Official reprint from UpToDate www.uptodate.

com 2013 UpToDate

Calcitriol: Pediatric drug information

Copyright 1978-2013 Lexicomp, Inc. All rights reserved. (For additional information see "Calcitriol: Drug information" and see "Calcitriol: Patient drug information") For abbreviations and symbols that may be used in Lexicomp (show table)

Brand Names: U.S.

Rocaltrol; Vectical Calcijex; Rocaltrol; Silkis Rickets, Treatment Agent; Vitamin D Analog; Vitamin, Fat Soluble

Brand Names: Canada Therapeutic Category Dosing: Neonatal

Hypocalcemia secondary to hypoparathyroidism: Oral: 1 mcg once daily for the first 5 days of life Alternate regimen: Oral: 0.02-0.06 mcg/kg/day; similar dosage has also been described in neonates with DiGeorge syndrome (Miller, 1983) Hypocalcemic tetany: I.V.: 0.05 mcg/kg once daily for 5-12 days Oral: Initial: 0.25 mcg/dose once daily, followed by 0.01-0.10 mcg/kg/day divided in 2 doses (maximum daily dose: 2 mcg)

Dosing: Usual
(For additional information see "Calcitriol: Drug information") Management of hypocalcemia in patients with chronic kidney disease (CKD): Indicated for therapy when serum levels of 25(OH)D are >30 ng/mL (75 nmol/L) and serum levels of intact parathyroid hormone (iPTH) are above the target range for the stage of CKD; serum levels of corrected total calcium are <9.5-10 mg/dL (2.37 mmol/L) and serum levels of phosphorus in children are less than age-appropriate upper limits of normal or in adults <4.6 mg/dL (1.49 mmol/L) (K/DOQI Guidelines, 2005): Children and Adolescents: CKD Stages 2-4: Oral: <10 kg: 0.05 mcg every other day 10-20 kg: 0.1-0.15 mcg daily >20 kg: 0.25 mcg daily Dosage adjustment: If iPTH decrease is <30% after 3 months of therapy and serum levels of calcium and phosphorus are within the target ranges based upon the CKD Stage, increase dosage by 50% If iPTH decrease < target range for CKD stage hold calcitriol therapy until iPTH increases to above

target range; resume therapy at half the previous dosage (if dosage <0.25 mcg capsule or 0.05 mcg liquid, use every other day therapy) If serum levels of total corrected calcium exceed 10.2 mg/dL (2.37 mmol/L) hold calcitriol therapy until serum calcium decreased to <9.8 mg/dL (2.37 mmol/L); resume therapy at half the previous dosage (if dosage <0.25 mcg capsule or 0.05 mcg liquid, use every other day therapy) If serum levels of phosphorus increase to > age-appropriate upper limits, hold calcitriol therapy (initiate or increase phosphate binders until the levels of serum phosphorus decrease to ageappropriate limits); resume therapy at half the previous dosage Children and Adolescents: CKD Stage 5: Oral, I.V.: Serum calcium times phosphorus product (Ca x P) should not exceed 65 mg2/dL2 for infants and children <12 years of age and 55 mg2/dL2 for adolescents, serum phosphorus should be within target, serum calcium <10 mg/dL (2.37 mmol/L): iPTH 300-500 pg/mL: 0.0075 mcg/kg per dialysis session (3 times/week); not to exceed 0.25 mcg daily iPTH >500-1000 pg/mL: 0.015 mcg/kg per dialysis session (3 times/week); not to exceed 0.5 mcg daily iPTH >1000 pg/mL: 0.025 mcg/kg per dialysis session (3 times/week); not to exceed 1 mcg daily Dosage adjustment: If iPTH decrease is <30% after 3 months of therapy and serum levels of calcium and phosphorus are within the target ranges based upon the CKD Stage 5, increase dosage by 50% Adult CKD Stages 3 or 4: Serum calcium <9.5 mg/dL (2.37 mmol/L), serum phosphorus <5.5 mg/dL (1.77 mmol/L), serum calcium times phosphorus product (Ca x P) <55 mg2/dL2: iPTH 300-600 pg/mL: Oral, I.V.: 0.5-1.5 mcg per dialysis session (3 times/week) iPTH 600-1000 pg/mL: I.V.: 1-3 mcg per dialysis session (3 times/week); Oral: 1-4 mcg per dialysis session (3 times/week) iPTH >1000 pg/mL: I.V. 3-5 mcg per dialysis session (3 times/week); Oral: 3-7 mcg per dialysis session (3 times/week) Dosage adjustment: If iPTH decrease < target range for CKD stage 5 hold calcitriol therapy until iPTH increases to above target range; resume therapy at half the previous dosage (if dosage <0.25 mcg capsule or 0.05 mcg liquid, use every other day therapy) If serum levels of total corrected calcium exceed 9.5 mg/dL (2.37 mmol/L) hold calcitriol therapy until serum calcium decreased to <9.5 mg/dL (2.37 mmol/L); resume therapy at half the previous dosage (if dosage <0.25 mcg capsule or 0.05 mcg liquid, use every other day therapy) If serum levels of phosphorus increase to >4.6 mg/dL (1.49 mmol/L), hold calcitriol therapy (initiate or increase phosphate binders until the levels of serum phosphorus decrease to 4.6 mg/dL (1.49 mmol/L); resume therapy at prior dosage Note: Intermittent administration of calcitriol by I.V. or oral routes is more effective than daily oral calcitriol in lowering iPTH levels. Hypoparathyroidism/pseudohypoparathyroidism: Oral (evaluate dosage at 2- to 4-week intervals): Infants <1 year: 0.04-0.08 mcg/kg once daily Children 1-5 years: 0.25-0.75 mcg once daily Children >6 years and Adults: 0.5-2 mcg once daily

Vitamin D-dependent rickets: Children and Adults: Oral: 1 mcg once daily Vitamin D-resistant rickets (familial hypophosphatemia): Children and Adults: Oral: Initial: 0.015-0.02 mcg/kg once daily; maintenance: 0.03-0.06 mcg/kg once daily; maximum dose: 2 mcg once daily Psoriasis: Adults: Topical: Apply twice daily to affected areas (maximum: 200 g/week)

Dosage Forms: U.S.

Capsule, Oral:

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Rocaltrol: 0.25 mcg, 0.5 mcg [contains fd&c yellow #6 (sunset yellow), methylparaben, propylparaben] Generic: 0.25 mcg, 0.5 mcg Ointment, External: Vectical: 3 mcg/g (100 g) Generic: 3 mcg/g (100 g) Solution, Intravenous: Generic: 1 mcg/mL (1 mL) Solution, Oral: Rocaltrol: 1 mcg/mL (15 mL) Generic: 1 mcg/mL (15 mL)

Generic Equivalent Available: U.S. Administration

Yes

Oral: May be administered with or without meals; when administering small doses from the liquid-filled capsules, consider the following concentration for Rocaltrol: 0.25 mcg capsule = 0.25 mcg per 0.17 mL 0.5 mcg capsule = 0.5 mcg per 0.17 mL Parenteral: May be administered undiluted as a bolus dose I.V. through the catheter at the end of hemodialysis Topical: Apply externally; not for ophthalmic, oral, or intravaginal use

Compatibility Stability Use

Stable in D5W, NS, sterile water for injection.

Store at room temperature; protect oral and I.V. formulations from light and heat. Do not refrigerate or freeze topical ointment.

Oral/Injection: Management of secondary hyperparathyroidism and resultant metabolic bone disease in patients with moderate-to-severe chronic renal failure not yet on dialysis (FDA approved in ages 3 years and adults); management of hypocalcemia and resultant metabolic bone disease in patients on chronic renal dialysis (FDA approved in ages 18 years); management of hypocalcemia in patients with hypoparathyroidism (FDA approved in ages 1 year and adults) and pseudohypoparathyroidism (FDA approved in ages 6 years and

adults) Topical: Management of mild-to-moderate plaque psoriasis (FDA approved in ages 18 years)

Medication Safety Issues

Sound-alike/look-alike issues: Calcitriol may be confused with alfacalcidol, Calciferol, calcitonin, calcium carbonate, captopril, colestipol, paricalcitol, ropinirole Administration issues: Dosage is expressed in mcg (micrograms), not mg (milligrams); rare cases of acute overdose have been reported

Adverse Reactions
Oral, I.V.: Cardiovascular: Cardiac arrhythmia, hypertension Central nervous system: Apathy, headache, hyperthermia, psychosis, sensory disturbances, somnolence Dermatologic: Erythema multiforme, erythematous skin disorders, pruritus, rash, urticaria Endocrine & metabolic: Dehydration, growth suppression, hypercalcemia, hypercholesterolemia, libido decreased, polydipsia Gastrointestinal: Abdominal pain, anorexia, constipation, metallic taste, nausea, pancreatitis, stomach ache, vomiting, weight loss, xerostomia Genitourinary: Nocturia, urinary tract infection Hepatic: ALT increased, AST increased Local: Injection site pain (mild) Neuromuscular & skeletal: Bone pain, myalgia, dystrophy, soft tissue calcification, weakness Ocular: Conjunctivitis, photophobia Renal: Albuminuria, BUN increased, creatinine increased, hypercalciuria, nephrocalcinosis, polyuria Respiratory: Rhinorrhea Miscellaneous: Allergic reaction, hypersensitivity reactions Rare but important or life-threatening: Anaphylaxis Topical: Dermatologic: Pruritus, psoriasis, skin discomfort Endocrine: Hypercalcemia Genitourinary: Urine abnormality Renal: Hypercalciuria

Rare but important or life-threatening: Kidney stones

Contraindications Precautions

Hypersensitivity to calcitriol or any component; hypercalcemia; vitamin D toxicity; abnormal sensitivity to the effects of vitamin D Hypercalcemia potentiates digoxin toxicity; use concomitantly with caution

Topical: For external use only; not for ophthalmic, oral, or intravaginal use. Do not apply to facial skin, eyes, or lips. Absorption may be increased with occlusive dressings. Avoid or limit excessive exposure to natural or artificial sunlight or phototherapy. The safety and effectiveness have not been evaluated in patients with erythrodermic, exfoliative, or pustular psoriasis. The parenteral product contains aluminum; toxic aluminum concentrations may be seen with high doses, prolonged use, or renal dysfunction. Premature neonates are at higher risk due to immature renal function and aluminum intake from other parenteral sources. Parenteral aluminum exposure of >4-5 mcg/kg/day is associated with CNS and bone toxicity and tissue loading may occur at lower doses.

Warnings

Excessive administration may lead to over suppression of PTH, hypercalcemia, hypercalciuria, hyperphosphatemia, and adynamic bone disease. Acute hypercalcemia may increase risk of cardiac arrhythmias and seizures. Chronic hypercalcemia may lead to generalized vascular and other soft-tissue calcification. Phosphate and vitamin D (and its derivatives) should be withheld during therapy to avoid hypercalcemia. Monitor serum calcium levels closely; the calcitriol dosage should be adjusted accordingly; serum calcium times phosphorus product (Ca x P) should not exceed 65 mg2/dL2 for infants and children <12 years of age and 55 mg2/dL2 for adolescents and adults. Not indicated for use in patients with rapidly worsening kidney function or those who are noncompliant with medications or follow-up (K/DOQI Guidelines, 2003). Topical: May cause hypercalcemia; if alterations in calcium occur, discontinue treatment until levels return to normal.

Metabolism/Transport Effects Drug Interactions

Substrate of CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Induces CYP3A4 (weak/moderate)

(For additional information: Launch Lexi-Interact Drug Interactions Program) Aluminum Hydroxide: Vitamin D Analogs may increase the serum concentration of Aluminum Hydroxide. Specifically, the absorption of aluminum may be increased, leading to increased serum aluminum concentrations. Risk X: Avoid combination ARIPiprazole: CYP3A4 Inducers may decrease the serum concentration of ARIPiprazole. Management: Double the oral aripiprazole dose and closely monitor clinical response. Reduce the oral aripiprazole dose to 10-15 mg/day if the inducer is discontinued. Avoid use of CYP3A4 inducers for more than 14 days with extendedrelease injectable aripiprazole. Risk D: Consider therapy modification Axitinib: CYP3A4 Inducers (Weakly to Moderately Effective) may decrease the serum concentration of Axitinib. Risk X: Avoid combination Bile Acid Sequestrants: May decrease the serum concentration of Vitamin D Analogs. More specifically, bile acid sequestrants may impair absorption of Vitamin D Analogs. Management: Avoid concomitant administration of vitamin D analogs and bile acid sequestrants (e.g., cholestyramine). Separate administration of these agents by several hours to minimize the potential risk of interaction. Monitor plasma calcium concentrations. Risk D: Consider therapy modification

Calcium Salts: May enhance the adverse/toxic effect of Vitamin D Analogs. Risk C: Monitor therapy Cardiac Glycosides: Vitamin D Analogs may enhance the arrhythmogenic effect of Cardiac Glycosides. Risk C: Monitor therapy Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Risk X: Avoid combination Corticosteroids (Systemic): May diminish the therapeutic effect of Calcitriol. Risk C: Monitor therapy CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Risk D: Consider therapy modification CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Risk D: Consider therapy modification Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Risk D: Consider therapy modification Danazol: May enhance the hypercalcemic effect of Vitamin D Analogs. Risk C: Monitor therapy Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy Herbs (CYP3A4 Inducers): May increase the metabolism of CYP3A4 Substrates. Management: Consider avoiding CYP3A4 inducing herbs in order to avoid therapeutic failure of the substrate. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Risk D: Consider therapy modification Ivacaftor: May increase the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy Magnesium Salts: Calcitriol may increase the serum concentration of Magnesium Salts. Risk D: Consider therapy modification Mifepristone: May increase the serum concentration of CYP3A4 Substrates. Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Risk D: Consider therapy modification Mineral Oil: May decrease the serum concentration of Vitamin D Analogs. More specifically, mineral oil may interfere with the absorption of Vitamin D Analogs. Management: Avoid concomitant, oral administration of mineral oil and vitamin D analogs. Consider separating the administration of these agents by several hours to minimize the risk of interaction. Monitor plasma calcium concentrations. Risk D: Consider therapy modification Multivitamins/Fluoride (with ADE): May enhance the adverse/toxic effect of Vitamin D Analogs. Risk X: Avoid combination Multivitamins/Minerals (with ADEK, Folate, Iron): May enhance the adverse/toxic effect of Vitamin D Analogs. Risk X: Avoid combination Orlistat: May decrease the serum concentration of Vitamin D Analogs. More specifically, orlistat may impair absorption of Vitamin D Analogs. Management: Monitor clinical response (including serum calcium) to oral vitamin D analogs closely if used with orlistat. If this combination must be used, consider giving the vitamin D analog at least 2 hrs before or after orlistat. Risk D: Consider therapy modification Saxagliptin: CYP3A4 Inducers may decrease the serum concentration of Saxagliptin. Risk C: Monitor therapy

Sevelamer: May decrease the serum concentration of Calcitriol. Risk C: Monitor therapy Sucralfate: Vitamin D Analogs may increase the serum concentration of Sucralfate. Specifically, the absorption of aluminum from sucralfate may be increased, leading to an increase in the serum aluminum concentration. Risk X: Avoid combination Thiazide Diuretics: May enhance the hypercalcemic effect of Vitamin D Analogs. Risk C: Monitor therapy Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy Vitamin D Analogs: May enhance the adverse/toxic effect of other Vitamin D Analogs. Risk X: Avoid combination

Pregnancy Risk Factor Pregnancy Implications

C (show table)

Teratogenic effects have been observed in some animal reproduction studies. Mild hypercalcemia has been reported in a newborn following maternal use of calcitriol during pregnancy. Adverse effects on fetal development were not observed with use of calcitriol during pregnancy in women (N=9) with pseudovitamin D-dependent rickets. Doses were adjusted every 4 weeks to keep calcium concentrations within normal limits (Edouard, 2011). If calcitriol is used for the management of hypoparathyroidism in pregnancy, dose adjustments may be needed as pregnancy progresses and again following delivery. Vitamin D and calcium levels should be monitored closely and kept in the lower normal range.

Monitoring Parameters
Serum calcium and phosphorus:

Signs and symptoms of vitamin D intoxication

I.V.: Twice weekly during initial phase, then at least monthly once dose established Oral: At least every 2 weeks for 3 months or following dose adjustment, then monthly for 3 months, then every 3 months Serum or plasma intact parathyroid hormone (iPTH): At least every 2 weeks for 3 months or following dose adjustment, then monthly for 3 months, then as per K/DOQI Guidelines below. Per Kidney Disease Outcome Quality Initiative Practice Guidelines: Children (K/DOQI, 2005): Stage 3 CKD: iPTH every 6 months Stage 4 CKD: iPTH every 3 months Stage 5 CKD: iPTH every 3 months Per Kidney Disease Outcome Quality Initiative Practice Guidelines: Adults (K/DOQI, 2003): Stage 3 CKD: iPTH every 12 months Stage 4 CKD: iPTH every 3 months Stage 5 CKD: iPTH every 3 months

Reference Range
Chronic kidney disease (CKD) is defined either as kidney damage or GFR <60 mL/minute/1.73 m2 for 3 months); stages of CKD are described below: CKD Stage 1: Kidney damage with normal or increased GFR; GFR >90 mL/minute/1.73m2 CKD Stage 2: Kidney damage with mild decrease in GFR; GFR 60-89 mL/minute/1.73 m2

CKD Stage 3: Moderate decrease in GFR; GFR 30-59 mL/minute/1.73 m2 CKD Stage 4: Severe decrease in GFR; GFR 15-29 mL/minute/1.73 m2 CKD Stage 5: Kidney failure; GFR <15 mL/minute/1.73 m2 or dialysis Target range for iPTH: Stage 2 CKD: Children: 35-70 pg/mL (3.85-7.7 pmol/L) Stage 3 CKD: Children and Adults: 35-70 pg/mL (3.85-7.7 pmol/L) Stage 4 CKD: Children and Adults: 70-110 pg/mL (7.7-12.1 pmol/L) Stage 5 CKD: Children: 200-300 pg/mL (22-33 pmol/L) Adults: 150-300 pg/mL (16.5-33 pmol/L) Serum phosphorous: Stages 1-4 CKD: Children: At or above the age-appropriate lower limits and no higher than age-appropriate upper limits Stage 3 and 4 CKD: Adults: 2.7 to <4.6 mg/dL (0.87 to <1.49 mmol/L) Stage 5 CKD: Children 1-12 years: 4-6 mg/dL (1.29-1.94 mmol/L) Children >12 years and Adults: 3.5-5.5 mg/dL (1.13-1.78 mmol/L)

Mechanism of Action

Calcitriol, the active form of vitamin D (1,25 hydroxyvitamin D3), binds to and

activates the vitamin D receptor in kidney, parathyroid gland, intestine, and bone, stimulating intestinal calcium transport and absorption. It reduces PTH levels and improves calcium and phosphate homeostasis by stimulating bone resorption of calcium and increasing renal tubular reabsorption of calcium. Decreased renal conversion of vitamin D to its primary active metabolite (1,25 hydroxyvitamin D) in chronic renal failure leads to reduced activation of vitamin D receptor, which subsequently removes inhibitory suppression of parathyroid hormone (PTH) release; increased serum PTH (secondary hyperparathyroidism) reduces calcium excretion and enhances bone resorption. The mechanism by which calcitriol is beneficial in the treatment of psoriasis has not been established.

Pharmacodynamics
Onset of action: 2 hours Maximum effect: 10 hours Duration: 3-5 days

Oral:

Pharmacokinetics (Adult data unless noted)

Distribution: Breast milk: Very low (levels 2.2 0.1 pg/mL) Protein binding: 99.9% Metabolism: Primarily to 1,24,25-trihydroxycholecalciferol and 1,24,25-trihydroxy ergocalciferol Half-life:

Children 1.8-16 years undergoing peritoneal dialysis: 27.4 hours Adults without renal dysfunction: 5-8 hours Adults with CRF: 16.2-21.9 hours Time to peak serum concentration: Oral: 3-6 hours Elimination: Feces 27% and urine 7% excreted unchanged in 24 hours Clearance: Children 1.8-16 years undergoing peritoneal dialysis: 15.3 mL/hour/kg Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Department Health and Human Services, Food Drug Administration, "Aluminum in Large and Small Volume Parenterals Used in
Total Parenteral Nutrition," Federal Register, 2000, 65(17):4103-11.

2. "K/DOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Children With Chronic Kidney Disease," Am J Kidney
Dis, 2005, 46(4 Suppl 1):S1-121.

3. "K/DOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease. Guideline 1. Evaluation of
Calcium and Phosphorus Metabolism," Am J Kidney Dis, 2003, 42(4 Suppl 3):52-7. [PubMed 14520607 ]

4. "K/DOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease. Guideline 3. Evaluation of
Serum Phosphorus Levels," Am J Kidney Dis , 2003, 42(4 Suppl 3):62-3. [PubMed 14520607 ]

5. "K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, and Stratification, Part 4. Definition
and Classification of Stages of Chronic Kidney Disease," Am J Kidney Dis, 2002, 39(2 Suppl 1):46-75. [PubMed 11904577 ]

6. Sanchez CP, Secondary Hyperparathyroidism in Children With Chronic Renal Failure: Pathogenesis and Treatment, Paediatr
Drugs, 2003, 5(11): 763-76. [PubMed 14580225]

7. Ziolkowska H, Minimizing Bone Abnormalities in Children With Renal Failure, Paediatr Drugs, 2006, 8(4):205-22. [PubMed
16898852]

Topic 13107 Version 43.0