VA Class:VT509

ATC Class:A11CC

AHFS Class:

• Vitamin D 88:16

Generic Name(s):

• Doxercalciferol

Chemical Name:

• (5 Z ,7 E ,22 E )-9,10-Secoergosta-5,7,10(19),22-tetraene-1α,3β-diol

Molecular Formula:

• C₂₈H₄₄O₂

Doxercalciferol (1-α-hydroxyvitamin D₂, 1-hydroxyvitamin D₂), the 1-hydroxylated form of ergocalciferol, is a synthetic vitamin D analog.1,3,4,7

Hyperparathyroidism Secondary to Chronic Renal Disease

Doxercalciferol is used for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease (CKD) undergoing dialysis.1,7 Oral doxercalciferol also is used for the treatment of secondary hyperparathyroidism in patients with stage 3 or 4 CKD who do not yet require maintenance dialysis (predialysis patients).1

Results of randomized clinical trials in patients with stage 5 CKD undergoing dialysis indicate that oral or IV doxercalciferol is more effective than placebo in decreasing plasma intact parathyroid hormone (iPTH) concentrations, with substantially more patients achieving and maintaining target plasma iPTH concentrations while receiving doxercalciferol.1,7 Approximately 54% of patients receiving oral doxercalciferol achieved plasma iPTH concentrations within the target range (150-300 pg/mL) during weeks 14-16 (reduction in iPTH was maintained until the end of the study at 24 weeks) while about 53% of those receiving IV doxercalciferol achieved plasma iPTH concentrations within the target range during weeks 10-12 (study duration was 12 weeks).1,7

Results of studies in patients with stage 3 or 4 CKD who do not yet require maintenance dialysis (predialysis patients) indicate that treatment with oral doxercalciferol is associated with substantially greater average decreases from baseline in plasma iPTH concentrations (101.4 pg/mL) than treatment with placebo (4.4 pg/mL).1,8 In these studies, mean plasma iPTH concentrations decreased by at least 30% from baseline for the last 4 weeks of therapy in 74 or 7% of patients receiving doxercalciferol or placebo, respectively.1,8

For additional information on the use of vitamin D analogs, see the Vitamin D Analogs General Statement 88:16.

Administration

Doxercalciferol is administered orally1 without regard to meals. The drug also is administered by direct IV injection.7

Dosage

Doxercalciferol dosage must be individualized carefully according to serum or plasma intact parathyroid hormone (iPTH) concentrations, with close monitoring of serum calcium and phosphorus concentrations.1,4,7 Serum calcium, phosphorus, and alkaline phosphatase, in addition to serum or plasma iPTH concentrations should be determined periodically; frequent monitoring may be necessary during doxercalciferol dosage adjustments.1,7 In patients undergoing dialysis, serum or plasma iPTH, serum calcium, and serum phosphorus concentrations should be determined prior to initiation of therapy with doxercalciferol and weekly during the early phase of therapy (i.e., the first 12 weeks).1,7 In predialysis patients, serum calcium, serum phosphorus, and plasma iPTH concentrations should be monitored 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

The manufacturer recommends that dosage of doxercalciferol be titrated to reduce iPTH concentrations to within a target ran specific target ranges are recommended based on the degree of renal impairment.1 The manufacturer states that the iPTH target range for those with chronic kidney disease (CKD) stage 3 (glomerular filtration rate [GFR] 30-59 mL/minute per 1.73 m²), stage 4 (GFR 15-29 mL/minute per 1.73 m²), or stage 5 (GFR less than 15 mL/minute per 1.73 m² or on dialysis) is 35-70, 70-110, or 150-300 pg/mL, respectively.1 However, the target ranges recommended by the manufacturer are based on the National Kidney Foundation's 2003 Kidney Disease Outcomes Quality Initiative (KDOQI) Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease.1 Nephrology experts currently state that the optimal iPTH concentration for patients with stage 3a (estimated GFR 45-59 mL/minute per 1.73 m²) to stage 5 CKD who are not undergoing dialysis is unknown, but modest increases in iPTH concentration may represent an appropriate adaptive response to declining renal function.128,129 For patients with stage 5 CKD undergoing dialysis, some experts suggest that iPTH concentrations may be maintained within a range of approximately 2-9 times the assay's upper limit of normal (ULN) (which may correspond to a range of approximately 130-600 pg/mL for commercially available assays130 ).128 Although some clinicians suggest that this range is too broad, available assays for PTH exhibit substantial variability; the 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 commercially available.126,130,131 Oversuppression of PTH may increase the risk of adynamic bone disease and should be avoided.126,131 (See Uses: Mineral and Bone Disorder Secondary to Chronic Renal Disease, in the Vitamin D Analogs General Statement 88:16.) Nephrology experts currently recommend that the individual values for serum calcium and phosphorus (evaluated together) be used instead of the mathematical construct of calcium times phosphorus product to guide clinical practice.126,128

Hyperparathyroidism Secondary to Chronic Renal Disease in Patients undergoing Dialysis

Oral Dosage

The manufacturer states that the initial oral dosage of doxercalciferol for the treatment of secondary hyperparathyroidism in adult patients with CKD undergoing dialysis who have a baseline iPTH concentration exceeding 400 pg/mL is 10 mcg 3 times weekly at dialysis (approximately every other day).1 The manufacturer states that the initial dosage is then titrated as needed to reduce serum iPTH concentrations to within the range of 150-300 pg/mL.1 If the response is inadequate (i.e., iPTH is not reduced by 50% and fails to reach the target range), the dosage may be increased at 8-week intervals by 2.5 mcg per dose.1 The maximum recommended dosage is 20 mcg 3 times weekly (60 mcg weekly).1 If serum or plasma iPTH concentrations decline to less than 100 pg/mL, doxercalciferol therapy should be withheld for 1 week and then therapy should be reinitiated at a dose at least 2.5 mcg lower than the last dose.1 The manufacturer states that if hypercalcemia, hyperphosphatemia, or a serum calcium (in mg/dL) times serum phosphorus (in mg/dL) product exceeds 55 mg²/dL², the dosage of doxercalciferol should be reduced or therapy withheld and/or the dosage of concomitantly administered phosphate binders be adjusted.1 If the serum calcium concentration is more than 1 mg/dL above the ULN, doxercalciferol should be discontinued immediately, a low-calcium diet should be instituted and calcium supplements withdrawn, and serum calcium concentrations should be measured at least weekly; therapy can be reinstituted when normocalcemia ensues (generally in 2-7 days).1 If therapy with doxercalciferol has been temporarily interrupted, doxercalciferol should be reinitiated at a dose that is at least 2.5 mcg lower than the last dose.1

IV Dosage

The manufacturer states that the initial IV dosage of doxercalciferol for the treatment of secondary hyperparathyroidism in adult patients with CKD undergoing dialysis who have a baseline iPTH concentration exceeding 400 pg/mL is 4 mcg 3 times weekly at the end of dialysis (approximately every other day).7 The manufacturer states that the initial dosage is then titrated as needed to reduce serum iPTH concentrations to within the range of 150-300 pg/mL.7 If the response is inadequate (i.e., iPTH is not reduced by 50% and fails to reach the target range), the dose given 3 times weekly may be increased by 1-2 mcg at 8-week intervals.7 IV dosages exceeding 18 mcg weekly have not been studied.7 If serum or plasma iPTH concentrations decline to less than 100 pg/mL, doxercalciferol therapy should be withheld for 1 week and then therapy should be reinitiated at a dose at least 1 mcg lower than the last dose.7 The manufacturer states that if hypercalcemia, hyperphosphatemia, or a serum calcium times serum phosphorus product exceeds 55 mg²/dL², the dosage of doxercalciferol should be reduced or therapy withheld and/or the dosage of concomitantly administered phosphate binders should be adjusted.7 If the serum calcium concentration is more than 1 mg/dL above the ULN, doxercalciferol should be discontinued immediately, a low-calcium diet should be instituted and calcium supplements withdrawn, and serum calcium concentrations should be measured at least weekly; therapy can be reinstituted when normocalcemia ensues (generally in 2-7 days).7 If therapy with doxercalciferol has been temporarily interrupted, doxercalciferol should be reinitiated at a dose that is at least 1 mcg lower than the last dose.7

Hyperparathyroidism Secondary to Chronic Renal Disease in Predialysis Patients

Oral Dosage

The manufacturer states that the initial oral dosage of doxercalciferol for the treatment of secondary hyperparathyroidism in adult patients with CKD who do not yet require maintenance dialysis (predialysis patients) and who have a baseline iPTH concentration of more than 70 pg/mL (stage 3 CKD) or 110 pg/mL (stage 4 CKD) is 1 mcg daily.1 The manufacturer states that the initial dosage is then titrated as needed to reduce serum iPTH concentrations to within the range of 35-70 pg/mL for those with stage 3 CKD or 70-110 pg/mL for those with stage 4 CKD.1 If the response is inadequate (i.e., iPTH fails to reach the target range), the dosage may be increased at 2-week intervals by 0.5 mcg per dose.1 The maximum recommended dosage is 3.5 mcg daily.1 If serum or plasma iPTH concentrations decline to less than 35 or 70 pg/mL in those with stage 3 or stage 4 CKD, respectively, doxercalciferol therapy should be withheld for 1 week and then therapy should be reinitiated at a dose at least 0.5 mcg lower than the last dose.1 The manufacturer states that if hypercalcemia, hyperphosphatemia, or a serum calcium times serum phosphorus product exceeds 55 mg²/dL², the dosage of doxercalciferol should be reduced or therapy withheld and/or the dosage of concomitantly administered phosphate binders should be adjusted.1 If the serum calcium concentration exceeds 10.7 mg/dL, doxercalciferol should be discontinued immediately, a low-calcium diet should be instituted and calcium supplements withdrawn, and serum calcium concentrations should be measured at least weekly; therapy can be reinstituted when normocalcemia ensues (generally in 2-7 days).1 If therapy with doxercalciferol has been temporarily interrupted, doxercalciferol should be reinitiated at a dose that is at least 0.5 mcg lower than the last dose.1

Special Populations

Doxercalciferol should be used with caution in patients with hepatic impairment since metabolism of the drug to the active form may be altered; specific recommendations for dosage adjustment have not been made.1,7 Hemodialysis can cause a temporary increase in serum concentrations of activated doxercalciferol (i.e., 1,25-dihydroxyvitamin D₂), probably secondary to volume contraction; the drug is not removed by hemodialysis.1,7

Contraindications

Tendency toward hypercalcemia.1,7

Evidence of vitamin D toxicity.1,7

Doxercalciferol injection is contraindicated in patients with known hypersensitivity to the drug or any ingredient in the formulation.7 (See Hypersensitivity Reactions under Warnings/Precautions: Sensitivity Reactions, in Cautions.)

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity Reactions

Serious, sometimes fatal, hypersensitivity reactions have been reported during postmarketing experience in hemodialysis patients receiving doxercalciferol injection.7 Hypersensitivity reactions have included anaphylaxis with angioedema (involving the face, lips, tongue, and airways), hypotension, unresponsiveness, chest discomfort, shortness of breath, and cardiopulmonary arrest, occurring either separately or concurrently.7 Patients receiving IV doxercalciferol should be monitored upon initiation of treatment for hypersensitivity reactions.7 If hypersensitivity reactions occur, the drug should be discontinued and appropriate treatment provided as clinically indicated.7

Hypercalcemia

Hypercalcemia may occur with vitamin D analog toxicity and may require emergency measures.1,7 (See Chronic Toxicity in the Vitamin D Analogs General Statement 88:16.) Acute hypercalcemia may increase the risk of cardiac arrhythmias and seizures, as well as having synergistic inotropic and toxic effects in the presence of cardiac glycosides.1,7 Chronic hypercalcemia increases the risk of soft-tissue calcification, including in the vasculature.1,7 If hypercalcemia occurs following initiation of doxercalciferol therapy, the dosage of doxercalciferol and/or calcium-containing phosphate binders should be reduced.1,7 Radiographic evaluation of suspected areas may be useful in early detection of calcification.1,7 Vitamin D and its analogs should not be used during doxercalciferol therapy because of possible additive effects.1,7

Hyperphosphatemia

Hyperphosphatemia may occur with vitamin D analog toxicity; calcium-containing or other non-aluminum-containing phosphate binders and a low-phosphate diet are recommended to control serum phosphate concentrations in patients with chronic kidney disease (CKD).1,7 Hyperphosphatemia exacerbates secondary hyperparathyroidism and diminishes the efficacy of doxercalciferol in intact parathyroid hormone (iPTH) suppression.1 If hyperphosphatemia occurs following initiation of doxercalciferol therapy, the dosage of doxercalciferol should be decreased and/or the dosage of the phosphate binder increased.1,7

Hypermagnesemia

Magnesium-containing antacids should not be used concomitantly with doxercalciferol.1,7

Vitamin D Deficiency

Doxercalciferol should not be used for the treatment of nutritional vitamin D deficiency.1 Patients should be evaluated for vitamin D deficiency prior to initiation of therapy with doxercalciferol; if indicated, vitamin D deficiency should be treated prior to initiating doxercalciferol.1

Metabolic Effects

Principal adverse effects of doxercalciferol are hypercalcemia, hyperphosphatemia, hypercalciuria, and excessive suppression of iPTH concentrations.1,7 In studies in patients with CKD undergoing dialysis, higher pretreatment serum calcium and phosphorus concentrations were associated with an increased risk of hypercalcemia or hyperphosphatemia during doxercalciferol therapy.1,7 (See Hypercalcemia and also Hyperphosphatemia under Cautions: Warnings/Precautions.) Hypercalciuria can accelerate the onset of renal failure through nephrocalcinosis.1 Excessive suppression of iPTH may result in adynamic bone syndrome.1,7 Management of such effects should include routine patient monitoring and appropriate dosage.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

Specific Populations

Pregnancy

Category B.1,7 (See Users Guide.)

Lactation

It is not known if doxercalciferol is distributed in 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; more frequent monitoring of iPTH, calcium, and phosphorus concentrations are recommended.1,7

Common Adverse Effects

In studies that evaluated use of oral doxercalciferol in patients with CKD requiring dialysis, adverse effects occurring in more than 2% of patients and more frequently than placebo include edema, headache, malaise, nausea/vomiting, dizziness, dyspnea, pruritus, bradycardia, anorexia, abscess, arthralgia, weight increase, constipation, and sleep disorder.1 In studies that evaluated oral doxercalciferol in predialysis patients with stage 3 or 4 CKD, adverse effects occurring in more than 5% of patients and more frequently than placebo include infection, chest pain, constipation, dyspepsia, anemia, dehydration, depression, hypertonia, insomnia, paresthesia, increased cough, dyspnea, and rhinitis.1

Potential adverse effects of doxercalciferol generally are similar to those of excessive vitamin D intake, with early manifestations of such toxicity (in association with hypercalcemia) including weakness, headache, somnolence, nausea, dry mouth, constipation, muscle or bone pain, and metallic taste and late manifestations including polyuria, polydipsia, anorexia, weight loss, nocturia, calcific conjunctivitis, pancreatitis, photophobia, rhinorrhea, pruritus, hyperthermia, decreased libido, elevated BUN, albuminuria, hypercholesterolemia, elevated serum AST and ALT, ectopic calcification, hypertension, cardiac arrhythmias, and rarely overt psychosis.1,7

Specific drug interaction studies have not been conducted.1,7

Bile Acid Sequestrants

Cholestyramine interaction reported with fat-soluble vitamins (decreased vitamin absorption); therefore, potential for interaction with oral doxercalciferol.1

Other Drugs Affecting Lipid Absorption

Potential interaction with drugs affecting lipid absorption (e.g., mineral oil, orlistat) resulting in decreased oral absorption of doxercalciferol.1,6

Magnesium-containing Antacids

Potential additive pharmacologic effect resulting in hypermagnesemia in chronic renal dialysis patients.1,7

Vitamin D and Analogs

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

Hepatic Enzyme Inducers or Inhibitors

Theoretic pharmacokinetic interaction affecting hepatic hydroxylation (activation) of doxercalciferol.1,7

Description

Doxercalciferol (1-α-hydroxyvitamin D₂, 1-hydroxyvitamin D₂), the 1-hydroxylated form of ergocalciferol, is a synthetic vitamin D analog.1,3,4,7 In the body, doxercalciferol is hydroxylated to the active moiety, 1,25-dihydroxyvitamin D₂ (1,25-dihydroxyergocalciferol), via the hepatic cytochrome P-450 (CYP) isoenzyme 27.1,7 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 parathyroid hormone (PTH).1,2,3,7 In patients with chronic kidney disease (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 unlike vitamin D₂ (ergocalciferol),2 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 (See Pharmacology and also see Uses in the Vitamin D Analogs General Statement 88:16.)

Advice to Patients

Importance of diet and calcium supplementation regimen adherence.1,7 Importance of not exceeding a combined dietary 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.)

Additional Information

Overview (see Users Guide). For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

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. [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; 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. [PubMed 15112179]

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. [PubMed 28941764]

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. [PubMed 20363541]

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. [PubMed 26224878]