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  • 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

    For the treatment of secondary hyperparathyroidism in patients with Stage 3 or 4 chronic kidney disease and serum total 25-hydroxyvitamin D levels less than 30 ng/mL.
    NOTE: Calcifediol is not indicated for the treatment of secondary hyperparathyroidism in patients with Stage 5 chronic kidney disease or in patients with end-stage renal disease on dialysis.
    Oral dosage
    Adults

    Initially, 30 mcg PO once daily at bedtime. Serum calcium should be less than 9.8 mg/dL prior to starting treatment. Increase the dose to 60 mcg PO once daily after 3 months if intact parathyroid hormone (iPTH) is above the treatment goal. Ensure serum calcium is less than 9.8 mg/dL, phosphorus is less than 5.5 mg/dL, and serum 25-hydroxyvitamin D is less than 100 ng/mL before increasing the dose. Hold dosing if iPTH is persistently abnormally low to reduce the risk of adynamic bone disease, if serum calcium is above the normal range to reduce the risk of hypercalcemia, or if serum 25-hydroxyvitamin D is consistently more than 100 ng/mL. Restart at a lower dose after these laboratory values normalize.

    MAXIMUM DOSAGE

    Adults

    60 mcg/day PO.

    Geriatric

    60 mcg/day PO.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

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

    Renal Impairment

    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

    Oral Administration
    Oral Solid Formulations

    Swallow capsules whole.

    STORAGE

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

    CONTRAINDICATIONS / PRECAUTIONS

    Cardiac arrhythmias, hypercalcemia, hypercalciuria, hyperphosphatemia, hypervitaminosis D, seizures

    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.

    Bone fractures

    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.

    Dialysis, renal disease

    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.

    Pregnancy

    Calcifediol is a vitamin D analog classified as FDA pregnancy category C. There are no adequate and well-controlled studies of calcifediol in pregnant women. Calcifediol has been shown to be teratogenic in animal studies when given in doses of 8 to 16 times the human dose of 60 mcg/day. Calcifediol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

    Breast-feeding

    According to the manufacturer, caution should be exercised when administering calcifediol to women who are breast-feeding. Limited data show that calcifediol is poorly excreted into breast milk.

    ADVERSE REACTIONS

    Severe

    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

    Moderate

    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

    Mild

    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; Amlodipine; Hydrochlorothiazide, HCTZ: (Major) Dose adjustment of vitamin D analogs may be necessary during coadministration with thiazide diuretics. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia. Hypercalcemia may be exacerbated by coadministration of vitamin D analogs and thiazide diuretics. Thiazide diuretics are known to induce hypercalcemia by reducing the excretion of calcium in the urine.
    Aliskiren; Hydrochlorothiazide, HCTZ: (Major) Dose adjustment of vitamin D analogs may be necessary during coadministration with thiazide diuretics. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia. Hypercalcemia may be exacerbated by coadministration of vitamin D analogs and thiazide diuretics. Thiazide diuretics are known to induce hypercalcemia by reducing the excretion of calcium in the urine.
    Aluminum Hydroxide: (Moderate) The chronic use of aluminum-containing antacids for hyperphosphatemia in conjunction with vitamin D analogs can lead to increased aluminum concentrations and toxicity. This is of primary significance in patients with chronic renal failure. Aluminum hydroxide may be used as a phosphate binder in patients receiving vitamin D analogs. The serum phosphate, calcium and calculated calcium-phosphate product (serum Ca x PO4) should be monitored closely. After initiating vitamin D analog therapy, the dose of phosphate binders should be decreased to correct persistent mild hypercalcemia or increased to correct persistent mild hyperphosphatemia.
    Aluminum Hydroxide; Magnesium Carbonate: (Moderate) The chronic use of aluminum-containing antacids for hyperphosphatemia in conjunction with vitamin D analogs can lead to increased aluminum concentrations and toxicity. This is of primary significance in patients with chronic renal failure. Aluminum hydroxide may be used as a phosphate binder in patients receiving vitamin D analogs. The serum phosphate, calcium and calculated calcium-phosphate product (serum Ca x PO4) should be monitored closely. After initiating vitamin D analog therapy, the dose of phosphate binders should be decreased to correct persistent mild hypercalcemia or increased to correct persistent mild hyperphosphatemia.
    Aluminum Hydroxide; Magnesium Hydroxide: (Moderate) Magnesium-containing antacids, such as magnesium hydroxide, should be used cautiously in patients receiving vitamin D analogs. Because vitamin D analogs can increase serum magnesium concentrations, concomitant use should be avoided, if possible, in patients with chronic renal failure. (Moderate) The chronic use of aluminum-containing antacids for hyperphosphatemia in conjunction with vitamin D analogs can lead to increased aluminum concentrations and toxicity. This is of primary significance in patients with chronic renal failure. Aluminum hydroxide may be used as a phosphate binder in patients receiving vitamin D analogs. The serum phosphate, calcium and calculated calcium-phosphate product (serum Ca x PO4) should be monitored closely. After initiating vitamin D analog therapy, the dose of phosphate binders should be decreased to correct persistent mild hypercalcemia or increased to correct persistent mild hyperphosphatemia.
    Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (Moderate) Magnesium-containing antacids, such as magnesium hydroxide, should be used cautiously in patients receiving vitamin D analogs. Because vitamin D analogs can increase serum magnesium concentrations, concomitant use should be avoided, if possible, in patients with chronic renal failure. (Moderate) The chronic use of aluminum-containing antacids for hyperphosphatemia in conjunction with vitamin D analogs can lead to increased aluminum concentrations and toxicity. This is of primary significance in patients with chronic renal failure. Aluminum hydroxide may be used as a phosphate binder in patients receiving vitamin D analogs. The serum phosphate, calcium and calculated calcium-phosphate product (serum Ca x PO4) should be monitored closely. After initiating vitamin D analog therapy, the dose of phosphate binders should be decreased to correct persistent mild hypercalcemia or increased to correct persistent mild hyperphosphatemia.
    Aluminum Hydroxide; Magnesium Trisilicate: (Moderate) The chronic use of aluminum-containing antacids for hyperphosphatemia in conjunction with vitamin D analogs can lead to increased aluminum concentrations and toxicity. This is of primary significance in patients with chronic renal failure. Aluminum hydroxide may be used as a phosphate binder in patients receiving vitamin D analogs. The serum phosphate, calcium and calculated calcium-phosphate product (serum Ca x PO4) should be monitored closely. After initiating vitamin D analog therapy, the dose of phosphate binders should be decreased to correct persistent mild hypercalcemia or increased to correct persistent mild hyperphosphatemia.
    Amiloride; Hydrochlorothiazide, HCTZ: (Major) Dose adjustment of vitamin D analogs may be necessary during coadministration with thiazide diuretics. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia. Hypercalcemia may be exacerbated by coadministration of vitamin D analogs and thiazide diuretics. Thiazide diuretics are known to induce hypercalcemia by reducing the excretion of calcium in the urine.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Major) Dose adjustment of vitamin D analogs may be necessary during coadministration with thiazide diuretics. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia. Hypercalcemia may be exacerbated by coadministration of vitamin D analogs and thiazide diuretics. Thiazide diuretics are known to induce hypercalcemia by reducing the excretion of calcium in the urine.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Major) Dose adjustment of vitamin D analogs may be necessary during coadministration with thiazide diuretics. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia. Hypercalcemia may be exacerbated by coadministration of vitamin D analogs and thiazide diuretics. Thiazide diuretics are known to induce hypercalcemia by reducing the excretion of calcium in the urine.
    Amoxicillin; Clarithromycin; Lansoprazole: (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.
    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: (Major) Dose adjustment of vitamin D analogs may be necessary during coadministration with thiazide diuretics. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia. Hypercalcemia may be exacerbated by coadministration of vitamin D analogs and thiazide diuretics. Thiazide diuretics are known to induce hypercalcemia by reducing the excretion of calcium in the urine.
    Azilsartan; Chlorthalidone: (Major) Dose adjustment of vitamin D analogs may be necessary during coadministration with thiazide diuretics. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia. Hypercalcemia may be exacerbated by coadministration of vitamin D analogs and thiazide diuretics. Thiazide diuretics are known to induce hypercalcemia by reducing the excretion of calcium in the urine.
    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: (Major) Dose adjustment of vitamin D analogs may be necessary during coadministration with thiazide diuretics. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia. Hypercalcemia may be exacerbated by coadministration of vitamin D analogs and thiazide diuretics. Thiazide diuretics are known to induce hypercalcemia by reducing the excretion of calcium in the urine.
    Bendroflumethiazide; Nadolol: (Major) Dose adjustment of vitamin D analogs may be necessary during coadministration with thiazide diuretics. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia. Hypercalcemia may be exacerbated by coadministration of vitamin D analogs and thiazide diuretics. Thiazide diuretics are known to induce hypercalcemia by reducing the excretion of calcium in the urine.
    Bisoprolol; Hydrochlorothiazide, HCTZ: (Major) Dose adjustment of vitamin D analogs may be necessary during coadministration with thiazide diuretics. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia. Hypercalcemia may be exacerbated by coadministration of vitamin D analogs and thiazide diuretics. Thiazide diuretics are known to induce hypercalcemia by reducing the excretion of calcium in the urine.
    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 Carbonate: (Moderate) Dose adjustment of vitamin D analogs may be necessary during coadministration with calcium salts. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia. Hypercalcemia may be exacerbated by coadministration of vitamin D analogs and high doses of calcium-containing salts.
    Calcium Carbonate; Magnesium Hydroxide: (Moderate) Dose adjustment of vitamin D analogs may be necessary during coadministration with calcium salts. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia. Hypercalcemia may be exacerbated by coadministration of vitamin D analogs and high doses of calcium-containing salts. (Moderate) Magnesium-containing antacids, such as magnesium hydroxide, should be used cautiously in patients receiving vitamin D analogs. Because vitamin D analogs can increase serum magnesium concentrations, concomitant use should be avoided, if possible, in patients with chronic renal failure.
    Calcium Carbonate; Risedronate: (Moderate) Dose adjustment of vitamin D analogs may be necessary during coadministration with calcium salts. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia. Hypercalcemia may be exacerbated by coadministration of vitamin D analogs and high doses of calcium-containing salts.
    Calcium Salts: (Moderate) Dose adjustment of vitamin D analogs may be necessary during coadministration with calcium salts. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia. Hypercalcemia may be exacerbated by coadministration of vitamin D analogs and high doses of calcium-containing salts.
    Calcium: (Moderate) Dose adjustment of vitamin D analogs may be necessary during coadministration with calcium salts. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia. Hypercalcemia may be exacerbated by coadministration of vitamin D analogs and high doses of calcium-containing salts.
    Calcium; Vitamin D: (Moderate) Dose adjustment of vitamin D analogs may be necessary during coadministration with calcium salts. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia. Hypercalcemia may be exacerbated by coadministration of vitamin D analogs and high doses of calcium-containing salts.
    Candesartan; Hydrochlorothiazide, HCTZ: (Major) Dose adjustment of vitamin D analogs may be necessary during coadministration with thiazide diuretics. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia. Hypercalcemia may be exacerbated by coadministration of vitamin D analogs and thiazide diuretics. Thiazide diuretics are known to induce hypercalcemia by reducing the excretion of calcium in the urine.
    Captopril; Hydrochlorothiazide, HCTZ: (Major) Dose adjustment of vitamin D analogs may be necessary during coadministration with thiazide diuretics. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia. Hypercalcemia may be exacerbated by coadministration of vitamin D analogs and thiazide diuretics. Thiazide diuretics are known to induce hypercalcemia by reducing the excretion of calcium in the urine.
    Chlorothiazide: (Major) Dose adjustment of vitamin D analogs may be necessary during coadministration with thiazide diuretics. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia. Hypercalcemia may be exacerbated by coadministration of vitamin D analogs and thiazide diuretics. Thiazide diuretics are known to induce hypercalcemia by reducing the excretion of calcium in the urine.
    Chlorthalidone: (Major) Dose adjustment of vitamin D analogs may be necessary during coadministration with thiazide diuretics. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia. Hypercalcemia may be exacerbated by coadministration of vitamin D analogs and thiazide diuretics. Thiazide diuretics are known to induce hypercalcemia by reducing the excretion of calcium in the urine.
    Chlorthalidone; Clonidine: (Major) Dose adjustment of vitamin D analogs may be necessary during coadministration with thiazide diuretics. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia. Hypercalcemia may be exacerbated by coadministration of vitamin D analogs and thiazide diuretics. Thiazide diuretics are known to induce hypercalcemia by reducing the excretion of calcium in the urine.
    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) Dose adjustment of vitamin D analogs may be necessary during coadministration with calcium salts. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia. Hypercalcemia may be exacerbated by coadministration of vitamin D analogs and high doses of calcium-containing salts.
    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.
    Collagenase: (Moderate) Dose adjustment of vitamin D analogs may be necessary during coadministration with calcium salts. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia. Hypercalcemia may be exacerbated by coadministration of vitamin D analogs and high doses of calcium-containing salts.
    Cyanocobalamin, Vitamin B12: (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. (Moderate) Dose adjustment of vitamin D analogs may be necessary during coadministration with calcium salts. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia. Hypercalcemia may be exacerbated by coadministration of vitamin D analogs and high doses of calcium-containing salts.
    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: (Major) Dose adjustment of vitamin D analogs may be necessary during coadministration with thiazide diuretics. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia. Hypercalcemia may be exacerbated by coadministration of vitamin D analogs and thiazide diuretics. Thiazide diuretics are known to induce hypercalcemia by reducing the excretion of calcium in the urine.
    Eprosartan; Hydrochlorothiazide, HCTZ: (Major) Dose adjustment of vitamin D analogs may be necessary during coadministration with thiazide diuretics. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia. Hypercalcemia may be exacerbated by coadministration of vitamin D analogs and thiazide diuretics. Thiazide diuretics are known to induce hypercalcemia by reducing the excretion of calcium in the urine.
    Fosinopril; Hydrochlorothiazide, HCTZ: (Major) Dose adjustment of vitamin D analogs may be necessary during coadministration with thiazide diuretics. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia. Hypercalcemia may be exacerbated by coadministration of vitamin D analogs and thiazide diuretics. Thiazide diuretics are known to induce hypercalcemia by reducing the excretion of calcium in the urine.
    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.
    Hetastarch; Dextrose; Electrolytes: (Moderate) Dose adjustment of vitamin D analogs may be necessary during coadministration with calcium salts. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia. Hypercalcemia may be exacerbated by coadministration of vitamin D analogs and high doses of calcium-containing salts. (Moderate) Magnesium-containing drug products should be used cautiously in patients receiving vitamin D analogs. Because vitamin D analogs can increase serum magnesium concentrations, the combined use of vitamin D analogs and magnesium-containing drug products should be avoided, if possible, in patients with chronic renal failure.
    Hydralazine; Hydrochlorothiazide, HCTZ: (Major) Dose adjustment of vitamin D analogs may be necessary during coadministration with thiazide diuretics. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia. Hypercalcemia may be exacerbated by coadministration of vitamin D analogs and thiazide diuretics. Thiazide diuretics are known to induce hypercalcemia by reducing the excretion of calcium in the urine.
    Hydrochlorothiazide, HCTZ: (Major) Dose adjustment of vitamin D analogs may be necessary during coadministration with thiazide diuretics. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia. Hypercalcemia may be exacerbated by coadministration of vitamin D analogs and thiazide diuretics. Thiazide diuretics are known to induce hypercalcemia by reducing the excretion of calcium in the urine.
    Hydrochlorothiazide, HCTZ; Irbesartan: (Major) Dose adjustment of vitamin D analogs may be necessary during coadministration with thiazide diuretics. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia. Hypercalcemia may be exacerbated by coadministration of vitamin D analogs and thiazide diuretics. Thiazide diuretics are known to induce hypercalcemia by reducing the excretion of calcium in the urine.
    Hydrochlorothiazide, HCTZ; Lisinopril: (Major) Dose adjustment of vitamin D analogs may be necessary during coadministration with thiazide diuretics. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia. Hypercalcemia may be exacerbated by coadministration of vitamin D analogs and thiazide diuretics. Thiazide diuretics are known to induce hypercalcemia by reducing the excretion of calcium in the urine.
    Hydrochlorothiazide, HCTZ; Losartan: (Major) Dose adjustment of vitamin D analogs may be necessary during coadministration with thiazide diuretics. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia. Hypercalcemia may be exacerbated by coadministration of vitamin D analogs and thiazide diuretics. Thiazide diuretics are known to induce hypercalcemia by reducing the excretion of calcium in the urine.
    Hydrochlorothiazide, HCTZ; Methyldopa: (Major) Dose adjustment of vitamin D analogs may be necessary during coadministration with thiazide diuretics. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia. Hypercalcemia may be exacerbated by coadministration of vitamin D analogs and thiazide diuretics. Thiazide diuretics are known to induce hypercalcemia by reducing the excretion of calcium in the urine.
    Hydrochlorothiazide, HCTZ; Metoprolol: (Major) Dose adjustment of vitamin D analogs may be necessary during coadministration with thiazide diuretics. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia. Hypercalcemia may be exacerbated by coadministration of vitamin D analogs and thiazide diuretics. Thiazide diuretics are known to induce hypercalcemia by reducing the excretion of calcium in the urine.
    Hydrochlorothiazide, HCTZ; Moexipril: (Major) Dose adjustment of vitamin D analogs may be necessary during coadministration with thiazide diuretics. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia. Hypercalcemia may be exacerbated by coadministration of vitamin D analogs and thiazide diuretics. Thiazide diuretics are known to induce hypercalcemia by reducing the excretion of calcium in the urine.
    Hydrochlorothiazide, HCTZ; Olmesartan: (Major) Dose adjustment of vitamin D analogs may be necessary during coadministration with thiazide diuretics. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia. Hypercalcemia may be exacerbated by coadministration of vitamin D analogs and thiazide diuretics. Thiazide diuretics are known to induce hypercalcemia by reducing the excretion of calcium in the urine.
    Hydrochlorothiazide, HCTZ; Propranolol: (Major) Dose adjustment of vitamin D analogs may be necessary during coadministration with thiazide diuretics. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia. Hypercalcemia may be exacerbated by coadministration of vitamin D analogs and thiazide diuretics. Thiazide diuretics are known to induce hypercalcemia by reducing the excretion of calcium in the urine.
    Hydrochlorothiazide, HCTZ; Quinapril: (Major) Dose adjustment of vitamin D analogs may be necessary during coadministration with thiazide diuretics. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia. Hypercalcemia may be exacerbated by coadministration of vitamin D analogs and thiazide diuretics. Thiazide diuretics are known to induce hypercalcemia by reducing the excretion of calcium in the urine.
    Hydrochlorothiazide, HCTZ; Spironolactone: (Major) Dose adjustment of vitamin D analogs may be necessary during coadministration with thiazide diuretics. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia. Hypercalcemia may be exacerbated by coadministration of vitamin D analogs and thiazide diuretics. Thiazide diuretics are known to induce hypercalcemia by reducing the excretion of calcium in the urine.
    Hydrochlorothiazide, HCTZ; Telmisartan: (Major) Dose adjustment of vitamin D analogs may be necessary during coadministration with thiazide diuretics. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia. Hypercalcemia may be exacerbated by coadministration of vitamin D analogs and thiazide diuretics. Thiazide diuretics are known to induce hypercalcemia by reducing the excretion of calcium in the urine.
    Hydrochlorothiazide, HCTZ; Triamterene: (Major) Dose adjustment of vitamin D analogs may be necessary during coadministration with thiazide diuretics. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia. Hypercalcemia may be exacerbated by coadministration of vitamin D analogs and thiazide diuretics. Thiazide diuretics are known to induce hypercalcemia by reducing the excretion of calcium in the urine.
    Hydrochlorothiazide, HCTZ; Valsartan: (Major) Dose adjustment of vitamin D analogs may be necessary during coadministration with thiazide diuretics. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia. Hypercalcemia may be exacerbated by coadministration of vitamin D analogs and thiazide diuretics. Thiazide diuretics are known to induce hypercalcemia by reducing the excretion of calcium in the urine.
    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.
    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.
    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.
    Magnesium Citrate: (Moderate) Magnesium-containing drug products, such as magnesium citrate, should be used cautiously in patients receiving vitamin D analogs. Because vitamin D analogs can increase serum magnesium concentrations, the combined use of vitamin D analogs and magnesium-containing drug products should be avoided, if possible, in patients with chronic renal failure.
    Magnesium Hydroxide: (Moderate) Magnesium-containing antacids, such as magnesium hydroxide, should be used cautiously in patients receiving vitamin D analogs. Because vitamin D analogs can increase serum magnesium concentrations, concomitant use should be avoided, if possible, in patients with chronic renal failure.
    Magnesium Salts: (Moderate) Magnesium-containing drug products should be used cautiously in patients receiving vitamin D analogs. Because vitamin D analogs can increase serum magnesium concentrations, the combined use of vitamin D analogs and magnesium-containing drug products should be avoided, if possible, in patients with chronic renal failure.
    Magnesium: (Moderate) Magnesium-containing drug products should be used cautiously in patients receiving vitamin D analogs. Because vitamin D analogs can increase serum magnesium concentrations, the combined use of vitamin D analogs and magnesium-containing drug products should be avoided, if possible, in patients with chronic renal failure.
    Methyclothiazide: (Major) Dose adjustment of vitamin D analogs may be necessary during coadministration with thiazide diuretics. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia. Hypercalcemia may be exacerbated by coadministration of vitamin D analogs and thiazide diuretics. Thiazide diuretics are known to induce hypercalcemia by reducing the excretion of calcium in the urine.
    Metolazone: (Major) Dose adjustment of vitamin D analogs may be necessary during coadministration with thiazide diuretics. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia. Hypercalcemia may be exacerbated by coadministration of vitamin D analogs and thiazide diuretics. Thiazide diuretics are known to induce hypercalcemia by reducing the excretion of calcium in the urine.
    Mineral Oil: (Moderate) Absorption of fat-soluble vitamins is reported to be decreased with prolonged oral administration of mineral oil. The bioavailability of orally administered vitamin D analogs may also be decreased. However, despite warnings in various texts, there is little direct evidence that the interaction is of practical/clinical importance with limited use as directed. It may be prudent for those taking Vitamin D analogs to separate administration by 1 hour before or 4 hours after a mineral oil oral dosage to help limit absorption interactions. Theoretically, the effect on fat-soluble vitamin absorption may more likely occur with prolonged or chronic administration of mineral oil.
    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.
    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.
    Pantothenic Acid, Vitamin B5: (Moderate) Dose adjustment of vitamin D analogs may be necessary during coadministration with calcium salts. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia. Hypercalcemia may be exacerbated by coadministration of vitamin D analogs and high doses of calcium-containing salts.
    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 Salts: (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; 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.
    Pyridoxine, Vitamin B6: (Moderate) Dose adjustment of vitamin D analogs may be necessary during coadministration with calcium salts. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia. Hypercalcemia may be exacerbated by coadministration of vitamin D analogs and high doses of calcium-containing salts.
    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.
    Telithromycin: (Moderate) Dose adjustment of calcifediol may be necessary during coadministration with telithromycin. Additionally, serum 25-hydroxyvitamin D, intact PTH, and calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with telithromycin. Telithromycin, which is a cytochrome P450 inhibitor, may inhibit enzymes involved in vitamin D metabolism (CYP24A1 and CYP27B1) and may alter serum concentrations of calcifediol.
    Thiazide diuretics: (Major) Dose adjustment of vitamin D analogs may be necessary during coadministration with thiazide diuretics. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia. Hypercalcemia may be exacerbated by coadministration of vitamin D analogs and thiazide diuretics. Thiazide diuretics are known to induce hypercalcemia by reducing the excretion of calcium in the urine.
    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.
    Zinc Salts: (Moderate) Dose adjustment of vitamin D analogs may be necessary during coadministration with calcium salts. Additionally, serum calcium concentrations should be monitored frequently. Monitor more frequently in patients with a history of hypercalcemia. Hypercalcemia may be exacerbated by coadministration of vitamin D analogs and high doses of calcium-containing salts.

    PREGNANCY AND LACTATION

    Pregnancy

    Calcifediol is a vitamin D analog classified as FDA pregnancy category C. There are no adequate and well-controlled studies of calcifediol in pregnant women. Calcifediol has been shown to be teratogenic in animal studies when given in doses of 8 to 16 times the human dose of 60 mcg/day. Calcifediol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

    According to the manufacturer, caution should be exercised when administering calcifediol to women who are breast-feeding. Limited data show that calcifediol is poorly excreted into breast milk.

    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.

    Oral Route

    Food effect studies were not conducted with calcifediol at the recommended doses of 30 mcg and 60 mcg; however, when a supratherapeutic dose of calcifediol (450 mcg) was given to healthy subjects, an approximately 5-fold increase in maximum serum calcifediol concentration and a 3.5-fold increase in AUC were observed when administered with a high fat, high calorie meal compared to fasting.