Introduction

A synthetic vitamin D analog.

Uses for Doxercalciferol

Hyperparathyroidism Secondary to Chronic Renal Disease

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

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).

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

Doxercalciferol Dosage and Administration

Administration

Administration

Administer orally without regard to meals or by direct IV injection.

Dosage

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

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

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.

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.

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

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.

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 assays ). 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. Avoid oversuppression of PTH, which may increase risk of adynamic bone disease.

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.

Adults

Dialysis Patients

Hyperparathyroidism Secondary to Chronic Renal Disease

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 2.5 mcg lower than the prior 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).

Predialysis Patients

Hyperparathyroidism Secondary to Chronic Renal Disease

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.

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).

Prescribing Limits

Adults

Oral

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

IV

Dosages >18 mcg weekly have not been studied.

Contraindications

Tendency toward hypercalcemia.

Evidence of vitamin D toxicity.

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

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity Reactions

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

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

Hypercalcemia

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

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

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

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

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

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

Hyperphosphatemia

May occur with vitamin D analog toxicity.

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

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

Hypermagnesemia

Do not use magnesium-containing antacids concomitantly with doxercalciferol.

Vitamin D Deficiency

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

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

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.

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. (See Dosage under Dosage and Administration.)

Specific Populations

Pregnancy

Category B.

Lactation

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

Pediatric Use

Safety and efficacy not established in pediatric patients.

Geriatric Use

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

Hepatic Impairment

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

Common Adverse Effects

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

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

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

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

Administration

Administration

Administer orally without regard to meals or by direct IV injection.

Dosage

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

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

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.

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.

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

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.

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 assays ). 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. Avoid oversuppression of PTH, which may increase risk of adynamic bone disease.

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.

Adults

Dialysis Patients

Hyperparathyroidism Secondary to Chronic Renal Disease

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 2.5 mcg lower than the prior 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).

Predialysis Patients

Hyperparathyroidism Secondary to Chronic Renal Disease

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.

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).

Prescribing Limits

Adults

Oral

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

IV

Dosages >18 mcg weekly have not been studied.

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.

Specific Drugs