Remitch Drug Interactions

This product is mainly metabolized by hepatic metabolizing enzyme CYP3A4: Precautions for coadministration, nalfurafine hydrochloride should be administered with care when coadministered with the following drugs. (See Table 16.)

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Coadministration with ketoconazole (oral formulation): Nalfurafine hydrochloride was administered to 22 healthy adult male volunteers at a single oral dose of 10 μg alone or co-administrated with repeated-dose of ketoconazole. The AUC_0-∞ of this product became 160.5% by co-administrating ketoconazole. Thus, ketoconazole affected the pharmacokinetics of nalfurafine hydrochloride.
Note: The recommended dose of this product is 2.5 μg.
In vitro study, metabolism: The influence on the AUC of nalfurafine hydrochloride was investigated using in vitro metabolism evaluation system. It was shown that the AUC can possibly become a maximum of 5.5, 2.5 and 2.3 times in co-administration with ketoconazole, midecamycin, and cyclosporin, respectively.
In vitro study, P-glycoprotein: An in vitro study with human P-glycoprotein (MDR1) expressing LLC-PK1 cells, has shown that nalfurafine hydrochloride is found to be a substrate for P-glycoprotein, but it does not affect the transport of digoxin via P-glycoprotein. In the other in vitro study with the same cells, the P-glycoprotein-mediated transport of nalfurafine hydrochloride is inhibited by ketoconazole, verapamil hydrochloride, cyclosporine, tacrolimus and cetirizine hydrochloride.
In vitro study, non-absorbable agents: In the result of the in vitro adsorption test with non-absorbable agents, the adsorption rate of nalfurafine hydrochloride with sevelamer hydrochloride (anion exchange resin agent), a drug to treat hyperphosphatemia, was 11.9%-14.7%, and the adsorption rates of the product with sodium polystyrene sulfonate (cation exchange resin agent) and calcium polystyrene sulfonate (cation exchange resin agent), drugs to treat hyperkalemia, were 62.4%-72.7% and 98.8%-98.9%, respectively.
Influence of Hemodialysis: The effect of frequency of dialysis (1, 2 or 3 times a week), dialysis time (2, 4 or 6 hours), treatment time of dialysis (morning, afternoon or night) and interval from medication to dialysis (4, 8 or 12 hours) on the plasma concentration of nalfurafine hydrochloride (capsule) from the time of medication was evaluated by a simulation method.
The results showed the plasma concentration may decline if the hemodialysis was conducted within 4 hours following medication administration. However, such a possibility was ruled out if the hemodialysis occurred 8 hours or more after drug administration. It was thought that the other factors do not influence the plasma concentration.