Hectorol

Generic Name: 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

Introduction

A synthetic vitamin D analog.1 3 4 7

Uses for Hectorol

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 chronic renal disease (stage 3 and 4) who do not yet require maintenance dialysis (predialysis patients).1

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Suppresses elevated serum or plasma parathyroid hormone (PTH) concentrations associated with secondary hyperparathyroidism in patients with CKD.1 8 Potential benefits on bone have not been established; however, deficient production of biologically active vitamin D metabolites leads to secondary hyperparathyroidism, which contributes to the development of metabolic bone disease.1

Hectorol Dosage and Administration

Administration

Administration

Doxercalciferol is administered 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 based on the degree of renal impairment.1

Based on National Kidney Foundation. KDOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease. Am J Kidney Dis. 2003; 42 (Suppl 3):1-202.

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

Adults

Dialysis Patients
Hyperparathyroidism Secondary to Chronic Renal Disease
Oral
Oral Doxercalciferol Dosage Regimen in Dialysis Patients 1

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

IV
IV Doxercalciferol Dosage Regimen in Dialysis Patients 7

Initial Dosing

iPTH Concentrations

Dosage

> 400 pg/mL

4 mcg (as a bolus) 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. 7

Predialysis Patients
Hyperparathyroidism Secondary to Chronic Renal Disease
Oral
Oral Doxercalciferol Dosage Regimen in Predialysis Patients 1

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

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 Hectorol

Contraindications

Risk or history of hypercalcemia or hyperphosphatemia.1 7

Evidence of vitamin D toxicity.1 7

Known hypersensitivity to doxercalciferol or any ingredient in the formulation.1 7

Warnings/Precautions

Major Toxicities

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

Maintain serum calcium-phosphorus product (Ca × P) <55 mg2/dL2 in patients with CKD.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

General Precautions

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 effect and sustain 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 children.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 Hectorol

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

Concurrent use of vitamin D analogs and cardiac glycosides may result in 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

Potential pharmacologic effect resulting in hypermagnesemia1 7

Mineral oil

Potential interaction with drugs affecting lipid absorption (e.g., mineral oil), resulting in decreased absorption of oral doxercalciferol1

Orlistat

Potential interaction with drugs affecting lipid absorption (e.g., orlistat), resulting in decreased absorption of oral doxercalciferol1 6

Vitamin D and its analogs

Potential additive pharmacologic effect resulting in increased adverse effects, including hypercalcemia.1 7

Phenobarbital

Metabolism of doxercalciferol may be altered1 7

Dosage adjustment of doxercalciferol may be needed1 7

Hectorol 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 cytochrome P-450 (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

Store at 15–25°C.7 Protect from light.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 chronic renal disease,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 chronic renal disease, 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 a combined dietary calcium and calcium-containing phosphate binder intake of 1.5–2 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.

Doxercalciferol

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules, liquid-filled

0.5 mcg

Hectorol (with alcohol and coconut oil)

Bone Care

2.5 mcg

Hectorol (with alcohol and coconut oil)

Bone Care

Parenteral

Injection, for IV use only

2 mcg/mL

Hectorol

Bone Care

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions August 1, 2007. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Genzyme. Hectorol (doxercalciferol) capsules prescribing information. Cambridge, MA; 2006 Aug.

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. [IDIS 427313] [PubMed 10210362]

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. [PubMed 8995749]

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. [PubMed 8840332]

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

7. Genzyme. Hectorol (doxercalciferol) injection prescribing information. Cambridge, MA; 2006 Jan.

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. [IDIS 519157] [PubMed 15112179]

b. AHFS drug information 2007. McEvoy GK, ed. Vitamin D Analogs General Statement. Bethesda, MD: American Society of Health-Systems Pharmacists; 2007: pages [3634-3640]

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