Zemplar Description

Paricalcitol, USP, the active ingredient in Zemplar Injection, is a synthetically manufactured analog of calcitriol, the metabolically active form of vitamin D indicated for the prevention and treatment of secondary hyperparathyroidism associated with chronic kidney disease(CKD) Stage 5. Zemplar is available as a sterile, clear, colorless, aqueous solution for intravenous injection. Each mL contains paricalcitol, 2 mcg or 5 mcg; propylene glycol, 30% (v/v); and alcohol, 20% (v/v).

Paricalcitol is a white powder chemically designated as 19-nor-1?,3?,25-trihydroxy-9,10-secoergosta-5(Z),7(E),22(E)-triene and has the following structural formula:

Molecular formula is C27 H44 O3 .

Molecular weight is 416.64.

Zemplar Indications And Usage

Zemplar is indicated for the prevention and treatment of secondary hyperparathyroidism associated with chronic kidney disease Stage 5.

Zemplar Contraindications

Zemplar should not be given to patients with evidence of vitamin D toxicity, hypercalcemia, or hypersensitivity to any ingredient in this product (see WARNINGS ).

Zemplar Side Effects

Acute overdose of Zemplar may cause hypercalcemia, and require emergency attention. During dose adjustment, serum calcium and phosphorus levels should be monitored closely (e.g., twice weekly). If clinically significant hypercalcemia develops, the dose should be reduced or interrupted. Chronic administration of Zemplar may place patients at risk of hypercalcemia, elevated Ca × P product, and metastatic calcification.

Treatment of patients with clinically significant hypercalcemia consists of immediate dose reduction or interruption of Zemplar therapy and includes a low calcium diet, withdrawal of calcium supplements, patient mobilization, attention to fluid and electrolyte imbalances, assessment of electrocardiographic abnormalities (critical in patients receiving digitalis), hemodialysis or peritoneal dialysis against a calcium-free dialysate, as warranted. Serum calcium levels should be monitored frequently until normocalcemia ensues.

Phosphate or vitamin D-related compounds should not be taken concomitantly with Zemplar.

Zemplar Precautions

General

Digitalis toxicity is potentiated by hypercalcemia of any cause, so caution should be applied when digitalis compounds are prescribed concomitantly with Zemplar. Adynamic bone lesions may develop if PTH levels are suppressed to abnormal levels.

Information For The Patient

The patient should be instructed that, to ensure effectiveness of Zemplar therapy, it is important to adhere to a dietary regimen of calcium supplementation and phosphorus restriction. Appropriate types of phosphate-binding compounds may be needed to control serum phosphorus levels in patients with chronic kidney disease (CKD) Stage 5, but excessive use of aluminum containing compounds should be avoided. Patients should also be carefully informed about the symptoms of elevated calcium (see ADVERSE REACTIONS ).

Laboratory Tests

During the initial phase of medication, serum calcium and phosphorus should be determined frequently (e.g., twice weekly). Once dosage has been established, serum calcium and phosphorus should be measured at least monthly. Measurements of serum or plasma PTH are recommended every 3 months. An intact PTH (iPTH) assay is recommended for reliable detection of biologically active PTH in patients with CKD Stage 5. During dose adjustment of Zemplar, laboratory tests may be required more frequently.

Drug Interactions

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 drug metabolized by CYP2B6, CYP2C9 or CYP3A.

Specific interaction studies were not performed with Zemplar Injection.

A multiple dose drug-drug interaction study with ketoconazole and paricalcitol capsule demonstrated that ketoconazole approximately doubled paricalcitol AUC0-? (see CLINICAL PHARMACOLOGY ). Since paricalcitol is partially metabolized by CYP3A and ketoconazole 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.

Digitalis toxicity is potentiated by hypercalcemia of any cause, so caution should be applied when digitalis compounds are prescribed concomitantly with Zemplar.

Carcinogenesis, Mutagenesis, Impairment Of Fertility

In a 104-week carcinogenicity study in CD-1 mice, an increased incidence of uterine leiomyoma and leiomyosarcoma was observed at subcutaneous doses of 1, 3, 10 mcg/kg (2 to 15 times the AUC at a human dose of 14 mcg, equivalent to 0.24 mcg/kg based on AUC). The incidence rate of uterine leiomyoma was significantly different than the control group at the highest dose of 10 mcg/kg.

In a 104-week carcinogenicity study in rats, there was an increased incidence of benign adrenal pheochromocytoma at subcutaneous doses of 0.15, 0.5, 1.5 mcg/kg (< 1 to 7 times the exposure following a human dose of 14 mcg, equivalent to 0.24 mcg/kg based on AUC). The increased incidence of pheochromocytomas in rats may be related to the alteration of calcium homeostasis by paricalcitol.

Paricalcitol did not exhibit genetic toxicity in vitro with or without metabolic activation in the microbial mutagenesis assay (Ames Assay), mouse lymphoma mutagenesis assay (L5178Y), or a human lymphocyte cell chromosomal aberration assay. There was also no evidence of genetic toxicity in an in vivo mouse micronucleus assay. Zemplar had no effect on fertility (male or female) in rats at intravenous doses up to 20 mcg/kg/dose [equivalent to 13 times the highest recommended human dose (0.24 mcg/kg) based on surface area, mg/m2 ].

Pregnancy

Pregnancy Category C

Paricalcitol has been shown to cause minimal decreases in fetal viability (5%) when administered daily to rabbits at a dose 0.5 times the 0.24 mcg/kg human dose (based on surface area, mg/m2 ) and when administered to rats at a dose 2 times the 0.24 mcg/kg human dose (based on plasma levels of exposure). At the highest dose tested (20 mcg/kg 3 times per week in rats, 13 times the 0.24 mcg/kg human dose based on surface area), there was a significant increase of the mortality of newborn rats at doses that were maternally toxic (hypercalcemia). No other effects on offspring development were observed. Paricalcitol was not teratogenic at the doses tested.

There are no adequate and well-controlled studies in pregnant women. Zemplar should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.

Nursing Mothers

Studies in rats have shown that paricalcitol is present in the milk. It is not known whether paricalcitol is excreted in human milk. In the nursing patient, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

The safety and effectiveness of Zemplar were examined in a 12-week randomized, double-blind, placebo-controlled study of 29 pediatric patients, aged 5-19 years, with end-stage renal disease on hemodialysis and nearly all had received some form of vitamin D prior to the study. Seventy-six percent of the patients were male, 52% were Caucasian and 45% were African-American. The initial dose of Zemplar was 0.04 mcg/kg 3 times per week based on baseline iPTH level of less than 500 pg/mL, or 0.08 mcg/kg 3 times a week, based on baseline iPTH level of ? 500 pg/mL, respectively. The dose of Zemplar was adjusted in 0.04 mcg/kg increments based on the levels of serum iPTH, calcium and Ca x P. The mean baseline levels of iPTH were 841 pg/mL for the 15 Zemplar-treated patients and 740 pg/mL for the 14 placebo-treated subjects. The mean dose of Zemplar administered was 4.6 mcg (range: 0.8 mcg ? 9.6 mcg). Ten of the 15 (67%) Zemplar-treated patients and 2 of the 14 (14%) placebo-treated patients completed the trial. Ten of the placebo patients (71%) were discontinued due to excessive elevations in iPTH levels as defined by 2 consecutive iPTH levels > 700 pg/mL and greater than baseline after 4 weeks of treatment.

In the primary efficacy analysis, 9 of 15 (60%) subjects in the Zemplar group had 2 consecutive 30% decreases from baseline iPTH compared with 3 of 14 (21%) patients in the placebo group (95% CI for the difference between groups ?1%, 63%). Twenty-three percent of Zemplar vs. 31% of placebo patients had at least one serum calcium level > 10.3 mg/dL, and 40% vs. 14% of Zemplar vs. placebo subjects had at least one Ca x P ion product > 72 (mg/dL)2 . The overall percentage of serum calcium measurements > 10.3 mg/dL was 7% in the Zemplar group and 7% in the placebo group; the overall percentage of patients with Ca x P product> 72 (mg/dL)2 was 8% in the Zemplar group and 7% in the placebo group. No subjects in either the Zemplar group or placebo group developed hypercalcemia (defined as at least one calcium value > 11.2 mg/dL) during the study.

Geriatric Use

Of the 40 patients receiving Zemplar in the three phase 3 placebo-controlled CKD Stage 5 studies, 10 patients were 65 years or over. In these studies, no overall differences in efficacy or safety were observed between patients 65 years or older and younger patients.

Zemplar Overdosage

Overdosage of Zemplar may lead to hypercalcemia, hypercalciuria, hyperphosphatemia, and over suppression of PTH. (see WARNINGS ).

Treatment Of Overdosage and Hypercalcemia

The treatment of acute overdosage should consist of general supportive measures. Serial serum electrolyte determinations (especially calcium), rate of urinary calcium excretion, and assessment of electrocardiographic abnormalities due to hypercalcemia should be obtained. Such monitoring is critical in patients receiving digitalis. Discontinuation of supplemental calcium and institution of a low calcium diet are also indicated in acute overdosage.

General treatment of hypercalcemia due to overdosage consists of immediate suspension of Zemplar therapy, institution of a low calcium diet, and withdrawal of calcium supplements. Serum calcium levels should be determined at least weekly until normocalcemia ensues. When serum calcium levels have returned to within normal limits, Zemplar may be reinitiated at a lower dose. If persistent and markedly elevated serum calcium levels occur, there are a variety of therapeutic alternatives that may be considered. These include the use of drugs such as phosphates and corticosteroids as well as measures to induce diuresis. Also, one may consider dialysis against a calcium-free dialysate.

Zemplar Treatment Of Overdosage and Hypercalcemia

The treatment of acute overdosage should consist of general supportive measures. Serial serum electrolyte determinations (especially calcium), rate of urinary calcium excretion, and assessment of electrocardiographic abnormalities due to hypercalcemia should be obtained. Such monitoring is critical in patients receiving digitalis. Discontinuation of supplemental calcium and institution of a low calcium diet are also indicated in acute overdosage.

General treatment of hypercalcemia due to overdosage consists of immediate suspension of Zemplar therapy, institution of a low calcium diet, and withdrawal of calcium supplements. Serum calcium levels should be determined at least weekly until normocalcemia ensues. When serum calcium levels have returned to within normal limits, Zemplar may be reinitiated at a lower dose. If persistent and markedly elevated serum calcium levels occur, there are a variety of therapeutic alternatives that may be considered. These include the use of drugs such as phosphates and corticosteroids as well as measures to induce diuresis. Also, one may consider dialysis against a calcium-free dialysate.