Cholecalciferol - Drug Monograph

Introduction

Cholecalciferol, also known as vitamin D3, is a secosteroid hormone that plays a critical role in calcium homeostasis and bone metabolism. It is the naturally occurring form of vitamin D produced in human skin through ultraviolet B radiation exposure. As a pharmaceutical agent, cholecalciferol is used to prevent and treat vitamin D deficiency and associated conditions. Unlike its synthetic analog ergocalciferol (vitamin D2), cholecalciferol is considered more potent and has a longer half-life, making it the preferred form for supplementation in clinical practice.

Mechanism of Action

Cholecalciferol requires two hydroxylation steps to become biologically active. First, it undergoes 25-hydroxylation in the liver by the enzyme CYP2R1 to form 25-hydroxyvitamin D [25(OH)D], the major circulating form. This metabolite then undergoes 1α-hydroxylation in the kidneys by CYP27B1 to form the active hormone 1,25-dihydroxyvitamin D [1,25(OH)2D], also known as calcitriol.

The active form binds to vitamin D receptors (VDR) in target tissues, primarily:

• Intestinal epithelium: Enhances calcium and phosphate absorption
• Bone: Promotes bone mineralization and regulates bone remodeling
• Parathyroid glands: Suppresses parathyroid hormone secretion
• Various other tissues: Exhibits pleiotropic effects including immunomodulation and cell differentiation

Indications

• Treatment and prevention of vitamin D deficiency
• Treatment of hypoparathyroidism
• Familial hypophosphatemia
• Refractory rickets (vitamin D-resistant rickets)

• Osteoporosis prevention and treatment (in combination with calcium)
• Chronic kidney disease-associated mineral and bone disorder
• Psoriasis (topical formulations)
• Prevention of falls in elderly patients with vitamin D insufficiency

Dosage and Administration

• Prevention of deficiency: 400-800 IU daily
• Treatment of deficiency: 50,000 IU weekly for 8 weeks, then maintenance dosing
• Maintenance therapy: 800-2000 IU daily or equivalent weekly dosing

• Geriatric patients: 800-2000 IU daily for fall prevention
• Obesity: Requires 2-3 times higher doses (vitamin D is sequestered in adipose tissue)
• Malabsorption syndromes: Higher doses required (10,000-50,000 IU daily)
• Chronic kidney disease: Dosing adjusted based on stage and serum levels

• Best absorbed with meals containing fat
• Once-daily or once-weekly regimens show equivalent efficacy
• Serum 25(OH)D levels should guide dosing adjustments

Pharmacokinetics

Contraindications

• Hypervitaminosis D
• Hypercalcemia
• Hypersensitivity to cholecalciferol or any product components
• Metastatic calcification
• Williams syndrome (idiopathic hypercalcemia)

Warnings and Precautions

• Risk of hypercalcemia and hypercalciuria with excessive dosing
• Use with caution in patients with sarcoidosis, tuberculosis, or other granulomatous diseases (may have increased sensitivity)
• Impaired renal function requires careful monitoring
• Concurrent use of thiazide diuretics increases hypercalcemia risk
• Patients with malabsorption may require specialized formulations

Drug Interactions

• Thiazide diuretics: Increased risk of hypercalcemia
• Cholestyramine, orlistat: Reduced absorption of vitamin D
• Anticonvulsants (phenobarbital, phenytoin): Increased vitamin D metabolism
• Corticosteroids: May antagonize vitamin D effects
• Calcium supplements: Additive effects on calcium levels
• Digoxin: Hypercalcemia may potentiate digitalis toxicity

Adverse Effects

• Hypercalcemia (dose-dependent)
• Hypercalciuria
• Constipation
• Nausea
• Pruritus

• Nephrolithiasis
• Nephrocalcinosis
• Pancreatitis
• Cardiac arrhythmias (secondary to hypercalcemia)
• Allergic reactions (rare)

Monitoring Parameters

• Serum 25(OH)D level
• Serum calcium (total and ionized)
• Phosphorus
• Renal function (BUN, creatinine)
• Parathyroid hormone level (if indicated)
• Urine calcium/creatinine ratio

• Serum 25(OH)D every 3-6 months until stable, then annually
• Serum calcium every 3-6 months
• Annual assessment of renal function
• Monitor for symptoms of hypercalcemia (fatigue, nausea, polyuria)

• 25(OH)D levels: 20-50 ng/mL (optimal range)
• Maintain serum calcium within normal range
• Urine calcium excretion <250 mg/24h in women, <300 mg/24h in men

Patient Education

• Take with meals containing fat for better absorption
• Do not exceed prescribed dosage
• Report symptoms of hypercalcemia: nausea, vomiting, constipation, excessive thirst, frequent urination
• Maintain adequate calcium intake (1000-1200 mg daily for most adults)
• Regular weight-bearing exercise supports bone health
• Sun exposure (15-20 minutes several times weekly) can help maintain vitamin D levels
• Inform all healthcare providers about vitamin D supplementation
• Store supplements properly at room temperature, away from moisture

• Elderly patients: Emphasize fall prevention benefits
• Patients with kidney disease: Stress importance of regular monitoring
• Breastfeeding mothers: Vitamin D requirements may be increased

References

1. Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357(3):266-281. 2. Institute of Medicine. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: National Academies Press; 2011. 3. Rosen CJ, et al. The nonskeletal effects of vitamin D: an Endocrine Society scientific statement. Endocr Rev. 2012;33(3):456-492. 4. Pludowski P, et al. Vitamin D supplementation guidelines. J Steroid Biochem Mol Biol. 2018;175:125-135. 5. Martineau AR, et al. Vitamin D supplementation to prevent acute respiratory tract infections: systematic review and meta-analysis of individual participant data. BMJ. 2017;356:i6583. 6. National Osteoporosis Foundation. Clinician's Guide to Prevention and Treatment of Osteoporosis. 2019. 7. KDIGO Clinical Practice Guideline for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). Kidney Int Suppl. 2009;(113):S1-S130.