Rayaldee (calcifediol)

Dosage of calcifediol, which is commercially available for oral use as the monohydrate, is calculated on the anhydrous basis.

The recommended initial dosage of calcifediol for the treatment of secondary hyperparathyroidism in adults with stage 3 or 4 chronic kidney disease (CKD) and vitamin D insufficiency (i.e., serum total 25-hydroxyvitamin D concentration of less than 30 ng/mL) is 30 mcg once daily (as extended-release capsules). Serum calcium concentration should be less than 9.8 mg/dL prior to initiation of calcifediol therapy. (See Hypercalcemia under Cautions: Warnings/Precautions.)

The maintenance dosage of calcifediol should be individualized to achieve a serum total 25-hydroxyvitamin D concentration within the range of 30-100 ng/mL, intact parathyroid hormone (iPTH) concentration within the desired therapeutic range, albumin-corrected serum calcium concentration within the normal range, and serum phosphorus concentration of less than 5.5 mg/dL. Serum calcium, phosphorus, total 25-hydroxyvitamin D, and iPTH concentrations should be monitored at a minimum of 3 months after initiation of therapy or dosage adjustment, and subsequently at least every 6-12 months during therapy. The dosage of calcifediol should be increased to 60 mcg once daily (as extended-release capsules) after approximately 3 months if iPTH concentration remains above the desired therapeutic range, provided that the serum calcium concentration is less than 9.8 mg/dL, serum phosphorus concentration is less than 5.5 mg/dL, and serum total 25-hydroxyvitamin D concentration is less than 100 ng/mL.

Calcifediol therapy should be interrupted if iPTH concentration is persistently and abnormally low (to reduce the risk of adynamic bone disease), if serum calcium concentration consistently exceeds the upper limit of normal (ULN) (to reduce the risk of hypercalcemia), or if serum total 25-hydroxyvitamin D concentration consistently exceeds 100 ng/mL. Calcifediol should be resumed at a lower dosage after the abnormal values have returned to normal.

Nephrology experts currently state that the optimal iPTH concentration for patients with stage 3a (estimated glomerular filtration rate (eGFR) 45-59 mL/minute per 1.73 m2) to stage 5 (eGFR less than 15 mL/minute per 1.73 m2) CKD who are not undergoing dialysis is unknown, but modest increases in iPTH concentration may represent an appropriate adaptive response to declining renal function. For patients with stage 5 CKD undergoing dialysis, some experts suggest that iPTH concentrations may be maintained within a range of approximately 2-9 times the assay's ULN (which may correspond to a range of approximately 130-600 pg/mL for commercially available assays ). Although some clinicians suggest that this range is too broad, available assays for PTH exhibit substantial variability; the 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 commercially available. Oversuppression of PTH may increase the risk of adynamic bone disease and should be avoided. (See Uses: Mineral and Bone Disorder Secondary to Chronic Renal Disease, in the Vitamin D Analogs General Statement 88:16.) Nephrology experts currently recommend that the individual values for serum calcium and phosphorus (evaluated together) be used instead of the mathematical construct of calcium times phosphorus product to guide clinical practice.

Calcifediol extended-release capsules are administered orally at bedtime and should be swallowed whole.

If a dose of calcifediol is missed, an extra dose should not be taken. Instead, the missed dose should be skipped and the next dose administered at the next regularly scheduled time.

No dosing information is available for this tab.

There is no enhanced messaging for this drug.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Oral Phosphates; Active Vitamin D Analogs/Burosumab

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Both burosumab and phosphates or vitamin D may increase serum phosphate levels. This combination may lead to greater increases in serum phosphate than anticipated.

CLINICAL EFFECTS: The combination of burosumab with oral phosphates or active vitamin D analogs may result in hyperphosphatemia and may increase the risk of nephrocalcinosis.(1)

PREDISPOSING FACTORS: Patients with renal impairment have alterations in mineral metabolism that may increase the risk of hyperphosphatemia.(1)

PATIENT MANAGEMENT: The concomitant use of burosumab with oral phosphates or active vitamin D analogs is contraindicated. Discontinue oral phosphate and/or active vitamin D analogs one week before starting burosumab.(1)

DISCUSSION: Burosumab restores dysfunctional renal phosphate reabsorption and renal production of 1,25-dihydroxyvitamin D to treat X-linked hypophosphatemia. Additional oral phosphates and/or active vitamin D analogs may raise serum phosphate higher than anticipated.

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Serum Phosphate Level-Altering Drugs/Erdafitinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Medications that alter serum phosphate may interfere with interpretation of phosphate levels that are needed to determine initial erdafitinib dose.(1)

CLINICAL EFFECTS: Serum phosphate levels that are elevated by concomitant medications may result in an inappropriately low dose and decreased effectiveness of erdafitinib. Serum phosphate levels that are decreased by concomitant medications may result in an inappropriately high dose and increased toxicity from erdafitinib.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of erdafitinib states that agents that alter serum phosphate levels should be avoided before the initial dose increase period for erdafitinib based on serum phosphate levels (days 14 to 21).(1)

DISCUSSION: Concomitant administration of serum phosphate level-altering agents during the initial dose increase period of erdafitinib based on serum phosphate levels (days 14 to 21) may interfere with serum phospate levels and lead to incorrect dosing of erdafitinib.(1) Agents that may alter serum phosphate levels linked to this monograph include: aluminum carbonate, aluminum hydroxide, calcium acetate, calcium carbonate, calcium citrate, cod liver oil, ferric citrate, lanthanum, magnesium carbonate, magnesium hydroxide, potassium phosphate, sevelamer, sodium phosphate, sucroferric oxyhydroxide, tenapanor, and vitamin D.(1)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Fat Soluble Vitamins/Colesevelam

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Colesevelam may decrease the absorption of fat-soluble vitamins A, D, E, and K.(1)

CLINICAL EFFECTS: Colesevelam may reduce absorption of fat soluble vitamins, leading to a deficiency state.

PREDISPOSING FACTORS: A pre-existing deficiency of fat soluble vitamins (A,D,E and K) or chronic malabsorption syndrome.

PATIENT MANAGEMENT: The inhibition of fat soluble vitamin absorption by colesevelam should be borne in mind during implementation of a vitamin supplementation strategy. Oral multivitamin supplements should be taken at least four hours before the dose of colesevelam.(1)

DISCUSSION: Colesevelam may decrease the absorption of fat-soluble vitamins A, D, E, and K.(1)

Fat Soluble Vitamins/Orlistat

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The acetate ester forms of vitamin A and vitamin E must undergo hydrolysis for absorption from the gastrointestinal tract.(1) The enzyme responsible for this hydrolysis is inhibited by orlistat.(2)

CLINICAL EFFECTS: Orlistat may reduce absorption of fat soluble vitamins, leading to a deficiency state.

PREDISPOSING FACTORS: A pre-existing deficiency of fat soluble vitamins (A,D,E and K) or chronic malabsorption syndrome.

PATIENT MANAGEMENT: The inhibition of fat soluble vitamin absorption by orlistat should be borne in mind during implementation of a vitamin supplementation strategy. Patients should be strongly encouraged to take a multivitamin supplement which contains fat soluble vitamins, particularly Vitamin D as it appears most susceptible to this interaction.(4,5) Multivitamin supplements should be taken at least two hours before or after the dose of orlistat, or at bedtime.(4) Patients with chronic malabsorption syndromes should not receive orlistat.(4)

DISCUSSION: Adult patients taking orlistat without supplementation showed a greater reduction in vitamin A,D,E and beta-carotene levels compared to placebo during two or more consecutive visits in studies of 1-2 years duration; these patients had normal baseline values prior to orlistat therapy. Low vitamin values in orlistat patients were as follows: low Vitamin D 12%, low beta-carotene 6.1%, low Vitamin E 5.8%, low Vitamin A 2.2%.(4) A pharmacokinetic interaction study showed a 30% reduction in beta-carotene supplement absorption and a 60% decreased in vitamin E acetate absorption with concomitant orlistat.(4) In a study, orlistat produced the vitamin net concentration by approximately 43%.(1) In a study, no statistically significant decrease in vitamin A absorption was observed with concurrent orlistat.(2) In a study, mean vitamin D levels were significantly reduced compared with baseline after one month of orlistat therapy despite multivitamin supplementation.(5)

The manufacturer states that there are no known contraindications to the use of calcifediol.

• Hypervitaminosis D

• Hypercalcemia
• Hyperphosphatemia
• Kidney stone

• Kidney disease with reduction in glomerular filtration rate (GFr)
• Sarcoidosis

Adverse effects reported during clinical trials in 1.4% or more of patients receiving calcifediol extended-release capsules and more frequently than in those receiving placebo include anemia, nasopharyngitis, increased serum creatinine concentrations, dyspnea, cough, congestive heart failure, constipation, bronchitis, hyperkalemia, osteoarthritis, hyperuricemia, contusion, pneumonia, and chronic obstructive pulmonary disease.

More Frequent

• Anemia
• Chronic heart failure

Less Frequent

• Chronic obstructive pulmonary disease
• Hyperkalemia
• Pneumonia

Rare or Very Rare

• Adynamic bone disease
• Hypercalcemia

More Frequent

• Constipation
• Dyspnea
• Pharyngitis

Less Frequent

• Arthritis
• Bruising
• Hyperuricemia

No enhanced messaging available.

Safety and efficacy of calcifediol extended-release capsules have not been established in pediatric patients.

Category C. (See Users Guide.)

Calcifediol has been shown to be teratogenic in rabbits when given at dosages of 8-16 times the recommended human dosage of 60 mcg daily (based on body surface area) but was not teratogenic in rats at dosages up to 60 mcg/kg daily. There are no adequate and well-controlled studies to date using calcifediol in pregnant women. Calcifediol should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.

Limited data indicate that calcifediol is minimally distributed into milk in humans. Calcifediol should be used with caution in nursing women.

Of the total number of patients studied in phase 3, placebo-controlled, clinical trials of calcifediol extended-release capsules, 63% were 65 years of age and older, while 22% were 75 years of age and older. No overall differences in safety or efficacy were observed between geriatric patients and younger adults.