Renal Impairment

Following administration of Zemplar Capsules, the pharmacokinetic profile of paricalcitol for CKD Stage 5 on hemodialysis (HD) or peritoneal dialysis (PD) was comparable to that in CKD 3 or 4 patients. Therefore, no special dosing adjustments are required other than those recommended in the Dosage and Administration section (see DOSAGE AND ADMINISTRATION).

Drug Interactions

An in vitro study indicates that paricalcitol is not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A at concentrations up to 50 nM (21 ng/mL) (approximately 20-fold greater than that obtained after highest tested dose). In fresh primary cultured hepatocytes, the induction observed at paricalcitol concentrations up to 50 nM was less than two-fold for CYP2B6, CYP2C9 or CYP3A, where the positive controls rendered a six- to nineteen-fold induction. Hence, paricalcitol is not expected to inhibit or induce the clearance of drugs metabolized by these enzymes.

Omeprazole: The pharmacokinetic interaction between paricalcitol capsule (16 mcg) and omeprazole (40 mg; oral) was investigated in a single dose, crossover study in healthy subjects. The pharmacokinetics of paricalcitol were unaffected when omeprazole was administered approximately 2 hour prior to the paricalcitol dose.

Ketoconazole: The effect of multiple doses of ketoconazole administered as 200 mg BID for 5 days on the pharmacokinetics of paricalcitol capsule has been studied in healthy subjects. The C_max of paricalcitol was minimally affected, but AUC_0-¥ approximately doubled in the presence of ketoconazole. The mean half-life of paricalcitol was 17.0 hours in the presence of ketoconazole as compared to 9.8 hours, when paricalcitol was administered alone (See PRECAUTIONS).

CLINICAL STUDIES

The safety and efficacy of Zemplar Capsules were evaluated in three, 24-week, double blind, placebo-controlled, randomized, multicenter, Phase 3 clinical studies in CKD Stage 3 and 4 patients. Two studies used an identical three times a week dosing design, and one study used a daily dosing design. A total of 107 patients received Zemplar Capsules and 113 patients received placebo. The mean age of the patients was 63 years, 68% were male, 71% were Caucasian, and 26% were African-American. The average baseline iPTH was 274 pg/mL (range: 145-856 pg/mL). The average duration of CKD prior to study entry was 5.7 years. At study entry 22% were receiving calcium based phosphate binders and/or calcium supplements. Baseline 25-hydroxyvitamin D levels were not measured.

The initial dose of Zemplar Capsules was based on baseline iPTH. If iPTH was ≤500 pg/mL, Zemplar Capsules were administered 1 mcg daily or 2 mcg three times a week, not more than every other day. If iPTH was >500 pg/mL, Zemplar Capsules were administered 2 mcg daily or 4 mcg three times a week, not more than every other day. The dose was titrated by 1 mcg daily or 2 mcg three times a week every 2 to 4 weeks until iPTH levels were reduced by at least 30% from baseline. The overall average weekly dose of Zemplar Capsules was 9.6 mcg/week in the daily regimen and 9.5 mcg/week in the three times a week regimen.

In the clinical studies, doses were titrated for any of the following reasons: if iPTH fell to <60 pg/mL, or decreased >60% from baseline, the dose was reduced or temporarily withheld; if iPTH decreased <30% from baseline and serum calcium was £ 10.3 mg/dL and serum phosphorus was £ 5.5 mg/dL, the dose was increased; and if iPTH decreased between 30 to 60% from baseline and serum calcium and phosphorus were ≤10.3 mg/dL and ≤5.5 mg/dL, respectively, the dose was maintained. Additionally, if serum calcium was between 10.4 to 11.0 mg/dL, the dose was reduced irrespective of iPTH, and the dose was withheld if serum calcium was >11.0 mg/dL. If serum phosphorus was > 5.5 mg/dL, dietary counseling was provided, and phosphate binders could have been initiated or increased. If the elevation persisted, the Zemplar Capsules dose was decreased. Seventy-seven percent (77%) of the Zemplar Capsules treated patients and 82% of the placebo treated patients completed the 24-week treatment. The primary efficacy endpoint of at least two consecutive ≥30% reductions from baseline iPTH was achieved by 91% of Zemplar Capsules treated patients and 13% of the placebo treated patients (p<0.001). The proportion of Zemplar Capsules treated patients achieving two consecutive ≥30% reductions was similar between the daily and the three times a week regimens (daily: 30/33, 91%; three times a week: 62/68, 91%).

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