The safety of Zemplar Capsules has been evaluated in three 24-week (approximately six-month), double-blind, placebo-controlled, multicenter clinical studies involving 220 CKD Stage 3 and 4 patients. Six percent (6%) of Zemplar Capsules treated patients and 4% of placebo treated patients discontinued from clinical studies due to an adverse event. All reported adverse events occurring in at least 2% in either treatment group are presented in Table 3.

Table 3. Treatment - Emergent Adverse Events by Body System Occurring in 2% of Subjects in the Zemplar-Treated Group of Three, Double-Blind, Placebo-Controlled, Phase 3, CKD Stage 3 and 4 Studies; All Treated Patients

                    a. Includes all patients with events in that body system.

Potential adverse effects of Zemplar Capsules are, in general, similar to those encountered with excessive vitamin D intake. The early and late signs and symptoms of hypercalcemia associated with vitamin D overdoses include:

Early: Weakness, headache, somnolence, nausea, vomiting, dry mouth, constipation, muscle pain, bone pain, and metallic taste.

Late: Anorexia, weight loss, conjunctivitis (calcific), pancreatitis, photophobia, rhinorrhea, pruritus, hyperthermia, decreased libido, elevated BUN, hypercholesterolemia, elevated AST and ALT, ectopic calcification, hypertension, cardiac arrhythmias, somnolence, death, and, rarely, overt psychosis.

Paricalcitol is not expected to inhibit the clearance of drugs metabolized by cytochrome P450 enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 CYP2E1 or CYP3A nor induce the clearance of drugs metabolized by CYP2B6, CYP2C9 or CYP3A.

A multiple dose drug-drug interaction study demonstrated that ketoconazole approximately doubled paricalcitol AUC_0-¥ (see CLINICAL PHARMACOLOGY).

Since paricalcitol is partially metabolized by CYP3A and ketoconazole le is known to be a strong inhibitor of cytochrome P450 3A enzyme, care should be taken while dosing paricalcitol with ketoconazole and other strong P450 3A inhibitors including atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole. Dose adjustment of Zemplar Capsules may be required, and iPTH and serum calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with a strong CYP3A4 inhibitor such as ketoconazole.

Drugs that impair intestinal absorption of fat-soluble vitamins, such as cholestyramine, may interfere with the absorption of Zemplar Capsules.

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