PEDIATRIC PHARMACOTHERAPY A Monthly Newsletter for Health Care Professionals from the University of Virginia Children’s Hospital Volume 1 5 Number 6 June 20 09 Preven tion and Management of Vitamin D Deficiency in Children : Part II. Vitamin D Supplementation Marcia L. Buck, Pharm.D., FCCP he previous issue of Pediatric Pharmacokinetics T Pharmacotherapy reviewed recent studies Oral v itamin D supplements are well -absorbed documenting the prevalence of vitamin D from the small intestine . The presence of bile is deficiency and the need to increase dietary necessary for absorption. Cholecalciferol vitamin D intake. Several papers published appears to be more rapidly and completely within the last five years have highlighted the absorbed than ergocalciferol. Circulating growing incidence of vitamin D deficiency, vitamin D is bound to serum proteins and is defined as a serum hydroxyvitamin D [ 25(OH)D ] widely distributed throughout the body . It is level less than 20 ng/mL, in infants, children, and stored primarily in the liver and fat .5-7 adolescents world -wide .1,2 As a result of these epidemiologic studies and new information on Both forms of vitamin D are inactive and must the role of vitamin D in preventing autoimmune undergo conversion in the liver and kidneys to diseases, cardiovascular disease, and cancer , the form biologically active compounds. American Academy of Pediatrics (AAP) and the Ergocalciferol and cholecalciferol are Lawson Wilkins Pediatric Endocrine Society hydroxylated by hepatic microsomal enzymes to have published updated guidelines which 25(OH)D , also referred to as calcifediol . recommend increasing the daily intake of vitamin Further conversion of th is intermediate form in D to 400 International Units for infants and the kidney s produces the physiologically active children. 3,4 Vitamin D supplements may be form, 1,25 -dihydroxy vitamin D , or calcitriol . necessary for those patients unable to meet this Vit amin D products are primarily eliminated st andard with dietary intake alone, including through excretion in the bile. The mean breast -fed infants. This issue of the newsletter elimination half -li fe of 1,25 -dihydroxyvitamin D will review the pharmacology of oral vitamin D is 5 to 8 hours in adults .5-7 supplements and provide recommendations for dosing and monitoring. Although it is not the biologically active form , the intermediate form, 25(OH)D, is used to Vitamin D Supplements assess vitamin D status since 1,25 - Exogenous vitamin D i s available as a dietary dihydroxyvitamin D levels do not typically supplement in two forms: ergocalciferol (vitamin decrease until clinical symptoms of vitamin D D2), derived from the irradiation of ergosterol in deficiency ha ve become severe. The yeast, and cholecalciferol (vitamin D 3), obtained intermediate 25( OH)D for m also has a longer from animal sources. The two forms are half -life (approximately 15 days) and is less regarded as equivalent in most dosing res ources, affected by parathyroid hormone, calcium, or with 1 mcg of either providing 40 International phosphate levels. There is a lag time of 10 to 24 Units of vitamin D activity. Several recent hours after administration of exogenous vitamin sources, however, suggest that cholecalciferol is D2 or D 3 until the biologically active forms have better absorbed and may raise serum 25(OH)D been produced. Maximum clinical response levels up to three -fold higher than ergocalciferol typically occurs approximately a month after in adults , produc ing more long -lasting therapy has been initiated. Pharmacologic physiologic results .3-7 effects may continue for more than 2 months after vitamin D administration. 5-7 Warnings and Precautions those consuming less than 1 L of infant Vitamin D su pplements are contraindicated in formula/day should receive 400 International patients with hypercalcemia or a known Units/day of an oral liquid vitamin D product. 3,4 hypersensitivity to any component of the product. The Lawson Wilkins Pediatric Endocrine Society Some vitamin D supplements contain tartrazine recommends that p reterm infants should receive (FD&C yellow dye no. 5) and may produce a 400 to 800 International Units of vitamin D (10 hypersensitivity reaction in susceptible to 20 mcg) per day to compensate for decreased indi viduals. Patients taking vitamin D placental transfer in utero and decreased supplements in doses above the recommended gastrointestinal absorption after birth .4 daily dietary intake should be monitored for hypercalcemia, impaired renal function, or other For treatment of documented vitamin D evidence of vitamin D toxicity. 5-7 deficiency, infants may be given 1,000 to 2,000 International Units/day (25 to 50 mcg) and older Adverse Effects children may be given up to 5,000 International Excessive administration of v itamin D may result Units/day (125 mcg) for 2 t o 3 months .4,8 A in weakne ss, hea dache , somnolence, nausea, variety of alternative dosing regimens have been vomiting, dry mouth, a metallic taste, published over the past decade. A high -dose co nstipation, muscle or bone pain. With short -course r egimen providing a total of continued high -dose vitamin D intake (> 10,000 100,000 to 600,000 International Units (2.5 to 15 International Units/day) or overdose (serum mg) over 1 to 5 days has been suggested for 25(OH)D levels > 100 ng /mL) , patients may patients who might not adhere to longer develop polyuria, polydipsia, anorexia, regimens. 4 irritability, mild acidosis, hypercalciuria, anemia, azotemia, nephrocalcinosis, vascular Vitamin D dosing in children with kidney disease calcifications, pancreatitis, photophobia, or other chronic illnesses shoul d be based on rhinorrhea, pruritus, hyperthermia, serum 25(OH)D levels . Table 1 provides general cardiovascular instability, bone demineralization, recommendations for these patients . Table 2 lists and hepatic or renal dysfunction . The se dosing recommendations for children with severe symptoms may persist for several months after or chronic deficiency states .3-7 discontinuing therapy .5-8 Table 1. Examples of Vitamin D Dosing Based Drug Interactions on Serum 25(OH)D Levels The absorption of vitamin D supplements may be decreased by administration with mineral oil , 25(OH)D Dose cholesty ramine , colestipol, or orlistat . Use of 16 -30 ng/mL 2,000 International Units/day magnesium -containing antacids during vitamin D (50 mcg) or 50,000 supplementation may result in hypermag nesemia, International Units (1.25 mg) especially in renal dialysis patients. 5-7 monthly for 3 months Administration of vitamin D supplements in 5-15 ng/mL 4,000 International Units /day patients with hypoparathyroidism wh o are also (100 mcg) or 50,000 taking thiazide diuretics may produce International Units (1.25 mg) hypercalcemia. Use of vitamin D and calcium every other week for 3 mont hs supplements may antagonize the effects of calcium channel blockers. This combination may < 5 ng/mL 8,000 International Units /day also increase the risk of toxicity in patients taking (200 mcg) or 50,000 digoxin. Administ ration of phenobarbital or International Units (1.25 mg) phenytoin may increase the rate of hepatic weekly for 1 month f ollowed metabolism of vitamin D to inactive compo unds by 4,000 International and reduce calcium absorption .5-7 Units /day or 50,000 International Units every other Dosing Recommendations week for a total of 3 months The current recommendation from both the AAP and the Lawson Wilkins Pediatric End ocrine Table 2. Examples of Vitamin D Dosing Based Society is a minimum dietary intake of 400 on Diagnosis International Units/day (10 mcg/day) for neonates, children, and adolescents. 3,4 If this Diagnosis Dose amount cannot be achieved through their normal Rickets 1,000 -10 ,000 International diet, a vitamin D supplement should be Units/day ( 25 to 25 0 mcg/day) administered. Exclusively bre astfed infants and for 2 to 3 months, followed by maintenance treatment with Summary 400 to 1,000 International Vitamin D supplementation for children has been Units/day the focus of a number of publications within the last year. New demographic data ha ve identified Malabsorption 25,000 International Unit s/day a growing number of children with vitamin D syndromes (625 mcg/day) deficiency at risk for rickets or impaired bone growth and mineralization . In addition, there is Familial hypo - 40,000 -80,000 International growing evidence of the role of vitamin D in the phosphatemia Units /day (1 to 2 mg/day) prevention of autoimmune and cardiovascular diseases, as well as cancer. The AAP and the Hypo para - 200,000 International Lawson Wilkins Pediatric Endocrine Society thyroidism Units /day (5 mg/day) , titrated have recently adopted new standards for daily to maintain optimal levels vitamin D requirements. As a result, more children will need vitamin D supplementation. Vitamin D supplements may be ta ken with or The choice of supplement , as well as dose and without food . A dministration with food may be dosing frequency, vary among references . useful to reduce stomach upset. Calcium Additional research is needed to identify the supplementation (30 to 75 mg/kg/day oral optimal dosing strategy for vitamin D elemental calcium) is often necessary to supplementation in pediatric patients . maximize response in patients with vitamin D deficiency. Patients receivi ng vitamin D References supplementation beyond the recommended daily 1. Gordon CM , Feldman HA, Sinclair L, et al. Prevalence of dietary intake sho uld undergo periodic vitamin D deficiency among healthy infants and toddlers. Arch Pediatr Adolesc Med 2008;162:505 -12. monitoring of serum 25(OH)D levels , using an 2. Saintonge S Bang H, Gerber JM. Implications of a new assay for both 25( OH)D 2 and 25(OH)D 3, as well definition of vitamin D deficiency in a multiracial US as serum calcium, phosphorus, and alkaline adolescent population: the National Health and Nutrition phosphatase at one and th ree months or until Examination Surv ey III.