Iloperidone: Package Insert / Prescribing Info

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

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.

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.

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/mm 3) should discontinue iloperidone and have their WBC followed until recovery.

5.11 Hyperprolactinemia

As with other drugs that antagonize dopamine D 2receptors, 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.

6.1 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).

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.

7.1 Potential for Other Drugs to Affect Iloperidone Tablets

Iloperidone is not a substrate for CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2E1 enzymes. This suggests that an interaction of iloperidone with inhibitors or inducers of these enzymes, or other factors, like smoking, is unlikely.

Both CYP3A4 and CYP2D6 are responsible for iloperidone metabolism. Inhibitors of CYP3A4 (e.g., ketoconazole) or CYP2D6 (e.g., fluoxetine, paroxetine) can inhibit iloperidone elimination and cause increased blood levels.

7.2 Potential for Iloperidone Tablets to Affect Other Drugs

In vitrostudies in human liver microsomes showed that iloperidone does not substantially inhibit the metabolism of drugs metabolized by the following cytochrome P450 isozymes: CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, or CYP2E1. Furthermore, in vitrostudies in human liver microsomes showed that iloperidone does not have enzyme inducing properties, specifically for the following cytochrome P450 isozymes: CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP3A4 and CYP3A5.

7.3 Drugs that Prolong the QT Interval

Iloperidone tablets should not be used with any other drugs that prolong the QT interval [see Warnings and Precautions (5.3)] .

8.1 Pregnancy

8.2 Lactation

8.3 Pediatric Use

Safety and effectiveness in pediatric and adolescent patients have not been established.

8.4 Geriatric Use

Clinical Studies of iloperidone tablets in the treatment of schizophrenia did not include sufficient numbers of patients aged 65 years and over to determine whether or not they respond differently than younger adult patients. Of the 3210 patients treated with iloperidone tablets in premarketing trials, 25 (0.5%) were ≥65 years old and there were no patients ≥75 years old.

Elderly patients with dementia-related psychosis treated with iloperidone tablets are at an increased risk of death compared to placebo. Iloperidone tablets are not approved for the treatment of patients with dementia-related psychosis [see Boxed Warningand Warnings and Precautions (5.1, 5.2)] .

8.5 Renal Impairment

Because iloperidone is highly metabolized, with less than 1% of the drug excreted unchanged, renal impairment alone is unlikely to have a significant impact on the pharmacokinetics of iloperidone. Renal impairment (creatinine clearance <30 mL/min) had minimal effect on C maxof iloperidone (given in a single dose of 3 mg) and its metabolites P88 and P95 in any of the 3 analytes measured. AUC 0–∞was increased by 24%, decreased by 6%, and increased by 52% for iloperidone, P88 and P95, respectively, in subjects with renal impairment.

8.6 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. Iloperidone tablets are not recommended for patients with severe hepatic impairment [see Dosage and Administration (2.2)] .

In adult subjects with mild hepatic impairment no relevant difference in pharmacokinetics of iloperidone, P88 or P95 (total or unbound) was observed compared to healthy adult controls. In subjects with moderate hepatic impairment a higher (2-fold) and more variable free exposure to the active metabolites P88 was observed compared to healthy controls, whereas exposure to iloperidone and P95 was generally similar (less than 50% change compared to control). Since a study in severe liver impaired subjects has not been conducted, iloperidone tablets are not recommended for patients with severe hepatic impairment.

8.7 Smoking Status

Based on in vitrostudies utilizing human liver enzymes, iloperidone is not a substrate for CYP1A2; smoking should therefore not have an effect on the pharmacokinetics of iloperidone.

9.1 Controlled Substance

Iloperidone is not a controlled substance.

9.2 Abuse

Iloperidone has not been systematically studied in animals or humans for its potential for abuse, tolerance, or physical dependence. While the clinical trials did not reveal any tendency for drug-seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this experience the extent to which a CNS active drug, iloperidone, will be misused, diverted, and/or abused once marketed. Consequently, patients should be evaluated carefully for a history of drug abuse, and such patients should be observed closely for signs of iloperidone tablet misuse or abuse (e.g., development of tolerance, increases in dose, drug-seeking behavior).

10.1 Human Experience

In pre-marketing trials involving over 3210 patients, accidental or intentional overdose of iloperidone tablets was documented in 8 patients ranging from 48 mg to 576 mg taken at once and 292 mg taken over a 3-day period. No fatalities were reported from these cases. The largest confirmed single ingestion of iloperidone was 576 mg; no adverse physical effects were noted for this patient. The next largest confirmed ingestion of iloperidone was 438 mg over a 4-day period; extrapyramidal symptoms and a QTc interval of 507 msec were reported for this patient with no cardiac sequelae. This patient resumed iloperidone tablet treatment for an additional 11 months. In general, reported signs and symptoms were those resulting from an exaggeration of the known pharmacological effects (e.g., drowsiness and sedation, tachycardia and hypotension) of iloperidone.

10.2 Management of Overdose

There is no specific antidote for iloperidone tablets. Therefore appropriate supportive measures should be instituted. In case of acute overdose, the physician should establish and maintain an airway and ensure adequate oxygenation and ventilation. Gastric lavage (after intubation, if patient is unconscious) and administration of activated charcoal together with a laxative should be considered. The possibility of obtundation, seizures or dystonic reaction of the head and neck following overdose may create a risk of aspiration with induced emesis. Cardiovascular monitoring should commence immediately and should include continuous ECG monitoring to detect possible arrhythmias. If antiarrhythmic therapy is administered, disopyramide, procainamide and quinidine should not be used, as they have the potential for QT-prolonging effects that might be additive to those of iloperidone. Similarly, it is reasonable to expect that the alpha-blocking properties of bretylium might be additive to those of iloperidone, resulting in problematic hypotension. Hypotension and circulatory collapse should be treated with appropriate measures such as intravenous fluids or sympathomimetic agents (epinephrine and dopamine should not be used, since beta stimulation may worsen hypotension in the setting of iloperidone-induced alpha blockade). In cases of severe extrapyramidal symptoms, anticholinergic medication should be administered. Close medical supervision should continue until the patient recovers.

12.1 Mechanism of Action

The mechanism of action of iloperidone in schizophrenia is unknown. However the efficacy of iloperidone could be mediated through a combination of dopamine type 2 (D 2) and serotonin type 2 (5-HT 2) antagonism. Iloperidone forms an active metabolite, P88, that has an in vitro receptor binding profile similar to the parent drug.

12.2 Pharmacodynamics

Iloperidone acts as an antagonist with high (nM) affinity binding to serotonin 5-HT 2Adopamine D 2and D 3receptors, and norepinephrine NE α1receptors (K ivalues of 5.6 nM, 6.3 nM, 7.1 nM, and 0.36 nM, respectively). Iloperidone has moderate affinity for dopamine D 4, and serotonin 5-HT 6and 5-HT 7receptors (K ivalues of 25 nM, 43 nM, and 22 nM respectively), and low affinity for the serotonin 5-HT 1A, dopamine D 1, and histamine H 1receptors (K ivalues of 168 nM, 216 nM and 437 nM, respectively). Iloperidone has no appreciable affinity (K i>1000 nM) for cholinergic muscarinic receptors. The affinity of the iloperidone metabolite P88 is generally equal to or less than that of the parent compound, while the metabolite P95 only shows affinity for 5-HT 2A(K ivalue of 3.91) and the NE α1A, NE α1B, NE α1D, and NE α2Creceptors (K ivalues of 4.7 nM, 2.7 nM, 8.8 nM and 4.7 nM respectively).

12.3 Pharmacokinetics

The observed mean elimination half-lives for iloperidone, P88 and P95 in CYP2D6 extensive metabolizers (EM) are 18 hours, 26 hours and 23 hours, respectively, and in poor metabolizers (PM) are 33 hours, 37 hours and 31 hours, respectively. Steady-state concentrations are attained within 3 days to 4 days of dosing. Iloperidone accumulation is predictable from single-dose pharmacokinetics. The pharmacokinetics of iloperidone is more than dose proportional. Elimination of iloperidone is mainly through hepatic metabolism involving 2 P450 isozymes, CYP2D6 and CYP3A4.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Storage

Store at 20° to 25°C (68° to 77°F)[see USP Controlled Room Temperature]. Protect iloperidone tablets from exposure to light and moisture.

QT Interval Prolongation

Patients should be advised to consult their physician immediately if they feel faint, lose consciousness or have heart palpitations. Patients should be counseled not to take iloperidone tablets with other drugs that cause QT interval prolongation [see Warnings and Precautions (5.3)] . Patients should be told to inform physicians that they are taking iloperidone tablets before any new drug is taken.

Neuroleptic Malignant Syndrome

Patients and caregivers should be counseled that a potentially fatal symptom complex sometimes referred to as NMS has been reported in association with administration of antipsychotic drugs, including iloperidone tablets. Signs and symptoms of NMS include hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia) [see Warnings and Precautions (5.4)] .

Metabolic Changes

Patients should be aware of the symptoms of hyperglycemia (high blood sugar) and diabetes mellitus. Patients who are diagnosed with diabetes, those with risk factors for diabetes, or those who develop these symptoms during treatment should have their blood glucose monitored at the beginning of and periodically during treatment. Patients should be counseled that weight gain has occurred during treatment with iloperidone tablets. Clinical monitoring of weight is recommended [see Warnings and Precautions (5.6)] .

Orthostatic Hypotension

Patients should be advised of the risk of orthostatic hypotension, particularly at the time of initiating treatment, re-initiating treatment, or increasing the dose [see Warnings and Precautions (5.8)] .

Interference with Cognitive and Motor Performance

Because iloperidone tablets may have the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that iloperidone therapy does not affect them adversely [see Warnings and Precautions (5.16)] .

Pregnancy

Advise patients that third trimester use of iloperidone tablets may cause extrapyramidal and/or withdrawal symptoms in a neonate. Advise patients to notify their healthcare provider with known or suspected pregnancy [see Use in Specific Populations (8)] .

Pregnancy Registry

Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to iloperidone during pregnancy [see Use in Specific Populations (8)].

Lactation

Advise women not to breastfeed during treatment with iloperidone tablets [see Use in Specific Populations (8.2)] .

Concomitant Medication

Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for interactions [see Drug Interactions (7)] .

Alcohol

Patients should be advised to avoid alcohol while taking iloperidone tablets.

Heat Exposure and Dehydration

Patients should be advised regarding appropriate care in avoiding overheating and dehydration.