Drug Interactions between iloperidone and lopinavir / ritonavir

ADJUST DOSE: Coadministration with inhibitors of CYP450 3A4 and/or 2D6 may increase the plasma concentrations of iloperidone, which is a substrate of the isoenzymes. In 19 healthy volunteers, administration of iloperidone (3 mg single dose) in combination with the potent CYP450 3A4 inhibitor ketoconazole (200 mg twice daily for 4 days) increased the systemic exposure (AUC) to iloperidone and its metabolites P88 and P95 by 57%, 55% and 35%, respectively, compared to iloperidone alone. Administration with the potent CYP450 2D6 inhibitor fluoxetine (20 mg twice daily for 21 days) to 23 healthy volunteers who were classified as CYP450 2D6 extensive metabolizers resulted in two- to threefold increases in the AUCs of iloperidone and P88 and a 50% decrease in the AUC of P95. In a multiple-dose study, coadministration of iloperidone (8 or 12 mg twice daily) with the potent CYP450 2D6 inhibitor paroxetine (20 mg/day on days 5 to 8) to patients with schizophrenia resulted in increased mean steady-state peak plasma concentrations (Cmax) of iloperidone and P88 by approximately 1.6-fold and decreased mean Cmax of P95 by 50%. Administration of multiple doses of iloperidone in combination with both paroxetine (20 mg once daily for 10 days) and ketoconazole (200 mg twice daily) did not add to the effect of either inhibitor given alone. High plasma levels of iloperidone may increase the risk of QT interval prolongation, which has been associated with ventricular arrhythmias including torsade de pointes and sudden death. The effect of iloperidone on the QT interval is augmented by the presence of CYP450 2D6 and/or 3A4 inhibitors. In an open-label study in patients with schizophrenia or schizoaffective disorder, an iloperidone dosage of 12 mg twice daily was associated with QTc prolongation of 9 msec. Under conditions of metabolic inhibition for both CYP450 2D6 and 3A4, a mean QTcF (Fridericia-corrected QT interval) increase from baseline of approximately 19 msec was observed. No cases of torsade de pointes or other severe cardiac arrhythmias were reported during the premarketing period. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: The dosage of iloperidone should be reduced by one-half when administered concomitantly with potent CYP450 3A4 inhibitors (e.g., itraconazole, ketoconazole, voriconazole, nefazodone, delavirdine, protease inhibitors, clarithromycin, telithromycin) and/or potent CYP450 2D6 inhibitors (e.g., dacomitinib, fluoxetine, paroxetine, quinidine). Patients should be advised to seek medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, palpitations, or syncope. Following discontinuation of the potent CYP450 3A4 or 2D6 inhibitor, the iloperidone dosage should be returned to the previous level.

GENERALLY AVOID: Iloperidone may cause dose-related prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval may result in additive effects and increased risk of ventricular arrhythmias including torsade de pointes and sudden death. In an open-label study in patients with schizophrenia or schizoaffective disorder, an iloperidone dosage of 12 mg twice daily was associated with QTc prolongation of 9 msec. The effect on the QT interval is augmented by the presence of CYP450 2D6 and/or 3A4 inhibitors. Under conditions of metabolic inhibition for both CYP450 2D6 and 3A4 using paroxetine 20 mg once daily and ketoconazole 200 mg twice daily, a mean QTcF (Fridericia-corrected QT interval) increase from baseline of approximately 19 msec was observed. No cases of torsade de pointes or other severe cardiac arrhythmias were reported during the premarketing period. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). The extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s). In addition, certain agents with anticholinergic properties (e.g., sedating antihistamines; antispasmodics; neuroleptics; phenothiazines; skeletal muscle relaxants; tricyclic antidepressants) may have additive parasympatholytic and central nervous system-depressant effects when used in combination with iloperidone. Excessive parasympatholytic effects may include paralytic ileus, hyperthermia, mydriasis, blurred vision, tachycardia, urinary retention, psychosis, and seizures.

MANAGEMENT: Coadministration of iloperidone with other drugs that can prolong the QT interval should generally be avoided. Caution and clinical monitoring are recommended if concomitant use is required; particularly in the situation where the concomitant medication is also a CYP450 2D6 and/or 3A4 inhibitor. Patients should have regular ECGs and be monitored for arrhythmias when the QT interval is prolonged. Persistent QTc measurements exceeding 500 msec will require suspension of iloperidone therapy and immediate action to correct any concomitant risk factors before resuming treatment. Patients should be advised to seek prompt medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitation, irregular heart rhythm, shortness of breath, or syncope. In addition, if combination therapy with agents with anticholinergic properties is required, caution is advised, particularly in the elderly and those with underlying organic brain disease. Patients should be advised to notify their physician promptly if they experience potential symptoms of anticholinergic intoxication such as abdominal pain, fever, heat intolerance, blurred vision, confusion, and/or hallucinations. Ambulatory patients should be counseled to avoid activities requiring mental alertness until they know how these agents affect them. A reduction in anticholinergic dosages may be necessary if excessive adverse effects develop.