Paricalcitol (Page 3 of 4)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In a 104-week carcinogenicity study in CD-1 mice conducted with paricalcitol, 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 conducted with paricalcitol, 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. Paricalcitol 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 ].

14 CLINICAL STUDIES

In three 12-week, placebo-controlled, phase 3 studies conducted with another paricalcitol injection product in patients with Stage 5 chronic kidney disease on dialysis, the dose of paricalcitol was started at 0.04 mcg/kg 3 times per week. The dose was increased by 0.04 mcg/kg every 2 weeks until intact parathyroid hormone (iPTH) levels were decreased at least 30% from baseline, or a fifth escalation brought the dose to 0.24 mcg/kg, or iPTH fell to less than 100 pg/mL, or the Ca x 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 achieved a mean iPTH reduction of 30% within 6 weeks. In these studies, there was no significant difference in the incidence of hypercalcemia or hyperphosphatemia between paricalcitol and placebo-treated patients. The results from these studies are as follows:

Table 4: Mean Changes from Baseline to Final Evaluation in PTH, Alkaline Phosphatase, Phosphorus and Calcium x Phosphorus Product in CKD Stage 5 Patients in Three Placebo-Controlled, Phase 3 Studies
Group(No. of Pts.) BaselineMean(Range) Mean (SE) Change From Baseline to Final Evaluation
PTH (pg/mL)paricalcitol(n=40)783 (291–2076)-379 (43.7)
placebo(n=38)745 (320 – 1671)-69.6 (44.8)
Alkaline Phosphatase (U/L)paricalcitol(n=31)150 (40 – 600)-41.5 (10.6)
placebo(n=34)169 (56 – 911)+2.6 (10.1)
Phosphorus (mg/dL)paricalcitol(n=40)5.8 (3.7 – 10.2)+0.47 (0.3)
placebo(n=38)6.0 (2.8 – 8.8)-0.47 (0.3)
Calcium x Phosphorus Productparicalcitol(n=40)54 (32 – 106)+7.9 (2.2)
placebo(n=38)54 (26 – 77)-3.9 (2.3)

A long-term, open-label safety study of 164 CKD Stage 5 patients conducted with another paricalcitol injection product (mean dose of 7.5 mcg three times per week), demonstrated that mean serum Ca, P, and Ca x P remained within clinically appropriate ranges with PTH reduction (mean decrease of 319 pg/mL at 13 months).

Figure 1: Mean Values for Serum iPTH, Calcium and Phosphorus Over Time in CKD Stage 5 Patients in a Phase 3 Study

Figure 1: Mean Values for Serum iPTH, Calcium and Phosphorus Over Time in CKD Stage 5 Patients in a Phase 3 Study
(click image for full-size original)

16 HOW SUPPLIED/STORAGE AND HANDLING

Paricalcitol Injection is available in 2 mcg/mL single dose vials (NDC 0143-9625-25), 5 mcg/mL single dose vials (NDC 0143-9624-25) and 10 mcg/2 mL (5 mcg/mL) multiple dose vials (NDC 0143-9596-25) in cartons of 25 vials.

NDC Number Volume/Container Concentration Total Content Vial Type
0143-9625-25 1 mL/Fliptop Vial 2 mcg/mL 2 mcg Single Dose
0143-9624-25 1 mL/Fliptop Vial 5 mcg/mL 5 mcg Single Dose
0143-9596-25 2 mL/Fliptop Vial 5 mcg/mL 10 mcg Multiple Dose

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Do not freeze. After initial vial use, the contents of the multiple dose vial remain stable up to seven days when stored at controlled room temperature. Discard unused portion of the single dose vial.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

17 PATIENT COUNSELING INFORMATION

Patients should be advised:

  • of the most common adverse reactions with use of Paricalcitol Injection, which include nausea, vomiting and fluid retention.
  • to adhere to instructions regarding diet and phosphorus restriction.
  • 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).
  • to return to their dialysis clinic/health care provider’s office for routine monitoring. More frequent monitoring is necessary during the initiation of therapy, following dose changes or when potentially interacting medications are started or discontinued.
  • to inform their health care provider of all medications, including prescription and nonprescription drugs, supplements, and herbal preparations they are taking and any change to their medical condition. Patients should also be advised to inform their health care provider prescribing a new medication that they are taking Paricalcitol Injection.

Manufactured by:
Exela Pharma Sciences, LLC
Lenoir, NC 28645 USA

Distributed by:
WEST-WARD PHARMACEUTICAL CORP.
Eatontown, NJ 07724 USA

9625-0415-00 April 2015

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