Alfacalcidol

Pharmacologic Category

Vitamin D Analog

Dosing: Adult

Chronic kidney disease-mineral and bone disorder (hypocalcemia, secondary hyperparathyroidism, or osteodystrophy): Note: Patients taking calcium supplements should limit intake to ≤500 mg/day (elemental calcium). Kidney Disease: Improving Global Outcomes (KDIGO) guidelines do not recommend routine use of vitamin D analogs in patients not on dialysis with chronic kidney disease (CKD) stages G3 to G5; it may be reasonable to reserve use for patients with CKD stages G4 or G5 and with severe and progressive hyperparathyroidism. Caution is advised to avoid hypercalcemia or elevated phosphate levels (KDIGO 2017).

Oral:

Predialysis patients:

Initial: 0.25 mcg/day for 2 months; if necessary, may titrate dose upward in increments of 0.25 mcg/day every 2 months.

Maintenance (usual dose): 0.5 mcg/day; up to 1 mcg/day may be necessary to maintain desired serum calcium concentrations.

Dialysis patients:

Initial: 1 mcg/day for up to 4 weeks; if necessary, may titrate dose upward in increments of 0.5 mcg/day every 2 to 4 weeks. Usual effective dose: 1 to 2 mcg/day; up to 3 mcg/day may be required in some patients.

Maintenance (usual dose): 0.25 to 1 mcg/day; dosing interval may be increased (every other day or less frequently) in patients who develop hypercalcemia.

Note: In some studies, intermittent dosing (on dialysis days) in dialysis patients has been shown as efficacious as daily dosing (Tarrass 2006).

IV: Dialysis patients:

Initial: 1 mcg per dialysis (2 to 3 times weekly); if inadequate response after 1 week, may titrate dose upward in weekly increments of 1 mcg per dialysis (maximum dose: 12 mcg/week). Total titration period should not exceed 6 weeks.

Maintenance: 1.5 to 12 mcg per week (divided equally between hemodialysis sessions); usual effective dose: 6 mcg/week.

Hypoparathyroidism, chronic (off-label use): Oral: Initial (low end of range): 0.5 mcg/day; may adjust dose carefully in increments of 0.25 to 0.5 mcg/day not more frequently than every 2 to 3 days to achieve desired calcium levels while avoiding hypercalcemia. Usual range: 0.5 to 4 mcg/day (Bilezikian 2016; ESE [Bollerslev 2015])

Dosing: Renal Impairment: Adult

No dosage adjustment necessary.

Dosing: Hepatic Impairment: Adult

There are no dosage adjustments provided in the manufacturer's labeling.

Dosing: Adjustment for Toxicity: Adult

Predialysis patients: If hypercalcemia develops within the first 2 months of therapy reduce dose to 0.25 mcg every other day; at any other time during therapy, reduce dose by 50% and discontinue all calcium supplements until serum calcium levels normalize.

Dialysis patients: Oral, IV: Discontinue immediately for hypercalcemia; may consider reintroducing therapy at a reduced dose after serum calcium levels normalize.

Use: Labeled Indications

Note: Not approved in the US

Chronic kidney disease-mineral and bone disorder: Management of hypocalcemia, secondary hyperparathyroidism, and osteodystrophy in patients with chronic renal failure

Use: Off-Label: Adult

Hypoparathyroidism (chronic)Level of Evidence [G]

Based on guidelines from the Endocrine Society and the European Society of Endocrinology (ESE) for management of hypoparathyroidism, active vitamin D or its analogs in conjunction with calcium (dietary, supplemental) is recommended in the treatment of hypocalcemia associated with chronic hypoparathyroidism Ref.

Level of Evidence Definitions

Level of Evidence Scale

Clinical Practice Guidelines

Chronic Kidney Disease:

Canadian Society of Nephrology, Guidelines for the Management of Chronic Kidney Disease, November 2008

KDIGO 2012 Clinical Practice Guidelines for the Evaluation and Management of Chronic Kidney Disease, January 2013

KDIGO Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD), 2017

K/DOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease, 2003

Hypoparathyroidism:

Endocrine Society, “Management of Hypoparathyroidism: Summary Statement and Guidelines,” 2016

European Society of Endocrinology Clinical Guideline: Treatment of Chronic Hypoparathyroidism in Adults, 2015

Administration: IV

Shake injection solution well prior to use and administer as bolus IV injection.

Administration: Oral

Administer oral solution (drops) and capsules with or without food and/or drink. Do not shake oral solution bottle.

Dietary Considerations

Adequate dietary calcium is necessary for clinical response to vitamin D. Recommended daily allowance of calcium in adults: 800 to 1,000 mg (from all sources of calcium intake such as dialysate, diet and calcium supplements). Patients taking calcium supplements should limit intake to ≤500 mg/day (elemental calcium) during therapy.

Storage/Stability

Oral capsule: Store between 15°C to 25°C (59°F to 77°F). Protect from direct sunlight.

Oral solution: Store between 2°C to 8°C (36°F to 46°F). Protect from direct sunlight.

Injection solution: Store between 2°C to 8°C (36°F to 46°F). Protect from light.

Medication Safety Issues

Sound-alike/look-alike issues:

Contraindications

Hypersensitivity to 1-α-hydroxyvitamin D3, vitamin D or its analogues and derivatives, or any component of the formulation; hypercalcemia; hyperphosphatemia; evidence of vitamin D toxicity

Warnings/Precautions

Concerns related to adverse effects:

• Excessive vitamin D: Excessive vitamin D administration may lead to over suppression of parathyroid hormone (PTH), progressive or acute hypercalcemia, hypercalciuria, hyperphosphatemia, and adynamic bone disease.

• Hypercalcemia: Monitor calcium levels closely; patients with chronic renal failure are at an increased risk for hypercalcemia. Dose reduction or discontinuation of therapy may be necessary. Withhold calcium supplementation until calcium levels normalize. Discontinue use with hypercalcemia in dialysis patients; may reinstitute therapy at 50% of previous dose 1 week after calcium levels have normalized. Chronic hypercalcemia may result in generalized vascular and soft tissue calcification, exacerbate nephrolithiasis, and has been associated with increased mortality in adults with chronic kidney disease (CKD) (KDIGO 2017).

• Hyperphosphatemia: Monitor serum phosphate; in cases of progressively or persistently elevated serum phosphate, the use of phosphate-lowering agents may be necessary.

Disease-related concerns:

• Cardiovascular: Avoid prolonged hypercalcemia; may aggravate arteriosclerosis or cardiac valve sclerosis. Use with caution in patients with calcification of pulmonary tissue; may result in cardiac disease. Severe hypercalcemia may increase risk of cardiac arrhythmias.

• Granulomatous diseases: Use with caution in patients with granulomatous diseases (eg, sarcoidosis) due to increased sensitivity to vitamin D.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Pregnancy Considerations

Adverse events have been observed in animal reproduction studies.

Breast-Feeding Considerations

Alfacalcidol may be present in breast milk. Breastfeeding is not recommended by the manufacturer.

Adverse Reactions

Frequency not defined; as associated with Hypervitaminosis D.

Cardiovascular: Cardiac arrhythmia, hypertension

Central nervous system: Headache, hyperthermia, psychosis (rare), drowsiness

Dermatologic: Pruritus

Endocrine & metabolic: Decreased libido, hypercalcemia, hypercholesterolemia, hyperphosphatemia, polydipsia, weight loss

Gastrointestinal: Anorexia, constipation, dysgeusia, nausea, pancreatitis, vomiting, xerostomia

Genitourinary: Nocturia

Hepatic: Increased serum ALT, increased serum AST

Neuromuscular & skeletal: Myalgia, ostealgia, weakness

Ophthalmic: Conjunctivitis, corneal deposits (calcification), photophobia

Renal: Increased blood urea nitrogen, polyuria

Respiratory: Rhinorrhea

Allergy and Idiosyncratic Reactions

• Vitamin D Analog Allergy

Toxicology

• Vitamin D

Metabolism/Transport Effects

None known.

Drug Interactions Open Interactions

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

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 (eg, 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

Burosumab: Vitamin D Analogs may enhance the adverse/toxic effect of Burosumab. Risk X: Avoid combination

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

Danazol: May enhance the hypercalcemic effect of Vitamin D Analogs. Risk C: Monitor therapy

Erdafitinib: Serum Phosphate Level-Altering Agents may diminish the therapeutic effect of Erdafitinib. Management: Avoid coadministration of serum phosphate level-altering agents with erdafitinib before initial dose increase period based on serum phosphate levels (Days 14 to 21). Risk D: Consider therapy modification

Magnesium Salts: Alfacalcidol may increase the serum concentration of Magnesium Salts. Management: Consider using a non-magnesium-containing antacid or phosphate-binding product in patients also receiving alfacalcidol. If magnesium-containing products must be used with alfacalcidol, serum magnesium concentrations should be monitored closely. 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

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 and Thiazide-Like Diuretics: May enhance the hypercalcemic effect of Vitamin D Analogs. Risk C: Monitor therapy

Vitamin D Analogs: May enhance the adverse/toxic effect of other Vitamin D Analogs. Risk X: Avoid combination

Monitoring Parameters

Secondary hyperparathyroidism (CKD patients)

Note: The frequency of serum calcium, phosphate, and parathyroid hormone (PTH) measurements may be dependent upon the presence and magnitude of abnormalities, the rate of progression of CKD, and the use of treatments for chronic kidney disease-mineral and bone disorder (KDIGO 2017)

During therapy initiation and dosage adjustments: Frequent monitoring of serum calcium and phosphate levels (eg, at least twice weekly) is recommended; (manufacturer’s labeling).

KDIGO guidelines (2017): Note: During treatment or when biochemical abnormalities are identified more frequent monitoring may be reasonable.

CKD stage G3a-G3b: Serum calcium and phosphate: Every 6 to 12 months; PTH: Frequency based on baseline level and progression of CKD; alkaline phosphatase

CKD stage G4: Serum calcium and phosphate: Every 3 to 6 months; PTH: Every 6 to 12 months; alkaline phosphatase every 12 months or more frequently in the presence of elevated PTH

CKD stage G5 and G5D: Serum calcium and phosphate: Every 1 to 3 months; PTH: Every 3 to 6 months; alkaline phosphatase every 12 months or more frequently in the presence of elevated PTH

Additionally, during maintenance therapy, periodic 24-hour urinary calcium and phosphate; periodic ophthalmologic exams (manufacturer’s labeling)

Hypoparathyroidism, chronic (off-label use) (Endocrine Society [Brandi 2016]):

Note: Frequency of measurement is dependent upon on how stable a patient is to a given dosage regimen with more frequent measurements (eg, weekly) required initially during dosage titration. Once patient is well controlled, monitoring may be required on a yearly or twice-yearly basis.

Serum calcium, phosphate, and magnesium; renal function [ie, 24-hour urinary calcium and creatinine, blood urea nitrogen (BUN), measured creatinine clearance or estimated glomerular filtration rate (eGFR)]; renal imaging (every 5 years in asymptomatic patients with a history of renal lithiasis or calcinosis or more frequently as indicated); CNS imaging (basal ganglia and other sites of calcification), ophthalmologic exam, and/or BMD as clinically indicated

Reference Range

Note: Due to the complexity and interdependency of the laboratory parameters used for therapeutic decisions in chronic kidney disease-mineral and bone disorder (CKD-MBD) patients, serial assessments of phosphate, calcium, and parathyroid hormone (PTH) levels should be considered together (KDIGO 2017)

Calcium (total): Adults: 9 to 11 mg/dL (2.05 to 2.54 mmol/L), may slightly decrease with aging. Avoid hypercalcemia for chronic kidney disease (CKD) stages G3a-G5D (KDIGO 2017)

Phosphorus: 2.5 to 4.5 mg/dL (0.81 to 1.45 mmol/L). Lower elevated phosphorus levels toward the normal range for CKD stages G3a-G5D (KDIGO 2017)

PTH:

CKD stage G3a-G5: Optimal PTH level is unknown; evaluate patients with progressively elevated intact PTH levels or if levels are consistently above the normal range (assay-dependent) (KDIGO 2017)

Dialysis patients: Maintain intact parathyroid hormone (iPTH) within 2 to 9 times the upper limit of normal for the assay used (KDIGO 2017)

Product Availability

Not available in the US

Dosage Forms: Canada

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

Capsule, Oral:

One Alpha: 0.25 mcg, 0.5 mcg, 1 mcg

Solution, Intravenous:

One-Alpha: 2 mcg/mL (0.5 mL, 1 mL) [contains alcohol, usp, propylene glycol]

Solution, Oral:

One-Alpha: 2 mcg/mL (10 mL) [contains alcohol, usp, methyl hydroxybenzoate]

Anatomic Therapeutic Chemical (ATC) Classification

• A11CC03

Generic Available (US)

No

Mechanism of Action

Alfacalcidol is rapidly converted to the active metabolite of vitamin D (1,25-dihydroxyvitamin D3) in the liver, effectively bypassing renal metabolic conversion; promotes intestinal absorption of calcium and phosphorous, resorption of calcium from the bone, and possibly renal reabsorption of calcium

Pharmacodynamics/Kinetics

Onset: 6 hours

Duration of effect on intestinal calcium absorption levels: 1,25-(OH)2 D3: 48 hours

Protein binding: Extensively to vitamin D-binding protein

Metabolism: Hepatic to 1,25-(OH)2 D3

Half-life elimination: ~3 hours in renal insufficiency

Time to peak of active vitamin D levels: Oral: 12 hours; IV: 4 hours

Local Anesthetic/Vasoconstrictor Precautions

No information available to require special precautions

Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Xerostomia (normal salivary flow resumes upon discontinuation) or abnormal taste.

Effects on Bleeding

No information available to require special precautions

Index Terms

1 alfa-Hydroxyvitamin D3; 1 Alfacalcidol; 1-α-Hydroxycholecalciferol; 1-α-Hydroxyvitamin D3

References

Bilezikian JP, Brandi ML, Cusano NE, et al. Management of hypoparathyroidism: present and future. J Clin Endocrinol Metab. 2016;101(6):2313-2324.[PubMed 26938200]

Bollerslev J, Rejnmark L, Marcocci C, et al; European Society of Endocrinology (ESE). European Society of Endocrinology Clinical Guideline: Treatment of chronic hypoparathyroidism in adults. Eur J Endocrinol. 2015;173(2):G1-G20.[PubMed 26160136]

Brandi ML, Bilezikian JP, Shoback D, et al. Management of hypoparathyroidism: summary statement and guidelines. J Clin Endocrinol Metab. 2016;101(6):2273-2283.[PubMed 26943719]

Hamdy N, Kanis JA, Beneton MN, et al, “Effect of Alfacalcidol on Natural Course of Renal Bone Disease in Mild to Moderate Renal Failure,” BMJ, 1995, 310(6976):358-63.[PubMed 7677827]

Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group, "KDIGO 2012 Clinical Practice Guidelines for the Evaluation and Management of Chronic Kidney Disease," Kidney Inter, Suppl, 2013, 3:1-150.

Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Update Work Group. KDIGO 2017 clinical practice guideline update for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease—mineral and bone disorder (CKD-MBD). Kidney Int. 2017;7(suppl 1):1-59. doi: 10.1016/j.kisu.2017.04.001.

Levin A, Hemmelgarn B, Culleton B, et al, “Canadian Guidelines for the Management of Chronic Kidney Disease,” CMAJ, 2008, 179(11):1154-62.[PubMed 19015566]

One-Alpha (alfacalcidol) [product monograph]. Thornhill, Ontario, Canada: LEO Pharma Inc; August 2017.

One-Alpha Injection (alfacalcidol) [summary of product characteristics]. Berkshire, United Kingdom: LEO Laboratories Limited; February 2013.

Tarrass F, Yazidi A, Sif H, et al, “A Randomized Trial of Intermittent Versus Continuous Oral Alfacalcidol Treatment of Hyperparathyroidism in End-Stage Renal Disease,” Clin Nephrol, 2006, 65(6):415-8.[PubMed 16792136]

Brand Names: International

1 Alpha Leo (BE); Alcidol (TH); Alfa Caps (IN); Alfa D (CR, DO, GT, HN, MT, NI, PA, SV); Alfabonid (EG); Alfacan (CN); Alfadiol (PL); Alfaget (LK); Alfarol (JP, TW); Alpha D3 (AR, CZ, EE, GR, HR, IL, IT, LI, LT, LV, PH, PY, RO, RU, SG, SI, SK, TR, UA, VE, VN); Alpha-D3 (LK); Alphacal (GR); Bon-One (CN, EG, HK, ID, MY, TH); Bondiol (DE); Bone Care (EG); Bone-One (VN); Calcicure (LK); EinsAlpha (DE); Etalpha (AT, CL, CN, DK, ES, FI, IS, LI, NL, NO, PT, RU, SE); Gr-Alfa (IN); Innosfen (BR, PY); Losefan (GR); Lusefan (LI); One Alpha (LK); One-Alpha (AE, BH, CY, EG, GB, HK, IE, IL, JO, KW, LB, LT, MT, MY, NZ, PL, QA, RO, RU, SA, SG, TH, TR, ZA); Onealfa (JP, KR, TW); Osteo-Afa (BH); Ostidil-D3 (IT); QTR-Alfa (IN); Sundiol (SK); Tevacidol (DE); Tevalfa (IL); Un Alfa (FR); Xbone (LK)

Last Updated 4/22/20