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Calcifediol

Class: Vitamin D
VA Class: VT509
Chemical Name: (3β,5Z,7E)-9,10-secocholesta-5,7,10(19)-triene-3,25-diol monohydrate
Molecular Formula: C27H44O2 • H2O
CAS Number: 63283-36-3
Brands: Rayaldee

Medically reviewed by Drugs.com. Last updated on Feb 11, 2019.

Introduction

A synthetic vitamin D analog.1

Uses for Calcifediol

Hyperparathyroidism Secondary to Chronic Renal Disease

Treatment of secondary hyperparathyroidism in patients with stage 3 or 4 chronic kidney disease (CKD) and vitamin D insufficiency (i.e., serum total 25-hydroxyvitamin D concentration <30 ng/mL).1 4

Efficacy and safety not established for the treatment of secondary hyperparathyroidism in patients with stage 5 CKD or in patients with end-stage renal disease requiring dialysis.1

Calcifediol Dosage and Administration

General

  • Ensure serum calcium concentration is <9.8 mg/dL prior to initiating calcifediol.1 (See Hypercalcemia under Cautions.)

  • Monitor serum calcium, phosphorus, total 25-hydroxyvitamin D, and intact parathyroid hormone (iPTH) concentrations at a minimum of 3 months after initiation of therapy or dosage adjustment, and subsequently at least every 6–12 months.1

Administration

Oral Administration

Administer extended-release capsules once daily at bedtime; swallow whole.1

Dosage

Available as calcifediol (as the monohydrate); dosage expressed in terms of the anhydrous drug.1

Nephrology experts currently state that optimal iPTH concentration for predialysis patients with stage 3a (eGFR 45–59 mL/minute per 1.73 m2) to stage 5 (eGFR <15 mL/minute per 1.73 m2) CKD is unknown, but modest elevations may represent an appropriate adaptive response to declining renal function.128 129

For patients with stage 5 CKD undergoing dialysis, some experts suggest maintaining iPTH concentrations within a range of approximately 2–9 times the assay's ULN (may correspond to range of approximately 130–600 pg/mL for commercial assays130 ).128 PTH assays exhibit substantial variability; previously recommended range of 150–300 pg/mL for patients with stage 5 CKD requiring dialysis was based on an assay that is no longer available.126 130 131

Avoid oversuppression of PTH, which may increase risk of adynamic bone disease.126 131

Nephrology experts currently recommend using individual values for serum calcium and phosphorus (evaluated together) instead of the mathematical construct of calcium times phosphorus product to guide clinical practice.126 128

Adults

Hyperparathyroidism Secondary to Chronic Renal Disease
Oral

Initial dosage: 30 mcg once daily (as extended-release capsules).1

Maintenance dosage: Individualize dosage to achieve serum total 25-hydroxyvitamin D concentration of 30–100 ng/mL, iPTH concentrations within desired therapeutic range, albumin-corrected serum calcium concentration within normal range, and serum phosphorus concentration <5.5 mg/dL.1

Increase dosage to 60 mcg once daily after approximately 3 months if iPTH remains above desired therapeutic range.1 Ensure serum calcium concentration is <9.8 mg/dL, serum phosphorus concentration is <5.5 mg/dL and serum total 25-hydroxyvitamin D concentration is <100 ng/mL prior to dosage increase.1

Interrupt calcifediol if iPTH is persistently and abnormally low (to reduce risk of adynamic bone disease), serum calcium is consistently above the normal range (to reduce risk of hypercalcemia), or serum total 25-hydroxyvitamin D concentration is consistently >100 ng/mL.1 Resume at a lower dosage after laboratory values return to normal.1

Special Populations

Hepatic Impairment

Manufacturer makes so specific dosage recommendations.1

Geriatric Patients

Manufacturer makes so specific dosage recommendations.1

Cautions for Calcifediol

Contraindications

  • Manufacturer states no known contraindications.1

Warnings/Precautions

Hypercalcemia

Risk of hypercalcemia.1 Severe hypercalcemia may require emergency treatment measures.1

Acute hypercalcemia may increase risk of cardiac arrhythmias and seizures and may potentiate cardiac effects of digitalis glycosides.1

Chronic hypercalcemia increases risk of soft-tissue calcification, including vascular calcification.1

Concomitant use of high doses of calcium-containing preparations, thiazide diuretics, or other vitamin D analogs may exacerbate hypercalcemia.1 High intake of calcium and phosphate concomitantly with vitamin D analogs may result in hypercalciuria and hyperphosphatemia.1 Frequent serum calcium monitoring and calcifediol dosage modifications may be required.1

Monitor patients with a history of hypercalcemia prior to calcifediol initiation more frequently for potential hypercalcemia.1 (See Advice to Patients.)

Cardiac Glycoside Toxicity

Hypercalcemia increases risk of cardiac glycoside toxicity; use concomitantly with caution.1 (See Specific Drugs under Interactions.)

Adynamic Bone Disease

Adynamic bone disease with subsequent increased risk of fractures may develop if iPTH concentrations suppressed to abnormally low levels.1 Monitor iPTH concentrations and adjust calcifediol dosage accordingly.1

Specific Populations

Pregnancy

Category C.1

Teratogenicity observed in rabbits but not in rats.1 No adequate and well-controlled studies to date in pregnant women.1 Use only if potential benefits justify possible fetal risks.1

Lactation

Limited data suggest distribution into milk is minimal.1 Use with caution in nursing women.1

Pediatric Use

Safety and efficacy of calcifediol extended-release capsules not established.1

Geriatric Use

No overall differences in safety or efficacy observed between geriatric patients and younger adults.1

Hepatic Impairment

Data lacking on pharmacokinetics of extended-release capsules in patients with hepatic impairment.1 Hepatic impairment not expected to alter exposure or efficacy since activation of calcifediol does not involve hepatic 25-hydroxylation.21

Renal Impairment

No difference in safety or efficacy between patients with stage 3 CKD and those with stage 4 CKD.1

Safety and efficacy for treatment of secondary hyperparathyroidism in patients with stage 2 or stage 5 CKD and in patients with end-stage renal disease requiring dialysis not established.1

Common Adverse Effects

Anemia,1 4 nasopharyngitis,1 4 increased Scr,1 4 dyspnea,1 4 cough,1 congestive heart failure,1 constipation,1 bronchitis,1 hyperkalemia,1 osteoarthritis,1 hyperuricemia,1 contusion,1 pneumonia,1 COPD.1

Interactions for Calcifediol

CYP Inhibitors

CYP inhibitors may alter calcifediol concentrations by inhibiting CYP27B1 (also known as 1α-hydroxylase), which metabolizes calcifediol to its active form (1,25-dihydroxyvitamin D3), and CYP24A1, which metabolizes calcifediol and 1,25-dihydroxyvitamin D3 to inactive metabolites.1

When a potent CYP3A4 inhibitor is initiated or discontinued, closely monitor serum total 25-hydroxyvitamin D, iPTH, and calcium concentrations; adjust calcifediol dosage as needed.1

Drugs that Stimulate Microsomal Hydroxylation

Possible increased calcifediol metabolism.1 21 Closely monitor serum total 25-hydroxyvitamin D, iPTH, and calcium concentrations when drugs that stimulate microsomal hydroxylation are initiated or discontinued; adjust calcifediol dosage as needed.1

Specific Drugs

Drug

Interaction

Comments

Anticonvulsants (e.g., phenobarbital, phenytoin)

Possible increased calcifediol metabolism1 21

Closely monitor serum total 25-hydroxyvitamin D, iPTH, and calcium concentrations when anticonvulsants that stimulate microsomal hydroxylation are initiated or discontinued; adjust calcifediol dosage as needed1

Antifungals, azole (e.g., itraconazole, ketoconazole, voriconazole)

Possible altered calcifediol concentrations1

Closely monitor serum total 25-hydroxyvitamin D, iPTH, and calcium concentrations when the antifungal is initiated or discontinued; adjust calcifediol dosage as needed1

Cardiac glycosides (e.g., digoxin)

Increased risk of cardiac glycoside toxicity1

Monitor serum calcium and monitor for manifestations of cardiac glycoside toxicity, particularly following calcifediol initiation or dosage adjustment1

Cholestyramine

Possible decreased intestinal absorption of calcifediol1

Closely monitor serum total 25-hydroxyvitamin D, iPTH, and calcium concentrations if cholestyramine is initiated or discontinued; adjust calcifediol dosage as needed1

HIV protease inhibitors (HIV PIs) (e.g., (atazanavir, indinavir, nelfinavir, ritonavir, saquinavir)

Possible altered calcifediol concentrations1

Closely monitor serum total 25-hydroxyvitamin D, iPTH, and calcium concentrations when the HIV PI is initiated or discontinued; adjust calcifediol dosage as needed1

Macrolide antibiotics (clarithromycin, telithromycin)

Possible altered calcifediol concentrations1

Closely monitor serum total 25-hydroxyvitamin D, iPTH, and calcium concentrations when the macrolide is initiated or discontinued; adjust calcifediol dosage as needed1

Nefazodone

Possible altered calcifediol concentrations1

Closely monitor serum total 25-hydroxyvitamin D, iPTH, and calcium concentrations when nefazodone is initiated or discontinued; adjust calcifediol dosage as needed1

Thiazide diuretics

Possible hypercalcemia, since thiazides reduce renal calcium excretion1

More frequent monitoring of serum calcium may be required1

Calcifediol Pharmacokinetics

Absorption

Bioavailability

Exposure increases in dose-proportional manner over dosage range of 30–90 mcg daily (as extended-release capsules).1

Steady-state concentrations of serum total 25-hydroxyvitamin D attained after approximately 3 months.1

Food

Effect of food on absorption of 30- or 60-mcg doses of calcifediol extended-release capsules not established.1

Special Populations

CKD stage: No meaningful difference in steady-state concentrations between stage 3 and stage 4.1

Age, gender, race, body weight, or diabetic status had no meaningful effect on pharmacokinetics of calcifediol extended-release capsules.1 2

Distribution

Extent

Minimally distributed into human milk.1

Plasma Protein Binding

>98%.1

Elimination

Metabolism

Hydroxylated to active form (1,25-dihydroxycholecalciferol, 1,25-dihydroxyvitamin D3, calcitriol) by CYP27B1 (also known as 1α-hydroxylase), principally in the kidneys.1

CYP24A1 (found in vitamin D-responsive tissues) metabolizes calcifediol and 1,25-dihydroxyvitamin D3 to inactive metabolites.1

Elimination Route

Eliminated principally in feces by biliary excretion.1

Half-life

Approximately 11 days in healthy individuals following a single dose of calcifediol extended-release capsules.1

Approximately 25 days in patients with stage 3 or 4 CKD following repeated once-daily dosing.1

Stability

Storage

Oral

Extended-release Capsules

20–25°C (may be exposed to 15–30°C).1

Actions

  • Calcifediol is 25-hydroxycholecalciferol (25-hydroxyvitamin D3).1 Hydroxylated to its active form (1,25-dihydroxycholecalciferol, 1,25-dihydroxyvitamin D3, calcitriol) by CYP27B1 (also known as 1α-hydroxylase), principally in the kidneys.1

  • 1,25-Dihydroxyvitamin D3 binds to the vitamin D receptor in target tissues and activates vitamin D-responsive pathways resulting in increased intestinal absorption of calcium and phosphorus and reduced PTH synthesis.1 3

  • In clinical studies of calcifediol extended-release capsules in patients with secondary hyperparathyroidism, stage 3 or 4 CKD, and vitamin D insufficiency, increases in serum total 25-hydroxyvitamin D concentrations were associated with corresponding increases in serum total 1,25-dihydroxyvitamin D concentrations and reductions in circulating plasma iPTH within first 2 weeks of therapy.1 4 5

Advice to Patients

  • Importance of routine laboratory monitoring (e.g., serum calcium, iPTH, and total 25-hydroxyvitamin D) during calcifediol therapy.1

  • Importance of contacting clinician if symptoms of hypercalcemia (e.g., tiredness, difficulty thinking clearly, loss of appetite, nausea, vomiting, constipation, increased thirst, increased urination, weight loss) develop.1

  • Importance of swallowing calcifediol extended-release capsules whole at bedtime.1 If a dose is missed, importance of resuming the regular schedule with the next scheduled dose; do not take an extra dose to replace the missed dose.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

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

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Calcifediol

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules, extended-release

30 mcg

Rayaldee

OPKO

AHFS DI Essentials™. © Copyright 2019, Selected Revisions February 11, 2019. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. OPKO Pharmaceuticals, LLC. Rayaldee (calcifediol) extended-release capsules prescribing information. Miami, FL; 2016 Jun.

2. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number2080102Orig1s000: Summary review. From FDA website. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/208010Orig1s000SumR.pdf

3. Petkovich M, Melnick J, White J et al. Modified-release oral calcifediol corrects vitamin D insufficiency with minimal CYP24A1 upregulation. J Steroid Biochem Mol Biol. 2015; 148:283-9. http://www.ncbi.nlm.nih.gov/pubmed/25446887?dopt=AbstractPlus

4. Sprague SM, Crawford PW, Melnick JZ et al. Use of Extended-Release Calcifediol to Treat Secondary Hyperparathyroidism in Stages 3 and 4 Chronic Kidney Disease. Am J Nephrol. 2016; 44:316-325. http://www.ncbi.nlm.nih.gov/pubmed/27676085?dopt=AbstractPlus

5. Sprague SM, Silva AL, Al-Saghir F et al. Modified-release calcifediol effectively controls secondary hyperparathyroidism associated with vitamin D insufficiency in chronic kidney disease. Am J Nephrol. 2014; 40:535-45. http://www.ncbi.nlm.nih.gov/pubmed/25572630?dopt=AbstractPlus

21. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number2080102Orig1s000: Clinical pharmacology and biopharmaceutics review(s). From FDA website. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/208010Orig1s000ClinPharmR.pdf

126. Kidney Disease: Improving Global Outcomes (KDIGO) CKD–MBD Work Group. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease—mineral and bone disorder (CKD–MBD). Kidney Int. 2009; 76 (Suppl 113): S1–S130.

128. Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Update Work Group. KDIGO 2017 clinical practice guideline update for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease—mineral and bone disorder (CKD-MBD). Kidney Int Suppl. 2017; 7:1-59.

129. Isakova T, Nickolas TL, Denburg M et al. KDOQI US Commentary on the 2017 KDIGO Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). Am J Kidney Dis. 2017; 70:737-751. http://www.ncbi.nlm.nih.gov/pubmed/28941764?dopt=AbstractPlus

130. Uhlig K, Berns JS, Kestenbaum B et al. KDOQI US commentary on the 2009 KDIGO Clinical Practice Guideline for the Diagnosis, Evaluation, and Treatment of CKD-Mineral and Bone Disorder (CKD-MBD). Am J Kidney Dis. 2010; 55:773-99. http://www.ncbi.nlm.nih.gov/pubmed/20363541?dopt=AbstractPlus

131. Bover J, Ureña P, Ruiz-García C et al. Clinical and Practical Use of Calcimimetics in Dialysis Patients With Secondary Hyperparathyroidism. Clin J Am Soc Nephrol. 2016; 11:161-74. http://www.ncbi.nlm.nih.gov/pubmed/26224878?dopt=AbstractPlus

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