modification when prescribing FANAPT with other drugs that inhibit
`FANAPT metabolism. Monitor serum potassium and magnesium in
`
`
`
`patients at risk for electrolyte disturbances. (1, 5.3, 7.1, 7.2, 12.3)
`
`
`
`
`
`
`• Neuroleptic Malignant Syndrome (NMS): Manage with immediate
`
`
`
`discontinuation of drug and close monitoring. (5.4)
`
`
`• Tardive dyskinesia: Discontinue if clinically appropriate. (5.5)
`
`
`
`• Metabolic Changes: Monitor for hyperglycemia/diabetes mellitus,
`
`
`
`dyslipidemia, and weight gain. (5.6)
`
`
`• Orthostatic hypotension and Syncope: Monitor heart rate and blood
`
`
`
`pressure and warn patients with known cardiovascular or cerebrovascular
`
`
`disease, and risk of dehydration or syncope. (5.7)
`
`• Seizures: Use cautiously in patients with a history of seizures or with
`
`
`
`conditions that lower seizure threshold. (5.9)
`
`• Leukopenia, Neutropenia, and Agranulocytosis have been reported with
`
`
`
`antipsychotics. Perform complete blood counts (CBC) in patients with pre-
`
`existing low white blood cell count (WBC) or a history of
`
`
`leukopenia/neutropenia. Consider discontinuing FANAPT if clinically
`
`
`
`
`
`significant decline in WBC occurs in the absence of other causative factors.
`
`
`
`(5.10)
`
`• Priapism: Cases have been reported in association with FANAPT
`
`
`
`treatment. Severe priapism may require surgical intervention. (5.14)
`
`
`
`
`• Potential for cognitive and motor impairment: Use caution when operating
`
`
`
`machinery. (5.15)
`
`• Intraoperative Floppy Iris Syndrome (IFIS): IFIS during cataract surgery
`
`
`
`may require modifications to the surgical technique. (5.16)
`
`
`
`
`-------------------------------- ADVERSE REACTIONS----------------------------
`
`
`Commonly observed adverse reactions (incidence ≥5% and 2-fold greater than
`
`
`
`
`
`
`
`placebo) were (6.1):
`
`
`• Schizophrenia: dizziness, dry mouth, fatigue, nasal congestion, orthostatic
`
`
`
`hypotension, somnolence, tachycardia, and weight increased.
`
`• Bipolar mania: tachycardia, dizziness, dry mouth, hepatic enzymes
`
`
`
`increased, nasal congestion, weight increased, hypotension, and
`
`
`somnolence.
`
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Vanda
`
`
`
`Pharmaceuticals Inc. at 1-844-GO-VANDA (1-844-468-2632) or FDA at
`
`
`
`
`1-800-FDA-1088 or www.fda.gov/medwatch.
`
`
`
`---------------------------------DRUG INTERACTIONS----------------------------
`
`The dose of FANAPT should be reduced in patients co-administered a strong
`
`
`CYP2D6 or CYP3A4 inhibitor. (2.2, 7.1)
`
`
`
`--------------------------USE IN SPECIFIC POPULATIONS---------------------
`• Pregnancy: May cause extrapyramidal and/or withdrawal symptoms in
`
`
`neonates with third trimester exposure. (8.1)
`
`
`• Lactation: Advise not to breast feed. (8.2)
`
`
`
`
`• Pediatric Use: Safety and effectiveness not established in children and
`
`
`adolescents. (8.4)
`
`• Hepatic Impairment: FANAPT is not recommended for patients with
`
`
`
`
`severe hepatic impairment. (2.3, 8.6)
`
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION
`
`
`
`
`
`
`
`
`Revised: 1/2025
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` --------------------------DOSAGE AND ADMINISTRATION------------------
`
` • Administer FANAPT orally twice daily without regard to meals. (2.1)
`
`
`
`
`
`
`
` • Titrate the dosage of FANAPT to avoid orthostatic hypotension. See Full
`
`
`
`
` Prescribing Information for titration schedule. (2.1)
`
`
` • Recommended Dosage:
`
` Starting Dosage
`
` Indication
`
` Schizophrenia
` (2.1)
`
`
` Bipolar Mania
`
` (2.1)
` • CYP2D6 Poor Metabolizers: See Full Prescribing Information for titration
`
`
`
` schedule and recommended dosage. (2.2)
`
`-------------------------DOSAGE FORMS AND STRENGTHS----------------
`
`1 mg, 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, and 12 mg tablets. (3)
`
`
`
`
`
`-----------------------------CONTRAINDICATIONS------------------------------
`
`Known hypersensitivity to FANAPT or to any components in the formulation.
`
`
`(4, 6.2)
`
`
`-------------------------WARNINGS AND PRECAUTIONS--------------------
`• Cerebrovascular Adverse Reactions in Elderly Patients with Dementia-
`
`
`Related Psychosis: Increased incidence of cerebrovascular adverse
`
`reactions (e.g., stroke, transient ischemic attack). (5.2)
`
`
`• QT prolongation: Prolongs QT interval and may be associated with
`
`
`
`arrhythmia and sudden death. Avoid use of FANAPT in combination with
`
`other drugs that are known to prolong QTc; use caution and consider dose
`
`
`
`
`
`
`
`
`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
` These highlights do not include all the information needed to use
` FANAPT safely and effectively. See full prescribing information for
`
`
`
` FANAPT.
`
` FANAPT® (iloperidone) tablets, for oral use
`
` Initial U.S. Approval: 2009
`
`
`
`
`
`
`
`
`WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS
`
` WITH DEMENTIA-RELATED PSYCHOSIS
` See full prescribing information for complete boxed warning.
`
`
` Elderly patients with dementia-related psychosis treated with
` antipsychotic drugs are at an increased risk of death. FANAPT is not
`
` approved for use in patients with dementia-related psychosis. (5.1)
`
`
`
`
`
`
`----------------------------RECENT MAJOR CHANGES------------------------
`
`
`
`
`
` 4/2024
` Indications and Usage (1)
` Dose and Administration (2.1, 2.2, 2.3, 2.4)
`
`
`
` 4/2024
` Warnings and Precautions (5.6, 5.7, 5.11, 5.15, 5.16)
`
`
` 4/2024
`
` Warnings and Precautions, (5.11)
`
`
` 1/2025
`
`
`Warnings and Precautions, Suicide (5.14)
`
`
` Removed 4/2024
`
`
`
` -----------------------------INDICATIONS AND USAGE------------------------
` FANAPT is an atypical antipsychotic indicated for:
`
`
` • Treatment of schizophrenia in adults. (1, 14.1)
`
`
`
` • Acute treatment of manic or mixed episodes associated with bipolar I
`
`
`
`
` disorder in adults. (1, 14.2)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Recommended Dosage
`
`
`
`
`
` 1 mg twice daily
`
`
`
`
`
` 6 mg to 12 mg twice daily
`
`
`
`
`
` 1 mg twice daily
`
`
`
`
`
` 12 mg twice daily
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 5516239
`
`
`
`
`
`
`
`

`

`
`
`
`
` 7
`
`
`
` 8
`
`
`
` 9
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 11
`
` 12
`
`
`
` 13
`
`
`
` 14
`
`
`
`
`
` 6.2
`
`
` Postmarketing Experience
` DRUG INTERACTIONS
`
`
`
` 7.1 Clinically Important Drug Interactions with FANAPT
`
` 7.2 Drugs that Prolong the QT Interval
`
`
`
` 7.3 Drugs that Lower Blood Pressure
`
`
`
` USE IN SPECIFIC POPULATIONS
`
`
`
`
`
` 8.1
` Pregnancy
`
` 8.2 Lactation
`
`
`
`
` 8.4
`
` Pediatric Use
`
`
` 8.5 Geriatric Use
`
`
` 8.6 Hepatic Impairment
`
` DRUG ABUSE AND DEPENDENCE
`
`
`
` 9.1 Controlled Substance
`
` 9.2 Abuse
`
`
`
` 10 OVERDOSAGE
`
`
`
` 10.1 Human Experience
`
` 10.2 Management of Overdose
` DESCRIPTION
`
`
` CLINICAL PHARMACOLOGY
`
`
`
` 12.1 Mechanism of Action
`
` 12.2 Pharmacodynamics
`
`
` 12.3 Pharmacokinetics
`
`
`
`
` 12.5 Pharmacogenomics
`
`
` NONCLINICAL TOXICOLOGY
` 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`
` CLINICAL STUDIES
`
`
` 14.1 Schizophrenia
` 14.2 Manic or Mixed Episodes Associated with Bipolar I Disorder
`
`
`
` 16 HOW SUPPLIED/STORAGE AND HANDLING
`
` 17
`
` PATIENT COUNSELING INFORMATION
`
`*Sections or subsections omitted from the full prescribing information are not
`listed.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
`
`
`WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS
`
` WITH DEMENTIA-RELATED PSYCHOSIS
`
`
` INDICATIONS AND USAGE
` DOSAGE AND ADMINISTRATION
`
`
`
`
` 2.1 Recommended Dosage
`
` 2.2 Dosage Recommendations for Use in Patients Who Are Known
`
`
` CYP2D6 Poor Metabolizers
`
` 2.3 Dosage Recommendations in Patients with Hepatic Impairment
`
` 2.4 Dosage Modifications for Concomitant Use with Strong
`
`
`
` CYP2D6 Inhibitors and Strong CYP3A4 Inhibitors
` 2.5 Reinitiation of Treatment in Patients Previously Discontinued
`
`
`
`
`
` DOSAGE FORMS AND STRENGTHS
`
` 3
` CONTRAINDICATIONS
`
`
` 4
`
`
` 5 WARNINGS AND PRECAUTIONS
`
`
`
`
` Increased Mortality in Elderly Patients with Dementia-Related
` 5.1
`
` Psychosis
`
` 5.2 Cerebrovascular Adverse Reactions, Including Stroke, in Elderly
`
` Patients with Dementia-Related Psychosis
`
`
`
` 5.3 QT Prolongation
`
` 5.4 Neuroleptic Malignant Syndrome (NMS)
`
` 5.5 Tardive Dyskinesia
`
`
` 5.6 Metabolic Changes
`
`
` 5.7 Orthostatic Hypotension and Syncope
`
` 5.8
`
` Falls
`
`
` 5.9
` Seizures
`
` 5.10 Leukopenia, Neutropenia and Agranulocytosis
`
` 5.11 Hyperprolactinemia
`
`
` 5.12 Body Temperature Regulation
`
` 5.13 Dysphagia
`
`
`
` 5.14 Priapism
`
`
` 5.15 Potential for Cognitive and Motor Impairment
`
` 5.16 Intraoperative Floppy Iris Syndrome (IFIS)
`
` ADVERSE REACTIONS
`
`
` 6.1 Clinical Studies Experience
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 1
`
` 2
`
`
`
` 6
`
`
`
`
`
`
`
`
`Reference ID: 5516239
`
`

`

`
`
`
`
`
`
`
`FULL PRESCRIBING 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.
`FANAPT is not approved for the treatment of patients with dementia-related psychosis [see Warnings and
`
`Precautions (5.1)].
`
`
`
`
`
` 1
` INDICATIONS AND USAGE
`
`
` FANAPT® is indicated for:
`
`
` • Treatment of schizophrenia in adults [see Clinical Studies (14.1)].
`
`
`
` • Acute treatment of manic or mixed episodes associated with bipolar I disorder in adults [see Clinical
`
`
`
` Studies (14.2)].
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Recommended
`
` Dosage
` 6 mg to 12 mg
`
`
` twice daily
`
`
`
` 2
`
` DOSAGE AND ADMINISTRATION
` 2.1 Recommended Dosage
`
`
`
`
` Titrate FANAPT to avoid orthostatic hypotension [see Warnings and Precautions (5.7)].
`
` Administer FANAPT orally with or without food.
` Table 1 includes dosage recommendations for FANAPT for the treatment of schizophrenia and the acute
`
`
`
` treatment of manic or mixed episodes associated with bipolar I disorder in adults.
`
`
` Table 1: Dosage Recommendations for FANAPT in Adults for the Treatment of Schizophrenia or Acute
`
`
`
`
`
` Treatment of Manic or Mixed Episodes Associated with Bipolar I Disorder
`
`
`
`
`
`
`
` Titration schedule
`
`Indication and
`
` Day 5
`
` Day 4
`
` Population
`
` 8 mg
`
` 6 mg
`
`
`
` Schizophrenia
`twice
`twice
`
`
` daily
` daily
`
` 9 mg
` 12 mg
`
`
`
`twice
`twice
`
`
` daily
` daily
`
`
`
`
` Day 1 Day 2 Day 3
`
`
` 4 mg
`
`
` 2 mg
`
`1mg
`twice
`twice
`twice
`
`
` daily
` daily
`
` daily
`
` 3 mg
`
` 6 mg
`
`
`
` 1 mg
`
`twice
`twice
`twice
`
`
`
` daily
` daily
` daily
`
` Bipolar I Disorder
`
`
` Manic or Mixed
`
` Episodes
`
`
`
`
` Day 6
`
` 10 mg
`
`twice
`
` daily
`
`
` Day 7
`
` 12 mg
`
`twice
`
` daily
`
`
`
` Titration complete
`
` 12 mg
`
`
` twice daily
`
`
`
`
`
`
` 2.2 Dosage Recommendations for Use in Patients Who Are Known CYP2D6 Poor
` Metabolizers
`
`
`
`
` Reduce the dose of FANAPT by one-half for CYP2D6 poor metabolizers [see Clinical Pharmacology (12.3,
`
`
` 12.5)]. Table 2 includes dosage recommendations for FANAPT in adults who are CYP2D6 poor metabolizers.
`
`
`
`
`
`
`
`
`
`Reference ID: 5516239
`
`

`

`
`
`
`
`
`
`
` Day 1 Day 2 Day 3
`
`
` 4 mg
`
`
` 2 mg
`
`1mg
`twice
`twice
`twice
`
`
` daily
` daily
`
` daily
`
` 3 mg
`
` 6 mg
`
`
`
` 1 mg
`
`twice
`twice
`twice
`
`
`
` daily
` daily
` daily
`
`
`
` Bipolar I Disorder
`
`
` Manic or Mixed
`
` Episodes
`
`
`
`
`I
`
`
`
` Day 6
`
`I
`
`
`
` Day 7
`
`
`
`
`
` Recommended
`
` Dosage
`
` 3 mg to 6 mg
`
` twice daily
`
`
` Table 2: Dosage Recommendations for FANAPT in Adults with Schizophrenia or Bipolar I Disorder
`
`
`
` Who are CYP2D6 Poor Metabolizers
` Titration schedule
`
`Indication and
`
` Day 4
` Day 5
`
`
` Population
`
` 6 mg
`
`
` Schizophrenia
`twice
`
`
` daily
`
`
`
` Titration complete
`
`
`
`
`
` Titration complete
`
` 6 mg
`
`
` twice daily
`
`
`
`
`
`
`
`
`
`
` 2.3 Dosage Recommendations in Patients with Hepatic Impairment
` No dose adjustment for FANAPT is needed in patients with mild hepatic impairment. Patients with moderate
`
`
`
`
`
`
` hepatic impairment may require dose reduction, if clinically indicated. FANAPT is not recommended for
` patients with severe hepatic impairment [see Use in Specific Populations (8.6)].
`
`
`
`
`
` 2.4 Dosage Modifications for Concomitant Use with Strong CYP2D6 Inhibitors and
`
` Strong CYP3A4 Inhibitors
` Coadministration with Strong CYP2D6 Inhibitors
`
`
` Reduce the dose of FANAPT one-half when administered concomitantly with strong CYP2D6 inhibitors such
`as fluoxetine or paroxetine. When the CYP2D6 inhibitor is withdrawn from the combination therapy, increase
`
`
`
`the dose of FANAPT to where it was before [see Drug Interactions (7.1)].
`
`
`
`
`
`Coadministration with Strong CYP3A4 Inhibitors
`
`
`
`Reduce the dose of FANAPT by one-half when administered concomitantly with strong CYP3A4 inhibitors
`
`such as ketoconazole or clarithromycin. When the CYP3A4 inhibitor is withdrawn from the combination
`
`
`
`
`therapy, increase the dose of FANAPT to where it was before [see Drug Interactions (7.1)].
`
`
`Coadministration with Strong CYP2D6 and Strong CYP3A4 Inhibitors
`
`
`Reduce the dose of FANAPT by about one-half if administered concomitantly with inhibitors of CYP2D6 and
`
`
`
`CYP3A4. When both CYP2D6 and CYP3A4 inhibitors are withdrawn from the combination therapy, increase
`
`
`the dose of FANAPT to where it was before [see Drug Interactions (7.1)].
`
`
`
` 2.5 Reinitiation of Treatment in Patients Previously Discontinued
` Although there are no data to specifically address reinitiation of treatment, it is recommended that the initiation
`
`
`
`
`
`
`
` titration schedule be followed whenever patients have had an interval off FANAPT of more than 3 days.
`
`
`
` 3
` DOSAGE FORMS AND STRENGTHS
`
`
`
`
`
` FANAPT tablets are available in the following strengths: 1 mg, 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, and 12 mg.
` The tablets are white, round, flat, beveled-edged, and identified with a logo “ ” debossed on one side and
`
`
` tablet strength “1”, “2”, “4”, “6”, “8”, “10”, or “12” debossed on the other side.
`
`
`
`Reference ID: 5516239
`
`

`

`
`
`
`
`
` 4 CONTRAINDICATIONS
`
`
`
`
` FANAPT is contraindicated in individuals with a known hypersensitivity reaction to the product. Anaphylaxis,
`
`
` angioedema, and other hypersensitivity reactions have been reported [see Adverse Reactions (6.2)].
`
`
`
`
`
`
`
`
` 5 WARNINGS AND PRECAUTIONS
` 5.1 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. Analyses of 17 dementia-related psychosis placebo-controlled trials (modal duration of 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 that 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 placebo-treated patients.
` 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. FANAPT is not approved for the treatment of
`
`
`
`
`
` patients with dementia-related psychosis [see Boxed Warning, Warnings and Precautions (5.2)].
`
`
`
` 5.2 Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with
` Dementia-Related Psychosis
`
`
`
`
` In placebo-controlled trials in elderly subjects with dementia, patients randomized to risperidone, aripiprazole,
`
` and olanzapine had a higher incidence of stroke and transient ischemic attack, including fatal stroke. FANAPT
`
` is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning, Warnings
`
`
`
` and Precautions (5.1)].
`
`
` 5.3 QT Prolongation
`
` In an open-label QTc study in patients with schizophrenia or schizoaffective disorder (n=160), 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
`
`
`
` (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 torsade de pointes or other severe cardiac arrhythmias were observed during the pre-marketing
`
` clinical program.
`
`
`
` The use of FANAPT should be avoided in combination with other drugs that are known to prolong QTc
`
`
` including Class 1A (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic
`
`medications, antipsychotic medications (e.g., chlorpromazine, thioridazine), antibiotics (e.g., gatifloxacin,
`moxifloxacin), or any other class of medications known to prolong the QTc interval (e.g., pentamidine,
`
`
`
`levomethadyl acetate, methadone). FANAPT should also be avoided in patients with a known genetic
`
`
`susceptibility to congenital long QT syndrome and in patients with a history of cardiac arrhythmias.
`
`
`Certain circumstances may increase the risk of torsade de pointes and/or sudden death in association with the
`
`
`
`
`use of drugs that prolong the QTc interval, including (1) bradycardia; (2) hypokalemia or hypomagnesemia; (3)
`
`
`
`
`
`
`
`
`
`
`Reference ID: 5516239
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
` concomitant use of other drugs that prolong the QTc interval; and (4) presence of congenital prolongation of the
` QT interval; (5) recent acute myocardial infarction; and/or (6) uncompensated heart failure.
`
`
` Caution is warranted when prescribing FANAPT with drugs that inhibit FANAPT metabolism [see Drug
`
`
` Interactions (7.1)], and in patients with reduced activity of CYP2D6 [see Clinical Pharmacology (12.3, 12.5)].
` It is recommended that patients being considered for FANAPT treatment who are at risk for significant
`
`
`
` electrolyte disturbances have baseline serum potassium and magnesium measurements with periodic
`
` monitoring. Hypokalemia (and/or hypomagnesemia) may increase the risk of QT prolongation and arrhythmia.
`
` FANAPT should be avoided in patients with histories of significant cardiovascular illness, e.g., QT
`
`
` prolongation, recent acute myocardial infarction, uncompensated heart failure, or cardiac arrhythmia. FANAPT
` should be discontinued in patients who are found to have persistent QTc measurements >500 msec.
`
`
`
`
`
` If patients taking FANAPT experience symptoms that could indicate the occurrence of cardiac arrhythmias,
` e.g., dizziness, palpitations, or syncope, the prescriber should initiate further evaluation, including cardiac
`
`
`
` monitoring.
`
`
` 5.4 Neuroleptic Malignant Syndrome (NMS)
` Neuroleptic Malignant Syndrome (NMS), a potentially fatal symptom complex, has been reported in association
`
`
`
` with administration of antipsychotic drugs, including FANAPT. Clinical manifestations 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). Additional signs may
` include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.
`
`
` If NMS is suspected, immediately discontinue FANAPT and provide intensive symptomatic treatment and
`
`
`
` monitoring.
`
`
`
` 5.5 Tardive Dyskinesia
` Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may
`
`
`
`
`
` develop in patients treated with antipsychotic drugs. The risk appears to be highest among the elderly,
` especially elderly women, but it is impossible to predict, which patients will develop the syndrome. Whether
`
`
`
`
`
` antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.
`
`
`
` The risk of developing tardive dyskinesia and the likelihood that it will become irreversible increase with the
`
`
`
`
` duration of treatment and cumulative dose. The syndrome can develop after relatively brief treatment periods at
`
`
`
` low doses. It may also occur after discontinuation of treatment.
`
`
`
`
` Tardive dyskinesia may remit, partially or completely, if antipsychotic treatment is discontinued. Antipsychotic
`
`
`
` treatment itself may suppress (or partially suppress) the signs and symptoms of the syndrome, possibly masking
`
`
` the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome
`
`
` is unknown.
`
`
`
`
`
`
`
`
`
`
` Given these considerations, FANAPT should be prescribed in a manner that is most likely to reduce the risk of
`
`
` tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients: 1) who suffer
`
`
`
` from a chronic illness that is known to respond to antipsychotic drugs, and (2) for whom alternative, equally
`
` effective, but potentially less harmful treatments are not available or appropriate. In patients who do require
`
`
` chronic treatment, use the lowest dose and the shortest duration of treatment producing a satisfactory clinical
`
`
`
`
` response. Periodically reassess the need for continued treatment.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 5516239
`
`

`

`
` If signs and symptoms of tardive dyskinesia appear in a patient on FANAPT, drug discontinuation should be
`
`
`
` considered. However, some patients may require treatment with FANAPT despite the presence of the
`
` syndrome.
`
`
` 5.6 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 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 FANAPT. Assess fasting plasma glucose
` before or soon after initiation of antipsychotic medication and monitor periodically during long-term treatment.
`
`
` Schizophrenia
` In a 4-week fixed-dose placebo-controlled study of adults with schizophrenia, the mean change from baseline in serum
`
`
`
`
`
`
` glucose was 6.6 mg/dL and -0.5 mg/dL for FANAPT and placebo treated patients, respectively. The proportion of patients
` with shifts in fasting glucose from normal (<100 mg/dL) to high (≥126 mg/dL) were 10.7% and 2.5% for FANAPT and
`
`
`
`
`
`
` placebo treated patients, respectively.
`
`
`
`
`
`
`
` In pooled analyses from clinical studies, for adults with schizophrenia remaining on treatment with FANAPT 10-16
`
`
` mg/day glucose increased, on average, from baseline by 1.8 mg/dL at 3-6 months (N=773) and by 5.4 mg/dL at 6-12
`
`
`
`
`
`
`
`
`
` months (N=723) and at >12 months (N=425) of treatment. In a smaller group of patients remaining on treatment with
`
`
`
`
`
`
`
`
` FANAPT 20-24 mg/day, glucose decreased by 3.6 mg/dL at 3-6 months (N=34); by 9 mg/dL at 6-12 months (N=31), and
`
`
`
`
`
`
`
`
`
`
`
` by 18 mg/dL at > 12 months (N=20) of treatment.
`
`
`
`
`
`
`
` Bipolar Mania
`
` In a 4-week fixed dose study of adults with bipolar mania, mean changes from baseline in serum glucose and the
`
`
`
`
`
`
` proportion of patients with shifts in fasting glucose from Normal (<100 mg/dL) to High (≥126 mg/dL) for patients
`
` receiving FANAPT were similar to those for patients receiving placebo.
`
`
`
`
`
` Dyslipidemia
`
`
` Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics. Before or
`
` soon after initiation of antipsychotic medications, obtain a fasting lipid profile at baseline and monitor
`
`
`
` periodically during treatment.
`
` Schizophrenia
`
`
`
` In a 4-week fixed dose study of adults with schizophrenia, the mean change from baseline in fasted total cholesterol was
`
` 8.2 mg/dL and -2.2 mg/dL for FANAPT and placebo treated patients, respectively. The effects on LDL were similar to
`
`
`
`
`
`
`
`
` those on total cholesterol (changes of 9 mg/dL and -1.4 mg/dL for FANAPT and placebo treated patients, respectively).
`
`
`
`
`
` Mean changes from baseline in fasted triglycerides were -0.8 mg/dL and 16.5 mg/dL for FANAPT and placebo treated
`
`
`
`
`
`
`
`
` patients, respectively.
`
` The proportion of patients with shifts from normal to high fasted total cholesterol, LDL, and triglycerides were similar for
`
`
`
`
`
`
`
`
`
` FANAPT and placebo-treated patients. The proportion of patients with shifts in fasted HDL from normal (≥40 mg/dL) to
` low (<40 mg/dL) was greater for placebo patients (23.8%) compared to patients treated with FANAPT (12.1%).
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 5516239
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`In pooled analysis from clinical studies, for adults with schizophrenia remaining on treatment with FANAPT, on average,
`
`
`both cholesterol and triglycerides decreased from baseline for adults with schizophrenia remaining on treatment at 3-6
`
`
`
`months, 6-12 months, and >12-month time points in both 10-16 mg/day and 20-24 mg/day dose groups.
`
`Bipolar Mania
`
`
`
`
`In a 4-week fixed dose study of adults with bipolar mania, the mean changes from baseline for fasted total cholesterol,
`
`
`
`
`
`
`
`LDL, HDL, and triglycerides for FANAPT were similar to those for placebo-treated patients. The proportion of patients
`
`
`
`
`
`
`
`with shifts in fasted total cholesterol from normal (<200 mg/dL) to high (≥240 mg/dL) was greater for FANAPT treated
`
`
`
`
`
`
`
`
`patients (10.7%) than placebo-treated patients (7.2%). Shifts from normal to high LDL and triglycerides and from normal
`
`
`
`
`
`to low HDL occurred at rates for FANAPT similar to those for placebo treated patients.
` Weight Gain
`
` Weight gain has been observed with atypical antipsychotic use. Monitor weight at baseline and frequently
`
` thereafter.
` Schizophrenia
`
` Across all short- and long-term studies of adults with schizophrenia, the overall mean change from baseline at endpoint
` was 2.1 kg.
`
`
`
`
`
`
` In 4 placebo-controlled, 4- or 6-week, fixed- or flexible-dose studies in adults with schizophrenia the mean change in
` weight (kg) was -0.1, 2, and 2.7 for placebo, FANAPT 10-16 mg/day, and FANAPT 20-24 mg/day groups, respectively.
`
`
`
`
`
` The proportion of patients with weight gain >7% increase from baseline was 4%, 12%, and 18% for placebo, FANAPT
` 10-16 mg/day, and FANAPT 20-24 mg/day groups, respectively.
`
`
`
`
` Bipolar Mania
` In a 4-week fixed dose study of adults with bipolar mania the mean change in weight (kg) was 1.6 and 4.6 kg for placebo
`
`
`
`
` and FANAPT 24 mg/day groups, respectively. The proportion of patients with weight gain ≥7% increase from baseline
` was 14% and 35%, for placebo and FANAPT 24 mg/day groups, respectively.
`
`
`
`
`
`
`
`
`
` 5.7 Orthostatic Hypotension and Syncope
` FANAPT can induce orthostatic hypotension associated with dizziness, tachycardia, and syncope. This reflects
`
`
`
`
` its alpha1-adrenergic antagonist properties. In double-blind placebo-controlled short-term studies in patients
` with schizophrenia, where the dose was increased slowly, as recommended above, syncope was reported in
`
`
`
`
` 0.4% (5/1,344) of patients treated with FANAPT, compared with 0.2% (1/587) on placebo. Orthostatic
` hypotension was reported in 5% of patients given 20 mg to 24 mg/day, 3% of patients given 10 mg to 16
`
`
`
`
`
`mg/day, and 1% of patients given placebo.
` In a double-blind placebo-controlled short-term study in patients with bipolar mania, syncope was reported in
`
`
`
`
` 0.5% (1/206) of patients treated with FANAPT, compared with 0% (0/208) on placebo. In this study, orthostatic
` hypotension was reported in 4% (9/206) of patients treated with FANAPT and 2% (5/208) of patients given
`
`
` placebo.
` More rapid titration would be expected to increase the rate of orthostatic hypotension and syncope.
`
`
`
`
` Orthostatic vital signs should be monitored in patients who are vulnerable to hypotension (e.g., elderly patients,
` patients with dehydration, hypovolemia, and concomitant treatment with antihypertensive medications), patients
`
`
`
` with known cardiovascular disease (history of myocardial infarction, ischemic heart disease, heart failure, or
` conduction abnormalities), and patients with cerebrovascular disease.
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 5516239
`
`

`

`
`
`
`
`
`
`
`
`
` 5.8 Falls
`
`
` Antipsychotics, including FANAPT, may cause somnolence, postural hypotension, motor and sensory
`
`
`
` instability, which may lead to falls and, consequently, fractures or other injuries. For patients with diseases,
` conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating
`
`
`
`
` antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.
`
`
` 5.9 Seizures
`
`
`
`
` Like other antipsychotic drugs, FANAPT may cause seizures. The risk is greatest in patients with a history of
`
` seizures or with conditions that lower the seizure threshold. Conditions that lower the seizure threshold may be
`
`
`
` more prevalent in older patients.
`
`
`
` 5.10 Leukopenia, Neutropenia and Agranulocytosis
` In clinical trial and postmarketing experience, leukopenia and neutropenia have been reported temporally
`
`
`
`
`
` related to antipsychotic agents. Agranulocytosis (including fatal cases) has also been reported.
` Possible risk factors for leukopenia/neutropenia include preexisting low white blood cell count (WBC) and
`
`
`
`history of drug induced leukopenia/neutropenia. Patients with a pre-existing low WBC 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.
`
`
`
`
`Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and
`
`
`treat promptly if such symptoms or signs occur. Discontinue FANAPT in patients with absolute neutrophil
`count <1000/mm3 and follow their WBC until recovery.
`
`
`
` 5.11 Hyperprolactinemia
`
`
`
`
` As with other drugs that antagonize dopamine D2 receptors, FANAPT elevates prolactin levels.
` Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion.
`
`
`
`
`
` This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male
` patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported with prolactin-elevating
`
`
` compounds. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased
`
`
` bone density in both female and male patients.
`Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin-
`dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient
`
`
`
`with previously detected breast cancer. Mammary gland proliferative changes and increases in serum prolactin
`
`
`
`
`were seen in mice and rats treated with FANAPT [see Nonclinical Toxicology (13)]. Published epidemiologic
`
`
`
`
`studies have shown inconsistent results when exploring the potential association between hyperprolactinemia
`
`and breast cancer.
`
`In a short-term placebo-controlled trial (4-weeks) in patients with schizophrenia, the mean change from baseline
`
`
`
`to endpoint in plasma prolactin levels for the FANAPT 24 mg/day-treated group was an increase of 2.6 ng/mL
`
`
`compared to a decrease of 6.3 ng/mL in the placebo-group. In placebo-controlled trials in patients with
`
`
`schizophrenia, elevated plasma prolactin levels (≥1.15xULN) were observed in 26% of adults treated with
`
`FANAPT compared to 12% in the placebo group. In the short-term trials, FANAPT was associated with modest
`
`
`levels of prolactin elevation compared to greater prolactin elevations observed with some other antipsychotic
`
`
`
`
`Reference ID: 5516239
`
`

`

`
`
`
`
`
`
`
`
`
` agents. In pooled analysis from clinical studies including longer term trials, in 3210 adults treated with
`
`
`
`
` iloperidone, gynecomastia was reported in 2 male subjects (0.1%) compared to 0% in placebo-treated patients,
` and galactorrhea was reported in 8 female subjects (0.2%) compared to 3 female subjects (0