Drug Interaction Report

MONITOR: Coadministration with ketoconazole or other potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of cinacalcet, which is partially metabolized by the isoenzyme. According to the product labeling, ketoconazole (200 mg twice a day for 7 days) increased the peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of cinacalcet (90 mg single dose on day 5) by over 2-fold compared to administration of cinacalcet alone.

MANAGEMENT: Pharmacologic response to cinacalcet (i.e., parathyroid hormone and serum calcium levels) should be monitored more closely whenever potent inhibitors of CYP450 3A4 are added to or withdrawn from therapy, and the cinacalcet dosage adjusted accordingly.

ADJUST DOSING INTERVAL: Food enhances the oral absorption and bioavailability of cinacalcet. According to the product labeling for cinacalcet, administration with a high-fat meal increased the peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of cinacalcet by 82% and 68%, respectively, compared to administration in the fasting state. The Cmax and AUC were increased 65% and 50%, respectively, when cinacalcet was administered with a low-fat meal compared to fasting.

MANAGEMENT: To ensure maximal oral absorption, cinacalcet should be administered with or immediately after a meal. The tablets should be taken whole and not divided or crushed.

Grapefruit juice may delay the gastrointestinal absorption of clarithromycin but does not appear to affect the overall extent of absorption or inhibit the metabolism of clarithromycin. The mechanism of interaction is unknown but may be related to competition for intestinal CYP450 3A4 and/or absorptive sites. In an open-label, randomized, crossover study consisting of 12 healthy subjects, coadministration with grapefruit juice increased the time to reach peak plasma concentration (Tmax) of both clarithromycin and 14-hydroxyclarithromycin (the active metabolite) by 80% and 104%, respectively, compared to water. Other pharmacokinetic parameters were not significantly altered. This interaction is unlikely to be of clinical significance.