Rocaltrol 0.25 MCG Oral Capsule
WARNINGS
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 calcify-cation, nephrocalcinosis and other soft-tissue calcification.
The serum calcium times phosphate (Ca x P) product should not be allowed to exceed 70 mg 2 /dL 2 .
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 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 nonaluminum 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.
DRUG INTERACTIONS
Drug Interactions Cholestyramine Cholestyramine has been reported to reduce intestinal absorption of fat-soluble vitamins; as such it may impair intestinal absorption of Rocaltrol (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 Rocaltrol 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 Rocaltrol 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 Rocaltrol 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 Rocaltrol 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 Rocaltrol 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 Rocaltrol by patients on chronic renal dialysis.
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 ADVERSE REACTIONS ).
High intake of calcium and phosphate concomitant with Rocaltrol may lead to similar abnormalities.
The serum calcium times phosphate (Ca x 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 Rocaltrol 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, Rocaltrol 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 Rocaltrol therapy from 0.5 mcg to 0.25 mcg daily.
If the patient is receiving a therapy of 0.25 mcg daily, discontinue Rocaltrol 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, Rocaltrol 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 Rocaltrol therapy was previously administered at a dosage of 0.25 mcg/day, Rocaltrol 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 Rocaltrol 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 Rocaltrol The treatment of acute accidental overdosage of Rocaltrol 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.
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, 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 3 , 1,25-DHCC, 1,25(OH) 2 D 3 and 1,25-diOHC.
rocaltrol-01
HOW SUPPLIED
Repackaged by Aphena Pharma Solutions – TN.
See Repackaging Information for available configurations.
Capsules: 0.25 mcg calcitriol in soft gelatin, light orange, oval capsules, imprinted with R25; bottles of 30 (NDC 30698-143-23), and bottles of 100 (NDC 30698-143-01).
Capsules: 0.5 mcg calcitriol in soft gelatin, dark orange, oblong capsules, imprinted with R50; bottles of 100 (NDC 30698-144-01).
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 30698-911-15).
Rocaltrol Capsules and Oral Solution should be protected from light.
Store at 59° to 86°F (15° to 30°C).
GERIATRIC USE
Geriatric Use Clinical studies of Rocaltrol 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.
INDICATIONS AND USAGE
Predialysis Patients Rocaltrol is indicated in the management of secondary hyperparathyroidism and resultant metabolic bone disease in patients with moderate to severe chronic renal failure (Ccr 15 to 55 mL/min) not yet on dialysis.
In children, the creatinine clearance value must be corrected for a surface area of 1.73 square meters.
A serum iPTH level of ≥ 100 pg/mL is strongly suggestive of secondary hyperparathyroidism.
Dialysis Patients Rocaltrol is indicated in the management of hypocalcemia and the resultant metabolic bone disease in patients undergoing chronic renal dialysis.
In these patients, Rocaltrol administration enhances calcium absorption, reduces serum alkaline phosphatase levels, and may reduce elevated parathyroid hormone levels and the histological manifestations of osteitis fibrosa cystica and defective mineralization.
Hypoparathyroidism Patients Rocaltrol is also indicated in the management of hypocalcemia and its clinical manifestations in patients with postsurgical hypoparathyroidism, idiopathic hypoparathyroidism, and pseudohypoparathyroidism.
PEDIATRIC USE
Pediatric Use 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 nonplacebo-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: Hypoparathyroidism ).
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 x P) product which are managed effectively by dosage adjustment or temporary discontinuation of the vitamin D derivative.
PREGNANCY
Pregnancy Teratogenic Effects Pregnancy Category C.
Rocaltrol 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.
Rocaltrol 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 Rocaltrol 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 Rocaltrol at a dose of 0.08 or 0.3 mcg/kg/day, and increased serum urea nitrogen in dams given Rocaltrol 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 Rocaltrol (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.
NUSRING MOTHERS
Nursing Mothers Calcitriol from ingested Rocaltrol 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 in nursing infants, a mother should not nurse while taking Rocaltrol.
INFORMATION FOR PATIENTS
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.
Patients and their caregivers should also be carefully informed about the symptoms of hypercalcemia (see ADVERSE REACTIONS ).
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.
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.
Dialysis Patients The recommended initial dose of Rocaltrol is 0.25 mcg/day.
If a satisfactory response in the biochemical parameters and clinical manifestations of the disease state is not observed, dosage may be increased by 0.25 mcg/day at 4- to 8-week intervals.
During this titration period, serum calcium levels should be obtained at least twice weekly, and if hypercalcemia is noted, the drug should be immediately discontinued until normocalcemia ensues (see PRECAUTIONS: General ).
Phosphorus, magnesium, and alkaline phosphatase should be determined periodically.
Patients with normal or only slightly reduced serum calcium levels may respond to Rocaltrol doses of 0.25 mcg every other day.
Most patients undergoing hemodialysis respond to doses between 0.5 and 1 mcg/day.
Oral Rocaltrol may normalize plasma-ionized calcium in some uremic patients, yet fail to suppress parathyroid hyperfunction.
In these individuals with autonomous parathyroid hyper-function, oral Rocaltrol may be useful to maintain normocalcemia, but has not been shown to be adequate treatment for hyperparathyroidism.
Hypoparathyroidism The recommended initial dosage of Rocaltrol is 0.25 mcg/day given in the morning.
If a satisfactory response in the biochemical parameters and clinical manifestations of the disease is not observed, the dose may be increased at 2- to 4-week intervals.
During the dosage titration period, serum calcium levels should be obtained at least twice weekly and, if hypercalcemia is noted, Rocaltrol should be immediately discontinued until normocalcemia ensues (see PRECAUTIONS: General ).
Careful consideration should also be given to lowering the dietary calcium intake.
Serum calcium, phosphorus, and 24-hour urinary calcium should be determined periodically.
Most adult patients and pediatric patients age 6 years and older have responded to dosages in the range of 0.5 mcg to 2 mcg daily.
Pediatric patients in the 1- to 5-year age group with hypoparathyroidism have usually been given 0.25 mcg to 0.75 mcg daily.
The number of treated patients with pseudohypoparathyroidism less than 6 years of age is too small to make dosage recommendations.
Malabsorption is occasionally noted in patients with hypoparathyroidism; hence, larger doses of Rocaltrol may be needed.
Predialysis Patients The recommended initial dosage of Rocaltrol is 0.25 mcg/day in adults and pediatric patients 3 years of age and older.
This dosage may be increased if necessary to 0.5 mcg/day.
For pediatric patients less than 3 years of age, the recommended initial dosage of Rocaltrol is 10 to 15 ng/kg/day.