2.1 Important Administration Information

• Ensure serum calcium is not above the upper limit of normal before initiating treatment [see Warnings and Precautions (5.1)].
• Administer Paricalcitol Injection intravenously through a hemodialysis vascular access port at any time during dialysis.
• Do not inject Paricalcitol Injection directly into a vein.
• Inspect Paricalcitol Injection visually prior to administration; the solution should appear clear and colorless. Do not use if the solution is not clear or particles are present.

2.2 Starting Dose and Dose Titration in Adults

• Initiate Paricalcitol Injection as an intravenous bolus dose of 0.04 mcg/kg to 0.1 mcg/kg (2.8 mcg to 7 mcg) no more frequently than every other day at any time during dialysis.
• Target the maintenance dose of Paricalcitol Injection to intact parathyroid hormone (PTH) levels within the desired therapeutic range and serum calcium within normal limits.
• Monitor serum calcium frequently (e.g., twice weekly) and phosphorus and intact PTH levels every 2 to 4 weeks after initiation of therapy or dose adjustment.
• Titrate the dose of Paricalcitol Injection based on intact PTH (see Table 1). Prior to raising the dose, ensure serum calcium is within normal limits. The maximum daily adult dose is 0.24 mcg/kg.
• Suspend or decrease the dose if intact PTH is persistently and abnormally low to reduce the risk of adynamic bone disease [see Warnings and Precautions (5.3)] or if serum calcium is consistently above the normal range to reduce the risk of hypercalcemia [see Warnings and Precautions (5.1)]. If dose suspension is necessary, restart at a reduced dose after laboratory values have normalized.

2.3 Starting Dose and Dose Titration for Pediatric Patients 5 Years of Age and Above

• Initiate Paricalcitol Injection as an intravenous bolus dose of:
  • 0.04 mcg/kg if baseline intact PTH is less than 500 pg/mL, or
  • 0.08 mcg/kg if baseline intact PTH is 500 pg/mL or greater
• Administer Paricalcitol Injection three times per week, no more frequently than every other day, at any time during dialysis.
• Target the maintenance dose of Paricalcitol Injection to intact PTH levels within the desired therapeutic range and serum calcium within normal limits.
• Monitor serum calcium frequently (e.g., twice weekly) and phosphorus and intact PTH levels every 2 to 4 weeks after initiation of therapy or dose adjustment.
• Titrate the dose of Paricalcitol Injection based on intact PTH (see Table 2). Prior to raising the dose, ensure serum calcium is within normal limits.
• Suspend or decrease the dose if intact PTH is persistently and abnormally low to reduce the risk of adynamic bone disease [see Warnings and Precautions (5.3)] or if serum calcium is consistently above the normal range to reduce the risk of hypercalcemia [see Warnings and Precautions (5.1)]. If dose suspension is necessary, restart at a reduced dose after laboratory values have normalized.

2.4 Drug Interactions that May Require Dosage Adjustments of Paricalcitol Injection

• Increased monitoring of serum calcium and dose adjustment of Paricalcitol Injection may be necessary when given concomitantly with drugs that may increase the risk of hypercalcemia [see Drug Interactions (7)].
• Increased monitoring of both serum calcium and intact PTH as well as dose adjustment of Paricalcitol Injection may be necessary when given concomitantly with strong CYP3A inhibitors [see Drug Interactions (7)].

5.1 Hypercalcemia

Hypercalcemia may occur during Paricalcitol Injection treatment. Acute hypercalcemia may increase the risk of cardiac arrhythmias and seizures and may potentiate the effect of digitalis on the heart [see Warnings and Precautions (5.2)]. Chronic hypercalcemia can lead to generalized vascular calcification and other soft-tissue calcification. Severe hypercalcemia may require emergency attention.

Hypercalcemia may be exacerbated by concomitant administration of high doses of calcium-containing preparations, thiazide diuretics, or other vitamin D compounds [see Drug Interactions (7)]. In addition, high intake of calcium and phosphate concomitantly with vitamin D compounds may lead to hypercalciuria and hyperphosphatemia. Patients with a history of hypercalcemia prior to initiating therapy may be at increased risk for development of hypercalcemia with Paricalcitol Injection. In these circumstances, frequent serum calcium monitoring and Paricalcitol Injection dose adjustments may be required.

When initiating Paricalcitol Injection or adjusting Paricalcitol Injection dose, measure serum calcium frequently (e.g., twice weekly). Once a maintenance dose has been established, measure serum calcium at least monthly. If hypercalcemia occurs, reduce the dose or discontinue Paricalcitol Injection until serum calcium is normal [see Dosage and Administration (2.2, 2.3)].

Inform patients about the symptoms of elevated calcium (feeling tired, difficulty thinking clearly, loss of appetite, nausea, vomiting, constipation, increased thirst, increased urination, and weight loss) and instruct them to report new or worsening symptoms when they occur.

5.2 Digitalis Toxicity

Paricalcitol Injection can cause hypercalcemia [see Warnings and Precautions (5.1)] which increases the risk of digitalis toxicity. In patients using Paricalcitol Injection concomitantly with digitalis compounds, monitor serum calcium and patients for signs and symptoms of digitalis toxicity. Increase the frequency of monitoring when initiating or adjusting the dose of Paricalcitol Injection [see Drug Interactions (7)].

5.3 Adynamic Bone Disease

Adynamic bone disease with subsequent increased risk of fractures may develop if intact PTH levels are suppressed by Paricalcitol Injection to abnormally low levels. Monitor intact PTH levels to avoid over suppression and adjust Paricalcitol Injection dose, if needed [see Dosage and Administration (2.2, 2.3)].

6.1 Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

The safety of Paricalcitol Injection has been established from adequate and well-controlled studies of another paricalcitol injection product [see Clinical Studies (14)]. Below is a display of the adverse reactions of paricalcitol injection in these adequate and well-controlled studies.

Four placebo-controlled, double-blind, multicenter studies were conducted in 113 patients (51% male, 10% Caucasian, 81% African-American and 9% Hispanic, ranging in age from 18 to 90 years). Sixty-two patients were exposed to paricalcitol injection and the average dose at the end of treatment was 0.12 mcg/kg/dose with a mean number of 55 days of dosing across the studies. Discontinuation of therapy due to any adverse reaction occurred in 6.5% of patients treated with paricalcitol injection and 2.0% of patients treated with placebo. Adverse reactions occurring with greater frequency in the group treated with paricalcitol injection and at a frequency of 2% or greater are presented in Table 3.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of paricalcitol injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Allergic reactions including rash, urticaria, and angioedema (including laryngeal edema) have been reported.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

The safety and efficacy of Paricalcitol Injection for the prevention and treatment of secondary hyperparathyroidism associated with CKD have been established in pediatric patients 5 years of age and older with CKD on dialysis. Use of Paricalcitol Injection in pediatric patients 5 years of age and older is supported by evidence from an adequate and well-controlled study with another paricalcitol product in 29 patients, 5 to 19 years of age, with CKD on hemodialysis [see Clinical Studies (14)].

The safety and efficacy of Paricalcitol Injection have not been established in pediatric patients less than 5 years old.

8.5 Geriatric Use

Clinical studies of paricalcitol injection did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

8.6 Hepatic Impairment

The pharmacokinetics of paricalcitol were studied in patients with mild and moderate hepatic impairment and were similar to that of patients with normal hepatic function. No dose adjustment is required in patients with mild or moderate hepatic function.

Paricalcitol Injection has not been studied in patients with severe hepatic impairment.

12.1 Mechanism of Action

Paricalcitol is a synthetic, biologically active vitamin D2 analog. Preclinical and in vitro studies have demonstrated that paricalcitol's biological actions are mediated through binding of the vitamin D receptor (VDR), which results in the selective activation of vitamin D responsive pathways. Vitamin D and paricalcitol have been shown to reduce parathyroid hormone levels by inhibiting PTH synthesis and secretion.

12.3 Pharmacokinetics

Within two hours after administering paricalcitol intravenous doses ranging from 0.04 to 0.24 mcg/kg, concentrations of paricalcitol decreased rapidly; thereafter, concentrations of paricalcitol declined log-linearly. No accumulation of paricalcitol was observed with three times a week dosing.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 104-week carcinogenicity study in CD-1 mice conducted with another paricalcitol product, an increased incidence of uterine leiomyoma and leiomyosarcoma was observed at subcutaneous doses of 1, 3, 10 mcg/kg administered 3 times per week (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 conducted with another paricalcitol product, there was an increased incidence of benign adrenal pheochromocytoma at subcutaneous doses of 0.15, 0.5, 1.5 mcg/kg administered 3 times per week (at less than clinical exposure 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.

Paricalcitol had no effect on fertility (male or female) in rats at intravenous doses up to 20 mcg/kg/dose (13 times a human dose of 14 mcg, equivalent to 0.24 mcg/kg based on body surface area, mg/m2).

Adult Studies in CKD on Dialysis

Three 12-week, placebo-controlled studies were conducted with paricalcitol injection in 78 patients with chronic kidney disease on dialysis. In these studies, patients ranged in age from 22 to 90 years, 51% were males, 13% were Caucasian, 79% were African-American, and 8% were Hispanic. The most common causes of renal failure were hypertension and diabetes. The dose of paricalcitol injection was started at 0.04 mcg/kg 3 times per week intravenously. The dose was increased by 0.04 mcg/kg every 2 weeks until intact PTH levels were decreased at least 30% from baseline or a fifth escalation brought the dose to 0.24 mcg/kg, or intact PTH fell to less than 100 pg/mL, or the Ca × P product was greater than 75 within any 2 week period, or serum calcium became greater than 11.5 mg/dL at any time.

Patients treated with paricalcitol injection achieved a mean intact PTH reduction of 30% within 6 weeks. The results from these studies are as follows:

Pediatric Study in CKD on Dialysis

Paricalcitol injection was evaluated in a 12-week randomized, double-blind, placebo-controlled study of 29 pediatric patients, aged 5 to 19 years, with CKD on hemodialysis; nearly all had received some form of vitamin D prior to the study. Of the 29 patients, 76% were male, 52% were Caucasian and 45% were African-American. The initial dose of paricalcitol injection was 0.04 mcg/kg 3 times per week, based on baseline intact PTH level of less than 500 pg/mL, or 0.08 mcg/kg 3 times per week, based on baseline intact PTH level of 500 pg/mL or greater. The dose of paricalcitol injection was adjusted in 0.04 mcg/kg increments based on the levels of serum intact PTH, calcium and Ca × P. The mean baseline levels of intact PTH were 841 pg/mL for the 15 patients treated with paricalcitol injection and 740 pg/mL for the 14 placebo-treated patients. The mean dose of paricalcitol injection administered was 4.6 mcg (range: 0.8 mcg to 9.6 mcg). Sixty-seven percent of the patients treated with paricalcitol injection and 14% of the placebo-treated patients completed the trial. Seventy-one percent of the placebo-treated patients discontinued due to excessive elevations in intact PTH levels, as defined by 2 consecutive intact PTH levels greater than 700 pg/mL and greater than baseline after 4 weeks of treatment.

The primary efficacy analysis demonstrated that 60% of patients treated with paricalcitol injection and 21% of placebo-treated patients achieved two consecutive greater than or equal to 30% reductions from baseline in intact PTH.

Store under normal lighting conditions at 20° – 25°C (68° – 77°F) [see USP controlled room temperature]. Do not freeze. After breakage of the seal for first use the multi-dose vials are stable for up to 28 days when stored between 20° – 25°C (68° – 77°F).

Hypercalcemia

Advise patients to contact a health care provider if they develop symptoms of elevated calcium (e.g. feeling tired, difficulty thinking clearly, loss of appetite, nausea, vomiting, constipation, increased thirst, increased urination, and weight loss) [see Warnings and Precautions (5.1)].

Monitoring

Inform patients that they will need routine monitoring of laboratory parameters such as calcium, phosphorus, and intact PTH while receiving Paricalcitol Injection. Inform patients that more frequent monitoring is necessary during the initiation of therapy, following dose changes or when potentially interacting medications are started or discontinued [see Dosage and Administration (2), Drug Interactions (7)].

Drug Interactions

Advise patients to inform their physician of all medications, including prescription and nonprescription drugs, and supplements they are taking. Advise patients to also inform their physician that they are receiving Paricalcitol Injection if a new medication is prescribed [see Drug Interactions (7)].

Diet

Advise patients to adhere to instructions regarding diet and phosphorus restriction [see Warnings and Precautions (5.1)].