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FANAPT may help with overall schizophrenia symptom control1

FANAPT is an atypical antipsychotic agent indicated for the treatment of schizophrenia in adults. In choosing among treatments, prescribers should consider the ability of FANAPT to prolong the QT interval and the use of
other drugs first. Prescribers should also consider the need to titrate FANAPT
slowly to avoid orthostatic hypotension, which may lead to delayed
effectiveness compared to some other drugs that do not require similar titration.

Efficacy

  • FANAPT improved overall symptoms in 2 clinical trials, as measured by the Positive and Negative Syndrome Scale (PANSS; 4-week trial) and the Brief Psychiatric Rating Scale (BPRS; 6-week trial)1

Drug-induced Akathisia

  • Incidence of drug-induced akathisia was similar to placebo1*

Drug-induced EPS

  • Incidence of drug-induced EPS was similar to placebo1*

Metabolics

  • Mean change in weight from baseline at end point for FANAPT patients was 2.1 kg across all short-term and long-term trials1†
  • The majority of patients taking FANAPT 24 mg/day did not experience a shift from normal to high in fasting lipid measurements in a 4-week study1

Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.

Tolerability

  • Discontinuation rates due to adverse events were similar for FANAPT (5%) and placebo (5%)1*

The most common adverse reactions were dizziness, dry mouth, fatigue, nasal congestion, somnolence, tachycardia, orthostatic hypotension, and weight increase.1*

*Based on treatment-emergent adverse events from pooled data from 4 placebo-controlled, 4- or
6-week, fixed- or flexible-dose studies.

Pooled data from 4 placebo-controlled, fixed- or flexible-dose studies show a change from baseline in body weight of 2.0 kg with FANAPT 10 to 16  mg/day (n=481), 2.7 kg with FANAPT 20 to 24 mg/day (n=391), and -0.1 kg with placebo (n=576).

EPS, extrapyramidal symptoms.

INDICATION

FANAPT is an atypical antipsychotic agent indicated for the treatment of schizophrenia in adults. In choosing among treatments, prescribers should consider the ability of FANAPT to prolong the QT interval and the use of other drugs first. Prescribers should also consider the need to titrate FANAPT slowly to avoid orthostatic hypotension, which may lead to delayed effectiveness compared to some other drugs that do not require similar titration.

IMPORTANT SAFETY INFORMATION

WARNING: 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. Analysis of seventeen placebo-controlled trials (modal duration 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in the drug-treated patients of between 1.6 to 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 the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. FANAPT is not approved for the treatment of patients with dementia-related psychosis.

Contraindications: FANAPT is contraindicated in individuals with a known hypersensitivity reaction to the product. Reactions have included pruritus and urticaria.

Cerebrovascular Adverse Events, Including Stroke: In placebo-controlled trials with risperidone, aripiprazole, and olanzapine in elderly patients with dementia, there was a higher incidence of cerebrovascular adverse events (cerebrovascular accidents and transient ischemic attacks) including fatalities compared to placebo-treated patients. FANAPT is not approved for treatment of patients with dementia-related psychosis.

QT Prolongation: FANAPT was associated with QTc prolongation of 9 msec at an iloperidone dose of 12 mg twice daily. The effect of FANAPT on the QT interval was augmented by the presence of CYP450 2D6 or 3A4 metabolic inhibition (e.g., paroxetine 20 mg once daily and ketoconazole 200 mg twice daily, respectively). Under conditions of metabolic inhibition for both 2D6 and 3A4, FANAPT 12 mg twice daily was associated with a mean QTcF increase from baseline of about 19 msec. No cases of torsades de pointes or other severe cardiac arrhythmias were observed during the premarketing clinical program. FANAPT should be avoided in combination with other drugs that are known to prolong QTc. FANAPT should also be avoided in patients with congenital long QT syndrome and in patients with history of cardiac arrhythmias, and in circumstances that may increase risk of torsades de pointes and/or sudden death in association with use of drugs that prolong the QTc interval. Use caution and consider dose modification. Patients being considered for FANAPT treatment who are at risk for significant electrolyte disturbances should have baseline serum potassium and magnesium measurements with periodic monitoring. FANAPT should be discontinued in patients who are found to have persistent QTc measurements >500 msec.

Neuroleptic Malignant Syndrome (NMS): NMS, a potentially fatal symptom complex, has been reported in association with administration of antipsychotic drugs, including FANAPT. NMS can cause hyperpyrexia, muscle rigidity, altered mental status, irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia. Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. Management should include immediate discontinuation of the antipsychotic drugs and other drugs not essential to concurrent therapy, intensive symptomatic treatment and medical monitoring, and treatment of any concomitant serious medical problems. If antipsychotic treatment is required after recovery from NMS, reintroduction should be carefully considered and patient should be carefully monitored.

Tardive Dyskinesia (TD): Risk of developing tardive dyskinesia, and the likelihood that it will become irreversible, may increase as the duration of treatment and the total cumulative dose increases. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses. Prescribing should be consistent with the need to minimize TD. If signs and symptoms appear, drug discontinuation should be considered.

Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all atypical antipsychotic drugs have been shown to produce some metabolic changes, each drug in the class has its own specific risk profile.

Hyperglycemia and Diabetes: Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics including FANAPT. Patients with an established diagnosis of, or with risk factors for, diabetes mellitus who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of antidiabetic treatment despite discontinuation of the antipsychotic.

Dyslipidemia: Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.

Weight Gain: Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.

Hepatic Impairment: No dosage adjustment is needed for patients with mild hepatic impairment. Exercise caution when administering FANAPT to patients with moderate hepatic impairment. Since a study in severe liver impaired subjects has not been conducted, FANAPT is not recommended for patients with severe hepatic impairment.

Seizures: As with other antipsychotics, FANAPT should be used cautiously in patients with a history of seizures or with conditions that potentially lower seizure threshold, e.g., Alzheimer's dementia.

Orthostatic Hypotension and Syncope: FANAPT must be titrated from a low starting dose to avoid orthostatic hypotension. FANAPT can induce orthostatic hypotension associated with dizziness, tachycardia, and syncope. Therefore FANAPT must be titrated as directed. Dose increases to reach the target range of 6-12 mg twice daily (12-24 mg/day) may be made with daily dosage adjustments not to exceed 2 mg twice daily (4 mg/day). The maximum recommended dose is 12 mg twice daily (24 mg/day). Control of symptoms may be delayed during the first 1 to 2 weeks of treatment. FANAPT should be used with caution in patients with known cardiovascular disease, cerebrovascular disease, or conditions that predispose the patient to hypotension. Monitoring of orthostatic vital signs should be considered in patients who are vulnerable to hypotension.

Leukopenia, Neutropenia, and Agranulocytosis: In clinical trial and postmarketing experience with antipsychotic agents, events of leukopenia/neutropenia have been reported temporally. Agranulocytosis (including death) has also been reported. Patients with a preexisting low white blood cell count or a history of drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and should discontinue FANAPT at the first sign of a decline in WBC in the absence of other causative factors.

Hyperprolactinemia: As with other drugs that antagonize dopamine D2 receptors, FANAPT elevates prolactin levels. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported with prolactin-elevating compounds.

Body Temperature Regulation: Appropriate care is advised when prescribing FANAPT for patients who will be experiencing conditions which may contribute to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration.

Dysphagia: Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients, in particular those with advanced Alzheimer's dementia. FANAPT and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.

Suicide: The possibility of a suicide attempt is inherent in psychotic illness, and close supervision of high-risk patients should accompany drug therapy. Prescriptions for FANAPT should be written for the smallest quantity of tablets in order to reduce the risk of overdose.

Priapism: Three cases of priapism have been reported in the premarketing FANAPT program. Severe priapism may require surgical intervention.

Cognitive and Motor Impairment: FANAPT, like other antipsychotics, has the potential to impair judgment, thinking, or motor skills. Patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that therapy with FANAPT does not affect them adversely.

Commonly observed adverse events: Commonly observed adverse reactions (incidence ≥5% and twofold greater than placebo) were: dizziness, dry mouth, fatigue, nasal congestion, orthostatic hypotension, somnolence, tachycardia, and weight increase.

Specific Populations

Pregnancy: FANAPT is Pregnancy Category C.

Hepatic Impairment: FANAPT is not recommended for patients with severe hepatic impairment.

Drug Interactions: Given the primary CNS effects of FANAPT, caution should be used when it is taken in combination with other centrally acting drugs and alcohol. FANAPT has the potential to enhance the effect of certain antihypertensive agents. Coadministration of FANAPT with potential CYP2D6 inhibitors (e.g., fluoxetine, paroxetine) and potential CYP3A4 inhibitors (e.g., ketoconazole) should be done with caution. FANAPT dose should be reduced by one-half. Cautiously approach coadministration of drugs mainly eliminated via CYP3A4 with FANAPT.

References: 1. FANAPT® (iloperidone) tablets [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; April 2014. 2. Data on file. CSR VP-VYV-683-3101. East Hanover, NJ: Novartis Pharmaceuticals Corp; July 2007. 3. Kay SR, Fiszbein A, Opler LA. The Positive and Negative Syndrome Scale (PANSS) for schizophrenia.Schizophr Bull. 1987;13(2):261-276. 4. Data on file. BPRS Analysis ILO522A3005. East Hanover, NJ: Novartis Pharmaceuticals Corp; December 2009. 5. Hedlund JL, Vieweg BW. The Brief Psychiatric Rating Scale (BPRS): a comprehensive review.J Oper Psychiatry. 1980;11(1):48-65. 6. Data on file. Integrated Summary of Safety. Rockville, MD: Vanda Pharmaceuticals Inc; August 2007. 7. Casey DE, Haupt DW, Newcomer JW, et al. Antipsychotic-induced weight gain and metabolic abnormalities: implications for increased mortality in patients with schizophrenia. J Clin Psychiatry. 2004;65(suppl 7):4-18. 8. Data on file. Alpha-1 Adrenergic Effects. East Hanover, NJ: Novartis Pharmaceuticals Corp; September 2012.