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. Calcitriol is available as capsules containing 0.25 mcg or 0.5 mcg calcitriol, USP. Each capsule contains butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) as antioxidants, and medium-chain triglycerides. Gelatin capsule shells contain gelatin, glycerin, noncrystallizing sorbitol solution, methyl paraben and propyl paraben with the following dye systems:

0.25 mcg –ferric oxide red, ferric oxide yellow and titanium dioxide; 0.5 mcg –ferric oxide red and titanium dioxide. The imprinting ink contains shellac, black iron oxide, N-butyl alcohol, propylene glycol, ammonium hydroxide. Calcitriol is a white, crystalline compound which occurs naturally in humans. It has a calculated molecular weight of 416.6 and is practically insoluble in water, soluble in alcohol and fatty oils. 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 D3, 1,25-DHCC, 1,25(OH)2D3 and 1,25-diOHC.

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 D3 (cholecalciferol). Vitamin D3 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 D3 is catalyzed by a vitamin D3-25-hydroxylase enzyme (25-OHase) present in the liver, and the product of this reaction is 25­-hydroxyvitamin D3 [25-(OH)D3]. Hydroxylation of 25-(OH)D3 occurs in the mitochondria of kidney tissue, activated by the renal 25-hydroxyvitamin D3-1 alpha-hydroxylase (alpha-OHase), to produce 1,25-(OH)2D3 (calcitriol), the active form of vitamin D3. 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 mcg to 1 mcg and is somewhat higher during periods of increased bone synthesis (e.g., growth or pregnancy).



Pharmacodynamics

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 D3 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 (e.g., aluminum) may also contribute.



The beneficial effect of calcitriol in renal osteodystrophy appears to result from correction of hypocalcemia and secondary hyperparathyroidism. It is uncertain whether calcitriol produces other independent beneficial effects. Calcitriol 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.



Pharmacokinetics

Absorption

Calcitriol is rapidly absorbed from the intestine. Peak serum concentrations (above basal values) were reached within 3 to 6 hours following oral administration of single doses of 0.25 mcg to 1 mcg of calcitriol. Following a single oral dose of 0.5 mcg, mean serum concentrations of calcitriol rose from a baseline value of 40 ± 4.4 (SD) pg/mL to 60 ± 4.4 pg/mL at 2 hours, and declined to 53 ± 6.9 at 4 hours, 50 ± 7 at 8 hours, 44 ± 4.6 at 12 hours, and 41.5 ± 5.1 at 24 hours. Following multiple-dose administration, serum calcitriol levels reached steady-state within 7 days.



Distribution

Calcitriol is approximately 99.9% bound in blood. Calcitriol and other vitamin D metabolites are transported in blood, by an alpha-globulin vitamin D binding protein. There is evidence that maternal calcitriol may enter the fetal circulation. Calcitriol is transferred into human breast milk at low levels (i.e., 2.2 ± 0.1 pg/mL).



Metabolism

In vivo and in vitro studies indicate the presence of two pathways of metabolism for calcitriol. The first pathway involves the 24-­hydroxylase as the first step in catabolism of calcitriol. There is definite evidence of 24-hydroxylase activity in the kidney; this enzyme is also present in many target tissues which possess the vitamin D receptor such as the intestine. The end product of this pathway is a side chain shortened metabolite, calcitroic acid. The second pathway involves the conversion of calcitriol via the stepwise hydroxylation of carbon-26 and carbon-23, and cyclization to yield ultimately 1α, 25R(OH)2-26, 23S-lactone D3. The lactone appears to be the major metabolite circulating in humans, with mean serum concentrations of 131 ± 17 pg/mL. In addition, several other metabolites of calcitriol have been identified: 1α, 25(OH)2-24-oxo-D3; 1α, 23,25(OH)3-24-oxo-D3; 1α, 24R,25(OH)3D3; 1α, 25S,26(OH)3D3; 1α, 25(OH)2-23-oxo-D3; 1α, 25R,26(OH)3-23-oxo-D3; 1α, (OH)24,25,26,27-tetranor-COOH-D3.



Excretion

Enterohepatic recycling and biliary excretion of calcitriol occur. The metabolites of calcitriol are excreted primarily in feces. Following intravenous administration of radiolabeled calcitriol in normal subjects, approximately 27% and 7% of the radioactivity appeared in the feces and urine, respectively, within 24 hours. When a 1 mcg oral dose of radiolabeled calcitriol was administered to normal subjects, approximately 10% of the total radioactivity appeared in urine within 24 hours. Cumulative excretion of radioactivity on the sixth day following intravenous administration of radiolabeled calcitriol averaged 16% in urine and 49% in feces. The elimination half-life of calcitriol in serum after single oral doses is about 5 to 8 hours in normal subjects.



Special Populations

Pediatric Pharmacokinetics

The steady-state pharmacokinetics of oral calcitriol were determined in a small group of pediatric patients (age range: 1.8 to 16 years) undergoing peritoneal dialysis. Calcitriol was administered for 2 months at an average dose of 10.2 ng/kg (SD 5.5 ng/kg). In this pediatric population, mean Cmax was 116 pmol/L, mean serum half-life was 27.4 hours, and mean clearance was 15.3 mL/hr/kg.1



Geriatric

No studies have examined the pharmacokinetics of calcitriol in geriatric patients.



Gender

Controlled studies examining the influence of gender on calcitriol have not been conducted.



Hepatic Insufficiency

Controlled studies examining the influence of hepatic disease on calcitriol have not been conducted.



Renal Insufficiency

Lower predose and peak calcitriol levels in serum were observed in patients with nephrotic syndrome and in patients undergoing hemodialysis compared with healthy subjects. The elimination half-life of calcitriol increased by at least two-fold in chronic renal failure and hemodialysis patients compared with healthy subjects. Peak serum levels in patients with nephrotic syndrome were reached in 4 hours. For patients requiring hemodialysis peak serum levels were reached in 8 to 12 hours; half-lives were estimated to be 16.2 and 21.9 hours, respectively.

Predialysis Patients

Calcitriol 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

Calcitriol is indicated in the management of hypocalcemia and the resultant metabolic bone disease in patients undergoing chronic renal dialysis. In these patients, calcitriol 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

Calcitriol is also indicated in the management of hypocalcemia and its clinical manifestations in patients with postsurgical hypoparathyroidism, idiopathic hypoparathyroidism, and pseudohypoparathyroidism. 

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. The serum calcium times phosphate (Ca x P) product should not be allowed to exceed 70 mg2/dL2. 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 avoid possible additive effects and hypercalcemia. If treatment is switched from ergocalciferol (vitamin D2) 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 (e.g., 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.

Since calcitriol 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, i.e., hypercalcemia syndrome or calcium intoxication, depending on the severity and duration of hypercalcemia (see WARNINGS). 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, i.e., much faster than in treatment with vitamin D3 preparations.



The early and late signs and symptoms of vitamin D intoxication associated with hypercalcemia include:

Early: weakness, headache, somnolence, nausea, vomiting, dry mouth, constipation, muscle pain, bone pain, metallic taste, and anorexia, abdominal pain or stomach ache.

Late: polyuria, polydipsia, anorexia, weight loss, nocturia, conjunctivitis (calcific), pancreatitis, photophobia, rhinorrhea, pruritus, hyperthermia, decreased libido, elevated BUN, albuminuria, hypercholesterolemia, elevated SGOT (AST) and SGPT (ALT), ectopic calcification, nephrocalcinosis, hypertension, cardiac arrhythmias, dystrophy, sensory disturbances, dehydration, apathy, arrested growth, urinary tract infections, and, rarely, overt psychosis.

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 WARNINGS).

In patients with normal renal function, chronic hypercalcemia may be associated with an increase in serum creatinine (see PRECAUTIONS: General).

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.

To report SUSPECTED ADVERSE REACTIONS, contact Sun Pharmaceutical Industries, Inc. at 1-800-818-4555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 may lead to similar abnormalities. The serum calcium times phosphate (Ca x P) product should not be allowed to exceed 70 mg2/dL2. 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 mg/dL to 5.5 mg/dL, a calcium-containing phosphate-binding agent (i.e., 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.

The optimal daily dose of calcitriol capsules must be carefully determined for each patient. Calcitriol can be administered orally as a capsule (0.25 mcg or 0.5 mcg). Calcitriol therapy should always be started at the lowest possible dose and should not be increased without careful monitoring of serum calcium.



The effectiveness of calcitriol 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 calcitriol 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 calcitriol, serum calcium levels should be checked at least twice weekly. When the optimal dosage of calcitriol 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 calcitriol 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 calcitriol doses of 0.25 mcg every other day. Most patients undergoing hemodialysis respond to doses between 0.5 and 1 mcg/day.



Oral calcitriol may normalize plasma-ionized calcium in some uremic patients, yet fail to suppress parathyroid hyperfunction. In these individuals with autonomous parathyroid hyper-function, oral calcitriol may be useful to maintain normocalcemia, but has not been shown to be adequate treatment for hyperparathyroidism.



Hypoparathyroidism

The recommended initial dosage of calcitriol 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, calcitriol 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 calcitriol may be needed.



Predialysis Patients

The recommended initial dosage of calcitriol 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 calcitriol is 10 to 15 ng/kg/day.

Calcitriol capsules are available as follows:



0.25 mcg - peach colored oval, soft gelatin capsule imprinted with ‘967’ in black ink, containing clear, colorless to slightly yellowish oily liquid.



Bottles of 30 with child-resistant cap…………………..NDC 62756-967-83

Bottles of 100 with child-resistant cap…………………NDC 62756-967-88

Bottles of 1000.............................................……….….NDC 62756-967-18



0.5 mcg - brown colored oval, soft gelatin capsule imprinted with ‘968’ in black ink, containing clear, colorless to slightly yellowish oily liquid.



Bottles of 30 with child-resistant cap…………………..NDC 62756-968-83

Bottles of 100 with child-resistant cap………………..NDC 62756-968-88

Bottles of 1000..........................................……….….NDC 62756-968-18



Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F) [see USP Controlled Room Temperature]. Calcitriol Capsules should be protected from light.

Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure.

1. Jones CL, et al. Comparisons between oral and intraperitoneal 1,25-dihydroxyvitamin D3 therapy in children treated with peritoneal dialysis. Clin Nephrol. 1994; 42:44 to 49.

Distributed by:

Sun Pharmaceutical Industries, Inc.

Cranbury, NJ 08512





Manufactured by:

Sun Pharmaceutical Industries Ltd.

Halol-Baroda Highway,

Halol-389 350, Gujarat, India.





ISS. 01/2020

NDC 62756-967-88

Calcitriol Capsules

0.25 mcg

Rx only

100 Capsules

SUN PHARMA

NDC 62756-968-88

Calcitriol Capsules

0.5 mcg

Rx only

100 Capsules

SUN PHARMA