falls, followed by fractures or other injuries. Therefore, the doctor must do complete fall risk assessments in patients with diseases, conditions, or medications that could exacerbate such side effects while initiating antipsychotic treatment and are on long-term antipsychotic therapy.

Priapism

Drugs with alpha-adrenergic blocking effects, such as Iloperidone, have been reported to induce priapism (prolonged penis erection without any sexual intercourse). Severe priapism may require surgical intervention.

Hyperprolactinemia

Iloperidone elevates prolactin levels (hyperprolactinemia) and is known to suppress hypothalamic GnRH, thus resulting in reduced pituitary gonadotropin secretion. This inhibits reproductive function by impairing gonadal steroidogenesis in both male and female patients. Prolactin-elevating compounds also lead to amenorrhea, galactorrhea, gynecomastia, and impotence. Long-standing hyperprolactinemia, associated with hypogonadism, may also lead to decreased bone density in both female and male patients.

Leukopenia, Agranulocytosis, and Neutropenia

Leukopenia and neutropenia have been reported as temporally related to antipsychotic agents. Also, agranulocytosis (including fatal cases) has been reported. Therefore, patients with clinically significant neutropenia should be monitored carefully for fever, other symptoms, or signs of infection and treated promptly if such symptoms or signs occur. Also, Iloperidone should be discontinued in patients with absolute neutrophil count less than 1000/mm3 and keep track of white blood cells until recovery.

Intraoperative Floppy Iris Syndrome (IFIS)

This condition is usually observed during cataract surgery in some cases or in those previously treated with alpha-1 adrenergic blockers. Therefore, eye surgeons should opt for possible modifications to their surgical technique in such cases, including using iris hooks, viscoelastic substances, or iris dilator rings. Stopping alpha1 blocker therapy before cataract surgery does not serve the purpose in such cases. Iloperidone therapy in patients scheduled for cataract or glaucoma surgery is not recommended.

Potential for Cognitive and Motor Impairment

Iloperidone, like other antipsychotics, is known to cause somnolence and also has the potential to impair thinking, judgment, and motor skills. Therefore, individuals should be cautioned about working with hazardous machinery or motor vehicles until they are declared reasonably fit after therapy with Iloperidone.

Drug Interactions

The drug is not a substrate for CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2E1 enzymes; therefore, it is unlikely for the drug to have interaction with inducers and inhibitors of these enzymes, such as smoking.

Also, the metabolism of Iloperidone is established by CYP3A4 and CYP2D6. Therefore, inhibitors of CYP3A4, such as Ketoconazole or inhibitors of CYP2D6, Fluoxetine, and Paroxetine, can inhibit drug elimination and cause elevated blood levels.

In addition, the drug should not be given in combination therapy with medications that cause QT prolongation.

Use in Specific Populations:

Pregnancy

The pregnancy outcomes of the drug are monitored through the pregnancy exposure registry. Neonates born to women taking antipsychotic drugs, including Iloperidone during pregnancy (third trimester) withdrawal or extrapyramidal symptoms post delivery. However, the risk of miscarriage or major birth defects is not known for this population group. Sometimes, neonates recover within a few hours or days without treatment or may also need hospitalization.

Breastfeeding

No specific information exists related to the excretion of Iloperidone and its metabolites in human milk. Also, no drug effects have been observed on human milk production or breastfed infants.

Hepatic Impairment

Patients with mild hepatic impairment require dose adjustments. Those with moderate hepatic impairment may require dose adjustments, and for people with severe hepatic impairment, Iloperidone is not recommended.

Renal Impairment

The drug and its metabolites (P88 and P95) do not show any significant change in the maximum serum concentration when administered in patients with renal impairment.

Geriatric Use

The safety and effectiveness of the drug are not established for this population group, as clinical studies did not include many patients aged 65 years and older. Therefore, it is unclear whether this population group reacts differently than younger people. Also, the drug is not recommended for elderly people suffering from dementia-related psychosis.

Pediatric Use

The safety and effectiveness of Iloperidone in this population group have yet to be established.