Iloperidone (iloperidone 1 mg) Dailymed

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. Iloperidone tablets are not approved for the treatment of patients with dementia-related psychosis [see Warnings and Precautions (5.1)].


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. Iloperidone tablets are not approved for use in patients with dementia-related psychosis. (5.1)

Iloperidone tablets are 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 iloperidone tablets are 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 iloperidone tablets 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 iloperidone tablets. 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)].


Iloperidone is an atypical antipsychotic indicated for the treatment of schizophrenia in adults. (1, 14) In choosing among treatments, prescribers should consider the ability of iloperidone to prolong the QT interval and the use of other drugs first. Prescribers should also consider the need to titrate iloperidone 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)

2 Dosage And Administration

The recommended target dosage of iloperidone tablets is 12 mg/day 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. Iloperidone tablets can be administered without regard to meals. (2.1)

2.1 Usual Dose

Iloperidone tablets 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 iloperidone tablets is 1 mg orally twice daily. Dose increases to reach the target range of 6 mg to 12 mg twice daily (12 mg/day to 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). Iloperidone doses above 24 mg/day have not been systematically evaluated in the clinical trials. Efficacy was demonstrated with iloperidone tablets in a dose range of 6 mg to 12 mg twice daily. Prescribers should be mindful of the fact that patients need to be titrated to an effective dose of iloperidone tablets. Thus, control of symptoms may be delayed during the first 1 week 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 iloperidone tablet use are dose related [see Adverse Reactions (6.1)].

Iloperidone tablets can be administered without regard to meals.

2.2 Dosage in Special Populations

Dosage adjustment for patients taking iloperidone tablets concomitantly with potential CYP2D6 inhibitors: Iloperidone tablet 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, iloperidone tablet dose should then be increased to where it was before [see Drug Interactions (7)].

Dosage adjustment for patients taking iloperidone tablets concomitantly with potential CYP3A4 inhibitors: Iloperidone tablet 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, iloperidone tablet dose should be increased to where it was before [see Drug Interactions (7)].

Dosage adjustment for patients taking iloperidone tablets who are poor metabolizers of CYP2D6: Iloperidone tablet dose should be reduced by one-half for poor metabolizers of CYP2D6 [see Clinical Pharmacology (12.3)].

Hepatic Impairment: No dose adjustment to iloperidone tablets is needed in patients with mild hepatic impairment. Patients with moderate hepatic impairment may require dose reduction, if clinically indicated. Iloperidone tablets are not recommended for patients with severe hepatic impairment [see Use in Specific Populations (8.6)].

2.3 Maintenance Treatment

In a longer-term study, iloperidone tablets were effective in delaying time to relapse in patients with schizophrenia who were stabilized on iloperidone tablets 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 iloperidone tablets of more than 3 days.

• 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. Avoid use of iloperidone tablets in combination with other drugs that are known to prolong QTc; use caution and consider dose modification when prescribing iloperidone tablets with other drugs that inhibit iloperidone 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 iloperidone tablets 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 iloperidone tablet treatment. (5.15)
• Potential for cognitive and motor impairment: Use caution when operating machinery. (5.16)

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 times 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. Iloperidone tablets are not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning, Warnings and Precautions (5.2)].

5.2 Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis

In placebo-controlled trials in elderly subjects with dementia, patients randomized to risperidone, aripiprazole, and olanzapine had a higher incidence of stroke and transient ischemic attack, including fatal stroke. Iloperidone tablets are 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), iloperidone was associated with QTc prolongation of 9 msec at an iloperidone dose of 12 mg twice daily. The effect of iloperidone 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, iloperidone tablets 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 iloperidone tablets 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). Iloperidone tablets 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 iloperidone tablets with drugs that inhibit iloperidone 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 iloperidone tablet 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. Iloperidone tablets 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. Iloperidone tablets should be discontinued in patients who are found to have persistent QTc measurements >500 msec.

If patients taking iloperidone tablets 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 iloperidone. 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.

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, iloperidone tablets 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 iloperidone tablets, drug discontinuation should be considered. However, some patients may require treatment with iloperidone tablets despite the presence of the syndrome.

5.6 Metabolic Changes

Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all atypical antipsychotic drugs have been shown to produce some metabolic changes, each drug in the class has its own specific risk profile.

Hyperglycemia and Diabetes Mellitus

Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics including iloperidone tablets. 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

	Placebo	Iloperidone Tablets24 mg/day
	Mean Change from Baseline (mg/dL)
	n=114	n=228
Serum Glucose Change from Baseline	-0.5	6.6
	Proportion of Patients with Shifts
Serum Glucose Normal to High (<100 mg/dL to ≥126 mg/dL)	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)
	3 months to 6 months	6 months to 12 months	>12 months
Iloperidone tablets 10 mg/day to 16 mg/day	1.8 (N=773)	5.4 (N=723)	5.4 (N=425)
Iloperidone tablets 20 mg/day to 24 mg/day	-3.6 (N=34)	-9 (N=31)	-18 (N=20)

Dyslipidemia

Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.

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

	Placebo	Iloperidone Tablets24 mg/day
	Mean Change from Baseline (mg/dL)
Cholesterol	n=114	n=228
Change from baseline	-2.17	8.18
LDL	n=109	n=217
Change from baseline	-1.41	9.03
HDL	n=114	n=228
Change from baseline	-3.35	0.55
Triglycerides	n=114	n=228
Change from baseline	16.47	-0.83
	Proportion of Patients with Shifts
Cholesterol
Normal to High	1.4%	3.6%
(<200 mg/dL to ≥240 mg/dL)	(1/72)	(5/141)
LDL
Normal to High	2.4%	1.1%
(<100 mg/dL to ≥160 mg/dL)	(1/42)	(1/90)
HDL
Normal to Low	23.8%	12.1%
(≥40 mg/dL to <40 mg/dL)	(19/80)	(20/166)
Triglycerides
Normal to High	8.3%	10.1%
(<150 mg/dL to ≥200 mg/dL)	(6/72)	(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)
	3 months to 6 months	6 months to 12 months	>12 months
Iloperidone tablets 10 mg/day to16 mg/day	-3.9 (N=783)	-3.9 (N=726)	-7.7 (N=428)
Iloperidone tablets 20 mg/day to 24 mg/day	-19.4 (N=34)	-23.2 (N=31)	-19.4 (N=20)

Table 5: Change in Triglycerides

Mean Change from Baseline (mg/dL)
	3 months to 6 months	6 months to 12 months	>12 months
Iloperidone tablets 10 mg/day to 16 mg/day	-8.9 (N=783)	-8.9 (N=726)	-17.7 (N=428)
Iloperidone tablets 20 mg/day to 24 mg/day	-26.6 (N=34)	-35.4 (N=31)	-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-week or 6-week, fixed- or flexible-dose studies in adult subjects are presented in Table 6.

Table 6: Change in Body Weight

	Placebon=576	Iloperidone Tablets10 mg/day to 16 mg/dayn=481	Iloperidone Tablets20 mg/day to 24 mg/dayn=391
Weight (kg)Change from Baseline	-0.1	2	2.7
Weight Gain ≥7% increase from Baseline	4%	12%	18%

5.7 Seizures

In short-term placebo-controlled trials (4-weeks to 6-weeks), seizures occurred in 0.1% (1/1344) of patients treated with iloperidone tablets compared to 0.3% (2/587) on placebo. As with other antipsychotics, iloperidone tablets 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

Iloperidone tablets 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 iloperidone tablets, compared with 0.2% (1/587) on placebo. Orthostatic hypotension was reported in 5% of patients given 20 mg/day to 24 mg/day, 3% of patients given 10 mg/day to 16 mg/day, and 1% of patients given placebo. More rapid titration would be expected to increase the rate of orthostatic hypotension and syncope.

Iloperidone tablets 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 Falls

Iloperidone tablets 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 iloperidone 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 iloperidone and have their WBC followed until recovery.

5.11 Hyperprolactinemia

As with other drugs that antagonize dopamine D₂ receptors, iloperidone tablets elevate 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 iloperidone [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 iloperidone tablets 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 iloperidone tablets compared to 12% in the placebo group. In the short-term trials, iloperidone 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.

5.12 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 iloperidone tablets 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.

5.13 Dysphagia

Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients. Iloperidone tablets and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia [see Boxed Warning].

5.14 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 iloperidone tablets should be written for the smallest quantity of tablets consistent with good patient management in order to reduce the risk of overdose.

5.15 Priapism

Three cases of priapism were reported in the pre-marketing iloperidone tablet program. Drugs with alpha-adrenergic blocking effects have been reported to induce priapism. Iloperidone shares this pharmacologic activity. Severe priapism may require surgical intervention.

5.16 Potential for Cognitive and Motor Impairment

Iloperidone tablets, 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 iloperidone tablets 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 iloperidone tablets does not affect them adversely.

6 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 Taro Pharmaceuticals U.S.A., Inc. at 1-866-923-4914 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Studies Experience

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 iloperidone tablets consisting of 3229 patients exposed to iloperidone tablets at doses of 10 mg/day or greater, for the treatment of schizophrenia. Of these, 999 received iloperidone tablets for at least 6 months, with 657 exposed to iloperidone tablets for at least 12 months. All of these patients who received iloperidone tablets were participating in multiple-dose clinical trials. The conditions and duration of treatment with iloperidone tablets 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.

The information presented in these sections was derived from pooled data from 4 placebo-controlled, 4-week or 6-week, fixed- or flexible-dose studies in patients who received iloperidone tablets at daily doses within a range of 10 mg to 24 mg (n=874).

Adverse Reactions Occurring at an Incidence of 2% or More among Iloperidone Tablet-Treated Patients and More Frequent than Placebo

Table 7 enumerates the pooled incidences of adverse reactions that were spontaneously reported in four placebo-controlled, 4-week or 6-week, fixed- or flexible-dose studies, uling those reactions that occurred in 2% or more of patients treated with iloperidone tablets in any of the dose groups, and for which the incidence in iloperidone tablet-treated patients in any dose group was greater than the incidence in patients treated with placebo.

Table 7: Percentage of Adverse Reactions in Short-Term, Fixed- or Flexible-Dose, Placebo-Controlled Trials in Adult PatientsTable includes adverse reactions that were reported in 2% or more of patients in any of the iloperidone tablets dose groups and which occurred at greater incidence than in the placebo group. Figures rounded to the nearest integer.

Body System or Organ Class	Placebo	Iloperidone Tablets10 mg/day to 16 mg/day	Iloperidone Tablets20 mg/day to 24 mg/day
	%	%	%
Dictionary-derived Term	(N=587)	(N=483)	(N=391)
Body as a Whole
Arthralgia	2	3	3
  Fatigue	3	4	6
  Musculoskeletal Stiffness	1	1	3
  Weight Increased	1	1	9
Cardiac Disorders
  Tachycardia	1	3	12
Eye Disorders
  Vision Blurred	2	3	1
Gastrointestinal Disorders
  Nausea	8	7	10
  Dry Mouth	1	8	10
  Diarrhea	4	5	7
  Abdominal Discomfort	1	1	3
Infections
  Nasopharyngitis	3	4	3
  Upper Respiratory Tract Infection	1	2	3
Nervous System Disorders
  Dizziness	7	10	20
  Somnolence	5	9	15
  Extrapyramidal Disorder	4	5	4
  Tremor	2	3	3
  Lethargy	1	3	1
Reproductive System
  Ejaculation Failure	<1	2	2
Respiratory
  Nasal Congestion	2	5	8
  Dyspnea	<1	2	2
Skin
  Rash	2	3	2
Vascular Disorders
  Orthostatic Hypotension	1	3	5
  Hypotension	<1	<1	3

Dose-Related Adverse Reactions in Clinical Trials

Based on the pooled data from 4 placebo-controlled, 4-week or 6-week, fixed- or flexible-dose studies, adverse reactions that occurred with a greater than 2% incidence in the patients treated with iloperidone tablets, and for which the incidence in patients treated with iloperidone tablets 20 mg/day to 24 mg/day were twice than the incidence in patients treated with iloperidone tablets 10 mg/day to 16 mg/day were: abdominal discomfort, dizziness, hypotension, musculoskeletal stiffness, tachycardia, and weight increased.

Common and Drug-Related Adverse Reactions in Clinical Trials

Based on the pooled data from 4 placebo-controlled, 4-week or 6-week, fixed- or flexible-dose studies, the following adverse reactions occurred in ≥5% incidence in the patients treated with iloperidone tablets and at least twice the placebo rate for at least 1 dose: dizziness, dry mouth, fatigue, nasal congestion, somnolence, tachycardia, orthostatic hypotension, and weight increased. Dizziness, tachycardia, and weight increased were at least twice as common on 20 mg/day to 24 mg/day as on 10 mg/day to 16 mg/day.

Extrapyramidal Symptoms (EPS) in Clinical Trials

Pooled data from the 4 placebo-controlled, 4-week or 6-week, fixed- or flexible-dose studies provided information regarding EPS. Adverse event data collected from those trials showed the following rates of EPS-related adverse events as shown in Table 8.

Table 8: Percentage of EPS Compared to Placebo

Adverse Event Term	Placebo (%)(N=587)	Iloperidone Tablets 10 mg/day to 16 mg/day (%)(N=483)	Iloperidone Tablets 20 mg/day to 24 mg/day (%)(N=391)
All EPS events	11.6	13.5	15.1
Akathisia	2.7	1.7	2.3
Bradykinesia	0	0.6	0.5
Dyskinesia	1.5	1.7	1
Dystonia	0.7	1	0.8
Parkinsonism	0	0.2	0.3
Tremor	1.9	2.5	3.1

Adverse Reactions Associated with Discontinuation of Treatment in Clinical Trials

Based on the pooled data from 4 placebo-controlled, 4-week or 6-week, fixed- or flexible-dose studies, there was no difference in the incidence of discontinuation due to adverse events between iloperidone tablet-treated (5%) and placebo-treated (5%) patients. The types of adverse events that led to discontinuation were similar for the iloperidone tablet- and placebo-treated patients.

Demographic Differences in Adverse Reactions in Clinical Trials

An examination of population subgroups in the 4 placebo-controlled, 4-week or 6-week, fixed- or flexible-dose studies did not reveal any evidence of differences in safety on the basis of age, gender or race.

Laboratory Test Abnormalities in Clinical Trials

There were no differences between iloperidone tablets and placebo in the incidence of discontinuation due to changes in hematology, urinalysis, or serum chemistry.

In short-term placebo-controlled trials (4-weeks to 6-weeks), there were 1% (13/1342) iloperidone-treated patients with hematocrit at least one time below the extended normal range during post-randomization treatment, compared to 0.3% (2/585) on placebo. The extended normal range for lowered hematocrit was defined in each of these trials as the value 15% below the normal range for the centralized laboratory that was used in the trial.

Other Reactions During the Pre-marketing Evaluation of Iloperidone Tablets

The following is a ul of MedDRA terms that reflect adverse reactions in patients treated with iloperidone tablets at multiple doses ≥ 4 mg/day during any phase of a trial with the database of 3210 iloperidone tablet-treated patients. All reported reactions are included except those already uled in Table 7, or other parts of the Adverse Reactions (6), those considered in the Warnings and Precautions (5), those reaction terms which were so general as to be uninformative, reactions reported in fewer than 3 patients and which were neither serious nor life-threatening, reactions that are otherwise common as background reactions, and reactions considered unlikely to be drug related.

Reactions are further categorized by MedDRA system organ class and uled in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring in at least 1/100 patients (only those not uled in Table 7 appear in this uling); infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients.

Blood and Lymphatic Disorders: Infrequent – anemia, iron deficiency anemia; Rare – leukopenia

Cardiac Disorders: Frequent – palpitations; Rare – arrhythmia, atrioventricular block first degree, cardiac failure (including congestive and acute)

Ear and Labyrinth Disorders: Infrequent – vertigo, tinnitus

Endocrine Disorders: Infrequent – hypothyroidism

Eye Disorders: Frequent – conjunctivitis (including allergic); Infrequent – dry eye, blepharitis, eyelid edema, eye swelling, lenticular opacities, cataract, hyperemia (including conjunctival)

Gastrointestinal Disorders: Infrequent – gastritis, salivary hypersecretion, fecal incontinence, mouth ulceration; Rare – aphthous stomatitis, duodenal ulcer, hiatus hernia, hyperchlorhydria, lip ulceration, reflux esophagitis, stomatitis

General Disorders and Administrative Site Conditions: Infrequent – edema (general, pitting, due to cardiac disease), difficulty in walking, thirst; Rare – hyperthermia

Hepatobiliary Disorders: Infrequent – cholelithiasis

Investigations: Frequent – weight decreased; Infrequent – hemoglobin decreased, neutrophil count increased, hematocrit decreased

Metabolism and Nutrition Disorders: Infrequent – increased appetite, dehydration, hypokalemia, fluid retention

Musculoskeletal and Connective Tissue Disorders: Frequent – myalgia, muscle spasms; Rare – torticollis

Nervous System Disorders: Infrequent – paresthesia, psychomotor hyperactivity, restlessness, amnesia, nystagmus; Rare – restless legs syndrome

Psychiatric Disorders: Frequent – restlessness, aggression, delusion; Infrequent – hostility, libido decreased, paranoia, anorgasmia, confusional state, mania, catatonia, mood swings, panic attack, obsessive-compulsive disorder, bulimia nervosa, delirium, polydipsia psychogenic, impulse-control disorder, major depression

Renal and Urinary Disorders: Frequent – urinary incontinence; Infrequent – dysuria, pollakiuria, enuresis, nephrolithiasis; Rare – urinary retention, renal failure acute

Reproductive System and Breast Disorders: Frequent – erectile dysfunction; Infrequent – testicular pain, amenorrhea, breast pain; Rare – menstruation irregular, gynecomastia, menorrhagia, metrorrhagia, postmenopausal hemorrhage, prostatitis.

Respiratory, Thoracic and Mediastinal Disorders: Infrequent – epistaxis, asthma, rhinorrhea, sinus congestion, nasal dryness; Rare – dry throat, sleep apnea syndrome, dyspnea exertional

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of iloperidone tablets: retrograde ejaculation and hypersensitivity reactions (including anaphylaxis; angioedema; throat tightness; oropharyngeal swelling; swelling of the face, lips, mouth, and tongue; urticaria; rash; and pruritus). Because these reactions were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.