Calcitriol

Calcitriol should not be given to patients with hypercalcemia or evidence of vitamin D toxicity. Use of calcitriol in patients with known hypersensitivity to calcitriol (or drugs of the same class) or any of the inactive ingredients is contraindicated.

• Overdosage of any form of vitamin D is dangerous (see OVERDOSAGE ).
• Progressive hypercalcemia due to overdosage of vitamin D and its metabolites may be so severe as to require emergency attention.
• Chronic hypercalcemia can lead to generalized vascular calcification, nephrocalcinosis and other soft-tissue calcification.
• Radiographic evaluation of suspect anatomical regions may be useful in the early detection of this condition.
• Calcitriol is the most potent metabolite of vitamin D available.
• The administration of calcitriol to patients in excess of their daily requirements can cause hypercalcemia, hypercalciuria, and hyperphosphatemia.
• Therefore, pharmacologic doses of vitamin D and its derivatives should be withheld during calcitriol treatment to
• If treatment is switched from ergocalciferol (vitamin D 2 ) to calcitriol, it may take several months for the ergocalciferol level in the blood to return to the baseline value (see OVERDOSAGE ).
• Calcitriol increases inorganic phosphate levels in serum.
• While this is desirable in patients with hypophosphatemia, caution is called for in patients with renal failure because of the danger of ectopic calcification.
• A non-aluminum phosphate-binding compound and a low-phosphate diet should be used to control serum phosphorus levels in patients undergoing dialysis.
• Magnesium-containing preparations (eg, antacids) and calcitriol should not be used concomitantly in patients on chronic renal dialysis because such use may lead to the development of hypermagnesemia.
• Studies in dogs and rats given calcitriol for up to 26 weeks have shown that small increases of calcitriol above endogenous levels can lead to abnormalities of calcium metabolism with the potential for calcification of many tissues in the body.
• General Excessive dosage of 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 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 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.
• 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.
• While this is usually reversible, it is important in such patients to pay careful attention to those factors which may lead to hypercalcemia.
• 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 calcitriol should avoid dehydration.
• Adequate fluid intake should be maintained.
• Information For Patients The patient and his or her caregivers should be informed about compliance with dosage instructions, adherence to instructions about diet and calcium supplementation, and avoidance of the use of unapproved nonprescription drugs.
• The U.S.
• Laboratory Tests 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 calcitriol, serum calcium levels should be checked at least twice weekly (see DOSAGE AND ADMINISTRATION ).
• Drug Interactions Cholestyramine Cholestyramine has been reported to reduce intestinal absorption of fat-soluble vitamins; as such it may impair intestinal absorption of calcitriol (see WARNINGS and PRECAUTIONS:
• General ).
• General ).
• General ).
• Carcinogenesis, Mutagenesis, Impairment Of Fertility Long-term studies in animals have not been conducted to evaluate the carcinogenic potential of calcitriol.
• 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 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 Teratogenic Effects Pregnancy Category C.
• Nursing Mothers Calcitriol from ingested calcitriol may be excreted in human milk.
• Pediatric Use Safety and effectiveness of calcitriol in pediatric patients undergoing dialysis have not been established.
• Geriatric Use Clinical studies of calcitriol did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
• General Excessive dosage of 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 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 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.
• 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.
• While this is usually reversible, it is important in such patients to pay careful attention to those factors which may lead to hypercalcemia.
• 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 calcitriol should avoid dehydration.
• Adequate fluid intake should be maintained.

• Teratogenic Effects Pregnancy Category C.
• 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/m 2 ).
• 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/m 2 ) showed no evidence of teratogenic potential.
• There are no adequate and well-controlled studies in pregnant women.
• Calcitriol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
• Nonteratogenic Effects 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 calcitriol at doses of 0.08 or 0.3 mcg/kg/day (approximately 1 and 3 times the maximum recommended dose based on mg/m 2 ), hypercalcemia and hypophosphatemia in dams given calcitriol at a dose of 0.08 or 0.3 mcg/kg/day, and increased serum urea nitrogen in dams given 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/m 2 ) administered on days 7 to 15 of gestation.
• The offspring of a woman administered 17 mcg/day to 36 mcg/day of 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 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 calcitriol in nursing infants, a mother should not nurse while taking calcitriol.

• Cholestyramine Cholestyramine has been reported to reduce intestinal absorption of fat-soluble vitamins; as such it may impair intestinal absorption of calcitriol (see WARNINGS and PRECAUTIONS:
• General ).
• Phenytoin/Phenobarbital The coadministration of phenytoin or phenobarbital will not affect plasma concentrations of calcitriol, but may reduce endogenous plasma levels of 25(OH)D 3 by accelerating metabolism.
• Since blood level of calcitriol will be reduced, higher doses of calcitriol may be necessary if these drugs are administered simultaneously.
• Thiazides Thiazides are known to induce hypercalcemia by the reduction of calcium excretion in urine.
• Some reports have shown that the concomitant administration of thiazides with Calcitriol causes hypercalcemia.
• Therefore, precaution should be taken when coadministration is necessary.
• Digitalis Calcitriol dosage must be determined with care in patients undergoing treatment with digitalis, as hypercalcemia in such patients may precipitate cardiac arrhythmias (see PRECAUTIONS:
• General ).
• Ketoconazole Ketoconazole may inhibit both synthetic and catabolic enzymes of calcitriol.
• Reductions in serum endogenous calcitriol concentrations have been observed following the administration of 300 mg/day to 1200 mg/day ketoconazole for a week to healthy men.
• However, in vivo drug interaction studies of ketoconazole with calcitriol have not been investigated.
• Corticosteroids A relationship of functional antagonism exists between vitamin D analogues, which promote calcium absorption, and corticosteroids, which inhibit calcium absorption.
• Phosphate-Binding Agents Since calcitriol also has an effect on phosphate transport in the intestine, kidneys and bones, the dosage of phosphate-binding agents must be adjusted in accordance with the serum phosphate concentration.
• Vitamin D Since calcitriol is the most potent active metabolite of vitamin D 3 , pharmacological doses of vitamin D and its derivatives should be withheld during treatment with calcitriol to
• avoid possible additive effects and hypercalcemia (see WARNINGS ).
• Calcium Supplements Uncontrolled intake of additional calcium-containing preparations should be avoided (see PRECAUTIONS:
• General ).
• Magnesium Magnesium-containing preparations (eg, antacids) may cause hypermagnesemia and should therefore not be taken during therapy with calcitriol by patients on chronic renal dialysis.

• Administration of calcitriol to patients in excess of their daily requirements can cause hypercalcemia, hypercalciuria, and hyperphosphatemia.
• Since calcitriol is a derivative of vitamin D, the signs and symptoms of overdose are the same as for an overdose of vitamin D (see ADVERSE REACTIONS ).
• High intake of calcium and phosphate concomitant with Calcitriol capsules may lead to similar abnormalities.
• The serum calcium times phosphate (Ca × P) product should not be allowed to exceed 70 mg 2 /dL 2 .
• High levels of calcium in the dialysate bath may contribute to the hypercalcemia (see WARNINGS ).
• Treatment of Hypercalcemia and Overdosage in Dialysis Patients and Hypoparathyroidism Patients General treatment of hypercalcemia (greater than 1 mg/dL above the upper limit of the normal range) consists of immediate discontinuation of calcitriol therapy, institution of a low-calcium diet and withdrawal of calcium supplements.
• Serum calcium levels should be determined daily until normocalcemia ensues.
• Hypercalcemia frequently resolves in 2 to 7 days.
• When serum calcium levels have returned to within normal limits, calcitriol therapy may be reinstituted at a dose of 0.25 mcg/day less than prior therapy.
• Serum calcium levels should be obtained at least twice weekly after all dosage changes and subsequent dosage titration.
• In dialysis patients, persistent or markedly elevated serum calcium levels may be corrected by dialysis against a calcium-free dialysate.
• Treatment of Hypercalcemia and Overdosage in Predialysis Patients If hypercalcemia ensues (greater than 1 mg/dL above the upper limit of the normal range), adjust dosage to achieve normocalcemia by reducing calcitriol therapy from 0.5 mcg to 0.25 mcg daily.
• If the patient is receiving a therapy of 0.25 mcg daily, discontinue calcitriol until patient becomes normocalcemic.
• Calcium supplements should also be reduced or discontinued.
• Serum calcium levels should be determined 1 week after withdrawal of calcium supplements.
• If serum calcium levels have returned to normal, calcitriol therapy may be reinstituted at a dosage of 0.25 mcg/day if previous therapy was at a dosage of 0.5 mcg/day.
• If calcitriol therapy was previously administered at a dosage of 0.25 mcg/day, calcitriol therapy may be reinstituted at a dosage of 0.25 mcg every other day.
• If hypercalcemia is persistent at the reduced dosage, serum PTH should be measured.
• If serum PTH is normal, discontinue calcitriol therapy and monitor patient in 3 months' time.
• Treatment of Hyperphosphatemia in Predialysis Patients If serum phosphorus levels exceed 5.0 mg/dL to 5.5 mg/dL, a calcium-containing phosphate-binding agent (ie, calcium carbonate or calcium acetate) should be taken with meals.
• Serum phosphorus levels should be determined as described earlier (see PRECAUTIONS:
• Laboratory Tests ).
• Aluminum-containing gels should be used with caution as phosphate-binding agents because of the risk of slow aluminum accumulation.
• Treatment of Accidental Overdosage of Calcitriol The treatment of acute accidental overdosage of calcitriol should consist of general supportive measures.
• If drug ingestion is discovered within a relatively short time, induction of emesis or gastric lavage may be of benefit in preventing further absorption.
• If the drug has passed through the stomach, the administration of mineral oil may promote its fecal elimination.
• Serial serum electrolyte determinations (especially calcium), rate of urinary calcium excretion, and assessment of electrocardiographic abnormalities due to hypercalcemia should be obtained.
• Such monitoring is critical in patients receiving digitalis.
• Discontinuation of supplemental calcium and a low-calcium diet are also indicated in accidental overdosage.
• Due to the relatively short duration of the pharmacological action of calcitriol, further measures are probably unnecessary.
• Should, however, persistent and markedly elevated serum calcium levels occur, there are a variety of therapeutic alternatives which may be considered, depending on the patient's underlying condition.
• These include the use of drugs such as phosphates and corticosteroids as well as measures to induce an appropriate forced diuresis.
• The use of peritoneal dialysis against a calcium-free dialysate has also been reported.