FANAPT™
`
`
`(iloperidone) Tablets
`
`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
`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)
`
`______________________
`______________________
`INDICATIONS AND USAGE
`FANAPT is an atypical antipsychotic agent indicated for the acute treatment of
`schizophrenia in adults (1). 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.
`
`___________________
`____________________
`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)
`
`____________________
`___________________
`WARNINGS AND PRECAUTIONS
`•
`Elderly patients with dementia-related psychosis who are treated with
`
`
`
`atypical antipsychotic drugs are at an increased risk of death and
`cerebrovascular-related adverse events, including stroke. (5.1)
`
`QT prolongation: Prolongs QT interval and may be associated with
`
`arrhythmia and sudden death—consider using other antipsychotics first.
`
`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, 5.2, 7.1, 7.3, 12.3)
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`•
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`Neuroleptic Malignant Syndrome: Manage with immediate discontinuation
`
`of drug and close monitoring. (5.3)
`
`Tardive dyskinesia: Discontinue if clinically appropriate. (5.4)
`
`
`Hyperglycemia and diabetes mellitus: Monitor glucose regularly in patients
`
`at risk for diabetes. (5.5)
`
`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. (5.9)
`Suicide: Close supervision of high risk patients. (5.13)
`Priapism: Cases have been reported in association with FANAPT
`
`treatment. (5.14)
`Potential for cognitive and motor impairment: Use caution when operating
`machinery. (5.15)
`•
`for additional WARNINGS and
`Information
`See Full Prescribing
`
`
`PREACUTIONS.
`________________________ADVERSE REACTIONS________________________
`
`Commonly observed adverse reactions (incidence ≥5% and two-fold greater than
`
`fatigue, nasal congestion, orthostatic
`placebo) were: dizziness, dry mouth,
`
`hypotension, somnolence, tachycardia, and weight increased. (6.1)
`To report SUSPECTED ADVERSE REACTIONS, contact Vanda Pharmaceuticals
`1-800-FDA-1088 or
`at
`1-888-49VANDA
`(1-888-498-2632) or FDA
`at
`
`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: No human or animal data. Use only if clearly needed. (8.1)
`
`•
`Nursing Mothers: Should not breast feed. (8.3)
`
`•
`Pediatric Use: Safety and effectiveness not established in children and
`
`
`adolescents. (8.4)
`Hepatic
`Impairment: Not
`impairment. (8.7)
`See 17 for PATIENT COUNSELING INFORMATION
`
`
`recommended
`
`for patients with hepatic
`
`
`Revised: 05/2009
`
`
`
`
`•
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-
`RELATED PSYCHOSIS
`INDICATIONS AND USAGE
`DOSAGE AND ADMINISTRATION
`2.1
`Usual Dose
`Dosage in Special Populations
`2.2
`2.3 Maintenance Treatment
`
`
`2.4
`Reinitiation of Treatment in Patients Previously Discontinued
`
`
`2.5
`Switching From Other Antipsychotics
`
`DOSAGE FORMS AND STRENGTHS
`CONTRAINDICATIONS
`WARNINGS AND PRECAUTIONS
`5.1
`Increased Risks in Elderly Patients with Dementia-Related Psychosis
`
`5.2
`QT Prolongation
`5.3
`Neuroleptic Malignant Syndrome (NMS)
`Tardive Dyskinesia
`5.4
`
`Hyperglycemia and Diabetes Mellitus
`5.5
`5.6 Weight Gain
`
`5.7
`Seizures
`
`5.8
`Orthostatic Hypotension and Syncope
`Leukopenia, Neutropenia and Agranulocytosis
` 5.9
`
`
`5.10 Hyperprolactinemia
`
`5.11 Body Temperature Regulation
`5.12 Dysphagia
`
`5.13 Suicide
`5.14 Priapism
`5.15 Potential for Cognitive and Motor Impairment
`
`ADVERSE REACTIONS
`6.1
`Clinical Studies Experience
`DRUG INTERACTIONS
`
`1
`2
`
`3
`4
`5
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`6
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`7
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`8
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`9
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`10
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`11
`12
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`13
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`14
`16
`17
`
`Potential for Other Drugs to Affect FANAPT
`7.1
`
`
`Potential for FANAPT to Affect Other Drugs
`7.2
`
`
`Drugs that Prolong the QT Interval
`7.3
`USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`8.2
`Labor and delivery
`8.3
`Nursing mothers
`8.4
`Pediatric use
`Geriatric use
`8.5
`
`Renal impairment
`8.6
`
`Hepatic impairment
`8.7
`
`8.8
`Smoking Status
`DRUG ABUSE AND DEPENDENCE
`9.1
`Controlled substance
`9.2
`Abuse
`OVERDOSAGE
`10.1 Human experience
`10.2 Management of overdose
`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
`HOW SUPPLIED/STORAGE AND HANDLING
`PATIENT COUNSELING INFORMATION
`17.1 QT Interval Prolongation
`17.2 Neuroleptic Malignant Syndrome
`
`17.3 Orthostatic Hypotension
`
`
`1
`
`
`
`
`

`

`Interference with Cognitive and Motor Performance
`17.4
`17.5 Pregnancy
`17.6 Nursing
`17.7 Concomitant Medication
`
`
`
`
` FULL PRESCRIBING INFORMATION
`
`
`17.8 Alcohol
`17.9 Heat Exposure and Dehydration
`*Sections or subsections omitted from the full prescribing information are not
`listed.
`
`
`
`
` IN ELDERLY PATIENTS WITH DEMENTIA-RELATED
`
`INCREASED MORTALITY
`
`WARNING:
`PSYCHOSIS
` Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an
`
`increased risk of death. Analysis of seventeen placebo controlled trials (modal duration 10 weeks),
`largely in patients taking atypical antipsychotic drugs, revealed a risk of death in the drug-treated
`patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of
`a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%,
`compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied,
`most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or
`infectious (e.g., pneumonia) in nature.
`Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with
`conventional antipsychotic drugs may increase mortality. The extent to which the findings of
`increased mortality in observational studies may be attributed to the antipsychotic drug as
`opposed to some characteristics(s) of the patients is not clear. FANAPT is not approved for the
`
`treatment of patients with Dementia-Related Psychosis. [see Warnings and Precautions (5.1)]
`
`
`
`INDICATIONS AND USAGE
`1
`FANAPT™ tablets are indicated for the acute treatment of adults with schizophrenia [see Clinical Studies
`
`(14)].
`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 Precaution
`(5.2)]. 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
`
`In many cases this would lead to the conclusion that other drugs should be tried first.
`sudden death.
`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
`acute treatment of schizophrenia [See Dosage and Administration (2.1) and Clinical Studies (14)].
`The effectiveness of FANAPT in long-term use, that is, for more than 6 weeks, has not been systematically
`
`evaluated in controlled trials. Therefore, the physician who elects to use FANAPT for extended periods
`should periodically re-evaluate the long-term usefulness of the drug for the individual patient [See Dosage
`
`and Administration (2.3)].
`
`
`2
`
`
`

`

`FANAPT™ (iloperidone) Tablets
`
`
`2
`
`DOSAGE AND ADMINISTRATION
`
`Usual Dose
`2.1
`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 twice daily.
`
`Increases to reach the target dose range of 6-12 mg twice daily may be made with daily dosage
`adjustments to 2 mg twice daily, 4 mg twice daily, 6 mg twice daily, 8 mg twice daily, 10 mg twice daily, and
`12 mg twice daily on days 2, 3, 4, 5, 6, and 7, respectively. 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.
`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.
`
`FANAPT can be administered without regard to meals.
`
`Dosage in Special Populations
`2.2
`Dosage adjustments are not routinely indicated on the bases of age, gender, race, or renal impairment
`status [see Use in Specific Populations (8.6, 8.7)].
`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 (7.1)].
`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 clarithomycin. When the CYP3A4 inhibitor is withdrawn from the
`combination therapy, FANAPT dose should be increased to where it was before [See Drug Interactions
`(7.1)].
` Hepatic Impairment: FANAPT is not recommended for patients with hepatic impairment.
`
`
`
`
`
`Maintenance Treatment
` 2.3
`
`Although there is no body of evidence available to answer the question of how long the patient treated with
`FANAPT should be maintained, it is generally recommended that responding patients be continued beyond
`the acute response. Patients should be periodically reassessed to determine the need for maintenance
`treatment.
`
`Reinitiation of Treatment in Patients Previously Discontinued
`2.4
`
`Although there are no data to specifically address re-initiation 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
`
`
`

`

`FANAPT™ (iloperidone) Tablets
`
`
`Switching From Other Antipsychotics
`2.5
`
`There are no specific data to address how patients with schizophrenia can be switched from other
`antipsychotics to FANAPT or how FANAPT can be used concomitantly with other antipsychotics. Although
`immediate discontinuation of the previous antipsychotic treatment may be acceptable for some patients
`with schizophrenia, more gradual discontinuation may be most appropriate for others. In all cases, the
`period of overlapping antipsychotic administration should be minimized.
`
`DOSAGE FORMS AND STRENGTHS
`3
`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-edge and identified with a logo “
`tablet strength “1”, “2”, “4”, “6”, “8”, “10”, or “12” debossed on the other side.
`
`” debossed on one side and
`
`CONTRAINDICATIONS
`4
` FANAPT is contraindicated in individuals with a known hypersensitivity reaction to the product. Reactions
`
` have included pruritus and urticaria.
`
`
`
`5
`
`WARNINGS AND PRECAUTIONS
`
`Increased Risks in Elderly Patients with Dementia-Related Psychosis
`5.1
`Increased Mortality
`Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an
`
`increased risk of death compared to placebo. FANAPT is not approved for the treatment of patients
`with dementia-related psychosis [see Boxed Warning].
`
`Cerebrovascular Adverse Events, Including Stroke
`
`In placebo-controlled trials with risperidone, aripiprazole, and olanzapine in elderly patients with dementia,
`
`there was a higher incidence of cerebrovascular adverse events (cerebrovascular accidents and transient
`
`ischemic attacks) including fatalities compared to placebo-treated patients. FANAPT is not approved for
`the treatment of patients with dementia-related psychosis [see Boxed Warning].
`
`QT Prolongation
`5.2
`
`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.
`
`4
`
`
`

`

`FANAPT™ (iloperidone) Tablets
`
`
`
`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, thiordazine), 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 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
`Interaction (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 ms.
`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.
`
`Neuroleptic Malignant Syndrome (NMS)
`5.3
`A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has
`been reported in association with administration of antipsychotic drugs. 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 dysarrhythmia).
`Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute
`renal failure.
`
`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
`
`
`

`

`FANAPT™ (iloperidone) Tablets
`
`
`Tardive Dyskinesia
`5.4
`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.
`
`Hyperglycemia and Diabetes Mellitus
`5.5
`
`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 treatment-emergent
`hyperglycemia-related adverse events in patients treated with the atypical antipsychotics included in these
`studies. Because FANAPT was not marketed at the time these studies were performed, it is not known if
`FANAPT is associated with this increased risk. Precise risk estimates for hyperglycemia-related adverse
`events in patients treated with atypical antipsychotics are not available.
`
`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
`
`6
`
`
`

`

`FANAPT™ (iloperidone) Tablets
`
`
`
`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.
`
`Weight Gain
`5.6
`Based on the pooled data from the four placebo-controlled, 4- or 6-week, fixed- or flexible-dose studies, the
`
`proportions of patients having a weight gain of ≥ 7% body weight was 12% for FANAPT 10-16 mg/day,
`18% for FANAPT 20-24 mg/day, and 13% for FANAPT (combined doses) versus 4% for placebo. The
`mean weight change from baseline to endpoint in the short-term studies was -0.1 kg for placebo versus 2.0
`kg for FANAPT-treated patients. Across all short- and long-term studies, the overall mean change from
`baseline at endpoint was 2.1 kg.
`
`
`Seizures
`5.7
`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, e.g., Alzheimer’s dementia. 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 α1-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.
`
`
`5.9
`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.
`
`
`7
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`FANAPT™ (iloperidone) Tablets
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`
`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.
`
`Hyperprolactinemia
`5.10
`
`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 (13.1)].
`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 level 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
`
`In the short-term trials,
`26% of adults treated with FANAPT compared to 12% in the placebo group.
`
`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.
`
`5.11 Body Temperature Regulation
`
`Disruption of the body’s ability to reduce core body temperature has been attributed to antipsychotic
`agents. Appropriate care is advised when prescribing FANAPT for patients who will be experiencing
`
`conditions which may contribute to an elevation in core body temperature, e.g., exercising strenuously,
`exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to
`dehydration.
`
`Dysphagia
`5.12
`Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration
`
`pneumonia is a common cause of morbidity and mortality in elderly patients, in particular those with
`advanced Alzheimer’s dementia. FANAPT and other antipsychotic drugs should be used cautiously in
`patients at risk for aspiration pneumonia [see Boxed Warning].
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`Suicide
`5.13
`The possibility of a suicide attempt is inherent in psychotic illness, and close supervision of high-risk
`
`patients should accompany drug therapy. Prescriptions for FANAPT should be written for the smallest
`quantity of tablets consistent with good patient management in order to reduce the risk of overdose.
`
`Priapism
`5.14
`
`Three cases of priapism were reported in the premarketing FANAPT program. Drugs with alpha-adrenergic
`blocking effects have been reported to induce priapism. FANAPT shares this pharmacologic activity.
`Severe priapism may require surgical intervention.
`
`Potential for Cognitive and Motor Impairment
`5.15
`FANAPT, like other antipsychotics, has the potential to impair judgment, thinking or motor skills. In short-
`
`term, placebo-controlled trials, somnolence (including sedation) was reported in 11.9% (104/874) of adult
`
`patients treated with FANAPT at doses of 10 mg/day or greater versus 5.3% (31/587) treated with placebo.
`Patients should be cautioned about operating hazardous machinery, including automobiles, until they are
`reasonably certain that therapy with FANAPT does not affect them adversely.
`
`
`
`ADVERSE REACTIONS
`6
`
`Clinical Studies Experience
`6.1
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in
`the clinical trial of a drug cannot be directly compared to rates in the clinical trials of another drug and may
`not reflect the rates observed in clinical practice. The information below is derived from a clinical trial
`database for FANAPT consisting of 2070 patients exposed to FANAPT at doses of 10 mg/day or greater,
`for the treatment of schizophrenia. All of these patients who received FANAPT were participating in
`multiple-dose clinical trials. The conditions and duration of treatment with FANAPT varied greatly and
`included (in overlapping categories), open-label and double-blind phases of studies, inpatients and
`outpatients, fixed-dose and flexible-dose studies, and sho