other drugs that are known to prolong QTc; use caution and consider dose
`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: 4/2024
`
`
`Recommended Dosage
`
`1 mg twice daily
`
`6 mg to 12 mg twice daily
`
`1 mg twice daily
`
`12 mg twice daily
`
`
`
`
`
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`
`
`
`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------------------------
`Indications and Usage (1)
`
`
`
`4/2024
`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, 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)
`
`
`--------------------------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:
`Indication
`Starting Dosage
`
`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
`
`
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`
`Reference ID: 5357650
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`
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`
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`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

`7
`
`8
`
`9
`
`11
`12
`
`13
`
`14
`
`
`Postmarketing Experience
`6.2
`
`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.
`
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`
`
`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
`5.1
`Increased Mortality in Elderly Patients with Dementia-Related
`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
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`Reference ID: 5357650
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

`
`
`
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`
`
`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)].
`
`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 4
`Day 5
`Population
`Schizophrenia
`6 mg
`8 mg
`twice
`twice
`daily
`daily
`9 mg
`12 mg
`twice
`twice
`daily
`daily
`
`Day 1 Day 2 Day 3
`1mg
`2 mg
`4 mg
`twice
`twice
`twice
`daily
`daily
`daily
`1 mg
`3 mg
`6 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
`
`Recommended
`Dosage
`6 mg to 12 mg
`twice daily
`
`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: 5357650
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

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`
`
`
`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
`Schizophrenia
`6 mg
`
`twice
`daily
`
`Day 6
`
`Day 7
`
`Titration complete
`
`Recommended
`Dosage
`3 mg to 6 mg
`twice daily
`
`Day 1 Day 2 Day 3
`1mg
`2 mg
`4 mg
`twice
`twice
`twice
`daily
`daily
`daily
`1 mg
`3 mg
`6 mg
`twice
`twice
`twice
`daily
`daily
`daily
`
`Titration complete
`
`6 mg
`twice daily
`
`Bipolar I Disorder
`Manic or Mixed
`Episodes
`
`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: 5357650
`
`
`
`
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

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`
`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: 5357650
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

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`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: 5357650
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

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`
`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.
`
`
`
`
`
`Reference ID: 5357650
`
`
`
`
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

`
`
`
`
`
`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%).
`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 to16
`mg/day, and 1% of patients given placebo.
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`Reference ID: 5357650
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`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
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`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.
`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.
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`Reference ID: 5357650
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`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
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`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)]. Neither clinical studies nor
`epidemiologic studies conducted to date have shown an association between chronic administration of this class
`of drugs and tumorigenesis in humans; the available evidence is considered too limited to be conclusive at this
`time.
`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
`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 (0.5%) in placebo-
`treated patients.
`In a short-term, placebo-controlled trial (4-weeks) in patients with bipolar mania, the mean change from
`baseline to endpoint in plasma prolactin levels for the FANAPT group was an increase of 15.66 ng/mL
`compared to a decrease of 0.58 ng/mL for the placebo group. In this trial, elevated plasma prolactin levels
`(≥1.15xULN) were observed in 35% of adults treated with FANAPT compared to 1% of the placebo group.
`5.12 Body Temperature Regulation
`Atypical antipsychotics may disrupt the body’s ability to reduce core body temperature. Strenuous exercise,
`exposure to extreme heat, dehydration, and anticholinergic medications may contribute to an elevation in core
`body temperature; use FANAPT with caution in patients who may experience these conditions.
`5.13 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. Antipsychotic dr