DEDROGYL

The major circulating metabolite of vitamin

D3 (cholecalciferol).

It is produced in the liver and is the best indicator of the body's vitamin D stores.

It is effective in the treatment of rickets and osteomalacia, both in azotemic and non-azotemic patients.

Calcifediol also has mineralizing properties.

Used to treat vitamin

D deficiency or insufficiency, refractory rickets (vitamin D resistant rickets), familial hypophosphatemia and hypoparathyroidism, and in the management of hypocalcemia and renal osteodystrophy in patients with chronic renal failure undergoing dialysis.

Also used in conjunction with calcium in the management and prevention of primary or corticosteroid-induced osteoporosis.

Calcidiol is the precursor of vitamin

D3 is a steroid hormone that has long been known for its important role in regulating body levels of calcium and phosphorus, in mineralization of bone, and for the assimilation of vitamin A.

Deficiency in adults leads to the disease osteomalacia.

Both rickets and osteomalacia reflect impaired mineralization of newly synthesized bone matrix, and usually result from a combination of inadequate exposure to sunlight and decreased dietary intake of vitamin D. Common causes of vitamin D deficiency include genetic defects in the vitamin D receptor, severe liver or kidney disease, and insufficient exposure to sunlight.

D plays an important role in maintaining calcium balance and in the regulation of parathyroid hormone (PTH).

It promotes renal reabsorption of calcium, increases intestinal absorption of calcium and phosphorus, and increases calcium and phosphorus mobilization from bone to plasma.

Readily absorbed.

Calcidiol undergoes hydroxylation in the mitochondria of kidney tissue, and this reaction is activated by the renal 25-hydroxyvitamin D3-1-(alpha)-hydroxylase to produce calcitriol (1,25 - dihydroxycholecalciferol), the active form of vitamin D3.

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Bone pain, constipation (especially in children or adolescents), diarrhea, drowsiness, dryness of mouth; headache (continuing), increased thirst, increase in frequency of urination, especially at night, or in amount of urine, irregular heartbeat, itching skin, loss of appetite, metallic taste, muscle pain, nausea or vomiting (especially in children or adolescents), unusual tiredness or weakness.

• The initial dose of RAYALDEE is 30 mcg administered orally once daily at bedtime.

Serum calcium should be below 9.8 mg/dL before initiating treatment.

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

• 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.

• 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. 2.1 Important Dosage and Administration Information.

• Ensure serum calcium is below 9.8 mg/dL before initiating treatment.

• Instruct patients to swallow RAYALDEE capsules whole.

• Instruct patients to skip a missed dose and to resume taking the medicine at the next regularly scheduled time.

Do not administer an extra dose. 2.2 Starting Dose and Dose Titration.

• The initial dose of RAYALDEE is 30 mcg administered orally once daily at bedtime.

• The maintenance dose of RAYALDEE should target serum total 25-hydroxyvitamin D levels between and 100 ng/mL, intact parathyroid hormone (PTH) levels within the desired therapeutic range, serum calcium (corrected for low albumin) within the normal range and serum phosphorus below 5.5 mg/dL.

• Monitor serum calcium, serum phosphorus, serum total 25-hydroxyvitamin D and intact PTH levels at a minimum of 3 months after initiation of therapy or dose adjustment, and subsequently at least every to 12 months.

• Increase the dose to 60 mcg orally once daily at bedtime after approximately 3 months, if intact PTH remains above the desired therapeutic range.

Prior to raising the dose, ensure serum calcium is below 9.8 mg/dL, serum phosphorus is below 5.5 mg/dL and serum total 25-hydroxyvitamin D is below 100 ng/mL.

• Suspend dosing if intact PTH is persistently and abnormally low to reduce the risk of adynamic bone disease, if serum calcium is consistently above the normal range to reduce the risk of hypercalcemia, or if serum total 25-hydroxyvitamin D is consistently above 100 ng/mL.

Restart at a reduced dose after these laboratory values have normalized.

is supplied as 30 mcg calcifediol in blue, oval extended-release soft capsules, imprinted O: Bottles of 30 [ NDC 70301-1001-1 ] Bottles of 60 [ NDC 70301-1001-2 ] RAYALDEE is also supplied as 30 mcg calcifediol in white extended-release two-piece banded hard capsules, imprinted O on the cap and on the body: Bottles of 30 [ NDC 70301-1002-1 ] Bottles of 60 [ NDC 70301-1002-2 ] Store at to 25°C (68 to 77°F); excursions permitted to to 30°C (59 to 86°F) .

There are no human data with calcifediol use in pregnant women to identify a drug-associated risk for major birth defects, miscarriage or adverse maternal or fetal outcomes.

There are risks to the mother and fetus associated with chronic kidney disease in pregnancy.

In animal reproduction studies, calcifediol increased skeletal and soft tissue malformation when rabbits were given once daily oral doses representing ≥8 times the human dose of 60 mcg/day, based on body surface area (mg/m 2 ), during the period of organogenesis.

No adverse developmental effects were observed in rats given up to 10 times the human dose, based on body surface area (mg/m 2 ), during organogenesis.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Disease-associated maternal and/or embryo/fetal risk Chronic kidney disease in pregnancy increases the maternal risk for hypertension, miscarriage, preterm labor, and preeclampsia.

Chronic kidney disease increases the fetal risk for intrauterine growth restriction (IUGR), prematurity, polyhydramnios, still birth, and low birth weight.

Calcifediol was given orally to pregnant rats and rabbits during the period of organogenesis (in rats, from gestation day [GD] 6 to 15; in rabbits, from GD to 18).

Rats were given 0, 12, 40, 60 mcg/kg/day; and rabbits were given 0, 5, 25, 50 mcg/kg/day, representing up to and 16 times, respectively, a human dose of 60 mcg/day, based on body surface area (mg/m 2 ).

In rats, no adverse developmental effects were observed at calcifediol doses up to 60 mcg/kg/day. In rabbits, increased incidences of domed skull, enlarged atrium of the heart, and dilatation of pulmonary artery, were observed at doses of and 50 mcg/kg/day (representing and 16 times the human dose of 60 mcg/day, respectively, based on body surface area (mg/m 2 ).

Rats were given calcifediol during the pre/postnatal period (GD to weaning).

No adverse effects on gestation, parturition, lactation or survival of offspring were observed at calcifediol doses up to 60 mcg/kg/day.

The safety and efficacy of

RAYALDEE have not been established in pediatric patients.

Of the total number of subjects in phase 3 placebo-controlled clinical studies of RAYALDEE, 63% were ≥65 years of age and 22% were ≥75 years of age.

No overall differences in the safety or efficacy of RAYALDEE were observed between subjects older than 65 years and younger subjects.