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 D Deficiency in Children : Part II. 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. vitamin D intake. Several papers published appears to be more rapidly and completely within the last five years have highlighted the absorbed than . Circulating growing incidence of , 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 to have published updated guidelines which 25(OH)D , also referred to as . 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 . 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 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 , , 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 . 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 , polydipsia, , regimens. 4 irritability, mild acidosis, hypercalciuria, anemia, azotemia, nephrocalcinosis, vascular Vitamin D dosing in children with 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 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 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 25,000 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. Pediatrics 2009;123:797 -803. 3. Wagner CL, Greer FR, American Academy of Pediatrics stabilized , followed by annual reassessment . Section on Breastfeeding, American Academy of Pediatrics Parathyroid and b one mineralization studies Committee on Nutrition. Prevention of rickets and vitamin D should be conducted as needed. 3-7 deficiency in infants, children, and adolescent s. Pediatrics 2008;122:1142 -52. 4. Misra M, Pacaud D, Petryk A, et al. Vitamin D deficiency Availability and Cost in children and its management: review of current knowledge ® Ergocalciferol (Drisdol or others ) is available and recommendations. Pediatrics 2008;122:398 -417. by prescription in 25,000 and 50,000 5. Vitamin D. Drug Facts and Comparisons . Efacts [onli ne]. International Units ( 0.625 and 1.25 mg) capsules. 2009. Available from Wolters Kluwer Health, Inc. (accessed 5/1//0 9). It is also available without a prescription in a n 6. Drisdol ® prescribing information. Sanofi -Aventis US, 8,000 International Unit s/mL (200 mcg/mL) LLC. March 2007 . Available at www.products.sanofi - liquid. 5,6 The liquid product contains propylene aventis.us/drisdol/drisdol.pdfb (accessed 5/1/09). 7. Ergocalciferol. In: Taketomo CK, Hodding JH, Kraus DM, glycol as a vehicle and should not be used for th high -dose thera py. 4 The average wholesale price eds. Pediatric Dosage Handbook. 14 ed. Hudson, OH: Lexi - Comp., 2007: 588 -91. (AWP) for a bottle of 50 capsules ranges from 8. Huh SY, Gordon CM. Vitamin D deficiency in children $75 to $ 100 . A 60 mL bottle of Drisdol ® liquid, and adolesc ents: epidemiology, impact and treatment. Rev which would provide 20 doses, has an AWP of Endocr Metab Disord 2008;9:161 -70. $149.13 .9 9. Drug Topics Red Book. Montvale, NJ: Thompson Healthcare (on -line via McKesson). 10 . Just D ® health care professional information. Sunlight Cholecalciferol (Delta D3 ® or others) is available , Unit Drug Co, 2005. Ava ilable at without a prescript ion in 400 , 1,000 , 2,000, and www.sunlightvitamins.com/Physician.php (accessed 5/5/09). 10,000 International Units tablets or capsules. 5 The cost of a bottle of 500 tablets/capsules The author and editors would like to thank Dr. ranges from $2.50 to $10.00. Cholecalciferol is ® Alan D. Rogol for reviewing this article prior to also available in a liquid formulation (Just D publication. infant drops, D -Drops ®, and other s) with 400, 1,000, or 2,000 International Units of vitamin D Pharmacology Literature Update per drop or per mL, depending on the product. The liquid formulations range in price from Effects of Valproate and Quetiapine on White $8.00 to $25.00. While cholecalciferol Blood Cell Count preparations are less expensive than After observing several cases of neutropenia and ergocalciferol , some patie nts will require leukopenia in children receiving valproate and multiple tablets/capsules or a larger liquid quetiapine, the authors of this paper conducted a volume to achieve the desired dose .9,10 retrospective study of this drug combination. A Formulary Update total of 131 patients who received either drug or The following actions were taken by the the combination were evaluated. The incidence Pharmacy and Therapeutics Committee at their of neutropenia and/or leukopenia was 44% in the meeting on 5/ 22 /09 : patients receiving both drugs, 26% in the patients receiving just valproate, and 6% in tho se taking 1. Lacosamide (Vimpat ®) was added for the only quetiapine. The combination therapy group treatment of partial -onset seizures in patients 17 had a significantly higher incidence of moderate - years of age and older. This agent is available in to -severe neutropenia (14 cases) compared to the oral tablets (restricted to Neurology) and an valproate and quetiapine groups (5 and 0 cases, injection (restricted to use in patients previously respectively). Based on their findings, the stabilized on oral therapy). Both forms were authors recommend that patients receiving approved for the Inpatient Formulary. The valproate or the combination of valproate and tablets were appro ved for addition to the quetiapine be monitored for leukopenia or Outpatient Formulary. neutropenia and that additional studies be conducted to evaluate a potential drug interaction 2. 6% hydroxyethyl starch 130/0.4 (Voluven ®), a between the two agents. Rahman A, Mican LM, colloid solution for management of hypovolemia Fischer C, et al. Evaluating the incidence of was also added to the Inpatient Formulary. leukopenia and neutropenia with valproate, quetiapine, or the combination in children and 3. Imiglucerase (Cerezyme ®), an analogue of adolescents. Ann Pharmacother 2009;43:822 - human β-glucocerebrosidase, was added 30. to the Outpatient Formulary for the treatment of patients with Type 1 Gaucher disease. Doses Off -labeling Prescribing typically range from 2.5 units/kg three times While recent changes in Food and Drug weekly to 60 units/kg every 2 weeks. Ad ministration (FDA) policies have been made Imiglucerase is administered as a 1 -2 hour to facilitate the approval process, many drugs inf usion. The drug will not be routinely stocked, needed by children are still not approved for but will be ordered as needed. pediatric use. Bazzano and colleagues have examined the frequency of off -label prescribing 4. All propoxyphene -containing products were for children in the outpatie nt setting. The authors deleted from the Outpatient Formulary. used data from the 2001 -2004 National Ambulatory Medical Care Surveys, which included a sample of 7,901 outpatient visits by Contributing Editor:Marcia L. Buck, Pharm.D. children under 18 years of age. A total of 62% Editorial Board: Kristi N. Hofer, Pharm.D. of the pediatric clinic visits included off -label Michelle W. McCarthy, Pharm.D. prescrib ing. Susan B. Cogut, Pharm.D. Website: Terry Bennett The most frequent therapeutic classes included If you have comments or suggestions for future were cardiovascular drugs (96% of prescriptions issues, please contact us at Box 800674, UVA were written off -label), analgesics (86%), Health System, Charlottesville, VA 22908 or gastrointestinal agents (80%), and pulmonary by e -mail to [email protected] . This drugs or for dermatologic conditions newsletter is also available at (each 67%). Chi ldren < 6 years of age had a www.healthsystem.virginia.edu/internet/pediatr significantly higher probability of receiving a ics/ pharma -news/home.cfm drug off -label (p<0.01) and visits to a subspecialist were more likely to result in off - label prescribing (p<0.01). The authors suggest that current measures to increase FDA appr oval for pediatric drugs ha ve not yet made a significant impact in reducing off -label prescribing and that additional measures are needed . Bazzano AFT, Mangione -Smith R, Schonlau M, et al. Off -label prescribing to children in the United States outpatient s etting. Academic Pediatr 2009;9:81 -8.