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Pronunciation

(doks er kal si fe FEER ole)

Generic Available (U.S.)

No

Index Terms

• 1α-Hydroxyergocalciferol

Brand Names: U.S.

• Hectorol®

Brand Names: Canada

• Hectorol®

Pharmacologic Category

• Vitamin D Analog

Use: Labeled Indications

Treatment of secondary hyperparathyroidism in patients with chronic kidney disease

Pregnancy Risk Factor

B

Pregnancy Considerations

Reproduction in animals (usual and high dose) do not reveal teratogenic or fetotoxic effects.

Lactation

Excretion in breast milk unknown/not recommended

Breast-Feeding Considerations

Excretion in breast milk is unknown. Other vitamin D derivatives are excreted in breast milk; there is a potential for adverse effects. Therefore, the manufacturer recommends that breast-feeding be discontinued or doxercalciferol discontinued, depending upon importance of the drug to the mother.

Contraindications

History of hypercalcemia or 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 PTH, progressive or acute hypercalcemia, hypercalciuria, hyperphosphatemia and adynamic bone disease.

• Hypercalcemia: Progressive and/or 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.

Disease-related concerns:

• Hepatic impairment: Use with caution in patients with hepatic impairment.

• Hyperphosphatemia: Should be corrected before initiating therapy; exacerbates secondary hyperparathyroidism, diminishing the effect of doxercalciferol.

Concurrent drug therapy issues:

• Cardiac glycosides: Use with caution in patients taking cardiac glycosides; digitalis toxicity is potentiated by hypercalcemia.

Special populations:

• Pediatrics: Safety and efficacy have not been established in children.

Dosage form specific issues:

• Injection: Intended for I.V. use only.

Other warnings/precautions:

• Appropriate use: Other forms of vitamin D should be discontinued when doxercalciferol is started.

Adverse Reactions

Note: As reported in dialysis patients.

>10%:

Cardiovascular: Edema (34%)

Central nervous system: Headache (28%), malaise (28%), dizziness (12%)

Gastrointestinal: Nausea/vomiting (21%)

Respiratory: Dyspnea (12%)

1% to 10%:

Cardiovascular: Bradycardia (7%)

Central nervous system: Sleep disorder (3%)

Dermatologic: Pruritus (8%)

Endocrine & metabolic: Hypercalcemia (I.V. ~1%), hyperphosphatemia (I.V. 2% to 4%)

Gastrointestinal: Anorexia (5%), dyspepsia (5%), weight gain (5%)

Neuromuscular & skeletal: Arthralgia (5%)

Miscellaneous: Abscess (3%)

Metabolism/Transport Effects

None known.

Drug 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 (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

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

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

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 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

Storage

Store at controlled room temperature of 15°C to 30°C (59°F to 86°F). The injection should be protected from light.

Mechanism of Action

Doxercalciferol is metabolized to the active form of vitamin D. The active form of vitamin D controls the intestinal absorption of dietary calcium, the tubular reabsorption of calcium by the kidneys, and in conjunction with PTH, the mobilization of calcium from the skeleton.

Pharmacodynamics/Kinetics

Metabolism: Hepatic via CYP27 to active metabolites

Half-life elimination: Active metabolite: 32-37 hours; up to 96 hours

Dosage

Oral:

Dialysis patients: Dose should be titrated to lower iPTH to 150-300 pg/mL; dose is adjusted at 8-week intervals (maximum dose: 20 mcg 3 times/week)

Initial dose: iPTH >400 pg/mL: 10 mcg 3 times/week at dialysis

Dose titration:

iPTH level decreased by 50% and >300 pg/mL: Dose can be increased to 12.5 mcg 3 times/week for 8 more weeks; this titration process can continue at 8-week intervals; each increase should be by 2.5 mcg/dose

iPTH level 150-300 pg/mL: Maintain current dose

iPTH level <100 pg/mL: Suspend doxercalciferol for 1 week; resume at a reduced dose; decrease each dose (not weekly dose) by at least 2.5 mcg

Predialysis patients: Dose should be titrated to lower iPTH to 35-70 pg/mL with stage 3 disease or to 70-110 pg/mL with stage 4 disease: Dose may be adjusted at 2-week intervals (maximum dose: 3.5 mcg/day)

Initial dose: 1 mcg/day

Dose titration:

iPTH level >70 pg/mL with stage 3 disease or >110 pg/mL with stage 4 disease: Increase dose by 0.5 mcg every 2 weeks as necessary

iPTH level 35-70 pg/mL with stage 3 disease or 70-110 pg/mL with stage 4 disease: Maintain current dose

iPTH level is <35 pg/mL with stage 3 disease or <70 pg/mL with stage 4 disease: Suspend doxercalciferol for 1 week, then resume at a reduced dose (at least 0.5 mcg lower)

I.V.:

Dialysis patients: Dose should be titrated to lower iPTH to 150-300 pg/mL; dose is adjusted at 8-week intervals (maximum dose: 18 mcg/week)

Initial dose: iPTH level >400 pg/mL: 4 mcg 3 times/week after dialysis, administered as a bolus dose

Dose titration:

iPTH level decreased by <50% and >300 pg/mL: Dose can be increased by 1-2 mcg at 8-week intervals, as necessary

iPTH level decreased by >50% and >300 pg/mL: Maintain current dose

iPTH level 150-300 pg/mL: Maintain current dose

iPTH level <100 pg/mL: Suspend doxercalciferol for 1 week; resume at a reduced dose (at least 1 mcg lower)

Hypercalcemia, hyperphosphatemia, or serum calcium times phosphorus product >55 mg²/dL²: Decrease or suspend dose and/or adjust dose of phosphate binders; if dose is suspended, resume at a reduced dose (at least 1 mcg lower)

Dosage adjustment in hepatic impairment: Use with caution; no guidelines for dosage adjustment

Monitoring Parameters

Serum calcium and phosphorus: Frequency of measurement may be dependent upon the presence and magnitude of abnormalities, the rate of progression of CKD, and the use of treatments for CKD-mineral and bone disorders (KDIGO, 2009):

CKD stage 3: Every 6-12 months

CKD stage 4: Every 3-6 months

CKD stage 5 and 5D: Every 1-3 months

Periodic 24-hour urinary calcium and phosphorus; magnesium; alkaline phosphatase every 12 months or more frequently in the presence of elevated PTH; creatinine, BUN, albumin; intact parathyroid hormone (iPTH) every 3-12 months depending on CKD severity

Reference Range

Corrected total serum calcium (K/DOQI, 2003): CKD stages 3 and 4: 8.4-10.2 mg/dL (2.1-2.6 mmol/L); CKD stage 5: 8.4-9.5 mg/dL (2.1-2.37 mmol/L); KDIGO guidelines recommend maintaining normal ranges for all stages of CKD (3-5D) (KDIGO, 2009)

Phosphorus (K/DOQI, 2003): CKD stages 3 and 4: 2.7-4.6 mg/dL (0.87-1.48 mmol/L); CKD stage 5 (including those treated with dialysis): 3.5-5.5 mg/dL (1.13-1.78 mmol/L); KDIGO guidelines recommend maintaining normal ranges for CKD stages 3-5 and lowering elevated phosphorus levels toward the normal range for CKD stage 5D (KDIGO, 2009)

Serum calcium-phosphorus product (K/DOQI, 2003): CKD stage 3-5: <55 mg²/dL²

PTH: Whole molecule, immunochemiluminometric assay (ICMA): 1.0-5.2 pmol/L; whole molecule, radioimmunoassay (RIA): 10.0-65.0 pg/mL; whole molecule, immunoradiometric, double antibody (IRMA): 1.0-6.0 pmol/L

Target ranges by stage of chronic kidney disease (KDIGO, 2009): CKD stage 3-5: Optimal iPTH is unknown; maintain normal range (assay-dependent); CKD stage 5D: Maintain iPTH within 2-9 times the upper limit of normal for the assay used

Dietary Considerations

Based on serum levels, dietary phosphorus may be restricted and/or controlled with calcium-based phosphorus binders. The daily combined calcium intake (dietary and calcium based phosphate binder) should be 1.5-2 g. Additional vitamin D supplements and magnesium-containing antacids should be avoided. Capsules contain coconut oil.

Patient Education

Stop other vitamin D products. Report headache, dizziness, weakness, sleepiness, severe nausea, vomiting, dry mouth, loss of appetite, constipation, metallic taste, muscle and/or bone pain, malaise, and difficulty thinking or concentrating. Follow diet and calcium supplements as directed by prescriber.

Geriatric Considerations

No special changes in dose are required. Caution should be used in the elderly using magnesium products (MOM, magnesium containing antacids, etc). These should be stopped if possible before initiating doxercalciferol.

Dental Health: Effects on Dental Treatment

No significant effects or complications reported

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

Dizziness and malaise are common; may cause confusion or sleep disorders

Mental Health: Effects on Psychiatric Treatment

Nausea and vomiting are common; use caution with SSRIs

Nursing: Physical Assessment/Monitoring

Provide appropriate nutritional counseling.

Dosage Forms

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

Capsule, softgel, oral:

Hectorol®: 0.5 mcg, 1 mcg, 2.5 mcg [contains coconut oil]

Injection, solution:

Hectorol®: 2 mcg/mL (1 mL, 2 mL) [contains edetate disodium, ethanol]

Pricing: U.S. (www.drugstore.com)

Capsules (Hectorol)

0.5 mcg (50): $453.99

2.5 mcg (50): $1259.96

References

Eknoyan G, Levin A, and Levin NW, “Bone Metabolism and Disease in Chronic Kidney Disease,” Am J Kidney Dis, 2003, 42(4 Suppl 3):1-201.

"K/DOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease, Guideline 1. Evaluation of Calcium and Phosphorus Metabolism." Available at http://www.kidney.org/professionals/KDOQI/guidelines_bone/Guide1.htm

"K/DOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease, Guideline 3. Evaluation of Serum Phosphorus Levels." Available at http://www.kidney.org/professionals/KDOQI/guidelines_bone/Guide3.htm

“K/DOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease, Guideline 6. Serum Calcium and Calcium-Phosphorus Product.” Available at http://www.kidney.org/professionals/KDOQI/guidelines_bone/Guide6.htm

"K/DOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease, Guideline 8A. Active Vitamin D Therapy in Patients With Stages 3 and 4 CKD." Available at http://www.kidney.org/professionals/KDOQI/guidelines_bone/Guide8A.htm

"K/DOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease, Guideline 8B. Vitamin D Therapy in Patients on Dialysis (CKD Stage 5)." Available at http://www.kidney.org/professionals/KDOQI/guidelines_bone/Guide8B.htm

"K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, and Stratification, Part 4. Definition and Classification of Stages of Chronic Kidney Disease." Available at http://www.kidney.org/professionals/KDOQI/guidelines_ckd/p4_class.htm

Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group, "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, 76(S113):1-130.

International Brand Names

• Hectorol (CA)

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Last full review/revision January 2012

Content last modified January 2012