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    Vitamin D Supplements

    DEA CLASS

    OTC, Rx

    DESCRIPTION

    A form of vitamin D; cholecalciferol is vitamin D3
    Found in fortified milk and cereal products, fish, liver, and egg yolks
    Used for prevention and treatment of vitamin D deficiency and rickets

    COMMON BRAND NAMES

    Calcidol, Calciferol, Deltalin, Drisdol, Ergo D

    HOW SUPPLIED

    Deltalin/Drisdol/Ergo D/Ergocalciferol Oral Cap: 1.25mg

    DOSAGE & INDICATIONS

    For nutritional supplementation of vitamin D based on recommended dietary reference intakes.
    NOTE: Patients with increased risk for deficiency of vitamin D (e.g., cystic fibrosis and other conditions causing chronic fat malabsorption, patients with chronic kidney disease, patients with HIV, or patients taking certain enzyme-inducing medications, etc.) may require higher supplemental doses than those recommended for healthy individuals to maintain normal vitamin D status. In such persons, 25(OH)D concentrations can be used to guide adequate dietary supplementation.
    Oral dosage
    Adults and Geriatrics 18 to 70 years

    15 mcg/day (600 International Units/day) PO is the RDA for vitamin D in adults and elderly up to 70 years of age.

    Geriatrics older than 70 years

    20 mcg/day (800 International Units/day) PO is the RDA for vitamin D in elderly older than 70 years of age.[52900]

    Adolescents

    15 mcg/day (600 International Units/day) PO is the RDA for vitamin D in adolescents. The AAP recommends 10 mcg/day (400 International Units/day) PO if the adolescent is not obtaining at least 10 mcg (400 International Units) PO through dietary sources. All dietary sources of vitamin D (e.g., fortified milk, eggs, other food) may be included in determining the daily intake.

    Children

    15 mcg/day (600 International Units/day) PO is the RDA for vitamin D in children. The AAP recommends 10 mcg/day (400 International Units/day) PO if the child is consuming less than 1,000 mL/day of vitamin D-fortified milk.

    Neonates and Infants

    10 mcg/day (400 International Units/day) PO beginning within the first few days of life is considered Adequate Intake (AI). RDAs have not been established for infants.[52900] Infants that are exclusively breast-fed without vitamin D supplements are at increased risk for deficiency of vitamin D. Because most exclusively formula-fed infants ingest nearly 1,000 mL/day of formula after the first month of life, they will achieve a vitamin D intake of 10 mcg/day (400 International Units/day). Infants who receive a mixture of human milk and formula should get a vitamin D supplement of 10 mcg/day (400 International Units/day) to ensure the AI value. As infants are weaned from human milk and/or formula, intake of vitamin D-fortified milk should be encouraged to provide at least 10 mcg/day (400 International Units/day) of vitamin D.[36895] Vitamin D supplementation should continue until the infant consumes at least 1,000 mL per day (1 quart per day) of vitamin D-fortified milk (Whole milk [cow's milk] is not recommended until after 12 months of age).

    Premature neonates weighing 1.5 kg or more

    10 mcg/day (400 International Units/day) PO is recommended by AAP. The Adequate Intake (AI) recommendation is 10 mcg/day (400 International Units/day) PO. There does not appear to be any benefit to intake of vitamin D doses more than 400 International Units/day in preterm infants.

    Premature neonates weighing less than 1.5 kg

    5 to 10 mcg/day (200 to 400 International Units/day) PO is recommended by AAP. If the infant is receiving less than 10 mcg/day (400 International Units/day), increase the dosage to 10 mcg/day (400 International Units/day) when a weight of more than 1.5 kg is reached and full enteral nutrition is tolerated. The Adequate Intake (AI) recommendation for neonates and infants 0 to 6 months is 10 mcg/day (400 International Units/day) PO; a recommended AI for premature neonates is not specified. Premature infants younger than 32 weeks gestational age and less than 1.25 kg who received a high-mineral containing cow milk based formula and daily vitamin D supplements of about 10 mcg (400 International Units) maintained normal serum 25-hydroxyvitamin D concentrations. There does not appear to be any benefit to intake of vitamin D doses more than 10 mcg/day (400 International Units/day) in preterm infants.

    For the treatment of vitamin D deficiency.
    NOTE: In adults, the Institute of Medicine (IOM) defines vitamin D deficiency as 25(OH)D concentrations of 30 nmol/L or less (12 ng/mL or less) and vitamin D insufficiency as 25(OH)D concentrations of 30 to 50 nmol/L (12 to less than 20 ng/mL). Generally all persons are sufficient at levels of 50 nmol/L or more (20 ng/mL or more). In pediatric patients, the American Academy of Pediatrics (AAP) and the IOM define vitamin D deficiency as 25(OH)D concentrations of 37.5 nmol/L or less (15 ng/mL or less) and vitamin D insufficiency as 25(OH)D concentrations of 50 nmol/L or less (20 ng/mL or less). The Endocrine Society and the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines both define insufficiency as 25(OH)D concentrations less than 75 nmol/L (less than 30 ng/mL); the Endocrine Society defines deficiency as 25(OH)D concentrations less than 50 nmol/L (less than 20 ng/mL) while the KDOQI defines deficiency as 25(OH)D concentrations less than 37.5 nmol/L (less than 15 ng/mL).
    NOTE: Patients with vitamin D deficiency due to GI or liver diseases (e.g., cystic fibrosis, cholestatic liver disease, celiac disease, gastric or small bowel resection, etc.), chronic kidney disease, HIV, or concomitant medications (e.g., anti-convulsants, corticosteroids, rifampin, etc.) may require higher doses and/or different treatment strategies.
    For the treatment of vitamin D deficiency in cystic fibrosis patients.
    Oral dosage
    Adults

    20 mcg/day (800 International Units/day) PO has been recommended by the Cystic Fibrosis Foundation; however, these doses may not maintain serum vitamin D concentrations in an adequate range. Therefore, maintenance doses up to 1,250 mcg (50,000 International Units) PO weekly or biweekly may be necessary to achieve target vitamin D concentrations.

    Children and Adolescents 5 to 17 years

    Initial doses up to 1,250 mcg (50,000 International Units) PO daily for several weeks or months may be necessary. A maintenance dose of 20 mcg/day (800 International Units/day) PO has been recommended by the Cystic Fibrosis Foundation; however, these doses may not maintain serum vitamin D concentrations in an adequate range. Therefore, maintenance doses up to 1,250 mcg (50,000 International Units) PO weekly or biweekly may be necessary to achieve target vitamin D concentrations.

    Infants and Children 1 to 4 years

    Initial doses up to 1,250 mcg (50,000 International Units) PO daily for several weeks or months may be necessary. A maintenance dose of 10 mcg/day (400 International Units/day) PO for infants and 20 mcg/day (800 International Units/day) PO for children older than 1 year has been recommended by the Cystic Fibrosis Foundation; however, these doses may not maintain serum vitamin D concentrations in an adequate range. Therefore, maintenance doses up to 300 mcg (12,000 International Units) PO weekly or biweekly may be necessary to achieve target vitamin D concentrations.

    For the treatment of vitamin D deficiency in patients with chronic kidney disease.
    NOTE: Recommendations are for adults with CKD Stages 3 to 4 and children with CKD Stages 2 to 4. Ergocalciferol (vitamin D2) is the preferred supplement in patients with CKD; however, cholecalciferol (vitamin D3) is considered an acceptable alternative.
    Oral dosage
    Adults with 25(OH)D less than 5 ng/mL

    1,250 mcg (50,000 International Units) PO weekly for 12 weeks, then 1,250 mcg (50,000 International Units) PO monthly for total duration of 6 months.[28125]

    Adults with 25(OH)D 5 to 15 ng/mL

    1,250 mcg (50,000 International Units) PO weekly for 4 weeks, then 1,250 mcg (50,000 International Units) PO monthly for total duration of 6 months.

    Adults with 25(OH)D 16 to 30 ng/mL

    1,250 mcg (50,000 International Units) PO monthly for 6 months.

    Infants, Children, and Adolescents with 25(OH)D less than 5 ng/mL

    Initial dose of 200 mcg (8,000 International Units) PO daily or 1,250 mcg (50,000 International Units) PO once weekly for 4 weeks, then 100 mcg (4,000 International Units) PO daily or 1,250 mcg (50,000 International Units) PO twice monthly for 2 months.[59376]

    Infants, Children, and Adolescents with 25(OH)D 5 to 15 ng/mL

    100 mcg (4,000 International Units) PO daily or 1,250 mcg (50,000 International Units) PO every other week for 3 months.

    Infants, Children, and Adolescents with 25(OH)D 16 to 30 ng/mL

    50 mcg (2,000 International Units) PO daily or 1,250 mcg (50,000 International Units) PO every 4 weeks for 3 months.

    Oral dosage
    Adults

    25 to 50 mcg (1,000 to 2,000 International Units) PO once daily. Short term use of doses up to 1,250 mcg (50,000 International Units) PO once weekly for 6 weeks have been studied. The dosage should be individualized and dependent on the clinical condition of the patient, serum 25(OH)D concentrations, and serum calcium concentrations. In malabsorption syndromes, significantly higher doses may be required; treatment with an oral active vitamin D sterol such as calcitriol may be considered.

    Children and Adolescents

    At least 125 mcg (5,000 International Units) PO once daily has been recommended to treat deficiency. High doses have been used: 225 to 250 mcg/day (9,000 to 10,000 International Units/day) or 5 to 7 mcg/kg/day (200 to 280 International Units/kg/day) PO. Also, weekly regimens (with higher doses once weekly or as a single course over 1 to 5 days) are occasionally used if compliance is an issue that prevents adequate repletion. One study demonstrated that 50 mcg/day (2,000 International Units/day) PO OR 1,250 mcg (50,000 International Units) PO once weekly resulted in equivalent outcomes in the short-term treatment of hypovitaminosis D among otherwise healthy toddlers 12 to 24 months of age, and appeared to be safe. Treatment may continue for 2 to 3 months to replete deficient stores, followed by maintenance dosing in accordance with RDAs. Individualize dose based upon 25(OH)D concentrations.

    Infants

    25 to 125 mcg (1,000 to 5,000 International Units) PO once daily has been recommended to treat deficiency. One study demonstrated that 50 mcg/day (2,000 International Units/day) PO OR 1,250 mcg (50,000 International Units) PO once weekly resulted in equivalent outcomes in the short-term treatment of hypovitaminosis D among otherwise healthy infants 8 months of age and older, and appeared to be safe. Treatment may continue for 2 to 3 months to replete deficient stores, followed by maintenance dosing in accordance with RDAs. Individualize dose based upon 25(OH)D concentrations.

    Neonates

    25 mcg (1,000 International Units) PO once daily has been recommended to treat deficiency. Treatment may continue for 2 to 3 months to replete deficient stores, followed by maintenance dosing in accordance with RDAs. Individualize dose based upon 25(OH)D concentrations.

    For the treatment of nutritional rickets.
    Oral dosage
    Children and Adolescents

    Typical dose ranges are 50 to 500 mcg (2,000 to 20,000 International Units) PO daily for 4 to 8 weeks, with the duration of treatment determined by evidence of radiologic healing. Thereafter, supplementation according to the RDA occurs for maintenance. Alternatively, at least 125 mcg (5,000 International Units) PO once daily has also been recommended for initial treatment; weekly regimens (e.g., high doses, such as 1,250 mcg [50,000 International Units] PO once weekly) or a single higher-dose course over 1 to 5 days may be considered if compliance is an issue that prevents adequate repletion. Large single dose regimens (5,000 to 15,000 mcg [200,000 to 600,000 International Units] PO divided into 2 to 4 doses administered over 1 day) have been used when compliance is a concern, but are controversial due to a purported risk for hypercalcemia. It is important to ensure adequate dietary intake of calcium and phosphorus. Active treatment may continue for 2 to 3 months to replete deficient stores, followed by maintenance dosing in accordance with RDAs. Individualize dose based upon 25(OH)D concentrations.

    Infants

    25 to 125 mcg (1,000 to 5,000 International Units) PO once daily has been recommended. Radiologic evidence of healing is usually observed in 2 to 4 weeks, and the active treatment duration is usually 2 to 3 months, after which the supplementation may be reduced to maintenance dosing in accordance with RDAs to prevent further deficiency. Supplementation with calcium is necessary due to the risk of hypocalcemia during bone remineralization. It is important to ensure adequate dietary intake of calcium and phosphorus. Weekly regimens (e.g., high doses, such as 1,250 mcg [50,000 International Units] PO once weekly) have been considered in older infants if compliance is an issue that prevents adequate repletion. Individualize dose based upon 25(OH)D concentrations.

    Neonates

    25 mcg (1,000 International Units) PO once daily has been recommended. Radiologic evidence of healing is usually observed in 2 to 4 weeks, and the active treatment duration is usually 2 to 3 months, after which the supplementation may be reduced to maintenance dosing in accordance with RDAs to prevent further deficiency. Supplementation with calcium is necessary due to the risk of hypocalcemia during bone remineralization. It is important to ensure adequate dietary intake of calcium and phosphorus. Individualize dose based upon 25(OH)D concentrations.

    For the treatment of Hereditary 1,25-Dihydroxyvitamin D Resistant Rickets (HVDRR), also known as hereditary vitamin D resistant rickets type 2.
    Oral dosage
    Children and Adolescents

    Treatment for HVDRR is not standardized. Despite significant improvements in vitamin D concentrations following high-dose ergocalciferol (or a vitamin D analog like calcitriol) alone, patients may remain hypocalcemic and hypophosphatemic. High doses of ergocalciferol (vitamin D2) have been used in these patients. The following regimens have been used with variable results: 100 to 1,000 mcg/day (4,000 to 40,000 International Units/day) PO or 5 to 7 mcg/kg/day (200 to 280 International Units/kg/day) PO. However, doses as high as 5,000 mcg/day (200,000 International Units/day) PO have not been effective in improving the disease in other patients. Patients should receive a 3 to 6 month trial of high dose vitamin D along with high-dose calcium therapy. Patients without alopecia appear more likely to respond. Individualize dose based upon 25(OH)D concentrations.

    For the treatment of familial hypocholesterolemia (e.g., abetalipoproteinemia, hypobetalipoproteinemia, and chylomicron retention disease, CRD).
    Oral dosage
    Infants, Children, and Adolescents

    20 to 30 mcg (800 to 1,200 International Units) PO daily has been recommended. If Vitamin D supplementation is started early, it prevents development of osteopenia in these patients. Alternative regimens for children 1 to 5 years of age are 2,500 mcg (100,000 International Units) PO once every 2 months; if older than 5 years of age, then 15,000 mcg (600,000 International Units) PO once every 2 months may be used.

    For the treatment and prevention of osteoporosis† in conjunction with calcium supplementation.
    For the prevention and treatment of glucocorticoid-induced osteoporosis†.
    NOTE: The American College of Rheumatology recommends supplementation of vitamin D and calcium in all patients receiving corticosteroid therapy, especially if treatment duration will exceed 3 months.
    Oral dosage
    Adults

    20 mcg (800 International Units) PO daily.

    Children and Adolescents

    20 mcg (800 International Units) PO daily.

    Oral dosage
    Adults

    17.5 to 20 mcg (700 to 800 International Units) PO once daily; alternatively, 250 mcg (10,000 International Units) PO administered once every four months. Supplementation regimen should include calcium for greatest benefit.[31561] [31562] [36896] Higher doses may be necessary, short-term, to correct a deficiency of vitamin D.

    For the prevention of premenstrual syndrome (PMS)†.
    Oral dosage
    Adult females

    A mean total dose of 17.5 mcg (700 International Units) PO daily from a combination of dietary and non-dietary sources has been found to be beneficial. In a population-based study of 3,025 females, the daily vitamin D (specific form not identified) and calcium intake was followed to determine if vitamin D or calcium had an impact on the risk of developing PMS. Women with the highest intake of vitamin D from both dietary sources and supplements (median 17.7 mcg [706 International Units] daily) had a reduced risk of developing PMS compared with those women with the lowest intake of vitamin D of 2.8 mcg (112 International Units) daily (RR of 0.59, 95% CI 0.4 to 0.86, p = 0.01 for the trend).[31641]

    For the treatment of hypoparathyroidism† with calcium supplementation.
    Oral dosage
    Adults

    1,250 to 5,000 mcg (50,000 to 200,000 International Units) PO once daily in combination with calcium supplementation. This dosing recommendation is based on ergocalciferol (vitamin D2); the dosing is expected to be the same for cholecalciferol (vitamin D3).

    Children and Adolescents

    1,250 to 5,000 mcg (50,000 to 200,000 International Units) PO once daily in combination with calcium supplementation. This dosing recommendation is based on ergocalciferol (vitamin D2); the dosing is expected to be the same for cholecalciferol (vitamin D3).

    For the treatment of secondary hyperparathyroidism and resultant bone disease (renal osteodystrophy†).
    Oral dosage
    Adults with 25(OH)D concentration less than 5 ng/mL

    1,250 mcg (50,000 International Units) PO once weekly for 12 weeks, then once monthly for a total of 6 months. The range between therapeutic and toxic doses is narrow and monitoring is required. If condition remains unresponsive to escalating doses of cholecalciferol, treatment with an oral active vitamin D analog such as calcitriol or doxercalciferol should be considered.[28125]

    Adults with 25(OH)D concentration 5 to 15 ng/mL

    1,250 mcg (50,000 International Units) PO once weekly for 4 weeks, then once monthly for a total of 6 months. The range between therapeutic and toxic doses is narrow and monitoring is required. If condition remains unresponsive to escalating doses of cholecalciferol, treatment with an oral active vitamin D analog such as calcitriol or doxercalciferol should be considered.

    Adults with 25(OH)D concentration 16 to 30 ng/mL

    1,250 mcg (50,000 International Units) PO once monthly for a total of 6 months. The range between therapeutic and toxic doses is narrow and monitoring is required. If condition remains unresponsive to escalating doses of cholecalciferol, treatment with an oral active vitamin D analog such as calcitriol or doxercalciferol should be considered.[28125]

    †Indicates off-label use

    MAXIMUM DOSAGE

    NOTE: The Tolerable Upper Intake Level (UL) is defined as the highest daily intake of a nutrient that is likely to pose no risk in otherwise healthy individuals. The ULs are not intended to apply to individuals with specific disease states. Maximum doses for other uses are indication specific.

    Adults

    The Tolerable Upper Intake Level (UL) is 100 mcg/day (4,000 International Units/day) PO.

    Geriatric

    The Tolerable Upper Intake Level (UL) is 100 mcg/day (4,000 International Units/day) PO.

    Adolescents

    The Tolerable Upper Intake Level (UL) is 100 mcg/day (4,000 International Units/day) PO.

    Children

    Children 9 to 12 years: The Tolerable Upper Intake Level (UL) is 100 mcg/day (4,000 International Units/day) PO.
    Children 4 to 8 years: The Tolerable Upper Intake Level (UL) is 75 mcg/day (3,000 International Units/day) PO.
    Children 1 to 3 years: The Tolerable Upper Intake Level (UL) is 62.5 mcg/day (2,500 International Units/day) PO.

    Infants

    Infants 7 to 12 months: The Tolerable Upper Intake Level (UL) is 37.5 mcg/day (1,500 International Units/day) PO.
    Infants 1 to 6 months: The Tolerable Upper Intake Level (UL) is 25 mcg/day (1,000 International Units/day) PO.

    Neonates

    The Tolerable Upper Intake Level (UL) is 25 mcg/day (1,000 International Units/day) PO.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; higher doses may be needed to compensate for reductions in intestinal absorption.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available. However, cholecalciferol is activated in the kidney; close monitoring is required to ensure the appropriate dose.

    ADMINISTRATION

    Oral Administration

    While vitamin D may be taken without regard to food, it is better absorbed when taken with foods containing fat.

    Oral Solid Formulations

    Chewable oral wafers (e.g., Replesta, Replesta NX): crush before administering, or have patients chew thoroughly before swallowing. Do not let patients swallow the wafers whole. Replesta NX is recommended to be taken with the largest meal of the day.

    Oral Liquid Formulations

    Administer using a calibrated measuring device to ensure dosage accuracy. Due to the risk of inadvertently administering an incorrect dose to infants, the FDA recommends using a product with a dropper that will measure no more than 10 mcg (400 International Units) per dose.
    Administer directly into the mouth or mix with breast milk, formula, fruit juice, cereal, or other foods. If mixed, make sure the patient drinks or eats the entire portion to ensure they receive the total amount of the medication.
    Storage: After opening, store away from direct light.

    STORAGE

    Calcidol:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Calciferol:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Deltalin:
    - Protect from light
    - Protect from moisture
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Drisdol:
    - Protect from light
    - Protect from moisture
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Ergo D:
    - Protect from light
    - Protect from moisture
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Clinically, cholecalciferol is similar to ergocalciferol; therefore, clinicians should also take contraindications and precautions for ergocalciferol into consideration when initiating cholecalciferol therapy.

    Hypercalcemia, hypervitaminosis D

    Cholecalciferol should not be used in patients with hypercalcemia, hypervitaminosis D, and vitamin D hypersensitivity or hypersensitivity to any of the excipients in the formulation. Hypersensitivity to vitamin D is one etiologic factor in infants of idiopathic hypercalcemia where vitamin D intake must be restricted.

    Renal disease, renal failure

    Patients with renal disease, especially renal failure, may be at increased risk for vitamin D-induced hypercalcemia even with usual dosages. Close clinical monitoring is needed to ensure adequate supplementation and, in pediatric patients, proper growth. In patients with stage 3 or higher kidney disease, use of a vitamin D analog appears preferred, following recommendations of the National Kidney Foundation.

    Biliary tract disease, Crohn's disease, cystic fibrosis, fat malabsorption, gallbladder disease, hepatic disease, malabsorption syndrome

    Patients with fat malabsorption due to malabsorption syndrome, cystic fibrosis, Crohn's disease, some forms of hepatic disease, gallbladder disease or biliary tract disease may require higher doses of vitamin D due to decreases in intestinal absorption. Some patients taking concurrent medications (e.g., certain anticonvulsants) may require higher doses as well. The prescription of active vitamin D analogs may be preferred in such cases.

    Pregnancy

    Adverse effects have not been reported with the normal daily intake of Vitamin D within the recommended dietary daily intakes for a pregnant female. Animal reproduction studies have shown fetal abnormalities in several species associated with hypervitaminosis D; therefore, the use of vitamin D in excess of the recommended dietary allowance during normal pregnancy should be avoided unless, in the judgment of the physician, potential benefits outweigh the hazards involved. The RDA of vitamin D during pregnancy is 15 mcg/day (600 International Units/day) with a Tolerable Upper Intake Limit of 100 mcg/day (4,000 International Units/day).

    Breast-feeding

    The 25-hydroxyvitamin D metabolite of vitamin D (cholecalciferol) is distributed into human breast milk at concentrations relative to the maternal serum concentration. Typical breast milk concentrations (without maternal supplementation) are not sufficient to prevent vitamin D deficiency in infants that are exclusively breast-fed and do not receive other vitamin D supplementation. Prolonged, exclusive breast-feeding of infants without recommended supplementation is a significant cause of rickets in infants, especially in dark-skinned infants breast-fed by mothers who are not vitamin D replete. Use of vitamin D within the recommended daily dietary intake for lactating women is generally recognized as safe. The recommended daily allowance of vitamin D during breast-feeding is 600 International Units/day with a Tolerable Upper Intake Limit of 4000 International Units/day. While high-dose vitamin D supplementation to nursing mothers has been shown to increase the concentration of vitamin D in breast milk and favorably increase 25(OH)D levels in infants, the results have not been validated and supplementation to infants is still recommended. Generally, the serum calcium concentrations of the infant should be monitored when a nursing mother is prescribed vitamin D in high doses, since hypercalcemia has been reported with high dose maternal use.

    ADVERSE REACTIONS

    Severe

    hypervitaminosis D / Delayed / 0-1.0

    Moderate

    hypercalciuria / Delayed / 0-1.0
    hypercalcemia / Delayed / 0-1.0
    constipation / Delayed / 0-1.0
    growth inhibition / Delayed / Incidence not known

    Mild

    polydipsia / Early / 0-1.0
    fatigue / Early / 0-1.0
    increased urinary frequency / Early / 0-1.0
    headache / Early / 0-1.0
    irritability / Delayed / 0-1.0
    nausea / Early / 0-1.0

    DRUG INTERACTIONS

    There are no drug interactions associated with Cholecalciferol, Vitamin D3 products.

    PREGNANCY AND LACTATION

    Pregnancy

    Adverse effects have not been reported with the normal daily intake of Vitamin D within the recommended dietary daily intakes for a pregnant female. Animal reproduction studies have shown fetal abnormalities in several species associated with hypervitaminosis D; therefore, the use of vitamin D in excess of the recommended dietary allowance during normal pregnancy should be avoided unless, in the judgment of the physician, potential benefits outweigh the hazards involved. The RDA of vitamin D during pregnancy is 15 mcg/day (600 International Units/day) with a Tolerable Upper Intake Limit of 100 mcg/day (4,000 International Units/day).

    The 25-hydroxyvitamin D metabolite of vitamin D (cholecalciferol) is distributed into human breast milk at concentrations relative to the maternal serum concentration. Typical breast milk concentrations (without maternal supplementation) are not sufficient to prevent vitamin D deficiency in infants that are exclusively breast-fed and do not receive other vitamin D supplementation. Prolonged, exclusive breast-feeding of infants without recommended supplementation is a significant cause of rickets in infants, especially in dark-skinned infants breast-fed by mothers who are not vitamin D replete. Use of vitamin D within the recommended daily dietary intake for lactating women is generally recognized as safe. The recommended daily allowance of vitamin D during breast-feeding is 600 International Units/day with a Tolerable Upper Intake Limit of 4000 International Units/day. While high-dose vitamin D supplementation to nursing mothers has been shown to increase the concentration of vitamin D in breast milk and favorably increase 25(OH)D levels in infants, the results have not been validated and supplementation to infants is still recommended. Generally, the serum calcium concentrations of the infant should be monitored when a nursing mother is prescribed vitamin D in high doses, since hypercalcemia has been reported with high dose maternal use.

    MECHANISM OF ACTION

    Cholecalciferol is metabolized to its active form, calcitriol (1.25-dihydroxyvitamin D); all vitamin D activity is due to this metabolite. Calcitriol promotes renal reabsorption of calcium, increases intestinal absorption of calcium and phosphorus, and increases calcium mobilization from bone to plasma. Calcitriol promotes intestinal absorption of calcium through binding to a specific receptor in the mucosal cytoplasm of the intestine. Subsequently, calcium is absorbed through formation of a calcium-binding protein. The synthesis of calcitriol is enhanced by elevated parathyroid hormone levels and low plasma phosphorus levels. Hypocalcemia causes release of parathyroid hormone, which stimulates the production of calcitriol.
     
    The vitamin D receptor (VDR) is present in numerous tissues throughout the body; the exact action of calcitriol within these tissues is not completely understood. There is evidence that calcitriol plays a role in the immune system. Calcitriol has been shown to inhibit cancer growth and stimulate cell differentiation.

    PHARMACOKINETICS

    Cholecalciferol is administered orally. Maximal clinical effects from a given dosage are usually observed in 4 weeks. Dietary vitamin D is absorbed from the GI tract in the presence of bile salts and is initially bound to chylomicrons, then is slowly transferred to vitamin D binding protein (DBP) in the serum. The uptake by chylomicrons results in vitamin D update by adipose tissue and muscle; remaining vitamin D in circulation is then metabolized by the liver. The uptake by the liver and other tissues accounts results in a plasma half-life of 4 to 6 hours for supplemental vitamin D. However, studies have shown that the whole-body half-life is about 2 months due to the stores in these tissues.[52879]
     
    Cholecalciferol is considered a prohormone and is converted in the liver by a group of activating cytochrome P450 (CYP) enzymes, CYP2R1, CYO27A1, and CYP27B1, to 25-hydroxyvitamin D (25(OH)D, calcidiol), the predominant form of vitamin D in the blood. This metabolite has a half-life of about 15 days. Serum 25(OH)D concentrations increase in a non-linear fashion in response to increased vitamin D intake based on baseline concentrations and duration of supplementation. Increasing serum 25(OH)D levels more than 50 nmol/L requires a greater amount of vitamin D than increasing baseline levels that are less than 50 nmol/L. The impact on serum 25(OH)D concentrations is less when doses are at least 25 mcg/day (1,000 International Units/day) compared to doses less than 25 mcg/day (1,000 International Units/day). For example, for vitamin D doses of at least 25 mcg/day (1,000 International Units/day), the increase in serum 25(OH)D concentrations is about 1 nmol/L for each 1 mcg (40 International Units) of vitamin D. Conversely, for vitamin D doses of 15 mcg (600 International Units) or less, the increase in 25(OH)D concentrations is about 2.3 nmol/L for each 1 mcg (40 International Units) of vitamin D.[52900] In the kidneys, 25-hydroxyvitamin D is further converted to its active, hormonal form, 1,25-dihydroxyvitamin D (1,25(OH)2D, calcitriol), which has a half-life of about 15 hours. Synthesis to this active form by renal CYP27B1 is tightly regulated and this form accounts for only a small portion of the total body amount of vitamin D.[52879]

    Oral Route

    Cholecalciferol is well absorbed orally in most individuals without conditions associated with fat malabsorption. There is a time lag between the oral administration of vitamin D and the initiation of its action in the body due to the necessity of synthesis of the active metabolites in the liver and kidneys.