ZEMPLAR- paricalcitol capsule, liquid filled
AbbVie Inc.
1 INDICATIONS AND USAGE
1.1 Chronic Kidney Disease Stages 3 and 4
? ZEMPLAR capsules are indicated in adults and pediatric patients 10 years of age and older for the prevention and treatment of secondary hyperparathyroidism associated with Chronic Kidney Disease (CKD) Stages 3 and 4.
1.2 Chronic Kidney Disease Stage 5
? ZEMPLAR capsules are indicated in adults and pediatric patients 10 years of age and older for the prevention and treatment of secondary hyperparathyroidism associated with CKD Stage 5 in patients on hemodialysis (HD) or peritoneal dialysis (PD).
2 DOSAGE AND ADMINISTRATION
2.1 Chronic Kidney Disease Stages 3 and 4 in Adults
Administer ZEMPLAR capsules orally once daily or three times a week [see Clinical Studies (14.1)]. When dosing three times weekly, do not administer more frequently than every other day.
2.2 Chronic Kidney Disease Stage 5 in Adults
Initial Dose
Administer the dose of ZEMPLAR capsules orally three times a week, no more frequently than every other day based upon the following formula:
Dose (micrograms) = baseline iPTH (pg/mL) divided by 80
Treat patients only after their baseline serum calcium has been adjusted to 9.5 mg/dL or lower to minimize the risk of hypercalcemia [see Clinical Pharmacology (12.2) and Clinical Studies (14.2)].
Dose Titration
Individualize the dose of ZEMPLAR based on iPTH, serum calcium and phosphorus levels. Titrate ZEMPLAR dose based on the following formula:
Dose (micrograms) = most recent iPTH level (pg/ml) divided by 80
If serum calcium is elevated, the dose should be decreased by 2 to 4 micrograms.
As iPTH approaches the target range, small, individualized dose adjustments may be necessary in order to achieve a stable iPTH. In situations where monitoring of iPTH, Ca or P occurs less frequently than once per week, a more modest initial and dose titration ratio (e.g., iPTH divided by 100) may be warranted.
2.3 Pediatric Patients (Ages 10 to 16 Years)
? CKD Stages 3 and 4
? Initial Dose
? Administer ZEMPLAR 1 mcg capsule orally three times a week, no more frequently than every other day.
? Dose Titration
? Individualize and titrate ZEMPLAR dose based on iPTH, serum calcium and phosphorus levels to maintain an iPTH level within target range.
? Every 4 weeks, each administered ZEMPLAR dose may be increased in 1 mcg increments, maintaining the three times per week regimen (e.g., increase from 1 mcg three times per week to 2 mcg three times per week). At any time, each administered dose may be decreased by 1 mcg. ZEMPLAR may be stopped if the patient requires reduction while receiving 1 mcg three times per week, resuming when appropriate.
? CKD Stage 5
? Initial Dose
? Administer the dose of ZEMPLAR capsules orally three times a week, no more frequently than every other day based upon the following formula:
Dose* (micrograms) = baseline iPTH (pg/mL) divided by 120 * Round down to the nearest whole number
? Dose Titration
? Subsequent dosing should be individualized and based on iPTH, serum calcium and phosphorus levels to maintain an iPTH level within target range.
? Every 4 weeks, each administered ZEMPLAR dose may be increased in 1 mcg increments, maintaining the three times per week regimen (e.g., increase from 1 mcg three times per week to 2 mcg three times per week). At any time, each administered dose may be decreased by 2 mcg. ZEMPLAR may be stopped if the patient requires reduction while receiving 2 mcg three times per week or 1 mcg three times per week, resuming when appropriate.
DESCRIPTION
Paricalcitol, USP, the active ingredient in ZEMPLAR capsules, is a synthetically manufactured, metabolically active vitamin D analog of calcitriol with modifications to the side chain (D2 ) and the A (19-nor) ring. ZEMPLAR is available as soft gelatin capsules for oral administration containing 1 microgram or 2 micrograms of paricalcitol. Each capsule also contains medium chain triglycerides, alcohol, and butylated hydroxytoluene. The medium chain triglycerides are fractionated from coconut oil or palm kernel oil. The capsule shell is composed of gelatin, glycerin, titanium dioxide, iron oxide red (2 microgram capsules only), iron oxide yellow (2 microgram capsules only), iron oxide black (1 microgram capsules only), and water.
Paricalcitol is a white, crystalline powder with the empirical formula of C27 H44 O3 , which corresponds to a molecular weight of 416.64. Paricalcitol is chemically designated as 19-nor-1?,3?,25-trihydroxy-9,10-secoergosta-5(Z),7(E),22(E)-triene
CLINICAL PHARMACOLOGY
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 as vitamin D3 and from dietary intake as either vitamin D2 or D3 . Both vitamin D2 and D3require 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)2 D3 ], 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. Decreased levels of 1,25(OH)2 D3 have been observed in early stages of chronic kidney disease. The decreased levels of 1,25(OH)2 D3 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.
12.1 Mechanism of Action
Paricalcitol is a synthetic, biologically active vitamin D2 analog of calcitriol. 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.
