Excessive dosage of Rocaltrol (calcitriol) induces hypercalcemia and in some instances hypercalciuria;
therefore, early in treatment during dosage adjustment, serum calcium should
be determined twice weekly. In dialysis patients, a fall in serum alkaline phosphatase
levels usually antedates the appearance of hypercalcemia and may be an indication
of impending hypercalcemia. An abrupt increase in calcium intake as a result
of changes in diet (eg, increased consumption of dairy products) or uncontrolled
intake of calcium preparations may trigger hypercalcemia.
Should hypercalcemia develop, treatment with Rocaltrol (calcitriol) should be stopped immediately. During periods of hypercalcemia, serum calcium and phosphate levels must be determined daily. When normal levels have been attained, treatment with Rocaltrol (calcitriol) can be continued, at a daily dose 0.25 mcg lower than that previously used. An estimate of daily dietary calcium intake should be made and the intake adjusted when indicated. Rocaltrol (calcitriol) should be given cautiously to patients on digitalis, because hypercalcemia in such patients may precipitate cardiac arrhythmias.
Immobilized patients, eg, those who have undergone surgery, are particularly exposed to the risk of hypercalcemia.
In patients with normal renal function, chronic hypercalcemia may be associated with an increase in serum creatinine. While this is usually reversible, it is important in such patients to pay careful attention to those factors which may lead to hypercalcemia. Rocaltrol (calcitriol) therapy should always be started at the lowest possible dose and should not be increased without careful monitoring of the serum calcium. An estimate of daily dietary calcium intake should be made and the intake adjusted when indicated.
Patients with normal renal function taking Rocaltrol (calcitriol) should avoid dehydration. Adequate fluid intake should be maintained.
For dialysis patients, serum calcium, phosphorus, magnesium, and alkaline phosphatase
should be determined periodically. For hypoparathyroid patients, serum calcium,
phosphorus, and 24-hour urinary calcium should be determined periodically. For
predialysis patients, serum calcium, phosphorus, alkaline phosphatase, creatinine,
and intact PTH (iPTH) should be determined initially. Thereafter, serum calcium,
phosphorus, alkaline phosphatase, and creatine should be determined monthly
for a 6-month period and then determined periodically. Intact PTH (iPTH) should
be determined periodically every 3 to 4 months at the time of visits. During
the titration period of treatment with Rocaltrol (calcitriol) , serum calcium levels should
be checked at least twice weekly (see DOSAGE AND ADMINISTRATION).
Carcinogenesis, Mutagenesis and Impairment of Fertility
Long-term studies in animals have not been conducted to evaluate the carcinogenic
potential of Rocaltrol (calcitriol) . Rocaltrol (calcitriol) is not mutagenic in vitro in the Ames
Test, nor is it genotoxic in vivo in the Mouse Micronucleus Test. No
significant effects of Rocaltrol (calcitriol) on fertility and/or general reproductive performances
were observed in a Segment I study in rats at doses of up to 0.3 mcg/kg (approximately
3 times the maximum recommended dose based on body surface area).
Pregnancy Category C. Rocaltrol (calcitriol) has been found to be teratogenic in rabbits
when given at doses of 0.08 and 0.3 mcg/kg (approximately 2 and 6 times the
maximum recommended dose based on mg/m2). All 15 fetuses in 3 litters
at these doses showed external and skeletal abnormalities. However, none of
the other 23 litters (156 fetuses) showed external and skeletal abnormalities
compared with controls.
Teratogenicity studies in rats at doses up to 0.45 mcg/kg (approximately 5
times maximum recommended dose based on mg/m2) showed no evidence
of teratogenic potential. There are no adequate and well-controlled studies
in pregnant women. Rocaltrol (calcitriol) should be used during pregnancy only if the potential
benefit justifies the potential risk to the fetus.
In the rabbit, dosages of 0.3 mcg/kg/day (approximately 6 times maximum recommended
dose based on surface area) administered on days 7 to 18 of gestation resulted
in 19% maternal mortality, a decrease in mean fetal body weight and a reduced
number of newborn surviving to 24 hours. A study of perinatal and postnatal
development in rats resulted in hypercalcemia in the offspring of dams given
Rocaltrol (calcitriol) at doses of 0.08 or 0.3 mcg/kg/day (approximately 1 and 3 times the
maximum recommended dose based on mg/m2), hypercalcemia and hypophosphatemia
in dams given Rocaltrol (calcitriol) at a dose of 0.08 or 0.3 mcg/kg/day, and increased serum
urea nitrogen in dams given Rocaltrol (calcitriol) at a dose of 0.3 mcg/kg/day. In another
study in rats, maternal weight gain was slightly reduced at a dose of 0.3 mcg/kg/day
(approximately 3 times the maximum recommended dose based on mg/m2)
administered on days 7 to 15 of gestation. The offspring of a woman administered
17 mcg/day to 36 mcg/day of Rocaltrol (calcitriol) (approximately 17 to 36 times the maximum
recommended dose), during pregnancy manifested mild hypercalcemia in the first
2 days of life which returned to normal at day 3.
Calcitriol from ingested Rocaltrol (calcitriol) may be excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from Rocaltrol (calcitriol) in nursing infants, a mother should not nurse while taking Rocaltrol (calcitriol) .
Safety and effectiveness of Rocaltrol (calcitriol) in pediatric patients undergoing dialysis
have not been established. The safety and effectiveness of Rocaltrol (calcitriol) in pediatric
predialysis patients is based on evidence from adequate and well-controlled
studies of Rocaltrol (calcitriol) in adults with predialysis chronic renal failure and additional
supportive data from non-placebo controlled studies in pediatric patients. Dosing
guidelines have not been established for pediatric patients under 1 year of
age with hypoparathyroidism or for pediatric patients less than 6 years of age
with pseudohypoparathyroidism (see DOSAGE AND ADMINISTRATION:
Oral doses of Rocaltrol (calcitriol) ranging from 10 to 55 ng/kg/day have been shown to improve calcium homeostasis and bone disease in pediatric patients with chronic renal failure for whom hemodialysis is not yet required (predialysis). Long-term calcitriol therapy is well tolerated by pediatric patients. The most common safety issues are mild, transient episodes of hypercalcemia, hyperphosphatemia, and increases in the serum calcium times phosphate (Ca x P) product which are managed effectively by dosage adjustment or temporary discontinuation of the vitamin D derivative.
Clinical studies of Rocaltrol (calcitriol) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.