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Doxercalciferol

Class: Vitamin D
ATC Class: A11CC
VA Class: VT509
Chemical Name: (5Z,7E,22E)-9,10-Secoergosta-5,7,10(19),22-tetraene-1α,3β-diol
Molecular Formula: C28H44O2
CAS Number: 54573-75-0
Brands: Hectorol

Medically reviewed by Drugs.com. Last updated on Feb 11, 2019.

Introduction

A synthetic vitamin D analog.1 3 4 7

Uses for Doxercalciferol

Hyperparathyroidism Secondary to Chronic Renal Disease

Treatment of secondary hyperparathyroidism in patients with chronic kidney disease (CKD) undergoing dialysis.1 7

Oral doxercalciferol also used in the treatment of secondary hyperparathyroidism in patients with stage 3 or 4 CKD who do not yet require maintenance dialysis (predialysis patients).1

Suppresses elevated serum or plasma parathyroid hormone (PTH) concentrations associated with secondary hyperparathyroidism in patients with CKD.1 8 Deficient production of biologically active vitamin D metabolites leads to secondary hyperparathyroidism, which contributes to the development of metabolic bone disease.1

Doxercalciferol Dosage and Administration

Administration

Administration

Administer orally1 without regard to meals or by direct IV7 injection.

Dosage

Individualize doxercalciferol dosage based on serum or plasma intact PTH (iPTH) concentrations, with close monitoring of serum calcium and phosphorus concentrations.1 4 7

In dialysis patients, measure serum iPTH, calcium, and phosphorus concentrations prior to initiation of the drug and weekly during first 12 weeks of therapy.1 7 Measure serum iPTH, calcium, phosphorus, and alkaline phosphatase concentrations periodically thereafter.1 7

In predialysis patients, monitor serum calcium, serum phosphorus, and plasma iPTH concentrations at least every 2 weeks for 3 months after initiation of therapy or after subsequent dosage changes, then monthly for 3 months (once dosage is stabilized), and every 3 months thereafter.1

Titrate dosage of doxercalciferol to reduce iPTH concentrations within a target range; specific target ranges recommended by manufacturer are based on the degree of renal impairment.1

Manufacturer's recommendations based on National Kidney Foundation's 2003 KDOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease.

Manufacturer-recommended Target Range of Intact Plasma PTH by Stage of CKD1

CKD Stage

GFR (mL/minute/1.73 m2)

Target iPTH (pg/mL)

3

30–59

35–70

4

15–29

70–110

5

<15 (or dialysis)

150–300

Nephrology experts currently state that optimal iPTH concentration for predialysis patients with stage 3a (eGFR 45–59 mL/minute per 1.73 m2) to stage 5 CKD is unknown, but modest elevations may represent an appropriate adaptive response to declining renal function.128 129

For patients with stage 5 CKD undergoing dialysis, some experts suggest maintaining iPTH concentrations within a range of approximately 2–9 times the assay's ULN (may correspond to range of approximately 130–600 pg/mL for commercial assays130 ).128 PTH assays exhibit substantial variability; previously recommended range of 150–300 pg/mL for patients with stage 5 CKD requiring dialysis was based on an assay that is no longer available.126 130 131 Avoid oversuppression of PTH, which may increase risk of adynamic bone disease.126 131

Nephrology experts currently recommend using individual values for serum calcium and phosphorus (evaluated together) instead of the mathematical construct of calcium times phosphorus product to guide clinical practice.126 128

Adults

Dialysis Patients
Hyperparathyroidism Secondary to Chronic Renal Disease
Oral
Manufacturer-recommended Oral Doxercalciferol Dosage Regimen in Dialysis Patients1

Initial Dosing

iPTH Concentrations

Dosage

>400 pg/mL

10 mcg 3 times weekly at dialysis (approximately every other day)

Dose Titration

iPTH Concentrations

Dosage

>300 pg/mL

Increase by 2.5 mcg at 8-week intervals as necessary; maximum recommended dosage is 20 mcg 3 times weekly (60 mcg weekly)

150–300 pg/mL

Maintain dosage

<100 pg/mL

Withhold for 1 week, reinitiate at a dose that is at least 2.5 mcg lower than the last dose

If hypercalcemia, hyperphosphatemia, or a serum calcium (in mg/dL) times serum phosphorus (in mg/dL) product >55 mg2/dL2, decrease dosage or withhold therapy and/or adjust dosage of concomitant phosphate binders.1

If serum calcium concentration >1 mg/dL above ULN, discontinue drug immediately, institute a low-calcium diet, withdraw calcium supplements, and measure serum calcium concentrations at least weekly; when normocalcemia ensues (generally in 2–7 days), reinstitute doxercalciferol at a reduced dose (at least 2.5 mcg lower than the prior dose).1

IV
Manufacturer-recommended IV Doxercalciferol Dosage Regimen in Dialysis Patients7

Initial Dosing

iPTH Concentrations

Dosage

> 400 pg/mL

4 mcg 3 times weekly at end of dialysis (approximately every other day)

Dose Titration

iPTH Concentrations

Dosage

Decreased by <50% and exceeding 300 pg/mL

Increase the dose given 3 times weekly by 1–2 mcg at 8-week intervals as necessary; IV dosages exceeding 18 mcg weekly have not been studied

Decreased by >50% and exceeding 300 pg/mL

Maintain dosage

150–300 pg/mL

Maintain dosage

<100 pg/mL

Withhold for 1 week, reinitiate at a dose at least 1 mcg lower than the last dose

If hypercalcemia, hyperphosphatemia, or a serum calcium (in mg/dL) times serum phosphorus (in mg/dL) product >55 mg2/dL2, decrease dosage or withhold therapy and/or adjust dosage of concomitant phosphate binders.

If serum calcium concentration >1 mg/dL above ULN, discontinue drug immediately, institute a low-calcium diet, withdraw calcium supplements, and measure serum calcium concentrations at least weekly; when normocalcemia ensues (generally in 2–7 days), reinstitute doxercalciferol at a reduced dose (at least 1 mcg lower than the prior dose).7

Predialysis Patients
Hyperparathyroidism Secondary to Chronic Renal Disease
Oral
Manufacturer-recommended Oral Doxercalciferol Dosage Regimen in Predialysis Patients1

Initial Dosing

iPTH Concentrations

Dosage

>70 pg/mL (Stage 3) and >110 pg/mL (Stage 4)

1 mcg once daily

Dose Titration

iPTH Concentrations

Dosage

> 70 pg/mL (Stage 3) and >110 pg/mL (Stage 4)

Increase by 0.5 mcg at 2-week intervals as necessary; maximum recommended dosage is 3.5 mcg once daily

35–70 pg/mL (Stage 3) and 70–110 pg/mL (Stage 4)

Maintain dosage

<35 pg/mL (Stage 3) and <70 pg/mL (Stage 4)

Withhold for 1 week, reinitiate at a dose that is at least 0.5 mcg lower than the last dose

If hypercalcemia, hyperphosphatemia, or a serum calcium (in mg/dL) times phosphorus (in mg/dL) product >55 mg2/dL2, decrease dosage or withhold therapy and/or adjust dosage of concomitant phosphate binders.1

If serum calcium concentration >10.7 mg/dL, discontinue drug immediately, institute a low-calcium diet, withdraw calcium supplements, and measure serum calcium concentrations at least weekly; when normocalcemia ensues (generally in 2–7 days), reinstitute doxercalciferol at a reduced dose (at least 0.5 mcg lower than the prior dose).1

Prescribing Limits

Adults

Oral

Maximum: 20 mcg 3 times weekly (60 mcg weekly).1

IV

Dosages >18 mcg weekly have not been studied.7

Cautions for Doxercalciferol

Contraindications

Tendency toward hypercalcemia.1 7

Evidence of vitamin D toxicity.1 7

Doxercalciferol injection: Known hypersensitivity to doxercalciferol or any ingredient in the formulation.7 (See Hypersensitivity Reactions under Cautions.)

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity Reactions

Serious, sometimes fatal, hypersensitivity reactions reported in hemodialysis patients receiving doxercalciferol injection.7 Reactions have included anaphylaxis with angioedema (involving the face, lips, tongue, and airways), hypotension, unresponsiveness, chest discomfort, shortness of breath, and cardiopulmonary arrest.7

Monitor patients for hypersensitivity reactions upon initiation of IV doxercalciferol treatment.7 If hypersensitivity reactions occur, discontinue the drug and provide clinically appropriate treatment.7

Hypercalcemia

Risk of vitamin D analog toxicity; may require emergency measures.1 7

Acute hypercalcemia may increase risk of cardiac arrhythmias, seizures, and also synergistic inotropic and toxic effects in presence of cardiac glycosides.1 7

Chronic hypercalcemia increases risk of soft-tissue calcification, including vascular calcification.1 7

If hypercalcemia develops following initiation of doxercalciferol therapy, decrease dosage of doxercalciferol and/or calcium-containing phosphate binders.1 7

Use radiographic evaluation of suspected areas for early detection of calcification.1 7

Do not use vitamin D and its analogs during doxercalciferol therapy; possible additive effects.1 7

Hyperphosphatemia

May occur with vitamin D analog toxicity.1 7

In patients with CKD, use calcium-containing or other non-aluminum-containing phosphate binders and a low-phosphate diet to control serum phosphate concentrations.1 7

If hyperphosphatemia develops following initiation of doxercalciferol therapy, decrease dosage of doxercalciferol and/or increase dosage of phosphate binder.1 7

Hypermagnesemia

Do not use magnesium-containing antacids concomitantly with doxercalciferol.1 7

Vitamin D Deficiency

Do not use doxercalciferol for treatment of nutritional vitamin D deficiency.1

Evaluate patients for vitamin D deficiency prior to initiation of doxercalciferol therapy; if indicated, vitamin D deficiency should be treated prior to initiating doxercalciferol.1

Metabolic Effects

Possible risk of hypercalcemia, hyperphosphatemia, hypercalciuria, and excessive suppression of iPTH concentrations; monitor and adjust dosages routinely to minimize risk of such effects. 1 7

Most patients require doxercalciferol dosage titration as well as adjustment of concomitant therapy (e.g., dietary phosphate binders) to optimize iPTH suppression while maintaining serum calcium and phosphorus within prescribed ranges.1 7 (See Dosage under Dosage and Administration.)

Specific Populations

Pregnancy

Category B.1 7

Lactation

Not known if doxercalciferol is distributed into milk; discontinue nursing or drug because of potential risk (e.g., hypercalcemia) in nursing infants.1 7

Pediatric Use

Safety and efficacy not established in pediatric patients.1 7

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults.1 7

Hepatic Impairment

Use with caution since doxercalciferol may not be metabolized appropriately.1 7 Monitor serum iPTH, calcium, and phosphorus concentrations more frequently.1 7

Common Adverse Effects

In dialysis patients: Edema,1 7 headache,1 7 malaise,1 7 nausea/vomiting,1 7 dizziness,1 7 dyspnea,1 7 pruritus,1 7 bradycardia.1 7

In predialysis patients with stage 3 or 4 CKD: Infection,1 chest pain,1 constipation,1 dyspepsia,1 anemia,1 dehydration,1 depression,1 hypertonia,1 insomnia,1 paresthesia,1 increased cough,1 dyspnea,1 rhinitis.1

Excessive vitamin D intake (early manifestations): Weakness,1 7 headache,1 7 somnolence,1 7 nausea,1 vomiting,7 dry mouth,1 7 constipation,1 7 bone pain,1 7 metallic taste,1 7 anorexia.1 7

Excessive vitamin D intake (late manifestations): Polyuria,1 7 polydipsia1 7 anorexia,1 7 weight loss,1 7 nocturia,1 7 calcific conjunctivitis,1 7 pancreatitis,1 7 photophobia,1 7 rhinorrhea,1 7 pruritus,1 7 hyperthermia,1 7 decreased libido,1 7 increased BUN,1 7 albuminuria,1 7 hypercholesterolemia,1 7 increased serum AST and ALT concentrations,1 7 ectopic calcification,1 7 hypertension,1 7 cardiac arrhythmias,1 7 sensory disturbances,1 7 dehydration,1 7 apathy,1 7 growth arrest,1 7 urinary tract infections.1 7

Interactions for Doxercalciferol

Drugs Affecting Hepatic Microsomal Enzymes

Possible pharmacokinetic interaction with hepatic enzyme inducers (e.g., glutethimide, phenobarbital) or inhibitors (e.g., erythromycin, ketoconazole) affecting hepatic hydroxylation (activation) of doxercalciferol.1 7

Specific Drugs

Drug

Interaction

Comments

Cardiac glycosides

Possible cardiac arrhythmias1

Cholestyramine

Intestinal absorption of oral doxercalciferol may be decreased1

Erythromycin

Serum concentrations of active moiety of doxercalciferol may be reduced1 7

Glutethimide

Metabolism of doxercalciferol may be altered1 7

Dosage adjustment of doxercalciferol may be needed1 7

Ketoconazole

Serum concentrations of active moiety of doxercalciferol may be reduced1 7

Magnesium-containing antacids

Possible hypermagnesemia1 7

Mineral oil

Possible decreased absorption of oral doxercalciferol1

Orlistat

Possible decreased absorption of oral doxercalciferol1 6

Vitamin D and its analogs

Potential additive pharmacologic effect resulting in increased adverse effects, including hypercalcemia1 7

Phenobarbital

Metabolism of doxercalciferol may be altered1 7

Dosage adjustment of doxercalciferol may be needed1 7

Doxercalciferol Pharmacokinetics

Absorption

Bioavailability

Absorbed from GI tract, with peak blood concentrations of 1α,25-dihydroxyergocalciferol (major metabolite) usually attained within 11–12 hours after repeated oral dosing.1 Following IV administration, peak blood concentrations of 1,25-dihydroxyergocalciferol are achieved in about 8 hours.7

Elimination

Metabolism

Hydroxylated to the active moiety, 1α,25-dihydroxyergocalciferol (1α,25-dihydroxyvitamin D2) via the hepatic CYP isoenzyme 27.1 7

Half-life

Active moiety (1α,25-dihydroxyvitamin D2): 32–37 hours (ranging up to 96 hours).1

Special Populations

Temporary increases in mean concentrations of 1α,25-dihydroxyvitamin D2 (major metabolite) occur in patients undergoing hemodialysis.1

Stability

Storage

Oral

Capsules

20–25°C.1

Parenteral

Injection

25°C (may be exposed to 15–30°C).7 Protect from light.7

Store multidose vial at 2–8°C after initial use; discard unused portions 3 days after initial use.7

Actions

  • Activated metabolites and analogs of vitamin D increase the intestinal absorption of dietary calcium and the renal tubular reabsorption of urinary calcium, as well as modulating bone formation and resorption, in conjunction with PTH.1 2 3 7

  • In patients with CKD,1 decreased metabolic activation of vitamin D in the kidneys results in secondary hyperparathyroidism and osteodystrophy or rickets.1 2 3 4 7

  • Because doxercalciferol,1 does not require renal hydroxylation for activation, this analog can reduce serum or plasma PTH concentrations in patients with CKD, which contributes to metabolic bone disease in these patients.1 7

Advice to Patients

Importance of diet and calcium supplementation regimen adherence.1 7

Importance of not exceeding a combined dietary calcium and calcium-containing phosphate binder intake of 2 g of calcium daily.1

Importance of serum iPTH, calcium, phosphorus, and alkaline phosphatase monitoring prior to initiation of therapy and periodically thereafter.1 7

Importance of immediate reporting of potential manifestations of hypercalcemia.1 7

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.1 7

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 7

Importance of informing patients of other precautionary information.1 7 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Doxercalciferol

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules, liquid-filled

0.5 mcg*

Doxercalciferol Capsules

Hectorol

Genzyme

1 mcg*

Doxercalciferol Capsules

Hectorol

Genzyme

2.5 mcg*

Doxercalciferol Capsules

Hectorol

Genzyme

Parenteral

Injection, for IV use only

2 mcg/mL*

Doxercalciferol Injection

Hectorol

Genzyme

AHFS DI Essentials™. © Copyright 2019, Selected Revisions February 11, 2019. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Genzyme. Hectorol (doxercalciferol) capsules prescribing information. Cambridge, MA; 2010 Dec.

2. Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, Food and Nutrition Board, Institute of Medicine. Vitamin D. In: Dietary reference intakes for calcium, phosphorus, magnesium, vitamin D, and fluoride. National Academy of Press: Washington, DC; 1997:250-87.

3. Sakhaee K, Gonzalez GB. Update on renal osteodystrophy: pathogenesis and clinical management. Am J Med Sci. 1999; 317:251-60. http://www.ncbi.nlm.nih.gov/pubmed/10210362?dopt=AbstractPlus

4. Tan AU Jr, Levine BS, Mazess RB et al. Effective suppression of parathyroid hormone by 1 alpha-hydroxy-vitamin D2 in hemodialysis patients with moderate to severe secondary hyperparathyroidism. Kidney Int. 1997; 51:317-23. http://www.ncbi.nlm.nih.gov/pubmed/8995749?dopt=AbstractPlus

5. Coburn JW, Tan AU Jr, Levine BS et al. 1 Alpha-hydroxy-vitamin D2: a new look at an “old” compound. Nephrol Dial Transplant. 1996; 11(Suppl 3):153-7. http://www.ncbi.nlm.nih.gov/pubmed/8840332?dopt=AbstractPlus

6. Roche Pharmaceuticals. Menical (orlistat) capsules prescribing information. Nutley, NJ; 1999 Apr.

7. Genzyme. Hectorol (doxercalciferol) injection prescribing information. Cambridge, MA; 2016 Jun.

8. Coburn JW, Maung HM, Elangovan L et al. Doxercalciferol safely suppresses PTH levels in patients with secondary hyperparathyroidism associated with chronic kidney disease stages 3 and 4. Am J Kidney Dis. 2004; 43:877-90. http://www.ncbi.nlm.nih.gov/pubmed/15112179?dopt=AbstractPlus

126. 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. 2009; 76 (Suppl 113): S1–S130.

128. 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 Suppl. 2017; 7:1-59.

129. Isakova T, Nickolas TL, Denburg M et al. KDOQI US Commentary on the 2017 KDIGO Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). Am J Kidney Dis. 2017; 70:737-751. http://www.ncbi.nlm.nih.gov/pubmed/28941764?dopt=AbstractPlus

130. Uhlig K, Berns JS, Kestenbaum B et al. KDOQI US commentary on the 2009 KDIGO Clinical Practice Guideline for the Diagnosis, Evaluation, and Treatment of CKD-Mineral and Bone Disorder (CKD-MBD). Am J Kidney Dis. 2010; 55:773-99. http://www.ncbi.nlm.nih.gov/pubmed/20363541?dopt=AbstractPlus

131. Bover J, Ureña P, Ruiz-García C et al. Clinical and Practical Use of Calcimimetics in Dialysis Patients With Secondary Hyperparathyroidism. Clin J Am Soc Nephrol. 2016; 11:161-74. http://www.ncbi.nlm.nih.gov/pubmed/26224878?dopt=AbstractPlus

b. AHFS Drug Information. McEvoy GK, ed. Vitamin D Analogs General Statement. Bethesda, MD: American Society of Health-Systems Pharmacists.

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