Interactions : אינטראקציות

8 DRUG INTERACTIONS
Given the primary CNS effects of FANAPT tablets, caution should be used when it is taken in combination with other centrally acting drugs and alcohol. Due to its - alpha1-adrenergic receptor antagonism, FANAPT tablets has the potential to enhance the effect of certain antihypertensive agents.
8.1 Potential for Other Drugs to Affect FANAPT 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.
Ketoconazole: Co-administration of ketoconazole (200 mg twice daily for 4 days), a potent inhibitor of CYP3A4, with a 3 mg single dose of iloperidone to 19 healthy volunteers, ages 18-45 years, increased the area under the curve (AUC) of iloperidone and its metabolites P88 and P95 by 57%, 55% and 35%, respectively. Iloperidone doses should be reduced by about one-half when administered with ketoconazole or other strong inhibitors of CYP3A4 (e.g., itraconazole). Weaker inhibitors (e.g., erythromycin, grapefruit juice) have not been studied. When the CYP3A4 inhibitor is withdrawn from the combination therapy, the iloperidone dose should be returned to the previous level.
Fluoxetine: Coadministration of fluoxetine (20 mg twice daily for 21 days), a potent inhibitor of CYP2D6, with a single 3 mg dose of iloperidone to 23 healthy volunteers, ages 29-44 years, who were classified as CYP2D6 extensive metabolizers, increased the AUC of iloperidone and its metabolite P88, by about 2- to 3- fold, and decreased the AUC of its metabolite P95 by one-half. Iloperidone doses should be reduced by one-half when administered with fluoxetine. When fluoxetine is withdrawn from the combination therapy, the iloperidone dose should be returned to the previous level.
Other strong inhibitors of CYP2D6 would be expected to have similar effects and would need appropriate dose 
reductions. When the CYP2D6 inhibitor is withdrawn from the combination therapy, iloperidone dose could then be increased to the previous level.
Paroxetine: Coadministration of paroxetine (20 mg/day for 5-8 days), a potent inhibitor of CYP2D6, with multiple doses of iloperidone (8 or 12 mg twice daily) to patients with schizophrenia ages 18-65 years resulted in increased mean steady- state peak concentrations of iloperidone and its metabolite P88, by about 1.6 fold, and decreased mean steady-state peak concentrations of its metabolite P95 by one-half. Iloperidone doses should be reduced by one-half when administered with paroxetine. When paroxetine is withdrawn from the combination therapy, the iloperidone dose should be returned to the previous level. Other strong inhibitors of CYP2D6 would be expected to have similar effects and would need appropriate dose reductions. When the CYP2D6 inhibitor is withdrawn from the combination therapy, iloperidone dose could then be increased to previous levels.
Paroxetine and Ketoconazole: Coadministration of paroxetine (20 mg once daily for 10 days), a CYP2D6 inhibitor, and ketoconazole (200 mg twice daily) with multiple doses of iloperidone (8 or 12 mg twice daily) to patients with schizophrenia ages 18-65 years resulted in a 1.4 fold increase in steady-state concentrations of iloperidone and its metabolite P88 and a 1.4 fold decrease in the P95 in the presence of paroxetine. So giving iloperidone with inhibitors of both of its metabolic pathways did not add to the effect of either inhibitor given alone. Iloperidone doses should therefore be reduced by about one-half if administered concomitantly with both a CYP2D6 and CYP3A4 inhibitor.
8.2 Potential for FANAPT tablets to Affect Other Drugs
In vitro studies 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 vitro studies 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.
Dextromethorphan: A study in healthy volunteers showed that changes in the pharmacokinetics of dextromethorphan (80 mg dose) when a 3 mg dose of iloperidone was co-administered resulted in a 17% increase in total exposure and a 26% increase in the maximum plasma concentrations Cmax of dextromethorphan. Thus, an interaction between iloperidone and other CYP2D6 substrates is unlikely.
Fluoxetine: A single 3 mg dose of iloperidone had no effect on the pharmacokinetics of fluoxetine (20 mg twice daily).
Midazolam (a sensitive CYP 3A4 substrate): A study in patients with schizophrenia showed a less than 50% increase in midazolam total exposure at iloperidone steady state (14 days of oral dosing at up to 10 mg iloperidone twice daily) and no effect on midazolam Cmax. Thus, an interaction between iloperidone and other CYP3A4 substrates is unlikely.

8.3 Drugs that Prolong the QT Interval
FANAPT tablets should not be used with any other drugs that prolong the QT interval [see Warnings and Precautions (6)].