iloperidone

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iloperidone

Fanapt

Pharmacologic class: Piperidinyl-benzisoxazole derivative

Therapeutic class: Antipsychotic

Pregnancy risk category C

FDA Box Warning

• Elderly patients with dementia-related psychosis treated with antipsychotics are at increased risk for death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotics, revealed a risk of death in the drug-treated patients of between 1.6 and 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although causes of death were varied, most of the deaths appeared to be either cardiovascular (for example, heart failure, sudden death) or infectious (for example, pneumonia) in nature.

• Observational studies suggest that, similar to atypical antipsychotics, treatment with conventional antipsychotics may increase mortality. The extent to which findings of increased mortality in observational studies may be attributed to the antipsychotic as opposed to some characteristic(s) of the patients isn't clear.

• Iloperidone isn't approved for treatment of patients with dementia-related psychosis.

Action

Unknown

Availability

Tablets: 1 mg, 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, 12 mg

Indications and dosages

Acute treatment of schizophrenia

Adults: Initially, 1 mg P.O. daily; may increase by daily adjustments to 2 mg b.i.d., 4 mg b.i.d., 6 mg b.i.d., 8 mg b.i.d., 10 mg b.i.d., and 12 mg b.i.d. on days 2, 3, 4, 5, 6, and 7, respectively, to reach target dosage range of 6 to 12 mg P.O. b.i.d.

Dosage adjustment

• Concomitant use of strong CYP2D6 inhibitors (such as fluoxetine, paroxetine) and strong CYP3A inhibitors (such as clarithromycin, ketoconazole)

Contraindications

• Hypersensitivity to drug or its components

Precautions

Use cautiously in:
• hepatic impairment (use not recommended)
• congenital long QTc syndrome, history of cardiac arrhythmias (avoid use)
• known cardiovascular disease, cerebrovascular disease, or conditions that predispose patient to hypotension
• seizures or conditions that lower seizure threshold (such as Alzheimer's dementia)
• history of neuroleptic malignant syndrome
• preexisting low WBC count, history of drug-induced leukopenia or neutropenia
• possibility of conditions contributing to an elevated core body temperature (strenuous exercise, exposure to extreme heat, concomitant medication with anticholinergic activity, dehydration)
• concomitant use of drugs known to prolong QTc interval, including Class 1A antiarrhythmics (such as procainamide quinidine), Class III antiarrhythmics (such as amiodarone, sotalol), antipsychotics (such as chlorpromazine, thioridazine), antibiotics (such as gatifloxacin, moxifloxacin), or other drug classes known to prolong QTc interval (avoid use)
• conditions that may increase risk of torsades de pointes or sudden death in association with use of drugs that prolong QTc interval, including bradycardia, hypokalemia, hypomagnesemia, recent acute myocardial infarction, uncompensated heart failure, and cardiac arrhythmia (avoid use)
• concomitant use of drugs that inhibit iloperidone metabolism, patients with reduced CYP2D6 activity
• concomitant use of other centrally acting drugs
• patients at risk for suicide or aspiration pneumonia
• pregnant or breastfeeding patients
• children and adolescents (safety and efficacy not established).

Administration

• Determine baseline serum potassium and magnesium levels in patients at risk for significant electrolyte imbalance before starting drug.
• Perform fasting glucose testing in patients at risk for diabetes mellitus before starting drug.
• Administer without regard to meals.
• Be aware that drug must be titrated slowly to avoid orthostatic hypotension.
• Follow initiation schedule if an interval between dosing of more than 3 days occurs.

Adverse reactions

CNS: fatigue, tardive dyskinesia, dizziness, somnolence, tremor, lethargy, extrapyramidal disorder, seizures, neuroleptic malignant syndrome

CV: hypotension, orthostatic hypotension, tachycardia, prolonged QTc interval

EENT: blurred vision, nasopharyngitis, nasal congestion

GI: nausea, diarrhea, dry mouth, abdominal discomfort, dysphagia

GU: ejaculation failure

Hematologic: leukopenia, neutropenia, agranulocytosis

Metabolic: hyperprolactinemia, hyperglycemia (with associated ketoacidosis, hyperosmolar coma, or death)

Musculoskeletal: arthralgia, stiffness

Respiratory: upper respiratory tract infection, dyspnea

Skin: rash

Other: weight gain, altered body temperature regulation, hypersensitivity (including pruritus, urticaria)

Interactions

Drug-drug.Drugs known to prolong QTc interval: increased risk of life-threatening arrhythmia

Strong CYP2D6 inhibitors (such as fluoxetine, paroxetine), strong CYP3A inhibitors (such as clarithromycin, ketoconazole): inhibited iloperidone elimination resulting in increased blood levels

Drug-diagnostic tests.Blood glucose: increased level

Prolactin: increased level

White blood cells (WBCs): decreased levels

Drug-behaviors.Alcohol use: increased CNS effects

Patient monitoring

Discontinue drug in patient with persistent QTc measurements above 500 ms.

Initiate further evaluation, including cardiac monitoring, if patient develops signs and symptoms of cardiac arrhythmias (such as dizziness, palpitations, or syncope).

Monitor patient for signs and symptoms of neuroleptic malignant syndrome, such as hyperpyrexia, muscle rigidity, altered mental status (including catatonic signs), and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, cardiac arrhythmia, elevated creatine kinase level, myoglobinuria from rhabdomyolysis, and renal failure). If such signs and symptoms occur, immediately discontinue drug and treat appropriately.

Frequently monitor CBC with differential, especially during first few months of therapy in patient with preexisting low WBC count or history of drug-induced leukopenia or neutropenia. Discontinue drug at first sign of decline in WBC count in absence of other causative factors.

Discontinue drug if patient develops severe neutropenia (absolute neutrophil count below 1,000/mm3) and continue to monitor WBC count until recovery.
• Periodically perform fasting glucose testing in patient at risk for diabetes mellitus; watch closely for worsening of glucose control in patient with diabetes mellitus.
• Periodically monitor serum potassium and magnesium levels; hypokalemia and hypomagnesemia may increase risk of QTc interval prolongation.
• Consider discontinuing drug if signs and symptoms of tardive dyskinesia occur (such as repetitive, involuntary, purposeless movements; grimacing; tongue protrusion; or lip smacking).
• Carefully evaluate patient for history of drug abuse; if history exists, observe patient for signs and symptoms of misuse or abuse (such as drug-seeking behavior and increases in dosage). Also evaluate patient for risk of suicide.

Patient teaching

• Instruct patient to take drug with or without food.

Instruct patient to immediately report signs and symptoms of cardiac arrhythmias (such as dizziness, palpitations, or syncope).

Instruct patient to immediately report signs and symptoms of neurologic malignant syndrome, such as fever, muscle rigidity, altered mental status (including catatonic signs), irregular pulse or blood pressure, rapid heartbeat, and excessive sweating.
• Tell patient to promptly report fever or other signs and symptoms of infection.
• Tell patient to promptly report signs and symptoms of tardive dyskinesia (such as repetitive, involuntary, purposeless movements; grimacing; tongue protrusion; or lip smacking).
• Tell patient to report signs and symptoms of high blood glucose level (such as weakness, or excessive thirst, hunger, or urination).
• Advise patient to move slowly on rising to avoid sudden drop in blood pressure.
• Advise patient to avoid excessive exercise, exposure to extreme heat, and dehydration.
• Caution patient to avoid driving and other hazardous activities until drug's effects on concentration and alertness are known.
• Advise patient to avoid alcohol use while taking drug.
• Advise patient to consult prescriber before taking other prescription or nonprescription drugs.
• As appropriate, review all other significant and life-threatening adverse reactions and interactions, especially those related to the drugs, tests, and behaviors mentioned above.

iloperidone

(eye-loe-per-i-done) ,

Fanapt

(trade name)

Classification

Therapeutic: antipsychotics
Pharmacologic: benzisoxazoles
Pregnancy Category: C

Indications

Schizophrenia.

Action

May act by antagonizing dopamine and serotonin in the CNS.

Therapeutic effects

Decreased symptoms of schizophrenia.

Pharmacokinetics

Absorption: Well absorbed (96%) following oral administration.
Distribution: Unknown.
Metabolism and Excretion: Extensively metabolized by the liver. genetic implication Metabolism is genetically determined; primarily by CYP3A4 and CYP2D6 enzyme systems, with individual variability in metabolism via CYP2D6 (extensive metabolizers [EM] and poor metabolizers [PM] and some in-between; 7–10% of Caucasians and 3–8% of Black/African Americans are considered PM). Two major metabolites (P88 and P95) may be partially responsible for pharmacologic activity. 58% excreted in urine as metabolites in EM and 45% in PM; 20% eliminated in feces in EM and 22.1% in PM.
Half-life: EMs—iloperidone–18 hr, P88–26 hr, P95–23 hr; PMs—iloperidone–33 hr, P88–37 hr, P95–31 hr.

Time/action profile (antipsychotic effect)

ROUTEONSETPEAKDURATION
PO2–4 wk2–4 hr†unknown
† Blood level

Contraindications/Precautions

Contraindicated in: Hypersensitivity;Concurrent use of drugs known to prolong QTc interval;Bradycardia, recent MI or uncompensated heart failure (↑ risk of serious arrhythmias);Congenital long QT syndrome, QTc interval >500 msec or history of cardiac arrhythmias;Hepatic impairment; Geriatric: Elderly patients with dementia-related psychoses (↑ risk of death, CVA or TIA); Lactation: Breast feeding should be avoided.
Use Cautiously in: Known cardiovascular disease including heart failure, history of MI/ischemia, conduction abnormalities, cerebrovascular disease, or other conditions known to predispose to hypotension including dehydration, hypovolemia, concurrent antihypertensive therapy (↑ risk of orthostatic hypotension);Electrolyte abnormalities, especially hypomagnesemia or hypokalemia (correct prior to therapy);Concurrent use of CYP3A4 or CYP2D6 inhibitors;Known ↓ WBC or history of drug-induced leukopenia/neutropenia;Circumstances that may result in ↑ body temperature, including strenuous exercise, exposure to extreme heat, concurrent anticholinergic activity, or dehydration (may impair thermoregulation);Patients at risk for aspiration; Geriatric: May have ↑ sensitivity and risk of adverse reactions; Obstetric: Neonates at ↑ risk for extrapyramidal symptoms and withdrawal after delivery when exposed during the 3rd trimester; use only if potential maternal benefit justifies potential fetal risk; Pediatric: Safety and effectiveness not established.

Adverse Reactions/Side Effects

Central nervous system

  • neuroleptic malignant syndrome (life-threatening)
  • suicidal thoughts (life-threatening)
  • dizziness (most frequent)
  • drowsiness (most frequent)
  • fatigue (most frequent)
  • agitation
  • delusion
  • restlessness
  • extrapyramidal disorders

Ear, Eye, Nose, Throat

  • nasal congestion (most frequent)

Cardiovascular

  • orthostatic hypotension (most frequent)
  • tachycardia (most frequent)
  • palpitations
  • QTc interval prolongation

Gastrointestinal

  • dry mouth (most frequent)
  • nausea (most frequent)
  • abdominal discomfort
  • diarrhea

Genitourinary

  • priapism
  • urinary incontinence

Endocrinologic

  • dyslipidemia
  • hyperglycemia
  • hyperprolactinemia

Neurologic

  • tardive dyskinesia

Metabolic

  • weight gain (most frequent)
  • weight loss

Musculoskeletal

  • ↓ bone density
  • musculoskeletal stiffness

Interactions

Drug-Drug interaction

Avoid use of drugs known to prolong QTc including the antiarrhythmicsquinidine, procainamide, amiodarone, and sotalol ; antipsychotics including chlorpromazine and thioridazine, the antibioticmoxifloxacin, or any other medications known to prolong the QTc interval including pentamidine, levomethadyl, and methadone ; concurrent use may result in serious, life-threatening arrhythmias.Concurrent use of strong CYP2D6 inhibitors including fluoxetine and paroxetine ↑ levels and the risk of toxicity; dose ↓ is required.Concurrent use of strong CYP3A4 inhibitors including ketoconazole and clarithromycin ↑ levels and the risk of toxicity; dosage ↓ is required.Concurrent use of antihypertensives including diuretics may ↑ risk of orthostatic hypotension.Concurrent anticholinergics may ↑ risk of impaired thermoregulation.

Route/Dosage

Oral (Adults) Initiate treatment with 1 mg twice daily on the first day, then 2 mg twice daily the second day, then ↑ by 2 mg/day every day until a target dose of 12–24 mg/day given in two divided doses is reached; Concurrent strong CYP2D6 or CYP3A4 inhibitors—↓ dose by 50%, if inhibitor is withdrawn ↑ dose to previous amount. Re-titration is required if iloperidone is discontinued >300 days; Poor metabolizers-↓ dose by 50%.

Availability

Tablets: 1 mg, 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, 12 mg

Nursing implications

Nursing assessment

  • Monitor patient’s mental status (delusions, hallucinations, and behavior) before and periodically during therapy.
  • Monitor mood changes. Assess for suicidal tendencies, especially during early therapy. Restrict amount of drug available to patient.
  • Monitor BP (sitting, standing, lying down) and pulse before and periodically during therapy. May cause prolonged QT interval, tachycardia, and orthostatic hypotension.
  • Assess weight and BMI initially and throughout therapy.
  • Observe patient when administering medication to ensure that medication is actually swallowed and not hoarded.
  • Monitor patient for onset of extrapyramidal side effects (akathisia—restlessness; dystonia—muscle spasms and twisting motions; or pseudoparkinsonism—mask-like face, rigidity, tremors, drooling, shuffling gait, dysphagia). Report these symptoms; reduction of dose or discontinuation of medication may be necessary.
  • Monitor for tardive dyskinesia (involuntary rhythmic movement of mouth, face, and extremities). Report immediately and discontinue therapy; may be irreversible.
  • Monitor for development of neuroleptic malignant syndrome (fever, respiratory distress, tachycardia, seizures, diaphoresis, hypertension or hypotension, pallor, tiredness). Discontinue iloperidone and notify health care professional immediately if these symptoms occur.
  • Monitor for symptoms related to hyperprolactinemia (menstrual abnormalities, galactorrhea, sexual dysfunction).
  • Lab Test Considerations: Monitor fasting blood glucose before and periodically during therapy in diabetic patients.
    • Monitor CBC frequently during initial months of therapy in patients with pre-existing or history of low WBC. May cause leukopenia, neutropenia, or agranulocytosis. Discontinue therapy if this occurs.
    • Monitor serum potassium and magnesium levels in patients at risk for electrolyte disturbances.
    • Monitor serum prolactin prior to and periodically during therapy. May cause ↑ serum prolactin levels.

Potential Nursing Diagnoses

Risk for self-directed violence (Indications)
Disturbed thought process (Indications)
Risk for injury (Side Effects)

Implementation

  • Do not confuse Fanapt (iloperidone) with Xanax (alprazolam).
  • Oral: Administer twice daily without regard to food.

Patient/Family Teaching

  • Instruct patient to take medication exactly as directed. Advise patient that appearance of tablets in stool is normal and not of concern.
  • Inform patient of the possibility of extrapyramidal symptoms. Instruct patient to report these symptoms immediately to health care professional.
  • Advise patient to change positions slowly to minimize orthostatic hypotension.
  • May cause drowsiness. Caution patient to avoid driving or other activities requiring alertness until response to medication is known.
  • Extremes in temperature should also be avoided; this drug impairs body temperature regulation.
  • Instruct patient to notify health care professional promptly if sore throat, fever, unusual bleeding or bruising, rash, tremors, palpitations, fainting, menstrual abnormalities, galactorrhea or sexual dysfunction occur.
  • Advise patient and family to notify health care professional if thoughts about suicide or dying, attempts to commit suicide; new or worse depression; new or worse anxiety; feeling very agitated or restless; panic attacks; trouble sleeping; new or worse irritability; acting aggressive; being angry or violent; acting on dangerous impulses; an extreme increase in activity and talking; other unusual changes in behavior or mood occur.
  • Caution patient to avoid concurrent use of alcohol and other CNS depressants.
  • Advise patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult with health care professional before taking other medications.
  • Advise patient to notify health care professional of medication regimen before treatment or surgery.
  • Advise female patients to notify health care professional if pregnancy is planned or suspected or if breast feeding or planning to breast feed.
  • Emphasize the need for continued follow-up for psychotherapy and monitoring for side effects.

Evaluation/Desired Outcomes

  • Decrease in excited, paranoid, or withdrawn behavior.

iloperidone

Zomaril An antipsychotic for treating schizophrenia and related disorders
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