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
Brands: Zemplar

Introduction

A synthetic vitamin D analog.^{110 111 112 113 117}

Uses for Paricalcitol

Secondary Hyperparathyroidism

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

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

Paricalcitol 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 Paricalcitol

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 Paricalcitol

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

Paricalcitol 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

ActionsActions

• 
  

  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 concentrations^{110 117} 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

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions May 01, 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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• Paricalcitol Professional Patient Advice (Wolters Kluwer)


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