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doxercalciferol 1 mcg capsule generic hectorol

Out of Stock Manufacturer ROXANE/WEST-WAR 00054038819
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Uses

Hyperparathyroidism Secondary to Chronic Renal Disease

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

Results of randomized clinical trials in patients with chronic kidney disease (stage 5) 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. 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). Limited data indicate that doxercalciferol-induced suppression of PTH may be associated with only a modest tendency to hypercalcemia.

Results of studies in patients with chronic kidney disease (stage 3 and 4) 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). 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.

For additional information on the use of vitamin D analogs, see the

Dosage and Administration

Administration

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

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. 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. 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). 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.

Dosage of doxercalciferol is titrated to reduce iPTH concentrations to within a target range; specific target ranges are recommended based on the degree of renal impairment. The iPTH target range for those with chronic kidney disease stage 3 (glomerular filtration rate [GFR] 30-59 mL/minute per 1.73 m), stage 4 (GFR 15-29 mL/minute per 1.73 m), or stage 5 (GFR less than 15 mL/minute per 1.73 m or on dialysis) is 35-70, 70-110, or 150-300 pg/mL, respectively.

Hyperparathyroidism Secondary to Chronic Renal Disease in Patients undergoing Dialysis

Oral Dosage

The initial oral dosage of doxercalciferol for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease undergoing dialysis and a baseline iPTH concentration exceeding 400 pg/mL is 10 mcg 3 times weekly at dialysis (approximately every other day). The initial dosage is then titrated as needed to reduce serum iPTH concentrations to within the range of 150-300 pg/mL. 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. The maximum recommended dosage is 20 mcg 3 times weekly (60 mcg weekly). If serum or plasma iPTH concentrations decline to less than 100 pg/mL, doxercalciferol therapy should be withheld for 1 week and then therapy be reinitiated at a dose 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 exceeds 55 mg/dL, the dosage of doxercalciferol should be reduced or therapy withheld and/or the dosage of concomitantly administered phosphate binders be adjusted. 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.

IV Dosage

The initial IV dosage of doxercalciferol for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease undergoing dialysis and a baseline iPTH concentration exceeding 400 pg/mL is 4 mcg 3 times weekly at the end of dialysis (approximately every other day). The initial dosage is then titrated as needed to reduce serum iPTH concentrations to within the range of 150-300 pg/mL. 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. IV dosages exceeding 18 mcg weekly have not been studied. If serum or plasma iPTH concentrations decline to less than 100 pg/mL, doxercalciferol therapy should be withheld for 1 week and then therapy be reinitiated at a dose at least 1 mcg lower than the last dose. If hypercalcemia, hyperphosphatemia, or a serum calcium times serum phosphorus product exceeds 55 mg/dL, the dosage of doxercalciferol should be reduced or therapy withheld and/or the dosage of concomitantly administered phosphate binders should be adjusted. 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.

Hyperparathyroidism Secondary to Chronic Renal Disease in Predialysis Patients

Oral Dosage

The initial oral dosage of doxercalciferol for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease who do not yet require maintenance dialysis (predialysis patients) and a baseline iPTH concentration of more than 70 or 110 pg/mL in those with stage 3 or 4 chronic kidney disease, respectively, is 1 mcg daily. 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 chronic kidney disease or 70-110 pg/mL for those with stage 4 chronic kidney disease. 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. The maximum recommended dosage is 3.5 mcg daily. If serum or plasma iPTH concentrations decline to less than 35 or 70 pg/mL, in those with stage 3 or stage 4 chronic renal disease, 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. If hypercalcemia, hyperphosphatemia, or a serum calcium times serum phosphorus product exceeds 55 mg/dL, the dosage of doxercalciferol should be reduced or therapy withheld and/or the dosage of concomitantly administered phosphate binders be adjusted. 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.

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. 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.

Cautions

Contraindications

Risk or history of hypercalcemia or hyperphosphatemia.

Evidence of vitamin D toxicity.

Known hypersensitivity to doxercalciferol or any ingredient in the formulation.

Warnings/Precautions

Major Toxicities

Hypercalcemia

May occur with vitamin D analog toxicity, and may require emergency measures. (See and 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. Chronic hypercalcemia increases the risk of soft-tissue calcification, including in the vasculature. The serum calcium-phosphorus product (Ca x P) should be maintained at less than 55 mg/dL in patients with chronic kidney disease. If hypercalcemia occurs following initiation of doxercalciferol therapy, the dosage of doxercalciferol and/or calcium-containing phosphate binders should be reduced.Radiographic evaluation of suspected areas may be useful in early detection of calcification. Vitamin D and its analogs should not be used during doxercalciferol therapy because of possible additive effects.

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. Hyperphosphatemia exacerbates secondary hyperparathyroidism and diminishes the efficacy of doxercalciferol in iPTH suppression. If hyperphosphatemia occurs following initiation of doxercalciferol therapy, the dosage of doxercalciferol should be decreased and/or the dosage of the phosphate binder increased.

Hypermagnesemia

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

General Precautions

Doxercalciferol should not be used for the treatment of nutritional vitamin D deficiency. 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.

Metabolic Effects

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

Specific Populations

Pregnancy

Category B.

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.

Pediatric Use

Safety and efficacy not established in children.

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; more frequent monitoring of iPTH, calcium, and phosphorus concentrations are recommended.

Common Adverse Effects

In studies that evaluated use of oral doxercalciferol in patients with chronic kidney disease on 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. In studies that evaluated oral doxercalciferol in predialysis patients with stage 3 or 4 chronic kidney disease, 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.

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.

Drug Interactions

Specific drug interaction studies have not been conducted.

Bile Acid Sequestrants

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

Other Drugs Affecting Lipid Absorption

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

Magnesium-containing Antacids

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

Vitamin D and Analogs

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

Hepatic Enzyme Inducers or Inhibitors

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

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