CENTER FOR DRUG EVALUATION AND
`RESEARCH
`'
`
`APPLICA TION NUMBER:
`
`22-192 .
`
`LABELING
`
`

`

`FANAPT"
`(iloperidone) Tablets
`
`.
`
`NorwaIean'Mfi'gnaIrté‘ynm: Manage with immediate discontinuation
`of drug and close monitoring. (5.3)
`Tactile dysthw’a. Discontinue if clinically appropriate. (5.4)
`o
`o mmmmnum 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)
`0mm? hypobnsim: Dizziness, tachycardia, and syncope can occur
`with standing. (5.8)
`Leukapm’a, Nauavparb, “/4ng have been reported with
`antipsychotics. Patients with a preexisting low white blood cell count
`(WBC) or a history of leukopenialneutropenia 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)
`Swade Close supervision of high risk patients. (5.13)
`anu'sm Cases have been reported in association with FANAPT
`treatment. (5.14)
`Pamfl foray/rifle and rnatan'mpa'flnent Use caution when operating
`machinery. (5.15)
`See Full Prescribing
`PREACWONS.
`
`o
`
`-
`
`o
`
`o
`o
`
`o
`
`0
`
`Information for
`
`additional WARN/N65 and
`
`mmormmmu
`mwammdmmmumm
`mum. mummmmm.
`FWW“
`. mmmumvummm
`transom
`mummmmwm.
`”MHWWWHW
`
`Mudlhflul‘lfldd‘t. FANTBMWMIIOh
`
`o
`
`-
`
`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.
`
`“MGEMWM
`The recommended target dosage of FANAPT tablets'Is 12 to 24 mglday 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 mglday to 24 mglday dose range. FANAPT
`
`can be administered without regard to meals. (2.1)
`none:WWM
`
`1 mg, 2 mg, 4 mg, 6 mg, 8 mg, 10 mg and 12 mg tablets. (3)
`WWW——
`
`Known hypersensitivity to FANAPT or to any components'In the formulation. (4)
`M MDmm
`Eldenypaa'mts mdenmtta-Ielatedpsydtasb manteated with
`atypical antipsychotic drugs are at an increased risk of death and
`cerebrovascular-related adverse events, including stroke. (5.1)
`0T mm 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)
`
`
`Commonly observed adverse reactions (incidence 25% and two-fold greater than
`placebo) were: dizziness,
`dry mouth,
`fatigue, nasal
`congestion, orthostatic
`hypotension, somnolence, tachycardia, and weight increased. (6.1)
`To not!mmm BEAM cum VIII.m
`lMWfl-lfl-“MWFDAItMFDAJMN
`Ill
`
`W
`automatons
`The dose of FANAPT should be reduced in patients co-administered a
`o
`
`strong CYP2D6 or CYP3A4 inhibitor. (2.2, 7.1)
`mummm
`Pregnancy: No human or animal data. Use only it clearly needed. (8.1)
`Nursing Mothers: Should notbreast feed. (8.3)
`Pediatric Use: Safety and effectiveness not established in children and
`adolescents. (8.4)
`Hepatic
`lmpairrnent: Not
`impairment. (8.7)
`8001110! ”WWW“
`
`recommended for patients with hepatic
`
`mm
`
`0
`0
`0
`
`-
`
`“‘9
`
`nu.mmmm comm
`mm WWMNMYPAMWW
`mmm
`1 WWWm
`2 mammmu
`2.1
`Usual Dose
`2.2
`Dosage in Special Populations
`2.3
`Maintenance Treatment
`2.4
`Reinitiation of Treatment in Patients Previously Discontinued
`2.5
`Switching From Other Antipsychotics
`mmmm
`WI”.
`MAIDmum
`Increased RisksIn Elderly Patients with Dementia-Related Psychosis
`QT Prolongation
`5.2
`Neuroleptic Malignant Syndrome (NMS)
`5.3
`Tardive Dyskinesia
`5.4
`Hyperglycemia and Diabetes Mellitus
`5.5
`5.6 Weight Gain
`5.7
`Seizures
`5.8
`Orthostatic Hypotension and Syncope
`5.9
`Leukopenia, Neutropenia and Agranulocytosis
`5.10 Hyperprolactinemia
`5.11
`Body Temperature Regulation
`5.12 Dysphagia
`5.13
`Suicide
`5.14
`Priapism
`5.15
`Potential for Cognitive and Motor lmpaim'rent
`I mm
`6.1
`Clinical Studies Experience
`1 mm
`
`I
`
`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
`I.“ I1 armmm
`8.1
`Pregnancy
`8.2
`Labor and delivery
`8.3
`Nursing mothers
`8.4
`Pediatric use
`8.5
`Geriatric use
`8.6
`Renal impairment
`8.7
`Hepatic impairment
`8.8
`Smoking Status
`8 mmwm
`9.1
`Controlled substance
`9.2
`Abuse
`10 M“
`10.1
`Human experience
`10.2 Management of overdose
`11 m
`12 wW
`12.1 Mechanism of action
`12.2
`Pharmacodynamics
`12.3
`Phannacokinetics
`1: WWW
`13.1
`Carcinogenesis mutagenesis, impairment of fertility
`numa
`mmoemMN
`MWmMM
`171
`QT interval Prolongation
`17.2 Neuroleptic Malignant Syndrome
`17.3 Orthostatic Hypotension
`
`=38:
`
`

`

`Interference with Cognitive and Motor Performance
`17.4
`Pregnancy
`17.5
`17.6 Nursing
`17.7 Concomitant Medication
`
`17.8 Alcohol
`17.9 Heat Exposure and Dehydration
`WNM‘WMNMMMIIM
`Iefl.
`
`FULL PRESCRIIING INFORMA‘HON
`
`WARNING:
`PSYCHOflS
`
`INCREASED MORTALITY lN ELDERLY PATIENTS MTH WRELATED
`
`treatment of pwents with Dementia-Rained Psychosis. [see Warnings ardhscaudens (5. 1)]
`
`Elderly patents with dementia-related psychosis traded with antipsychotic drugs are at an
`Increased risk of dean. Analysis of seventun placebo controlled trids (modal duration 10 weeks),
`largely in palenb taking atpr antipsychotic drugs. maded a risk of death in the drug-treated
`patients of between 1.6 to 1.7 times the risk of dam in placebo-traded patents. Over the course of
`a typical 10-week- controliad trial. the rats of death In drug-traded patients was about 4.5%,
`compared to a rate of about 2.6% in the placebo group. Although the causes of dam were varied,
`most- of the deaths appaaed to be either cadlovascuiar (e.g., hem filers. sudden deah) or
`infecflous (e.g., pneumonia) In name.
`
`treatment with
`that. similar to atypical antipsychotic drugs,
`Observaionai studies suggest
`conventiond antipsychotic drugs may loom mortdity. The extent to which the findings of
`increased mortality in observaiond studies may be attributed to the antipsychotic drug as
`opposed to some characteristlcqs) of the patents is not clear. FANAPT is not approved for the
`
`1
`
`iNDlCATlONS AND USAGE
`
`FANAPT” tablets are indicated for the acute treatment of adults with schizophrenia [see C/Ihical Stutfies
`(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 [sea Warm/rigs and Pro-caution
`(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
`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
`acute treatment of schizophrenia [See DosageWWW» (2. 1) and Clim'ml 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
`andAdmimsm (2.3)]
`
`

`

`FANAPT" giloperidone) Tablets
`
`, 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 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.
`
`2.2
`
`Dosage in Special Populations
`
`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)]
`
`003m atl/ushnant forWis taking FANAPT comm/tardy with potential cypzas 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 Intelactlbns (7. 1)]
`
`Dosage adjustment for paints tat-hwy FANAPT concomitantly with palmfld CW4 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 0mg lnterachbns
`{7-1)}
`
`W Impdnmnt: FANAPT is not recommended for patients with hepatic impairment.
`
`23
`
`Waterman Tmt
`
`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.
`
`2.4 Mum of Trauma: In Mona Previously Discontinued
`
`it is recommended that the
`Although there are no data to- specifically address re-initiation of treatment,
`initiation titration schedule be followed whenever patients have had an interval off FANAPT of more than 3
`days.
`'
`
`

`

`FANAPT“ ilo erldone Tablets
`
`2.5
`
`Switching From Other Antipsychotics
`
`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.
`
`3
`
`DOSAGE FORKS 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.
`6’09
`The tablets are white, round, flat, beveled-edge and identified with a logo “‘9"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. Reactions
`have included pruritus and urticaria.
`
`5
`
`5.1
`
`WARNINGS AND PRECAUflONs
`
`lncresed Risks in Elderly Patients with Dementia-Rum Psychosis
`
`Increased MortdIty
`
`Eideriy Merits with dementieirelated psychosis treaed with atypical mtipsychotic drugs are at an
`Increased risk of death compared to placebo. FANAPT is not approved for the treament of patients
`with dementia-related psychosis [see Boxed Warning].
`
`Cerebmvasculs Adverse Events, Including Skoke
`
`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 Wain/fig]
`
`5.2
`
`01’ Prolongdon
`
`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 206 and 3A4, FANAPT 12 mg twice daily was associated with a mean QTcF
`inorease 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.
`
`

`

`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 historyof 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) bradycardla;
`(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
`/nteractian(7.1)1 and in patients with reduced activity of CYP2D6 [see CIinrba/Pharrnacalogy/123)1
`
`It is recommended that patients being considered for FANAPT treatment who are at risk for significant
`electrolyte disturbances have baseline serumpotassium 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.
`-
`
`5.3
`
`Nourobptlc Mdlgnant syndrome (HMS)
`
`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.
`
`In arriving at a diagnosis, it is
`The diagnostic evaluation of patients with this syndrome is complicated.
`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.
`
`

`

`FANAPT" ilo eridone Tablets
`
`5.4
`
`Tardive Dyektneeie
`
`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.
`‘
`
`5.5
`
`Hyperglycemia and Diabetes Melitta:
`
`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
`
`

`

`FANAPT" ilo eridone Tablets
`
`treated with atypical antipsychotics should be monitored for symptoms of
`treatment. Any patient
`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
`suspectdrug.
`
`5.6
`
`WelghtGaln
`
`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 2 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.
`
`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, 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 at-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
`
`Loukeponta. Wponta aid Agmulocytosls
`
`trial and postmarketing experience, events of leukopenia/neutropenia have been reported
`In clinical
`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.
`
`

`

`FANAPT" ilo eridone Tablets
`
`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.
`
`5.10
`
`Hyperprolactinemia
`
`As with other drugs that antagonize dopamine D2 receptors, FANAPT elevates prolactin levels.
`
`resulting in reduced pituitary gonadotropin
`Hyperprolactinemia may suppress hypothalamic GnRH,
`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 Who, 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 Nona/Wool 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
`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.
`
`5.11
`
`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.
`
`5.12
`
`Dysphagia
`
`Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration
`pneumonia is a common cause of morbidity and mortality in elderly patients,
`in particular those with
`advanced Alzheimer’s dementia. FANAPT and other antipsychotic drugs should be used cautiously in
`patients at risk for aspiration pneumonia [see Boxed Waming].
`
`

`

`FANAPT“ ilo eridone Tablets
`
`5.13
`
`Suicide
`
`The possibility of a suicide attempt is inherent in psychotic illness, and close supervision of high-risk
`patients should accompany drug therapy. Prescriptions for FANAPT should be written for the smallest
`quantity of tablets consistent with good patient management in order to reduce the risk of overdose.
`
`5.14
`
`Prlapism
`
`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
`In short-
`FANAPT, like other antipsychotics, has the potential to impair judgment, thinking or motor skills.
`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.
`
`6
`
`6.1
`
`ADVERSE REACTIONS
`
`Clinlcd Studies Expoflonco
`
`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 short-term and longer-term exposure.
`
`Adverse reactions during exposure were obtained by general inquiry and recorded by clinical investigators
`using their own terminology. Consequently,
`to provide a meaningful estimate of the proportion of
`individuals experiencing adverse reactions,
`reactions were grouped in standardized categories using
`MedDRA terminology.
`
`The stated frequencies of adverse reactions represent the proportions of individuals who experienced a
`treatment-emergent adverse reaction of the type listed. A reaction was considered treatment emergent if it
`occurred for the first time or worsened while receiving therapy following baseline evaluation.
`
`The information presented in these sections was derived from pooled data from four placebo-controlled, 4-
`or 6-week, fixed- or flexible-dose studies in patients who received FANAPT at daily doses within a range of
`10 to 24 mg (n=874).
`
`

`

`FANAPT“ ilo eridone Tablets
`
`Adverse Reactions Occurring at an Incidence of 2% or More among FANAPT-Treated Patients and
`More Frequent than Placebo
`
`treatment-emergent adverse reactions that were
`Table 1 enumerates the pooled incidences of
`spontaneously reported in four placebo-controlled, 4- or 6-week, fixed- or flexible-dose studies, listing those
`reactions that occurred in 2% or more of patients treated with FANAPT in any of the dose groups, and for
`which the incidence in FANAPT-treated patients in any dose group was greater than the incidence in
`patients treated with placebo.
`
`Treainent-Emergent Adverse Reactions in snort-Term, Fixed- or Flexible-Dose,
`Table 1:
`Placebo-Controlled Trials in Adult Patents'
`
`Body System or Organ Class
`
`Placebo
`
`FANAPT 10-16 mglday
`
`FANAPT 20-24 moldey
`
`
`Dictionary-derived Term
`(H87)
`(#483)
`'
`(143391)
`Body as a Whole
`1
`
`Percentage of Meme Reporting Reaction
`
`Arthralgia
`
`Fatigue
`
`Musculoskeletal Stiffness
`
`Weight Increased
`
`MM Disorders
`
`Tachycardia
`
`Eye DieoMere
`
`Vision Blurred
`
`entrainment“ Dim
`
`Nausea
`
`Dry Mouth
`
`Diarrhea
`
`Abdominal Discomfort
`
`Infections
`Nasopharyngitis
`
`Upper Respiratory Tract Infection
`
`Nervous system Disorders
`
`Dizziness
`
`Somnolence
`
`Extrapyramidal Disorder
`
`Tremor
`
`Lethargy
`
`3
`
`4
`
`1
`
`1
`
`3
`
`3
`
`7
`
`8
`
`5
`
`1
`
`4
`
`2
`
`10
`
`9
`
`5
`
`3
`
`3
`
`2
`
`3
`
`1
`
`1
`
`1
`
`2
`
`8
`
`1
`
`4
`
`1
`
`3
`
`1
`
`7
`
`5
`
`4
`
`2
`
`1
`
`10
`
`3
`
`6
`
`3
`
`9
`
`12
`
`1
`
`i
`
`10
`
`10
`
`7
`
`3
`
`3
`
`3
`
`20
`
`15
`
`4
`
`3
`
`1
`
`

`

`FANAPT" (iloperidonei Tablets
`
`
`
`Body Systom or 0mm Ola:
`
`Hm FANAPT 10-16 mgldny
`
`FANAPT 20-24 rnglday
`
`
`Dictionary-derived Term
`(H87)
`(W483)
`(N3391)
`Reproductive System
`
`‘
`
`m of Monte Reporting Mon
`
`Ejaculation Failure
`Roairdory
`
`Nasal Congestion
`
`Dyspnea
`
`Skin
`
`Rash
`
`Vasculu Disomrs
`
`Orthostatic Hypotension
`
`<1
`
`2
`
`<1
`
`2
`
`1
`
`\
`
`2
`
`5
`
`2
`
`3
`
`3
`
`2
`
`8
`
`'2
`
`2
`
`5
`
`‘Hypotension 3 <1 <1
`
`
`
`*Table includes advers