Vitamin D3 - Drug Monograph

Introduction

Vitamin D3 (cholecalciferol) is a fat-soluble vitamin that functions as a prohormone in the human body. It is essential for calcium homeostasis, bone metabolism, and numerous other physiological processes. While technically a vitamin, it is often managed as a medication due to its hormonal activity and therapeutic applications.

Mechanism of Action

Vitamin D3 requires two hydroxylation steps for activation. Initially, it undergoes 25-hydroxylation in the liver by cytochrome P450 enzymes (primarily CYP2R1) to form 25-hydroxyvitamin D [25(OH)D], the major circulating form. Subsequently, 1α-hydroxylation occurs in the kidneys via CYP27B1 to produce the biologically active form, 1,25-dihydroxyvitamin D [1,25(OH)2D]. This active metabolite binds to vitamin D receptors (VDR) in target tissues, regulating gene expression involved in:

• Intestinal calcium and phosphate absorption
• Bone mineralization and remodeling
• Modulation of immune function
• Cell proliferation and differentiation

Indications

• Treatment and prevention of vitamin D deficiency
• Management of hypoparathyroidism
• Treatment of familial hypophosphatemia
• Management of refractory rickets (vitamin D-resistant rickets)

• Prevention and treatment of osteoporosis
• Adjunct therapy in chronic kidney disease (CKD) with secondary hyperparathyroidism
• Psoriasis treatment (topical formulations)
• Prevention of falls in elderly patients

Dosage and Administration

• Adults: 600-800 IU daily
• Adults >70 years: 800-1,000 IU daily

• Loading dose: 50,000 IU weekly for 8 weeks, then maintenance
• Maintenance: 1,000-2,000 IU daily or equivalent weekly dosing

• Renal impairment: Dose adjustment required; may need calcitriol in advanced CKD
• Hepatic impairment: Monitor levels closely; impaired 25-hydroxylation may occur
• Obesity: Higher doses often required (2-3 times standard dosing)
• Malabsorption syndromes: Higher doses or specialized formulations needed

• Oral administration with meals containing fat enhances absorption
• Available as tablets, capsules, softgels, drops, and injectable forms

Pharmacokinetics

• Well absorbed from small intestine via lymphatic transport
• Bioavailability: Approximately 60-80% with adequate fat intake

• Widely distributed throughout body fat and muscle
• Extensive protein binding (primarily to vitamin D-binding protein)

• Hepatic hydroxylation to 25(OH)D (major circulating form)
• Renal hydroxylation to 1,25(OH)2D (active form)

• Primarily biliary excretion
• Elimination half-life of 25(OH)D: 2-3 weeks

Contraindications

• Hypervitaminosis D
• Hypercalcemia
• Hypersensitivity to vitamin D or product components
• Malabsorption syndromes where response cannot be monitored

Warnings and Precautions

• Risk of hypercalcemia with excessive dosing
• Monitor serum calcium in patients with renal impairment
• Use caution in patients with sarcoidosis, lymphoma, or other granulomatous diseases
• May exacerbate arterial calcification in patients with CKD
• Pregnancy Category C: Use only if potential benefit justifies potential risk

Drug Interactions

• Thiazide diuretics: Increased risk of hypercalcemia
• Corticosteroids: May reduce vitamin D effects
• Anticonvulsants (phenobarbital, phenytoin): Increased metabolism of vitamin D
• Cholestyramine/orlistat: Reduced absorption of vitamin D
• Calcium supplements: Increased risk of hypercalcemia when combined

Adverse Effects

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

• Nephrolithiasis
• Renal impairment
• Soft tissue calcification
• Pancreatitis (with severe hypercalcemia)

Monitoring Parameters

• Serum 25(OH)D levels
• Serum calcium (total and ionized)
• Phosphorus
• Renal function (BUN, creatinine)
• Parathyroid hormone (PTH) if indicated

• Serum calcium every 3-6 months during dose titration
• 25(OH)D levels 3 months after initiation or dose change
• Annual monitoring in stable patients
• Urine calcium:creatinine ratio in patients with history of stones

• 25(OH)D levels: 20-50 ng/mL (optimal range)
• Maintain serum calcium within normal range

Patient Education

• Take with meals containing fat for better absorption
• Do not exceed recommended dosage without medical supervision
• Report symptoms of hypercalcemia: nausea, vomiting, constipation, weakness, confusion
• Maintain adequate calcium intake through diet or supplements as recommended
• Regular weight-bearing exercise supports bone health
• Sun exposure (15-20 minutes several times weekly) can contribute to vitamin D synthesis

• Store at room temperature away from moisture and heat
• Keep out of reach of children

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 effects on musculoskeletal health, immunity, autoimmunity, cardiovascular disease, cancer, fertility, pregnancy, dementia and mortality. Autoimmun Rev. 2013;12(10):976-989. 5. National Osteoporosis Foundation. Clinician's Guide to Prevention and Treatment of Osteoporosis. 2014. 6. FDA prescribing information for various vitamin D3 preparations. 7. Lips P et al. Current vitamin D status in European and Asian countries. Osteoporos Int. 2014;25(12):2699-2701.