Rocaltrol Information
Rocaltrol () Description
Rocaltrol () (calcitriol) is a synthetic vitamin D analog which is active in the regulation of the absorption of calcium from the gastrointestinal tract and its utilization in the body. Rocaltrol () is available as capsules containing 0.25 mcg or 0.5 mcg calcitriol and as an oral solution containing 1 mcg/mL of calcitriol. All dosage forms contain butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) as antioxidants. The capsules contain a fractionated triglyceride of coconut oil, and the oral solution contains a fractionated triglyceride of palm seed oil. Gelatin capsule shells contain glycerin, parabens (methyl and propyl) and sorbitol, with the following dye systems: 0.25 mcg — FD&C Yellow No. 6 and titanium dioxide; 0.5 mcg — FD&C Red No. 3, FD&C Yellow No. 6 and titanium dioxide. The oral solution contains no additional adjuvants or coloring principles.
Calcitriol is a white, crystalline compound which occurs naturally in humans. It has a calculated molecular weight of 416.65 and is soluble in organic solvents but relatively insoluble in water. Chemically, calcitriol is 9,10- seco(5Z,7E)-5,7,10(19)-cholestatriene-1α, 3β, 25-triol and has the following structural formula:
The other names frequently used for calcitriol are 1α,25-dihydroxycholecalciferol, 1,25-dihydroxyvitamin D, 1,25-DHCC, 1,25(OH)D and 1,25-diOHC.
Rocaltrol () Clinical Pharmacology
Man's natural supply of vitamin D depends mainly on exposure to the ultraviolet rays of the sun for conversion of 7-dehydrocholesterol in the skin to vitamin D (cholecalciferol). Vitamin D must be metabolically activated in the liver and the kidney before it is fully active as a regulator of calcium and phosphorus metabolism at target tissues. The initial transformation of vitamin D is catalyzed by a vitamin D-25-hydroxylase enzyme (25-OHase) present in the liver, and the product of this reaction is 25 hydroxyvitamin D [25-(OH)D]. Hydroxylation of 25-(OH)D occurs in the mitochondria of kidney tissue, activated by the renal 25-hydroxyvitamin D-1 alpha-hydroxylase (alpha-OHase), to produce 1,25-(OH)2D (calcitriol), the active form of vitamin D. Endogenous synthesis and catabolism of calcitriol, as well as physiological control mechanisms affecting these processes, play a critical role regulating the serum level of calcitriol. Physiological daily production is normally 0.5 to 1.0 mcg and is somewhat higher during periods of increased bone synthesis (eg, growth or pregnancy).
The two known sites of action of calcitriol are intestine and bone. A calcitriol receptor-binding protein appears to exist in the mucosa of human intestine. Additional evidence suggests that calcitriol may also act on the kidney and the parathyroid glands. Calcitriol is the most active known form of vitamin D in stimulating intestinal calcium transport. In acutely uremic rats calcitriol has been shown to stimulate intestinal calcium absorption.
The kidneys of uremic patients cannot adequately synthesize calcitriol, the active hormone formed from precursor vitamin D. Resultant hypocalcemia and secondary hyperparathyroidism are a major cause of the metabolic bone disease of renal failure. However, other bone-toxic substances which accumulate in uremia (eg, aluminum) may also contribute.
The beneficial effect of Rocaltrol () in renal osteodystrophy appears to result from correction of hypocalcemia and secondary hyperparathyroidism. It is uncertain whether Rocaltrol () produces other independent beneficial effects. Rocaltrol () treatment is not associated with an accelerated rate of renal function deterioration. No radiographic evidence of extraskeletal calcification has been found in predialysis patients following treatment. The duration of pharmacologic activity of a single dose of calcitriol is about 3 to 5 days.
Rocaltrol () Contraindications
Rocaltrol () should not be given to patients with hypercalcemia or evidence of vitamin D toxicity. Use of Rocaltrol () in patients with known hypersensitivity to Rocaltrol () (or drugs of the same class) or any of the inactive ingredients is contraindicated.
Rocaltrol () Warnings
Overdosage of any form of vitamin D is dangerous (see). 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.
Rocaltrol () is the most potent metabolite of vitamin D available. The administration of Rocaltrol () 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 Rocaltrol () treatment to avoid possible additive effects and hypercalcemia. If treatment is switched from ergocalciferol (vitamin D) to calcitriol, it may take several months for the ergocalciferol level in the blood to return to the baseline value (see ).
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 Rocaltrol () 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.
Rocaltrol () Precautions
Excessive dosage of Rocaltrol () 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 () 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 () 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 () 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 () 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 () should avoid dehydration. Adequate fluid intake should be maintained.
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. Patients and their caregivers should also be carefully informed about the symptoms of hypercalcemia (see ).
The effectiveness of Rocaltrol () therapy is predicated on the assumption that each patient is receiving an adequate daily intake of calcium. Patients are advised to have a dietary intake of calcium at a minimum of 600 mg daily. The U.S. RDA for calcium in adults is 800 mg to 1200 mg.
Safety and effectiveness of Rocaltrol () in pediatric patients undergoing dialysis have not been established. The safety and effectiveness of Rocaltrol () in pediatric predialysis patients is based on evidence from adequate and well-controlled studies of Rocaltrol () 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 ).
Oral doses of Rocaltrol () 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 × P) product which are managed effectively by dosage adjustment or temporary discontinuation of the vitamin D derivative.
Rocaltrol () Adverse Reactions
Since Rocaltrol () is believed to be the active hormone which exerts vitamin D activity in the body, adverse effects are, in general, similar to those encountered with excessive vitamin D intake, ie, hypercalcemia syndrome or calcium intoxication (depending on the severity and duration of hypercalcemia) (see ). Because of the short biological half-life of calcitriol, pharmacokinetic investigations have shown normalization of elevated serum calcium within a few days of treatment withdrawal, ie, much faster than in treatment with vitamin D preparations.
The early and late signs and symptoms of vitamin D intoxication associated with hypercalcemia include:
In clinical studies on hypoparathyroidism and pseudohypoparathyroidism, hypercalcemia was noted on at least one occasion in about 1 in 3 patients and hypercalciuria in about 1 in 7 patients. Elevated serum creatinine levels were observed in about 1 in 6 patients (approximately one half of whom had normal levels at baseline).
In concurrent hypercalcemia and hyperphosphatemia, soft-tissue calcification may occur; this can be seen radiographically (see ).
In patients with normal renal function, chronic hypercalcemia may be associated with an increase in serum creatinine (see ).
Hypersensitivity reactions (pruritus, rash, urticaria, and very rarely severe erythematous skin disorders) may occur in susceptible individuals. One case of erythema multiforme and one case of allergic reaction (swelling of lips and hives all over the body) were confirmed by rechallenge.
Rocaltrol () Overdosage
Administration of Rocaltrol () 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 ). High intake of calcium and phosphate concomitant with Rocaltrol () may lead to similar abnormalities. The serum calcium times phosphate (Ca × P) product should not be allowed to exceed 70 mg/dL. High levels of calcium in the dialysate bath may contribute to the hypercalcemia (see ).
Rocaltrol () Dosage And Administration
The optimal daily dose of Rocaltrol () must be carefully determined for each patient. Rocaltrol () can be administered orally either as a capsule (0.25 mcg or 0.50 mcg) or as an oral solution (1 mcg/mL). Rocaltrol () therapy should always be started at the lowest possible dose and should not be increased without careful monitoring of serum calcium.
The effectiveness of Rocaltrol () therapy is predicated on the assumption that each patient is receiving an adequate but not excessive daily intake of calcium. Patients are advised to have a dietary intake of calcium at a minimum of 600 mg daily. The U.S. RDA for calcium in adults is 800 mg to 1200 mg. To ensure that each patient receives an adequate daily intake of calcium, the physician should either prescribe a calcium supplement or instruct the patient in proper dietary measures.
Because of improved calcium absorption from the gastrointestinal tract, some patients on Rocaltrol () may be maintained on a lower calcium intake. Patients who tend to develop hypercalcemia may require only low doses of calcium or no supplementation at all.
During the titration period of treatment with Rocaltrol () , serum calcium levels should be checked at least twice weekly. When the optimal dosage of Rocaltrol () has been determined, serum calcium levels should be checked every month (or as given below for individual indications). Samples for serum calcium estimation should be taken without a tourniquet.
Rocaltrol () How Supplied
Capsules: 0.25 mcg calcitriol in soft gelatin, light orange, oval capsules, imprinted with Rocaltrol () 0.25 ROCHE; bottles of 30 (NDC 0004-0143-23), and bottles of 100 (NDC 0004-0143-01).
Capsules: 0.5 mcg calcitriol in soft gelatin, dark orange, oblong capsules, imprinted with Rocaltrol () 0.5 ROCHE; bottles of 100 (NDC 0004-0144-01).
Oral Solution: a clear, colorless to pale yellow oral solution containing 1 mcg/mL of calcitriol; each amber glass bottle of 15 mL of oral solution supplied with 20 single-use, graduated oral dispensers (NDC 0004-9115-00).
Store at 59° to 86°F (15° to 30°C).
Rocaltrol ()
