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 not be allowed to exceed 70. Radiographic evaluation of suspect anatomical regions may be useful in the early detection of this condition.
Since doxercalciferol is a precursor for 1(alpha),25-(OH) 2 D2, a potent metabolite of vitamin D, pharmacologic doses of vitamin D and its derivatives should be withheld during doxercalciferol treatment to avoid possible additive effects and hypercalcemia.
Oral calcium-based or other nonaluminum-containing phosphate binders and a low phosphate diet should be used to control serum phosphorus levels in patients undergoing dialysis. Uncontrolled serum phosphorus exacerbates secondary hyperparathyroidism and can lessen the effectiveness of doxercalciferol in reducing blood PTH levels. After initiating doxercalciferol therapy, the dose of phosphate binders should be decreased to correct persistent mild hypercalcemia (10.6 to 11.2 mg/dL for 3 consecutive determinations), or increased to correct persistent mild hyperphosphatemia (7.0 to 8.0 mg/dL for 3 consecutive determinations).
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
The principal adverse effects of treatment with Hectorol Injection are hypercalcemia, hyperphosphatemia, and oversuppression of iPTH (less than 150 pg/mL). Prolonged hypercalcemia can lead to calcification of soft tissues, including the heart and arteries, and hyperphosphatemia can exacerbate hyperparathyroidism. 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 maximize iPTH suppression while maintaining serum calcium and phosphorus levels within prescribed ranges.
In two open-label, single-arm, multi-centered studies, the incidence of hypercalcemia and hyperphosphatemia increased during therapy with Hectorol Injection (see ADVERSE REACTIONS section). The observed increases during Hectorol treatment 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.
Incidence Rates of Hypercalcemia and Hyperphosphatemia in
Two Phase 3 Studies with Hectorol Injection
|
Study |
Hypercalcemia
(per 100 patient weeks) |
Hyperphosphatemia
(per 100 patient weeks) |
Washout
(Off Treatment)
|
Open-Label
(Treatment)
|
Washout
(Off Treatment)
|
Open-Label
(Treatment)
|
|
Study C
|
0.9
|
0.9
|
0.9
|
2.4
|
|
Study D
|
0.3
|
1.0
|
1.2
|
3.7
|
|
INFORMATION FOR THE PATIENT
The patient, spouse, or guardian should be informed about 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).
LABORATORY TESTS
Serum levels of iPTH, calcium, and phosphorus should be determined prior to initiation of Hectorol treatment. During the early phase of treatment (i.e., first 12 weeks), serum iPTH, calcium, and phosphorus levels should be determined weekly. For dialysis patients in general, serum or plasma iPTH and serum calcium, phosphorus, and alkaline phosphatase should be determined periodically.
DRUG INTERACTIONS
Specific drug interaction studies have not been conducted. Magnesium-containing antacids and Hectorol should not be used concomitantly, because such use may lead to the development of hypermagnesemia (see WARNINGS). Although not examined specifically, enzyme inducers (such as glutethimide and phenobarbitol) may affect the 25-hydroxylation of Hectorol and may necessitate dosage adjustments.
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 oral dose of 60 mcg/wk based on mcg/m2 body surface area).
USE IN PREGNANCY
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 oral 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 70 patients treated with Hectorol Injection in the two Phase 3 clinical studies, 12 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
Studies examining the influence of hepatic insufficiency on the metabolism of Hectorol were inconclusive. Since patients with hepatic insufficiency may not metabolize doxercalciferol 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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