CLASSES

Vitamin D Supplements

DEA CLASS

Rx

DESCRIPTION

Fat-soluble vitamin D3 analog (prohormone)
Used for secondary hyperparathyroidism in patients with stage 3 or 4 chronic kidney disease and serum total 25-hydroxyvitamin D concentrations less than 30 ng/mL
Associated with clinically insignificant elevations in serum calcium and phosphorus concentrations

COMMON BRAND NAMES

RAYALDEE

HOW SUPPLIED

RAYALDEE Oral Cap ER: 30mcg

DOSAGE & INDICATIONS

MAXIMUM DOSAGE

60 mcg/day PO.

60 mcg/day PO.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

DOSING CONSIDERATIONS

Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed. Calcifediol is not indicated for patients with Stage 5 chronic kidney disease or end-stage renal disease on dialysis.

ADMINISTRATION

STORAGE

RAYALDEE:
- Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

CONTRAINDICATIONS / PRECAUTIONS

Hypercalcemia may occur with 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 may lead to generalized vascular calcification and other soft-tissue calcifications. Severe hypercalcemia due to substantial overdosage of vitamin D (hypervitaminosis D) and its metabolites may require emergency treatment. Hypercalcemia may be worsened by concomitant administration of high doses of calcium containing preparations, thiazide diuretics, or other vitamin D compounds. Additionally, high intake of calcium and phosphate concomitantly with vitamin D compounds may lead to hypercalciuria and hyperphosphatemia. Monitor serum calcium frequently in these situations; dose adjustments of calcifediol may be necessary. Monitor patients with a history of hypercalcemia prior to starting treatment more frequently during therapy. Instruct patients to be aware of the symptoms of elevated calcium, such as feeling tired, difficulty thinking clearly, loss of appetite, nausea, vomiting, constipation, increased thirst and urination, and weight loss.

Adynamic bone disease with subsequent increased risk of bone fractures may develop if intact parathyroid hormone (iPTH) is suppressed to abnormally low concentrations. Monitor iPTH concentrations during therapy and adjust calcifediol dose if needed.

The safety and efficacy of calcifediol in patients with Stage 2 or Stage 5 chronic kidney disease and patients with end-stage renal disease on dialysis have not been established.

There are no adequate and well-controlled studies of calcifediol use in human pregnancy. In animal reproduction studies in rabbits, calcifediol increased skeletal and soft tissue malformation when given in doses of 6 to 13 times the human dose of 60 mcg/day, based on body surface area, during organogenesis. No adverse developmental outcomes were noted in rats given up to 15 times the human dose, based on body surface area, during organogenesis.

There are no data available on the presence of calcifediol in human milk, the effect on the breastfed infant or the effect on milk production. Monitor infants exposed to calcifediol through breast milk for signs and symptoms of hypercalcemia, including seizures, vomiting, constipation, and weight loss. Consider monitoring of serum calcium in the infant. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for calcifediol and any potential adverse effects on the breast-fed infant from calcifediol or the underlying maternal condition.

ADVERSE REACTIONS

heart failure / Delayed / 3.5-3.5
hyperkalemia / Delayed / 2.5-2.5
pancreatitis / Delayed / Incidence not known
hypervitaminosis D / Delayed / Incidence not known
coma / Early / Incidence not known

anemia / Delayed / 4.9-4.9
dyspnea / Early / 4.2-4.2
constipation / Delayed / 3.2-3.2
hypercalcemia / Delayed / 2.0-2.0
hyperuricemia / Delayed / 1.8-1.8
hyperphosphatemia / Delayed / 0.4-0.4
psychosis / Early / Incidence not known
dehydration / Delayed / Incidence not known
elevated hepatic enzymes / Delayed / Incidence not known
hypertension / Early / Incidence not known
bone pain / Delayed / Incidence not known
hyperthermia / Delayed / Incidence not known
hypercalciuria / Delayed / Incidence not known
hypercholesterolemia / Delayed / Incidence not known
photophobia / Early / Incidence not known
confusion / Early / Incidence not known

pharyngitis / Delayed / 4.9-4.9
cough / Delayed / 3.5-3.5
weakness / Early / Incidence not known
fatigue / Early / Incidence not known
anorexia / Delayed / Incidence not known
libido decrease / Delayed / Incidence not known
xerostomia / Early / Incidence not known
weight loss / Delayed / Incidence not known
rhinorrhea / Early / Incidence not known
polydipsia / Early / Incidence not known
nocturia / Early / Incidence not known
polyuria / Early / Incidence not known
metallic taste / Early / Incidence not known
drowsiness / Early / Incidence not known

DRUG INTERACTIONS

Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum calcium concentrations during concomitant use of thiazide diuretics and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
Aluminum Hydroxide; Magnesium Hydroxide: (Major) Avoid vitamin D analog coadministration with magnesium hydroxide in persons on chronic hemodialysis due to the risk for hypermagnesemia.
Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (Major) Avoid vitamin D analog coadministration with magnesium hydroxide in persons on chronic hemodialysis due to the risk for hypermagnesemia.
Amiloride; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum calcium concentrations during concomitant use of thiazide diuretics and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum calcium concentrations during concomitant use of thiazide diuretics and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
Amoxicillin; Clarithromycin; Omeprazole: (Moderate) Dose adjustment of calcifediol may be necessary during coadministration with clarithromycin. Additionally, serum 25-hydroxyvitamin D, intact PTH, and calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with clarithromycin. Clarithromycin, which is a cytochrome P450 inhibitor, may inhibit enzymes involved in vitamin D metabolism (CYP24A1 and CYP27B1) and may alter serum concentrations of calcifediol.
Atazanavir: (Moderate) Dose adjustment of calcifediol may be necessary during coadministration with atazanavir. Additionally, serum 25-hydroxyvitamin D, intact PTH, and calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with atazanavir. Atazanavir, which is a cytochrome P450 inhibitor, may inhibit enzymes involved in vitamin D metabolism (CYP24A1 and CYP27B1) and may alter serum concentrations of calcifediol.
Atazanavir; Cobicistat: (Moderate) Dose adjustment of calcifediol may be necessary during coadministration with atazanavir. Additionally, serum 25-hydroxyvitamin D, intact PTH, and calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with atazanavir. Atazanavir, which is a cytochrome P450 inhibitor, may inhibit enzymes involved in vitamin D metabolism (CYP24A1 and CYP27B1) and may alter serum concentrations of calcifediol.
Atenolol; Chlorthalidone: (Moderate) Monitor serum calcium concentrations during concomitant use of thiazide diuretics and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
Azilsartan; Chlorthalidone: (Moderate) Monitor serum calcium concentrations during concomitant use of thiazide diuretics and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
Barbiturates: (Moderate) Dose adjustment of calcifediol may be necessary during coadministration with barbiturates. Additionally, serum 25-hydroxyvitamin D, intact PTH, and calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with barbiturates. Barbiturates stimulate microsomal hydroxylation and reduce the half-life of calcifediol. In rare cases, this has caused anticonvulsant-induced rickets and osteomalacia.
Benazepril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum calcium concentrations during concomitant use of thiazide diuretics and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
Bendroflumethiazide; Nadolol: (Moderate) Monitor serum calcium concentrations during concomitant use of thiazide diuretics and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum calcium concentrations during concomitant use of thiazide diuretics and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
Burosumab: (Contraindicated) Vitamin D analogs are contraindicated in patients receiving burosumab; discontinue vitamin D analogs 1 week prior to initiation of burosumab.
Calcitonin: (Moderate) Calcitonin is given to hypercalcemic patients to reduce serum calcium concentrations. For the treatment of hypercalcemia, vitamin D preparations should be avoided. Vitamin D analogs can elevate serum calcium concentrations and antagonize the effects of the calcitonin for this condition. For the treatment of osteoporosis adequate intake of vitamin D is necessary in conjunction with calcitonin. An increase in serum calcium concentrations helps to reduce bone resorption and loss of bone mass, and offsets the effect of calcitonin in lowering serum calcium levels.
Calcitriol: (Major) Withhold calcifediol treatment when using other vitamin D analogs, like calcitrol, due to the risk of additive toxicity including hypercalcemia, hypercalciuria, and hyperphosphatemia.
Calcium Acetate: (Moderate) Monitor serum calcium concentrations during concomitant use of high doses of calcium and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
Calcium Carbonate: (Moderate) Monitor serum calcium concentrations during concomitant use of high doses of calcium and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
Calcium Carbonate; Famotidine; Magnesium Hydroxide: (Moderate) Monitor serum calcium concentrations during concomitant use of high doses of calcium and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
Calcium Carbonate; Magnesium Hydroxide: (Moderate) Monitor serum calcium concentrations during concomitant use of high doses of calcium and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
Calcium Carbonate; Magnesium Hydroxide; Simethicone: (Moderate) Monitor serum calcium concentrations during concomitant use of high doses of calcium and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
Calcium Carbonate; Risedronate: (Moderate) Monitor serum calcium concentrations during concomitant use of high doses of calcium and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
Calcium Carbonate; Simethicone: (Moderate) Monitor serum calcium concentrations during concomitant use of high doses of calcium and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
Calcium Chloride: (Moderate) Monitor serum calcium concentrations during concomitant use of high doses of calcium and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
Calcium Gluconate: (Moderate) Monitor serum calcium concentrations during concomitant use of high doses of calcium and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
Calcium: (Moderate) Monitor serum calcium concentrations during concomitant use of high doses of calcium and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
Calcium; Vitamin D: (Moderate) Monitor serum calcium concentrations during concomitant use of high doses of calcium and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
Candesartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum calcium concentrations during concomitant use of thiazide diuretics and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
Captopril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum calcium concentrations during concomitant use of thiazide diuretics and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
Chlorothiazide: (Moderate) Monitor serum calcium concentrations during concomitant use of thiazide diuretics and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
Chlorthalidone: (Moderate) Monitor serum calcium concentrations during concomitant use of thiazide diuretics and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
Chlorthalidone; Clonidine: (Moderate) Monitor serum calcium concentrations during concomitant use of thiazide diuretics and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
Cholestyramine: (Moderate) Separate administration of calcifediol by 1 hour before or 4 hours after a cholestyramine dose to limit effects on oral absorption. Dose adjustment of calcifediol may be necessary during coadministration with cholestyramine. Additionally, serum 25-hydroxyvitamin D, intact PTH, and calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with cholestyramine. Cholestyramine can decrease the intestinal absorption of fat-soluble vitamins like calcifediol.
Chromium: (Moderate) Monitor serum calcium concentrations during concomitant use of high doses of calcium and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
Clarithromycin: (Moderate) Dose adjustment of calcifediol may be necessary during coadministration with clarithromycin. Additionally, serum 25-hydroxyvitamin D, intact PTH, and calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with clarithromycin. Clarithromycin, which is a cytochrome P450 inhibitor, may inhibit enzymes involved in vitamin D metabolism (CYP24A1 and CYP27B1) and may alter serum concentrations of calcifediol.
Colestipol: (Moderate) Separate administration of calcifediol by 1 hour before or 4 hours after a colestipol dose to limit effects on oral absorption. Because it sequesters bile acids, colestipol may interfere with normal fat absorption and thus may reduce absorption of fat-soluble vitamins like calcifediol.
Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Dose adjustment of calcifediol may be necessary during coadministration with ritonavir. Additionally, serum 25-hydroxyvitamin D, intact PTH, and calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with ritonavir. Ritonavir, which is a cytochrome P450 inhibitor, may inhibit enzymes involved in vitamin D metabolism (CYP24A1 and CYP27B1) and may alter serum concentrations of calcifediol.
Digoxin: (Moderate) Monitor serum calcium and patients for signs of digitalis toxicity in patients receiving calcifediol and digoxin concurrently. Monitor more frequently when initiating or adjusting the dose of calcifediol. Hypercalemia of any cause, including calcifediol therapy, increases the risk of digitalis toxicity.
Dihydrotachysterol: (Major) Withhold calcifediol treatment when using other vitamin D analogs, like dihydrotachysterol, due to the risk of additive toxicity including hypercalcemia, hypercalciuria, and hyperphosphatemia.
Doxercalciferol: (Major) Withhold calcifediol treatment when using other vitamin D analogs, like doxercalciferol, due to the risk of additive toxicity including hypercalcemia, hypercalciuria, and hyperphosphatemia.
Enalapril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum calcium concentrations during concomitant use of thiazide diuretics and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
Eprosartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum calcium concentrations during concomitant use of thiazide diuretics and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
Folic Acid, Vitamin B9: (Moderate) Monitor serum calcium concentrations during concomitant use of high doses of calcium and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
Fosinopril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum calcium concentrations during concomitant use of thiazide diuretics and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
Fosphenytoin: (Moderate) Dose adjustment of calcifediol may be necessary during coadministration with fosphenytoin. Additionally, serum 25-hydroxyvitamin D, intact PTH, and calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with fosphenytoin. Fosphenytoin stimulates microsomal hydroxylation and reduces the half-life of calcifediol. In rare cases, this has caused anticonvulsant-induced rickets and osteomalacia.
Hydralazine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum calcium concentrations during concomitant use of thiazide diuretics and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum calcium concentrations during concomitant use of thiazide diuretics and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
Hydrochlorothiazide, HCTZ; Methyldopa: (Moderate) Monitor serum calcium concentrations during concomitant use of thiazide diuretics and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
Hydrochlorothiazide, HCTZ; Moexipril: (Moderate) Monitor serum calcium concentrations during concomitant use of thiazide diuretics and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
Ibritumomab Tiuxetan: (Major) High intake of phosphates concomitantly with vitamin D analogs may lead to hyperphosphatemia. Dose adjustment of vitamin D analogs may be necessary during coadministration with phosphorus salts. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia.
Irbesartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum calcium concentrations during concomitant use of thiazide diuretics and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
Itraconazole: (Moderate) Dose adjustment of calcifediol may be necessary during coadministration with itraconazole. Additionally, serum 25-hydroxyvitamin D, intact PTH, and calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with itraconazole. Itraconazole, which is a cytochrome P450 inhibitor, may inhibit enzymes involved in vitamin D metabolism (CYP24A1 and CYP27B1) and may alter serum concentrations of calcifediol.
Ketoconazole: (Moderate) Dose adjustment of calcifediol may be necessary during coadministration with ketoconazole. Additionally, serum 25-hydroxyvitamin D, intact PTH, and calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with ketoconazole. Ketoconazole, which is a cytochrome P450 inhibitor, may inhibit enzymes involved in vitamin D metabolism (CYP24A1 and CYP27B1) and may alter serum concentrations of calcifediol.
Lansoprazole; Amoxicillin; Clarithromycin: (Moderate) Dose adjustment of calcifediol may be necessary during coadministration with clarithromycin. Additionally, serum 25-hydroxyvitamin D, intact PTH, and calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with clarithromycin. Clarithromycin, which is a cytochrome P450 inhibitor, may inhibit enzymes involved in vitamin D metabolism (CYP24A1 and CYP27B1) and may alter serum concentrations of calcifediol.
Levoketoconazole: (Moderate) Dose adjustment of calcifediol may be necessary during coadministration with ketoconazole. Additionally, serum 25-hydroxyvitamin D, intact PTH, and calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with ketoconazole. Ketoconazole, which is a cytochrome P450 inhibitor, may inhibit enzymes involved in vitamin D metabolism (CYP24A1 and CYP27B1) and may alter serum concentrations of calcifediol.
Lisinopril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum calcium concentrations during concomitant use of thiazide diuretics and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
Lopinavir; Ritonavir: (Moderate) Dose adjustment of calcifediol may be necessary during coadministration with ritonavir. Additionally, serum 25-hydroxyvitamin D, intact PTH, and calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with ritonavir. Ritonavir, which is a cytochrome P450 inhibitor, may inhibit enzymes involved in vitamin D metabolism (CYP24A1 and CYP27B1) and may alter serum concentrations of calcifediol.
Losartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum calcium concentrations during concomitant use of thiazide diuretics and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
Magnesium Citrate: (Major) Avoid vitamin D analog coadministration with magnesium citrate in persons on chronic hemodialysis due to the risk for hypermagnesemia.
Magnesium Hydroxide: (Major) Avoid vitamin D analog coadministration with magnesium hydroxide in persons on chronic hemodialysis due to the risk for hypermagnesemia.
Magnesium Salts: (Major) Avoid vitamin D analog coadministration with magnesium-containing products, such as antacids, in persons on chronic hemodialysis due to the risk for hypermagnesemia.
Magnesium: (Major) Avoid vitamin D analog coadministration with magnesium-containing products, such as antacids, in persons on chronic hemodialysis due to the risk for hypermagnesemia.
Methyclothiazide: (Moderate) Monitor serum calcium concentrations during concomitant use of thiazide diuretics and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
Metolazone: (Moderate) Monitor serum calcium concentrations during concomitant use of thiazide diuretics and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
Metoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum calcium concentrations during concomitant use of thiazide diuretics and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
Mineral Oil: (Moderate) Separate administration of oral vitamin D analogs by 1 hour before or 4 to 6 hours after mineral oil to limit effects on absorption and availability of the vitamin D analog. Absorption of fat-soluble vitamins may be decreased with concomitant administration of mineral oil. The bioavailability of orally administered vitamin D analogs may also be decreased.
Nefazodone: (Moderate) Dose adjustment of calcifediol may be necessary during coadministration with nefazodone. Additionally, serum 25-hydroxyvitamin D, intact PTH, and calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with nefazodone. Nefazodone, which is a cytochrome P450 inhibitor, may inhibit enzymes involved in vitamin D metabolism (CYP24A1 and CYP27B1) and may alter serum concentrations of calcifediol.
Nelfinavir: (Moderate) Dose adjustment of calcifediol may be necessary during coadministration with nelfinavir. Additionally, serum 25-hydroxyvitamin D, intact PTH, and calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with nelfinavir. Nelfinavir, which is a cytochrome P450 inhibitor, may inhibit enzymes involved in vitamin D metabolism (CYP24A1 and CYP27B1) and may alter serum concentrations of calcifediol.
Nirmatrelvir; Ritonavir: (Moderate) Dose adjustment of calcifediol may be necessary during coadministration with ritonavir. Additionally, serum 25-hydroxyvitamin D, intact PTH, and calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with ritonavir. Ritonavir, which is a cytochrome P450 inhibitor, may inhibit enzymes involved in vitamin D metabolism (CYP24A1 and CYP27B1) and may alter serum concentrations of calcifediol.
Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum calcium concentrations during concomitant use of thiazide diuretics and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
Olmesartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum calcium concentrations during concomitant use of thiazide diuretics and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Dose adjustment of calcifediol may be necessary during coadministration with ritonavir. Additionally, serum 25-hydroxyvitamin D, intact PTH, and calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with ritonavir. Ritonavir, which is a cytochrome P450 inhibitor, may inhibit enzymes involved in vitamin D metabolism (CYP24A1 and CYP27B1) and may alter serum concentrations of calcifediol.
Orlistat: (Moderate) Orlistat reduced the absorption of fat-soluble vitamins absorption during clinical trials. The bioavailability of orally administered vitamin D analogs may also be decreased. In patients receiving orally-administered vitamin D analogs along with orlistat, close monitoring is recommended. In addition, the manufacturer recommends that fat-soluble vitamin analogs be administered at least 2 hours before or after the administration of orlistat to limit effects on oral absorption.
Paricalcitol: (Major) Withhold calcifediol treatment when using other vitamin D analogs, like paricalcitol, due to the risk of additive toxicity including hypercalcemia, hypercalciuria, and hyperphosphatemia.
Phenytoin: (Moderate) Dose adjustment of calcifediol may be necessary during coadministration with phenytoin. Additionally, serum 25-hydroxyvitamin D, intact PTH, and calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with phenytoin. Phenytoin stimulates microsomal hydroxylation and reduces the half-life of calcifediol. In rare cases, this has caused anticonvulsant-induced rickets and osteomalacia.
Phosphorated Carbohydrate Solution: (Major) High intake of phosphates concomitantly with vitamin D analogs may lead to hyperphosphatemia. Dose adjustment of vitamin D analogs may be necessary during coadministration with phosphorus salts. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia.
Phosphorus: (Major) High intake of phosphates concomitantly with vitamin D analogs may lead to hyperphosphatemia. Dose adjustment of vitamin D analogs may be necessary during coadministration with phosphorus salts. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia.
Polycarbophil: (Moderate) The concurrent use of vitamin D analogs, like calcifediol with calcium polycarbophil may contribute to vitamin D-induced hypercalcemia. Each 625 mg of calcium polycarbophil contains a substantial amount of calcium (approximately 125 mg).
Potassium Phosphate: (Major) High intake of phosphates concomitantly with vitamin D analogs may lead to hyperphosphatemia. Dose adjustment of vitamin D analogs may be necessary during coadministration with phosphorus salts. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia.
Potassium Phosphate; Sodium Phosphate: (Major) High intake of phosphates concomitantly with vitamin D analogs may lead to hyperphosphatemia. Dose adjustment of vitamin D analogs may be necessary during coadministration with phosphorus salts. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia.
Propranolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum calcium concentrations during concomitant use of thiazide diuretics and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
Pyridoxine, Vitamin B6: (Moderate) Monitor serum calcium concentrations during concomitant use of high doses of calcium and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
Quinapril; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum calcium concentrations during concomitant use of thiazide diuretics and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
Ritonavir: (Moderate) Dose adjustment of calcifediol may be necessary during coadministration with ritonavir. Additionally, serum 25-hydroxyvitamin D, intact PTH, and calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with ritonavir. Ritonavir, which is a cytochrome P450 inhibitor, may inhibit enzymes involved in vitamin D metabolism (CYP24A1 and CYP27B1) and may alter serum concentrations of calcifediol.
Saquinavir: (Moderate) Dose adjustment of calcifediol may be necessary during coadministration with saquinavir. Additionally, serum 25-hydroxyvitamin D, intact PTH, and calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with saquinavir. Saquinavir, which is a cytochrome P450 inhibitor, may inhibit enzymes involved in vitamin D metabolism (CYP24A1 and CYP27B1) and may alter serum concentrations of calcifediol.
Sodium Sulfate; Magnesium Sulfate; Potassium Chloride: (Major) Avoid vitamin D analog coadministration with magnesium-containing products, such as antacids, in persons on chronic hemodialysis due to the risk for hypermagnesemia.
Spironolactone; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum calcium concentrations during concomitant use of thiazide diuretics and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
Telmisartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum calcium concentrations during concomitant use of thiazide diuretics and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
Thiazide diuretics: (Moderate) Monitor serum calcium concentrations during concomitant use of thiazide diuretics and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
Triamterene; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum calcium concentrations during concomitant use of thiazide diuretics and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor serum calcium concentrations during concomitant use of thiazide diuretics and vitamin D analogs; a dosage adjustment of the vitamin D analog may be needed. Hypercalcemia may be exacerbated by concomitant administration.
Vonoprazan; Amoxicillin; Clarithromycin: (Moderate) Dose adjustment of calcifediol may be necessary during coadministration with clarithromycin. Additionally, serum 25-hydroxyvitamin D, intact PTH, and calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with clarithromycin. Clarithromycin, which is a cytochrome P450 inhibitor, may inhibit enzymes involved in vitamin D metabolism (CYP24A1 and CYP27B1) and may alter serum concentrations of calcifediol.
Voriconazole: (Moderate) Dose adjustment of calcifediol may be necessary during coadministration with voriconazole. Additionally, serum 25-hydroxyvitamin D, intact PTH, and calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with voriconazole. Voriconazole, which is a cytochrome P450 inhibitor, may inhibit enzymes involved in vitamin D metabolism (CYP24A1 and CYP27B1) and may alter serum concentrations of calcifediol.

PREGNANCY AND LACTATION

There are no adequate and well-controlled studies of calcifediol use in human pregnancy. In animal reproduction studies in rabbits, calcifediol increased skeletal and soft tissue malformation when given in doses of 6 to 13 times the human dose of 60 mcg/day, based on body surface area, during organogenesis. No adverse developmental outcomes were noted in rats given up to 15 times the human dose, based on body surface area, during organogenesis.

There are no data available on the presence of calcifediol in human milk, the effect on the breastfed infant or the effect on milk production. Monitor infants exposed to calcifediol through breast milk for signs and symptoms of hypercalcemia, including seizures, vomiting, constipation, and weight loss. Consider monitoring of serum calcium in the infant. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for calcifediol and any potential adverse effects on the breast-fed infant from calcifediol or the underlying maternal condition.

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 CYP27B1, also called 1-alpha hydroxylase, primarily in the kidneys. 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. Unlike nutritional vitamin D, calcifediol does not require hepatic conversion to correct serum total 25-hydroxyvitamin D concentrations, a process which may be impaired in chronic kidney disease.

PHARMACOKINETICS

Calcifediol is administered orally. Calcifediol is extensively bound to plasma proteins (> 98%). The mean apparent volume of distribution is 8.8 L in healthy subjects following a single oral dose and 30.1 L in subjects with stage 3 or 4 chronic kidney disease following repeated dosing. Calcifediol is converted to calcitriol by the 1-alpha-hydroxylase enzyme, CYP27B1, which is located in the kidney and other tissues. CYP24A1, located in all vitamin D-responsive tissues, catabolizes both calcifediol and calcitriol to inactive metabolites. Excretion of calcifediol primarily occurs through the biliary fecal route. The mean elimination half-life of calcifediol is approximately 11 days in healthy subjects following a single dose and 25 days in patients with stage 3 or 4 chronic kidney disease following repeated once daily dosing. Exposure to calcifediol increased proportionally over the dose range of 30 to 90 mcg following repeated daily administration in subjects with secondary hyperparathyroidism, chronic kidney disease, and vitamin D insufficiency. Steady-state concentrations of serum total 25-hydroxyvitamin D are achieved after approximately 3 months.