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Calcifediol

Class: Vitamin D
Chemical Name: (1S,3Z)-3-[(2E)-2-[(1R,3aS,7aR)-1-[(2R)-6-hydroxy-6-methylheptan-2-yl]-7a-methyl-2,3,3a,5,6,7-hexahydro-1H-inden-4-ylidene]ethylidene]-4-methylidenecyclohexan-1-ol;hydrate
Molecular Formula: C27H46O3
CAS Number: 19356-17-3
Brands: Rayaldee

Introduction

Calcifediol is a vitamin D preparation.

Uses for Calcifediol

Calcifediol has the following uses:

Calcifediol is a vitamin D3 analog indicated for the treatment of secondary hyperparathyroidism in adults with stage 3 or 4 chronic kidney disease and serum total 25-hydroxyvitamin D levels less than 30 ng/mL.1

Calcifediol has the following limitations of use:

Calcifediol is not indicated in patients with stage 5 chronic kidney disease or end-stage renal disease on dialysis.1

Calcifediol Dosage and Administration

General

Calcifediol is available in the following dosage form(s) and strength(s):

Extended-release 30 mcg capsules.1

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

  • The initial dose of calcifediol is 30 mcg administered orally once daily at bedtime. Serum calcium should be below 9.8 mg/dL before initiating treatment.1

  • Monitor serum calcium, phosphorus, 25-hydroxyvitamin D, and intact parathyroid hormone (PTH) 3 months after starting therapy or changing dose.1

  • Increase the dose to 60 mcg once daily after 3 months if intact PTH is above the treatment goal. Ensure serum calcium is below 9.8 mg/dL, phosphorus is below 5.5 mg/dL, and 25-hydroxyvitamin D is below 100 ng/mL before increasing the dose.1

  • Suspend dosing if intact PTH is persistently abnormally low, serum calcium is consistently above the normal range, or serum 25-hydroxyvitamin D is consistently above 100 ng/mL.1

Cautions for Calcifediol

Contraindications

None.1

Warnings/Precautions

Hypercalcemia

Hypercalcemia may occur during calcifediol treatment. Acute hypercalcemia may increase the risk of cardiac arrhythmias and seizures and may potentiate the effect of digitalis on the heart. Chronic hypercalcemia can lead to generalized vascular calcification and other soft-tissue calcification. Severe hypercalcemia may require emergency attention.1

Hypercalcemia may be exacerbated by concomitant administration of high doses of calcium-containing preparations, thiazide diuretics, or other vitamin D compounds. In addition, high intake of calcium and phosphate concomitantly with vitamin D compounds may lead to hypercalciuria and hyperphosphatemia. In these circumstances, frequent serum calcium monitoring and calcifediol dose adjustments may be required. Patients with a history of hypercalcemia prior to initiating therapy with calcifediol should be monitored more frequently for possible hypercalcemia during therapy.1

Patients should be informed about the symptoms of elevated serum calcium, which include feeling tired, difficulty thinking clearly, loss of appetite, nausea, vomiting, constipation, increased thirst, increased urination, and weight loss.1

Digitalis Toxicity

Hypercalcemia of any cause, including calcifediol, increases the risk of digitalis toxicity. In patients using calcifediol concomitantly with digitalis compounds, monitor both serum calcium and patients for signs and symptoms of digitalis toxicity and increase the frequency of monitoring when initiating or adjusting the dose of calcifediol. 1

Adynamic Bone Disease

Adynamic bone disease with subsequent increased risk of fractures may develop if intact PTH levels are suppressed by calcifediol to abnormally low levels. Monitor intact PTH levels and adjust calcifediol dose, if needed.1

Specific Populations

Pregnancy

Pregnancy Category C. Calcifediol has been shown to be teratogenic in rabbits when given in doses of 8 to 16 times the human dose of 60 mcg/day, based on body surface area. There are no adequate and well-controlled studies in pregnant women. Calcifediol should be used during pregnancy only if the potential benefit justifies potential risk to the fetus.1

When calcifediol was given orally to bred rabbits on the 6th through the 18th day of gestation, gross visceral and skeletal examination of pups indicated that the compound was teratogenic at doses of 25 and 50 mcg/kg/day. A dose of 5 mcg/kg/day was not teratogenic. In a similar study in rats, calcifediol was not teratogenic at doses up to and including 60 mcg/kg/day.1

The effect of this drug on the mother and fetus during labor and delivery is not known.1

Lactation

Limited available evidence indicates that calcifediol is poorly excreted in human milk. Caution should be exercised when calcifediol is administered to a nursing woman.1

Pediatric Use

The safety and efficacy of calcifediol have not been established in pediatric patients.1

Geriatric Use

Of the total number of subjects in phase 3 placebo-controlled clinical studies of calcifediol, 63% were ≥65 years of age and 22% were ≥75 years of age. No overall differences in the safety or efficacy of calcifediol were observed between subjects older than 65 years and younger subjects.1

Renal Impairment

No difference in efficacy was observed between patients with stage 3 chronic kidney disease or those with stage 4 disease in subgroup analysis. Safety outcomes were similar in these subgroups. The safety and efficacy of calcifediol in the treatment of secondary hyperparathyroidism in patients with stage 2 or stage 5 chronic kidney disease and patients with end-stage renal disease on dialysis have not been established.1

Common Adverse Effects

The most common adverse reactions (≥3% and more frequent than placebo) were anemia, nasopharyngitis, increased blood creatinine, dyspnea, congestive heart failure, and constipation.1

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

  • Co-administration of cytochrome P-450 inhibitors, such as ketoconazole, may alter serum levels of calcifediol.1

  • Co-administration of thiazides may cause hypercalcemia.1

  • Cholestyramine may impair the absorption of calcifediol.1

  • The half-life of calcifediol is reduced by drugs stimulating microsomal hydroxylation, such as phenobarbital or other anticonvulsants.1

Actions

Mechanism Of Action

Calcifediol (25-hydroxyvitamin D3) is a prohormone of the active form of vitamin D3, calcitriol (1,25-dihydroxyvitamin D3). Calcifediol is converted to calcitriol by cytochrome P-450 27B1 (CYP27B1), also called 1-alpha hydroxylase, primarily in the kidney. Calcitriol binds to the vitamin D receptor in target tissues and activates vitamin D-responsive pathways that result in increased intestinal absorption of calcium and phosphorus and reduced parathyroid hormone synthesis. 1

Advice to Patients

Patient Counseling Information

Tell patients to take calcifediol at bedtime and to swallow the capsules whole.1

Inform patients if they miss a dose, to take calcifediol at the next scheduled time. Do not take an extra dose to make up for the missed dose.1

Inform patients that they will need routine monitoring of laboratory parameters such as calcium, intact PTH and total 25-hydroxyvitamin D while taking calcifediol.1

Advise patients to contact a health care provider if they develop symptoms of elevated calcium (e.g., feeling tired, having difficulty thinking clearly, loss of appetite, nausea, vomiting, constipation, increased thirst, increased urination, or weight loss).1

Advise patients to inform their physician of all use of medications, including prescription and nonprescription drugs, supplements, and herbal preparations, and of any changes in medical condition. Patients should also be advised to inform their physicians, when receiving a newly prescribed medication, that they are taking calcifediol.1

Additional Information

AHFS First Release. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

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

Capsule, Extended Release

30 mcg

Rayaldee

OPKO

AHFS Drug Information. © Copyright 2017, Selected Revisions March 6, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. OPKO Pharmaceuticals LLC. Rayaldee (calcifediol) ORAL prescribing information. 2016 Jun.

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