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-----------------------­
`5/2016
`Boxed Warning
`
`
`
`
`
`5/2016
`Indications and Usage (1)
`
`
`
`
`5/2016
`Dose and Administration (2.3)
`
`
`
`
`5/2016
`Warnings and Precautions (5.1 , 5.2)
`
`
`
`
` 2/2017
`Warnings and Precautions (5.3, 5.9)
`
`
`
`
`
` -----------------------------INDICATIONS AND USAGE-----------------------­
`FANAPT is an atypical antipsychotic indicated for the treatment of
`
`schizophrenia in adults. (1, 14) 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. (2, 5, 14)
`
`--------------------------DOSAGE AND ADMINISTRATION-----------------­
`The recommended target dosage of FANAPT tablets is 12 to 24 mg/day
`administered twice daily. This target dosage range is achieved by daily dosage
`adjustments, alerting patients to symptoms of orthostatic hypotension, starting
`at a dose of 1 mg twice daily, then moving to 2 mg, 4 mg, 6 mg, 8 mg, 10 mg,
`
`and 12 mg twice daily on Days 2, 3, 4, 5, 6, and 7 respectively, to reach the 12
`mg/day to 24 mg/day dose range. FANAPT can be administered without
`
`regard to meals. (2.1)
`
`
`-------------------------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—consider using other antipsychotics first.
`
`
`
`
`
`
`
`
`
`
`
`
` 
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
`
`1
`
`2
`
`
`WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS
`WITH DEMENTIA-RELATED PSYCHOSIS
`
`INDICATIONS AND USAGE
`
`
`DOSAGE AND ADMINISTRATION
`
`2.1 Usual Dose
`
`
`
`2.2 Dosage in Special Populations
`
`
`2.3 Maintenance Treatment
`
`
`
`2.4 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)
`
`
`
`
`
`
`
`Reference ID: 4060034
`
`Avoid use of FANAPT in combination with 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, 7.3, 12.3)
`
`
` Neuroleptic Malignant Syndrome: 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)
`
` Seizures: Use cautiously in patients with a history of seizures or with
`conditions that lower seizure threshold. (5.7)
`
` Orthostatic hypotension: Dizziness, tachycardia, and syncope can occur
`with standing. (5.8)
`
`
` Leukopenia, Neutropenia, and Agranulocytosis have been reported with
`antipsychotics. Patients with a pre-existing low white blood cell count
`(WBC) or a history of 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. (5.10)
`
` Suicide: Close supervision of high risk patients. (5.14)
`
` Priapism: Cases have been reported in association with FANAPT
`treatment. (5.15)
`
` Potential for cognitive and motor impairment: Use caution when operating
`
`machinery. (5.16)
`
`
`
`
`
`
`-------------------------------- ADVERSE REACTIONS---------------------------­
`
`Commonly observed adverse reactions (incidence ≥5% and 2-fold greater than
`
`placebo) were: dizziness, dry mouth, fatigue, nasal congestion, orthostatic
`
`hypotension, somnolence, tachycardia, and weight increased. (6.1)
`
`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)
`
` Lactation: Advise not to breast feed. (8.2)
`
`
` Pediatric Use: Safety and effectiveness not established in children and
`adolescents. (8.3)
`
` Hepatic Impairment: FANAPT is not recommended for patients with
`severe hepatic impairment. (2.2 , 8.6)
`
`
` The dose of FANAPT should be reduced in patients who are poor
`metabolizers of CYP2D6. (2.2, 12.3)
`
`
`See 17 for PATIENT COUNSELING INFORMATION
`
`
`
`
`
`
`
` Revised: 2/2017
`
`
`
`
` Tardive Dyskinesia
`5.5
`
`5.6 Metabolic Changes
`
`5.7
` Seizures
`
`
`5.8 Orthostatic Hypotension and Syncope
`
`5.9 Falls
`
`5.10 Leukopenia, Neutropenia and Agranulocytosis
`
`
`5.11 Hyperprolactinemia
`
`
`
`5.12 Body Temperature Regulation
`
`
`5.13 Dysphagia
`
`
`
`5.14 Suicide
`
`
`5.15 Priapism
`
`
` 5.16 Potential for Cognitive and Motor Impairment
`
`
`ADVERSE REACTIONS
`
`
`6.1 Clinical Studies Experience
`
`
`
`6.2
`Postmarketing Experience
`
`
`
`DRUG INTERACTIONS
`
`
`Potential for Other Drugs to Affect FANAPT
`7.1
`
`
`7.2
`Potential for FANAPT to Affect Other Drugs
`
`
`7.3 Drugs that Prolong the QT Interval
`
`
`
`
`
`6
`
`
`7
`
`
`
`
`
`
`
`

`

`USE IN SPECIFIC POPULATIONS
`
`8.1
`Pregnancy
`
`
`
`8.2 Lactation
`
`
`
`8.3
`Pediatric Use
`
`
`
`8.4 Geriatric Use
`
`
`
`8.5 Renal Impairment
`
`
`
`8.6 Hepatic Impairment
`
`
`8.7
`Smoking Status
`
`
`
`DRUG ABUSE AND DEPENDENCE
`
`9.1 Controlled Substance
`
`
`
`9.2 Abuse
`
`
`
`10 OVERDOSAGE
`
`
`
`10.1 Human Experience
`
`
`10.2 Management of Overdose
`
`
`
`8
`
`
`9
`
`
`
` 
`
`
`
`11
`
`12
`
`
`13
`
`
`DESCRIPTION
`
`
`CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`
`
`
`12.2 Pharmacodynamics
`
`
`12.3 Pharmacokinetics
`
`
`
`NONCLINICAL TOXICOLOGY
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`CLINICAL STUDIES
`14
`
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`17
`PATIENT COUNSELING INFORMATION
`
`
`
`*Sections or subsections omitted from the full prescribing information are not
`
`listed.
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4060034
`
`

`

`
`
`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)].
`
`
`INDICATIONS AND USAGE
`
`1
`FANAPT® is indicated for the treatment of schizophrenia in adults.
`When deciding among the alternative treatments available for this condition, the prescriber should consider the
`
`finding that FANAPT is associated with prolongation of the QTc interval [see Warnings and Precautions (5.3)].
`Prolongation of the QTc interval is associated in some other drugs with the ability to cause torsade de pointes­
`type arrhythmia, a potentially fatal polymorphic ventricular tachycardia which can result in sudden death. In
`many cases this would lead to the conclusion that other drugs should be tried first. Whether FANAPT will cause
`torsade de pointes or increase the rate of sudden death is not yet known.
`
`
`Patients must be titrated to an effective dose of FANAPT. Thus, control of symptoms may be delayed during the
`first 1 to 2 weeks of treatment compared to some other antipsychotic drugs that do not require a similar titration.
`Prescribers should be mindful of this delay when selecting an antipsychotic drug for the treatment of
`schizophrenia [see Dosage and Administration (2.1) and Clinical Studies (14)].
`
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Usual Dose
`FANAPT must be titrated slowly from a low starting dose to avoid orthostatic hypotension due to its alpha­
`adrenergic blocking properties. The recommended starting dose for FANAPT tablets is 1 mg orally twice daily.
`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). FANAPT doses above 24 mg/day have not been systematically evaluated in the clinical trials.
`Efficacy was demonstrated with FANAPT in a dose range of 6 to 12 mg twice daily. Prescribers should be
` mindful of the fact that patients need to be titrated to an effective dose of FANAPT. Thus, control of symptoms
`
`may be delayed during the first 1 to 2 weeks of treatment compared to some other antipsychotic drugs that do
`not require similar titration. Prescribers should also be aware that some adverse effects associated with
`FANAPT use are dose related [see Adverse Reactions (6.1)].
`FANAPT can be administered without regard to meals.
`
`2.2 Dosage in Special Populations
`Dosage adjustment for patients taking FANAPT concomitantly with potential CYP2D6 inhibitors: FANAPT
`dose should be reduced by one-half when administered concomitantly with strong CYP2D6 inhibitors such as
`
`fluoxetine or paroxetine. When the CYP2D6 inhibitor is withdrawn from the combination therapy, FANAPT
`dose should then be increased to where it was before [see Drug Interactions (7)].
`
`Reference ID: 4060034
`
`

`

`
`
`Dosage adjustment for patients taking FANAPT concomitantly with potential CYP3A4 inhibitors: FANAPT
`dose should be reduced 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,
`FANAPT dose should be increased to where it was before [see Drug Interactions (7)].
`Dosage adjustment for patients taking FANAPT who are poor metabolizers of CYP2D6: FANAPT dose
`
` should be reduced by one-half for poor metabolizers of CYP2D6 [see Clinical Pharmacology (12.3)].
`Hepatic Impairment: No dose adjustment to 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)].
`
`2.3 Maintenance Treatment
`In a longer-term study, FANAPT was effective in delaying time to relapse in patients with schizophrenia who
`were stabilized on FANAPT up to 24 mg/day [see Clinical Studies (14)]. Patients should be periodically
`reassessed to determine the need for maintenance treatment.
`
`2.4 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.
`
`
`
`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
`Antipsychotic drugs increase the all-cause risk of death in elderly patients with dementia-related psychosis.
`Analyses of 17 dementia-related psychosis placebo-controlled trials (modal duration of 10 weeks and 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)].
` 
`
`Reference ID: 4060034
`
`

`

`
`
`
`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)
`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 )].
`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)
`A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) 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.
`
`Reference ID: 4060034
`
`

`

`
`
`The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is
`important to identify cases in which the clinical presentation includes both serious medical illness (e.g.,
` pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms
`
`(EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat
`stroke, drug fever, and primary central nervous system (CNS) pathology.
`The management of this syndrome should include: (1) immediate discontinuation of the antipsychotic drugs and
`other drugs not essential to concurrent therapy, (2) intensive symptomatic treatment and medical monitoring,
`and (3) treatment of any concomitant serious medical problems for which specific treatments are available.
`There is no general agreement about specific pharmacological treatment regimens for NMS.
`If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug
`therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS
`have been reported.
`
`
` 5.5 Tardive Dyskinesia
`Tardive dyskinesia is a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements,
`which may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome
`appears to be highest among the elderly, especially elderly women, it is impossible to rely on prevalence
`estimates to predict, at the inception of antipsychotic treatment, which patients are likely to 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 are believed to
`increase as the duration of treatment and the total cumulative dose of antipsychotic administered increases.
`However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at
`low doses.
`There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit,
`partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment itself, however, may
`suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask 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 minimize the
`occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who
`suffer from a chronic illness that (1) 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, the smallest dose and the shortest duration of treatment producing a satisfactory
`clinical response should be sought. The need for continued treatment should be reassessed periodically.
`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
`
`Reference ID: 4060034
`
`

`

`
`
`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. Assessment of the
`relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of
`an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of
`diabetes mellitus in the general population. Given these confounders, the relationship between atypical
`antipsychotic use and hyperglycemia-related adverse events is not completely understood. However,
`epidemiological studies suggest an increased risk of hyperglycemia-related adverse events in patients treated
`with the atypical antipsychotics included in these studies.
`Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be
`monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g.,
`obesity, family history of diabetes) 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 suspect drug.
`Data from a 4- week, fixed-dose study in adult subjects with schizophrenia, in which fasting blood samples
`were drawn, are presented in Table 1 .
` 
`Table 1: Change in Fasting Glucose
`
`
`
`
`
`
`
`
`
`Serum Glucose Change from Baseline
`
`Serum Glucose Normal to High
`(<100 mg/dL to ≥126 mg/dL)
`
`FANAPT-
`
`
`Placebo
` 24 mg/day
`
`Mean Change from Baseline(mg/dL)
`
` n=228
`n=114
`-0.5
`6.6
`Proportion of Patients with Shifts
`2.5 %
`10.7 %
`
`
`(2/80)
`(18/169)
`
`
`
`
`Pooled analyses of glucose data from clinical studies including longer term trials are shown in Table 2.
`
`Table 2:
` 
`
`Change in Glucose
`
`
`Mean Change from Baseline (mg/dL)
`6-12 months
`3-6 months
`5.4 (N=723)
`1.8 (N=773)
`
`
`-9.0 (N=31)
`-3.6 (N=34)
`
`
`
`
`FANAPT 10-16 mg/day
`FANAPT 20-24 mg/day
`
`Dyslipidemia
`
`Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.
`
`>12 months
`5.4 (N=425)
`
`-18.0 (N=20)
`
`
`Reference ID: 4060034
`
`

`

`
`
`Data from a placebo-controlled, 4-week, fixed-dose study, in which fasting blood samples were drawn, in adult
`subjects with schizophrenia are presented in Table 3 .
`Table 3:
`Change in Fasting Lipids
`
`
`
`
`Cholesterol
`Change from baseline
`LDL
`Change from baseline
`HDL
`Change from baseline
`Triglycerides
`Change from baseline
`
`
`Cholesterol
`
`Normal to High
`
`(<200 mg/dL to ≥240 mg/dL)
`
` LDL
`Normal to High
`(<100 mg/dL to ≥160 mg/dL)
`
`HDL
`Normal to Low
`( ≥40 mg/dL to <40 mg/dL)
`Triglycerides
`Normal to High
`(<150 mg/dL to ≥200 mg/dL)
`
`FANAPT-
`
`
` 24 mg/day
`
`Placebo
`Mean Change from Baseline (mg/dL)
`
`
`n= 114
`n=228
`
`8.18
`-2.17
`
`
`n=217
`n=109
`
`9.03
`-1.41
`
`
`n=228
`n= 114
`
`0.55
`-3.35
`n=228
`n= 114
`16.47
`-0.83
`Proportion of Patients with Shifts
`
`
`1.4 %
`
`(1/72)
`
`
`2.4%
`
`(1/42)
`
`
`23.8%
`
`(19/80)
`
`
`8.3%
`
`(6/72)
`
`
`3.6%
`
`(5/141)
`
`
`1.1%
`
`(1/90)
`
`
`12.1%
`
`(20/166)
`
`
`10.1%
`
`(15/148)
`
` 
`
`Pooled analyses of cholesterol and triglyceride data from clinical studies including longer term trials are shown
`in Table 4 and Table 5 .
`
`
`Table 4:
` 
`
`Change in Cholesterol
`
`
`Mean Change from Baseline (mg/dL)
`6-12 months
`3-6 months
`
`
`-3.9 (N=726)
`-3.9 (N=783)
`
`
`-23.2 (N=31)
`-19.4 (N=34)
`
`>12 months
`
`-7.7 (N=428)
`
`-19.4 (N=20)
`
`
`FANAPT 10-16 mg/day
`FANAPT 20-24 mg/day
` 
`
`Table 5:
` 
`
`Reference ID: 4060034
`
`Change in Triglycerides
`
`

`

`
`
`
`FANAPT 10-16 mg/day
`FANAPT 20-24 mg/day
`
`
`Mean Change from Baseline (mg/dL)
`6-12 months
`3-6 months
`
`
`-8.9 (N=726)
`-8.9 (N=783)
`
`
`-35.4 (N=31)
`-26.6 (N=34)
`
`>12 months
`-17.7 (N=428)
`
`-17.7 (N=20)
`
`
`Weight Gain
`Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.
`
`Across all short- and long-term studies, the overall mean change from baseline at endpoint was 2.1 kg.
`Changes in body weight (kg) and the proportion of subjects with ≥7% gain in body weight from 4 placebo-controlled, 4­
`or 6-week, fixed- or flexible-dose studies in adult subjects are presented in Table 6.
`Table 6:
`Change in Body Weight
`
`
`
`
`
`
`
`
`
`Weight (kg)
`
`Change from Baseline
`
`
`Weight Gain
`≥7% increase from Baseline
`
` 
`
`Placebo
`
`n=576
`
`-0.1
`
`
`4%
`
`FANAPT
`
`10-16 mg/day
`
`
`n=481
`
`2.0
`
`
`12%
`
`FANAPT
`
`20-24 mg/day
`
`
`n=391
`
`2.7
`
`
`18%
`
`
`5.7 Seizures
`In short-term placebo-controlled trials (4- to 6-weeks), seizures occurred in 0.1% (1/1344) of patients treated
`with FANAPT compared to 0.3% (2/587) on placebo. As with other antipsychotics, FANAPT should be used
`cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold.
`Conditions that lower the seizure threshold may be more prevalent in a population of 65 years or older.
`
`5.8 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, where the
`dose was increased slowly, as recommended above, syncope was reported in 0.4% (5/1344) of patients treated
`with FANAPT, compared with 0.2% (1/587) on placebo. Orthostatic hypotension was reported in 5% of
`patients given 20-24 mg/day, 3% of patients given 10-16 mg/day, and 1% of patients given placebo. More rapid
`titration would be expected to increase the rate of orthostatic hypotension and syncope.
`FANAPT should be used with caution in patients with known cardiovascular disease (e.g., heart failure, history
`of myocardial infarction, ischemia, or conduction abnormalities), cerebrovascular disease, or conditions that
`predispose the patient to hypotension (dehydration, hypovolemia, and treatment with antihypertensive
`medications). Monitoring of orthostatic vital signs should be considered in patients who are vulnerable to
`hypotension.
`
`Reference ID: 4060034
`
`

`

`
`
`
`5.9 Falls
`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.
`
`
`
`5.10 Leukopenia, Neutropenia and Agranulocytosis
`In clinical trial and postmarketing experience, events of leukopenia/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.
`Patients with neutropenia should be carefully monitored for fever or other symptoms or signs of infection and
`treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count
`<1000/mm3) should discontinue FANAPT and have their WBC followed 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 gonadalsteroidogenesis 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)]. 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), 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 this trial, elevated plasma prolactin levels 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.
`
`Reference ID: 4060034
`
`

`

`
`
`
`5.12 Body Temperature Regulation
`Disruption of the body’s ability to reduce core body temperature has