Generic Name: Paricalcitol
Class: Vitamin D
ATC Class: A11CC
VA Class: VT509
Chemical Name: (1α,3β,7E,22E)-19-Nor-9,10-secoergosta-5,7,22-triene-1α,3β,25-triol
Molecular Formula: C27H44O3

Introduction

A synthetic vitamin D analog.110 111 112 113 117

Uses for Zemplar

Secondary Hyperparathyroidism

IV paricalcitol used for prevention and treatment of secondary hyperparathyroidism associated with stage 5 chronic kidney disease (CKD).110

Slideshow: View Frightful (But Dead Serious) Drug Side Effects

Oral paricalcitol used for prevention and treatment of secondary hyperparathyroidism associated with stage 3 and 4 CKD. 117

Zemplar Dosage and Administration

General

  • Individualize dosage according to serum or plasma parathyroid hormone (PTH) concentrations. 110 111 113 117

  • Closely monitor serum calcium and phosphate concentrations during therapy.110 117 (See Patient Monitoring under Cautions.)

Administration

Oral Administration

Administer orally once daily or 3 times weekly without regard to meals.117

If paricalcitol is administered 3 times weekly, administer no more frequently than every other day.117

IV Administration

Administer by direct IV injection at (before, during, or after) dialysis, no more frequently than every other day.110

Dosage

Pediatric Patients

Secondary Hyperparathyroidism
Stage 5 CKD (Dialysis)
IV

Children and adolescents 5–19 years of age: Initial dosage of 0.04 mcg/kg 3 times weekly if iPTH concentration is <500 pg/mL or 0.08 mcg/kg 3 times weekly if iPTH concentration is ≥500 pg/mL.110

Adjust dosage in increments of 0.04 mcg/kg based on serum concentrations of iPTH, calcium, and calcium times serum phosphorus (Ca × P) product.110 Mean dose in one study was 4.6 mcg (range: 0.8–9.6 mcg).110

Adults

Secondary Hyperparathyroidism
Stage 3 or 4 CKD
Oral

If baseline iPTH concentration is ≤500 pg/mL, initial dosage of 1 mcg once daily or 2 mcg 3 times weekly.117 If baseline iPTH concentration is >500 pg/mL, initial dosage of 2 mcg once daily or 4 mcg 3 times weekly.117

Adjust dosage at 2- to 4-week intervals based on iPTH response.117

Maintain current dosage if decrease in iPTH concentration from baseline is ≥30% but ≤60%.117

If response is inadequate (i.e., iPTH concentration increases, remains unchanged, or is reduced by <30% from baseline), increase dosage in increments of 1 mcg daily (e.g., from 1 mcg daily to 2 mcg daily) or 2 mcg 3 times weekly (e.g., from 2 mcg 3 times weekly to 4 mcg 3 times weekly).117

If iPTH concentration is decreased from baseline by >60% or declines to a value of <60 pg/mL, decrease dosage by 1 mcg daily or by 2 mcg 3 times weekly.117

If patient is receiving dosage of 1 mcg once daily and requires dosage reduction, reduce dosage to 1 mcg 3 times weekly; if further reduction is needed, withhold the drug as needed and reinitiate therapy at a lower dosage.117

If hypercalcemia or elevated serum calcium times serum phosphorus product (Ca × P) is observed, reduce dosage or withhold therapy until these parameters are normalized.117

In patients receiving a calcium-containing phosphate binder, dosage of the phosphate binder may be reduced or withheld; alternatively, the patient can be switched to a non-calcium-containing phosphate binder.117

Stage 5 CKD (Dialysis)
IV

Initial dosage of 0.04–0.1 mcg/kg (2.8–7 mcg) at dialysis (no more often than every other day).110

Adjust dosage at 2- to 4-week intervals with the goal of reducing iPTH concentration to no more than 1.5–3 times ULN.110

Maintain current dosage if decrease in iPTH concentration from baseline is ≥30% but ≤60% or if iPTH concentration is 1.5–3 times the ULN.110

If response is inadequate (i.e., iPTH concentration increases, remains unchanged, or is reduced by <30% from baseline), increase dose by 2–4 mcg per dose at 2- to 4-week intervals.110

If iPTH concentration is decreased from baseline by >60%, reduce dosage.110

If serum calcium (in mg/dL) times serum phosphorus (in mg/dL) (Ca × P) product is >75, reduce or withhold dosage immediately until parameters are normalized; reinitiate drug at a lower dosage. 110

In patients receiving a calcium-containing phosphate binder, dosage of the phosphate binder may be reduced or withheld; alternatively, the patient can be switched to a non-calcium-containing phosphate binder.110

Cautions for Zemplar

Contraindications

  • Hypercalcemia.110 117

  • Evidence of vitamin D toxicity.110 117

  • Known hypersensitivity to paricalcitol or any ingredient in the formulation.110 117

Warnings/Precautions

Warnings

Acute or chronic administration of excessive doses of vitamin D analogs (e.g., paricalcitol) may result in excessive suppression of PTH concentrations, hypercalcemia, hypercalciuria, hyperphosphatemia, increased Ca x P product, metastatic calcification, and adynamic bone disease.110 117

Early manifestations of excessive vitamin D intake include weakness,110 117 headache,110 117 somnolence,110 117 nausea,110 117 vomiting,110 117 dry mouth,110 117 constipation,110 117 muscle pain,110 117 bone pain,110 117 and metallic taste.110 117

Late manifestations of excessive vitamin D intake include anorexia,110 117 weight loss,110 117 calcific conjunctivitis,110 117 pancreatitis,110 117 photophobia,110 117 rhinorrhea,110 117 pruritus,110 117 hyperthermia,110 117 decreased libido,110 117 increased BUN,110 117 hypercholesterolemia,110 117 increased AST and ALT concentrations,110 117 ectopic calcification,110 117 hypertension,110 117 cardiac arrhythmias,110 117 somnolence,110 117 overt psychosis,110 117 and death.110 117

Monitor patients and adjust or withhold doses routinely to minimize risk of such effects.117 (See Dosage under Dosage and Administration.)

Hypercalcemia

Progressive hypercalcemia may require emergency treatment measures.110 117 If clinically important hypercalcemia develops, reduce or withhold paricalcitol therapy immediately, withdraw calcium supplements, administer a low-calcium diet, and monitor closely for changes in fluid and electrolyte balance and ECG (especially in those receiving a cardiac glycoside).110

Acute hypercalcemia may increase risk of cardiac arrhythmias, seizures, and also synergistic inotropic and toxic effects in presence of cardiac glycosides.110 117

Chronic hypercalcemia or administration of high dosages of calcium and phosphates with vitamin D analogs increases risk of soft-tissue calcification, including vascular calcification.110 117

Do not use vitamin D and its analogs during paricalcitol therapy; possible additive effects.110 117

In dialysis patients with chronic renal failure receiving calcium salts, adjustments in calcium concentrations in the dialysate may be necessary to reduce the risk of hypercalcemia.110

General Precautions

Patient Monitoring

In patients with stage 3 or 4 CKD receiving oral paricalcitol, monitor serum calcium, serum phosphorus, and serum or plasma iPTH concentrations at least every 2 weeks for 3 months after initiation of therapy or following any dosage adjustment, then monthly for 3 months, and every 3 months thereafter.117

In patients with stage 5 CKD receiving IV paricalcitol, monitor serum calcium and phosphorus at initiation of therapy and every 2 weeks thereafter; once dosage has been established, monitor at least monthly.110 Monitor serum or plasma iPTH concentrations every 3 months.110 Monitor serum calcium and phosphorus concentrations more frequently during dosage adjustments.110

Specific Populations

Pregnancy

Category C.110 117

Lactation

Distributed into milk in rats;110 117 not known whether distributed into human milk.110 117

Discontinue nursing or the drug.110 117

Pediatric Use

Safety and efficacy of oral paricalcitol have not been established in pediatric patients. 117

Safety and efficacy of IV paricalcitol not established in pediatric patients <5 years of age.110

Geriatric Use

No substantial differences in safety and efficacy in those ≥65 years of age relative to younger adults,110 117 but increased sensitivity cannot be ruled out.117

Hepatic Impairment

Not studied in patients with severe hepatic impairment.110 117

No dosage adjustment needed in mild or moderate hepatic impairment.110 117

Common Adverse Effects

Oral administration in patients with stage 3 or 4 CKD: Accidental injury,117 pain,117 viral infection,117 allergic reaction,117 rash,117 headache,117 hypertension,117 hypotension,117 diarrhea,117 nausea,117 vomiting,117 edema,117 uremia,117 pharyngitis,117 dizziness,117 vertigo.117

IV administration in patients with stage 5 CKD: Chills,110 fever,110 flu,110 sepsis,110 GI bleeding,110 nausea,110 vomiting,110 edema,110 lightheadedness,110 pneumonia.110

Interactions for Zemplar

Partially metabolized by CYP3A.117

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Potent CYP3A inhibitors: Potential pharmacokinetic interaction (increased plasma paricalcitol concentrations). 117

CYP substrates: Does not appear to inhibit clearance of drugs metabolized by CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A, or induce clearance of drugs metabolized by CYP isoenzymes 2B6, 2C9, or 3A.110 117

Specific Drugs

Drug

Interaction

Comments

Antifungals, azoles (itraconazole, voriconazole)

Possible increased plasma paricalcitol concentrations110 117

Dosage adjustment of paricalcitol may be needed117

Closely monitor iPTH and serum calcium concentrations when initiating or discontinuing therapy with a potent CYP3A4 inhibitor117

Bile acid sequestrants (cholestyramine, colestipol)

Intestinal absorption of paricalcitol may be decreased117 d

Allow as long a time interval as possible between ingestion of paricalcitol and bile acid sequestrantd

Cardiac glycosides

Possible cardiac arrhythmiasd

Use concomitantly with caution110 117 d

Clarithromycin

Possible increased plasma paricalcitol concentration110 s117

Dosage adjustment of paricalcitol may be needed117

Closely monitor iPTH and serum calcium concentrations when initiating or discontinuing clarithromycin therapy117

HIV protease inhibitors (atazanavir, indinavir, nelfinavir, ritonavir, saquinavir)

Possible increased plasma paricalcitol concentrations110 117

Dosage adjustment of paricalcitol may be needed117

Closely monitor iPTH and serum calcium concentrations when initiating or discontinuing therapy with an HIV protease inhibitor117

Mineral oil

Excessive use of mineral oil may interfere with intestinal absorption of vitamin D analogsd

Nefazodone

Possible increased plasma paricalcitol concentrations110 117

Dosage adjustment of paricalcitol may be needed117

Closely monitor iPTH and serum calcium concentrations when initiating or discontinuing nefazodone therapy117

Telithromycin

Possible increased plasma paricalcitol concentrations110 117

Dosage adjustment of paricalcitol may be needed117

Closely monitor iPTH and serum calcium concentrations when initiating or discontinuing telithromycin therapy117

Thiazide diuretics

Possible hypercalcemia in patients with hypoparathyroidismd

May be transient and self-limited or may require discontinuance of vitamin D analogd

Zemplar Pharmacokinetics

Absorption

Bioavailability

Well absorbed following oral administration; absolute bioavailability is about 72%.117

Food

Food does not appear to affect extent of absorption (AUC) of paricalcitol capsules.117

Food increases time to peak plasma concentration of paricalcitol capsules by about 2 hours.117

Special Populations

Hemodialysis does not appear to affect plasma concentrations.

Distribution

Crosses the placenta in animals not known whether paricalcitol crosses placenta in women.117

Distributed into milk in rats; not known whether distributed into human milk.117

Plasma Protein Binding

≥99.8%.110 117

Elimination

Metabolism

Extensively metabolized (about 98%) by multiple hepatic and nonhepatic enzymes (e.g., CYP24, CYP3A4, uridine diphosphate-glucuronosyltransferase [UGT] 1A4).110 117

Elimination Route

Paricalcitol and its metabolites eliminated principally in feces via biliary excretion.110 117

Excreted in feces mainly (about 63–70%) as metabolites (2% as unchanged drug), and in urine as metabolites (18–19%).110 117

Half-Life

In healthy individuals: 4–7 hours.110 117

Special Populations

Half-life following oral administration: 17 hours in patients with stage 3 CKD and 20 hours in those with stage 4 CKD.117

Half-life following IV administration: 13.9 hours in patients with stage 5 CKD undergoing hemodialysis and 15.4 hours in those with stage 5 CKD undergoing peritoneal dialysis.110

Stability

Storage

Oral

Capsules

25°C (may be exposed to 15–30°C).117

Parenteral

Injection

25°C (may be exposed to 15–30°C).110

Discard unused portion.110

Actions

  • A synthetic vitamin D analog of calcitriol (the metabolically active form of vitamin D).110 111 112 113 117

  • In patients with CKD, decreased metabolic activation of vitamin D in the kidneys results in secondary hyperparathyroidism, characterized by increased PTH concentrations110 117 and disturbances in calcium and phosphorus homeostasis.110 117 These effects may affect bone turnover rate and may result in renal osteodystrophy.110 d

  • Biologic actions of paricalcitol are mediated through binding of the vitamin D receptor, which results in selective activation of vitamin D responsive pathways.110

  • Paricalcitol reduces serum or plasma PTH concentrations in patients with CKD.110 Although paricalcitol appears to be as effective as calcitriol in suppressing PTH secretion, the drug appears to have minimal effect on serum calcium and phosphate concentrations, possibly because the drug may only modestly enhance intestinal absorption of calcium and phosphorus.

Advice to Patients

  • Importance of adherence to diet and calcium supplementation regimen.110 117

  • Importance that patients with CKD use appropriate types of phosphate-binding compounds to control serum phosphate concentrations; however, they should avoid excessive use of aluminum-containing compounds.110 117

  • Importance of serum calcium, phosphorus, iPTH, and alkaline phosphatase monitoring prior to initiation of therapy and periodically thereafter.110 117

  • Importance of immediate reporting of potential manifestations of hypercalcemia.110 117

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.110 117

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.110 117

  • Importance of informing patients of other important precautionary information.110 117 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Paricalcitol

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules, liquid-filled

1 mcg

Zemplar (with coconut oil, palm kernel oil, and alcohol)

Abbott

2 mcg

Zemplar (with coconut oil, palm kernel oil, and alcohol)

Abbott

4 mcg

Zemplar (with coconut oil, palm kernel oil, and alcohol)

Abbott

Parenteral

Injection, for IV use only

2 mcg/mL

Zemplar (with alcohol 20% v/v and propylene glycol 30% v/v)

Abbott

5 mcg/mL

Zemplar (with alcohol 20% v/v and propylene glycol 30% v/v)

Abbott

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions May 1, 2009. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

110. Abbott Laboratories. Zemplar (paricalcitol) injection prescribing information. North Chicago, IL; 2005 Sep.

111. Goldenberg MM. Paricalcitol, a new agent for the management of secondary hyperparathyroidism in patients undergoing chronic renal dialysis. Clin Ther. 1999; 21:432-41. [IDIS 427442] [PubMed 10321413]

112. Slatopolsky E, Finch J, Ritter C et al. A new analog of calcitriol, 19- nor-1,25-(OH)2D2 suppresses parathyroid hormone secretion in uremic rats in the absence of hypercalcemia. Am J Kidney Dis. 1995; 26:852-60. [PubMed 7485144]

113. Martin KJ, Gonzalez EA, Gellens M et al. 19-nor-1-α-25-dihydroxyvitamin D2(paricalcitol) safely and effectively reduces the levels of intact parathyroid hormone in patients on hemodialysis. J Am Soc Nephrol. 1998; 9:1427-32. [PubMed 9697664]

116. Abbott, Abbott Park, IL: Personal communication.

117. Abbott Laboratories. Zemplar (paricalcitol) capsules prescribing information. North Chicago, IL; 2005 May.

a. AHFS drug information 2007. McEvoy GK, ed. Paricalcitol. Bethesda, MD: American Society of Health-System Pharmacists; 2007:3644-5.

d. AHFS drug information 2007. McEvoy GK, ed. Vitamin D Analogs General Statement. Bethesda, MD: American Society of Health-Systems Pharmacists; 2007: 3634-40.

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