Approved May 6, 2009

ILOPERIDONE
(FDA Category 1S)

FANAPT(TM) (Vanda Pharmaceuticals Inc.) is an atypical antipsychotic agent belonging to the chemical class of piperidinyl-benzisoxazole derivatives.

DOSING INFORMATION: The recommended initial dose of iloperidone is 1 milligram (mg) orally twice daily on day 1. The dose should be titrated slowly to avoid orthostatic hypotension. The recommended titration is 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, and 12 mg orally twice daily on days 2, 3, 4, 5, 6, and 7 respectively, to reach a target maintenance dose of 6 to 12 mg orally twice daily. The maximum recommended dose is 12 mg orally twice daily. The efficacy of using iloperidone for more than 6 weeks has not been systematically studied in clinical trials.

PHARMACOKINETICS: Iloperidone is well absorbed following tablet administration, may be given without regard to meals, and reaches maximum concentrations within 2 to 4 hours. The relative bioavailability of the tablet formulation compared to oral solution is 96%. Steady state serum concentrations are attained within 3 to 4 days of dosing. Iloperidone is eliminated mainly through hepatic metabolism involving two isozymes, CYP2D6 and CYP3A4. Coadministration of iloperidone with known strong inhibitors of CYP2D6 like fluoxetine results in a 2.3-fold increase in iloperidone and dosing adjustment is needed. Accumulation of iloperidone is predictable from single-dose pharmacokinetics. There are 2 predominant iloperidone metabolites, P95 and P88. P95 represents 47.9% of the area under the curve of iloperidone for extensive metabolizers and 25% for poor metabolizers; P88 accounts for 19.5% in extensive metabolizers and 34% in poor metabolizers. At therapeutic concentrations, iloperidone and its metabolites are approximately 95% bound to serum proteins. The mean terminal half-lives for iloperidone, P88, and P95 in CYP2D6 extensive metabolizers are 18, 26, and 23 hours, respectively, and in poor metabolizers are 33, 37 and 31 hours, respectively.

CAUTIONS: Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo. Although the causes of death in clinical trials were varied, most of the deaths appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature. Observational studies suggest that antipsychotic drugs may increase mortality. It is unclear from the observational studies to what extent these mortality findings may be attributed to the antipsychotic drug as opposed to patient characteristics. Iloperidone is not approved for the treatment of patients with dementia-related psychosis . Avoid using iloperidone with any drug class that are known to prolong QTc interval, in patients with congenital long QT syndrome, and in patients with a history of cardiac arrhythmias. Commonly observed adverse events included dizziness, dry mouth, fatigue, nasal congestion, somnolence, tachycardia, orthostatic hypotension, and weight gain.

FDA APPROVED INDICATIONS: Iloperidone is indicated for the acute treatment of schizophrenia in adults.