Paricalcitol Tablets

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

Zemplar Injection is available as 2 mcg/mL (NDC 0074-4637-01) and 5 mcg/mL (NDC 0074-1658-01 and NDC 0074–1658–05) in trays of 25 vials.

Store at 25°C (77°F). Excursions permitted between 15° - 30°C (59° - 86°F).

Manufactured for: AbbVie Inc., North Chicago, IL 60064, U.S.A. Revised: July, 2013.

Zemplar has been evaluated for safety in clinical studies in 609 CKD Stage 5 patients. In four, placebocontrolled, double-blind, multicenter studies, discontinuation of therapy due to any adverse event occurred in 6.5% of 62 patients treated with Zemplar (dosage titrated as tolerated, see Clinical Studies) and 2.0% of 51 patients treated with placebo for 1 to 3 months. Adverse events occurring in the Zemplar group at a frequency of 2% or greater and with an incidence greater than that in the placebo group, regardless of causality, are presented in the following table:

Adverse Event Incidence Rates for All Treated Patients In All Placebo-Controlled Studies

A patient who reported the same medical term more than once was counted only once for that medical term.

Safety parameters (changes in mean Ca, P, Ca × P) in an open-label safety study up to 13 months in duration support the long-term safety of Zemplar in this patient population (see Clinical Studies).

The following adverse reactions, with a causal relationship to Zemplar, occurred in < 2% of the Zemplar treated patients in the above double-blind, placebo-controlled clinical trial data set. In addition,the following also includes adverse reactions reported in Zemplar-treated patients who participated in other studies (non placebo-controlled), including double-blind, active-controlled and open-label studies:

Blood and Lymphatic System Disorders:

Anemia, lymphadenopathy

Cardiac Disorders:

Arrhythmia, atrial flutter, cardiac arrest

Ear and Labyrinth Disorders:

Ear discomfort

Endocrine Disorders:

Hyperparathyroidism, hypoparathyroidism

Eye Disorders:

Conjunctivitis, glaucoma, ocular hyperemia

Gastrointestinal Disorders:

Abdominal discomfort, constipation, diarrhea, dysphagia, gastritis, intestinal ischemia, rectal hemorrhage

General Disorders and Administration Site Conditions:

Asthenia, chest discomfort, chest pain, condition aggravated, edema peripheral, fatigue, feeling abnormal, gait disturbance, injection site extravasation, injection site pain, pain, swelling, thirst

Infections and Infestations:

Nasopharyngitis, upper respiratory tract infection, vaginal infection

Investigations:

Aspartate aminotransferase increased, bleeding time prolonged, heart rate irregular, laboratory test abnormal, weight decreased

Metabolism and Nutrition Disorders:

Decreased appetite, hypercalcemia, hyperkalemia, hyperphosphatemia, hypocalcemia

Musculoskeletal and Connective Tissue Disorders:

Joint stiffness, muscle twitching, myalgia

Neoplasms Benign, Malignant and Unspecified:

Breast cancer

Nervous System Disorders:

Cerebrovascular accident, dizziness, dysgeusia, headache, hypoesthesia, myoclonus, paresthesia, syncope, unresponsive to stimuli

Psychiatric Disorders:

Agitation, confusional state, delirium, insomnia, nervousness, restlessness

Reproductive System and Breast Disorders:

Breast pain, erectile dysfunction

Respiratory, Thoracic and Mediastinal Disorders:

Cough, dyspnea, orthopnea, pulmonary edema, wheezing

Skin and Subcutaneous Tissue Disorders:

Alopecia, blister, hirsutism, night sweats, rash pruritic, pruritus, skin burning sensation

Vascular Disorders:

Hypertension, hypotension

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

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 and the following inactive ingredients: alcohol, 20% (v/v) and propylene glycol, 30% (v/v).

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

Molecular formula is C27H44O3.

Molecular weight is 416.64.

Acute overdose of Zemplar may cause hypercalcemia, and require emergency attention (see OVERDOSAGE). 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. Chronic hypercalcemia can lead to generalized vascular calcification and other soft-tissue calcification.

Concomitant administration of high doses of calcium-containing preparations or thiazide diueretics with Zemplar may increase the risk of hypercalcemia. High intake of calcium and phosphate concomitant with vitamin D compounds may lead to serum abnormalities requiring more frequent patient monitoring and individualized dose titration. Patients also should be informed about the symptoms of elevated calcium, which include feeling tired, difficulty thinking clearly, loss of appetite, nausea, vomiting, constipation, increased thirst, increased urination and weight loss.

Prescription-based doses of vitamin D and its derivatives should be withheld during Zemplar treatment to avoid hypercalcemia.

Aluminum-containing preparations (e.g., antacids, phosphate binders) should not be administered chronically with Zemplar, as increased blood levels of aluminum and aluminum bone toxicity may occur.

Secondary hyperparathyroidism is characterized by an elevation in parathyroid hormone (PTH) associated with inadequate levels of active vitamin D hormone. The source of vitamin D in the body is from synthesis in the skin and from dietary intake. Vitamin D requires two sequential hydroxylations in the liver and the kidney to bind to and to activate the vitamin D receptor (VDR). The endogenous VDR activator, calcitriol [1,25(OH)2D3], is a hormone that binds to VDRs that are present in the parathyroid gland, intestine, kidney, and bone to maintain parathyroid function and calcium and phosphorus homeostasis, and to VDRs found in many other tissues, including prostate, endothelium and immune cells. VDR activation is essential for the proper formation and maintenance of normal bone. In the diseased kidney, the activation of vitamin D is diminished, resulting in a rise of PTH, subsequently leading to secondary hyperparathyroidism, and disturbances in the calcium and phosphorus homeostasis. The decreased levels of 1,25(OH)2D3 and resultant elevated PTH levels, both of which often precede abnormalities in serum calcium and phosphorus, affect bone turnover rate and may result in renal osteodystrophy.

Mechanism Of Action

Paricalcitol is a synthetic, biologically active vitamin D analog of calcitriol with modifications to the side chain (D2) and the A (19-nor) ring. Preclinical and in vitro studies have demonstrated that paricalcitol's biological actions are mediated through binding of the 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.

Pharmacokinetics

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

Paricalcitol is extensively bound to plasma proteins ( ≥ 99.8%). In healthy subjects, the steady state volume of distribution is approximately 23.8 L. The mean volume of distribution following a 0.24 mcg/kg dose of paricalcitol in CKD Stage 5 subjects requiring hemodialysis (HD) and peritoneal dialysis (PD) is between 31 and 35 L.

After IV administration of a 0.48 mcg/kg dose of 3H-paricalcitol, parent drug was extensively metabolized, with only about 2% of the dose eliminated unchanged in the feces and no parent drug found in the urine. Several metabolites were detected in both the urine and feces. Most of the systemic exposure was from the parent drug. Two minor metabolites, relative to paricalcitol, were detected in human plasma. One metabolite was identified as 24(R)-hydroxy paricalcitol, while the other metabolite was unidentified. The 24(R)-hydroxy paricalcitol is less active than paricalcitol in an in vivo rat model of PTH suppression.

In vitro data suggest that paricalcitol is metabolized by multiple hepatic and non-hepatic enzymes, including mitochondrial CYP24, as well as CYP3A4 and UGT1A4. The identified metabolites include the product of 24(R)-hydroxylation (present at low levels in plasma), as well as 24,26- and 24,28- dihydroxylation and direct glucuronidation.

Paricalcitol is excreted primarily by hepatobiliary excretion. Approximately 63% of the radioactivity was eliminated in the feces and 19% was recovered in the urine in healthy subjects. In healthy subjects, the mean elimination half-life of paricalcitol is about five to seven hours over the studied dose range of 0.04 to 0.16 mcg/kg. The pharmacokinetics of paricalcitol has been studied in CKD Stage 5 subjects requiring hemodialysis (HD) and peritoneal dialysis (PD). The mean elimination half-life of paricalcitol after administration of 0.24 mcg/kg paricalcitol IV bolus dose in CKD Stage 5 HD and PD patients is 13.9 and 15.4 hours, respectively (Table 1).

Table 1 : Mean ± SD Paricalcitol Pharmacokinetic Parameters in CKD Stage 5 Subjects Following Single 0.24 mcg/kg IV Bolus Dose

No accumulation of paricalcitol was observed with three times a week dosing which is consistent with the observed half-life.

Special Populations

The pharmacokinetics of paricalcitol have not been investigated in geriatric patients greater than 65 years.

The pharmacokinetics of paricalcitol have not been investigated in patients less than 18 years of age.

The pharmacokinetics of paricalcitol were gender independent.

The disposition of paricalcitol (0.24 mcg/kg) was compared in patients with mild (n=5) and moderate (n=5) hepatic impairment (as indicated by the Child-Pugh method) and subjects with normal hepatic function (n=10). The pharmacokinetics of unbound paricalcitol were similar across the range of hepatic function evaluated in this study. No dose adjustment is required in patients with mild and moderate hepatic impairment. The influence of severe hepatic impairment on the pharmacokinetics of paricalcitol has not been evaluated.

The pharmacokinetics of paricalcitol have been studied in CKD Stage 5 subjects requiring hemodialysis (HD) and peritoneal dialysis (PD). Hemodialysis procedure has essentially no effect on paricalcitol elimination. However, compared to healthy subjects, CKD Stage 5 subjects showed a decreased CL and increased half-life (see Pharmacokinetics -Elimination).

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.

Drug interactions with paricalcitol injection have not been studied.

The pharmacokinetic interaction between paricalcitol capsule (16 mcg) and omeprazole (40 mg; oral), a strong inhibitor of CYP2C19, was investigated in a single dose, crossover study in healthy subjects. The pharmacokinetics of paricalcitol were unaffected when omeprazole was administrated approximately 2 hours prior to the paricalcitol dose.

Although no data are available for the drug interaction between paricalcitol injection and ketoconazole, a strong inhibitor of CYP3A, 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 Cmax of paricalcitol was minimally affected, but AUC0-∞ 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

In three 12-week, placebo-controlled, phase 3 studies in chronic kidney disease Stage 5 patients on dialysis, the dose of Zemplar 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 × 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 Zemplar 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 Zemplar and placebo-treated patients. The results from these studies are as follows:

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