WARNINGS
Overdosage of any form of vitamin D, including Hectorol®, is dangerous (see OVERDOSAGE). Progressive hypercalcemia due to overdosage of vitamin D and its metabolites may be so severe as to require emergency attention. Acute hypercalcemia may exacerbate tendencies for cardiac arrhythmias and seizures and may potentiate the action of digitalis drugs. Chronic hypercalcemia can lead to generalized vascular calcification and other soft-tissue calcification. The serum calcium times serum phosphorus (Ca X P) product should be maintained at<55 mg2/dL2 in patients with chronic kidney disease. Radiographic evaluation of suspect anatomical regions may be useful in the early detection of this condition.
Since doxercalciferol is a precursor for 1α,25-(OH)2D2, a potent metabolite of vitamin D2, pharmacologic doses of vitamin D and its derivatives should be withheld during Hectorol® treatment to avoid possible additive effects and hypercalcemia.
Oral calcium-based or other non-aluminum-containing phosphate binders and a low phosphate diet should be used to control serum phosphorus levels in patients with chronic kidney disease. Uncontrolled serum phosphorus exacerbates secondary hyperparathyroidism and can lessen the effectiveness of Hectorol® in reducing blood PTH levels. If hypercalcemia occurs after initiating Hectorol® therapy, the dose of Hectorol® and/or calcium-containing phosphate binders should be decreased. If hyperphosphatemia occurs after initiating Hectorol®, the dose of Hectorol® should be decreased and/or the dose of phosphate binders increased. (See dosing recommendations for Hectorol® under DOSAGE AND ADMINISTRATION section.)
Magnesium-containing antacids and Hectorol® should not be used concomitantly in patients on chronic renal dialysis because such use may lead to the development of hypermagnesemia.
PRECAUTIONS
General
Active vitamin D sterols should not be used as initial treatment of nutritional vitamin D deficiency (as defined by low 25-hydroxy vitamin D). Patients should be checked and treated for nutritional vitamin D deficiency prior to initiating treatment with Hectorol®.
The principal adverse effects of treatment with Hectorol® are hypercalcemia, hyperphosphatemia, hypercalciuria, and oversuppression of iPTH. Prolonged hypercalcemia can lead to calcification of soft tissues, including the heart and arteries, and hyperphosphatemia can exacerbate hyperparathyroidism. Hypercalciuria can accelerate the onset of renal failure through nephrocalcinosis. Oversuppression of iPTH may lead to adynamic bone syndrome. All of these potential adverse effects should be managed by regular patient monitoring and appropriate dosage adjustments. During treatment with Hectorol®, patients usually require dose titration, as well as adjustment in co-therapy (i.e., dietary phosphate binders) in order to effect and sustain PTH suppression while maintaining serum calcium and phosphorus within prescribed ranges.
Dialysis:
In four adequate and well-controlled studies, the incidence of hypercalcemia and hyperphosphatemia increased during therapy with Hectorol®. The observed increases during Hectorol® treatment, although occurring at a low rate, underscore the importance of regular safety monitoring of serum calcium and phosphorus levels throughout treatment. Patients with higher pre-treatment serum levels of calcium (>10.5 mg/dL) or phosphorus (>6.9 mg/dL) were more likely to experience hypercalcemia or hyperphosphatemia. Therefore, Hectorol® should not be given to patients with a recent history of hypercalcemia or hyperphosphatemia, or evidence of vitamin D toxicity.
Pre-dialysis:
In two clinical studies, the incidences of hypercalcemia and hyperphosphatemia during therapy with Hectorol® were similar to placebo therapy, and no episodes of hypercalciuria were observed. The baseline median 25-(OH) vitamin D levels of patients enrolled in these studies was 17.2 ng/mL. Ninety-three percent of patients had 25-(OH) vitamin D levels less than 30 ng/mL; 26% had 25-(OH) vitamin D levels ≥20 to <30 ng/mL; 58% had levels>10 to <20 ng/mL; 7% had levels >5 to <10 ng/mL; and 2% had levels <5 ng/mL. The incidences of hypercalcemia, hyperphosphatemia, and hypercalciuria in patients treated with Hectorol® for hyperparathyroidism related to pre-dialysis renal insufficiency has not been fully studied when 25-OH vitamin D levels are greater than or equal to 30 ng/mL.
Information for the Patient
The patient, spouse, or guardian should be informed about compliance with dosage instructions, adherence to instructions about diet, calcium supplementation, and avoidance of the use of nonprescription drugs without prior approval from their physician. Patients should also be carefully informed about the symptoms of hypercalcemia (see ADVERSE REACTIONS section).
Patients should have a combined (dietary and calcium based phosphate binder) daily intake of 1.5 to 2 g of calcium.
Laboratory Tests
Serum or plasma iPTH and serum calcium, phosphorus, and alkaline phosphatase should be determined periodically. In the early phase of treatment for dialysis patients, iPTH, serum calcium, and serum phosphorus should be determined prior to initiation of Hectorol® treatment and weekly thereafter. For pre-dialysis patients, serum levels of calcium and phosphorus and plasma levels of iPTH should be monitored at least every two weeks for 3 months after initiation of Hectorol® therapy or following dose-adjustments in Hectorol® therapy, then monthly for 3 months, and every 3 months thereafter.
Drug Interactions
Specific drug interaction studies have not been conducted. Cholestyramine has been reported to reduce intestinal absorption of fat-soluble vitamins; therefore, it may impair intestinal absorption of doxercalciferol. Magnesium-containing antacids and Hectorol® should not be used concomitantly because such use may lead to the development of hypermagnesemia (see WARNINGS). The use of mineral oil or other substances that may affect absorption of fat may influence the absorption and availability of Hectorol®. Although not examined specifically, enzyme inducers (such as glutethimide and phenobarbital) may affect the 25-hydroxylation of Hectorol® and may necessitate dosage adjustments. Cytochrome P450 inhibitors (such as ketoconazole and erythromycin) may inhibit the 25-hydroxylation of Hectorol®. Hence, formation of the active Hectorol® moiety may be hindered.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term studies in animals to evaluate the carcinogenic potential of doxercalciferol have not been conducted. No evidence of genetic toxicity was observed in an in vitro bacterial mutagenicity assay (Ames test) or a mouse lymphoma gene mutation assay. Doxercalciferol caused structural chromatid and chromosome aberrations in an in vitro human lymphocyte clastogenicity assay with metabolic activation. However, doxercalciferol was negative in an in vivo mouse micronucleus clastogenicity assay. Doxercalciferol had no effect on male or female fertility in rats at oral doses up to 2.5 mcg/kg/day (approximately 3 times the maximum recommended human dose of 60 mcg/week based on mcg/m2 body surface area).
Pregnancy Category B
Reproduction studies in rats and rabbits, at doses up to 20 mcg/kg/day and 0.1 mcg/kg/day (approximately 25 times and less than the maximum recommended human dose of 60 mcg/week based on mcg/m2 body surface area, respectively) have revealed no teratogenic or fetotoxic effects due to doxercalciferol. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Nursing Mothers
It is not known whether doxercalciferol is excreted in human milk. Because other vitamin D derivatives are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from doxercalciferol, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use
Safety and efficacy of Hectorol® in pediatric patients have not been established.
Geriatric Use
Of the 138 patients treated with Hectorol® Capsules in two Phase 3 clinical studies, 30 patients were 65 years or over. In these studies, no overall differences in efficacy or safety were observed between patients 65 years or older and younger patients.
Hepatic Insufficiency
Since patients with hepatic insufficiency may not metabolize Hectorol® appropriately, the drug should be used with caution in patients with impaired hepatic function. More frequent monitoring of iPTH, calcium, and phosphorus levels should be done in such individuals.
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