Iloperidone

ILOPERIDONE- iloperidone tablet
ILOPERIDONE-
Taro Pharmaceuticals U.S.A., Inc.

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)].

1 INDICATIONS AND USAGE

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)].

2 DOSAGE AND ADMINISTRATION

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.

3 DOSAGE FORMS AND STRENGTHS

Iloperidone tablets are available in the following strengths: 1 mg, 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, and 12 mg. The oval (1 mg) white tablets are engraved with “T” on one side and on the other side the tablet strength. The round (2 mg, 4 mg, 6 mg, 8 mg, 10 mg, or 12 mg) white tablets are engraved with “T” on one side and on the other side the tablet strength.

4 CONTRAINDICATIONS

Iloperidone tablets are contraindicated in individuals with a known hypersensitivity reaction to the product. Anaphylaxis, angioedema, and other hypersensitivity reactions have been reported [see Adverse Reactions (6.2)].

5 WARNINGS AND PRECAUTIONS

5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis

Antipsychotic drugs increase the all-cause risk of death in elderly patients with dementia-related psychosis. Analyses of 17 dementia-related psychosis placebo-controlled trials (modal duration of 10 weeks and largely in patients taking atypical antipsychotic drugs) revealed a risk of death in the drug-treated patients of between 1.6 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.

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