Calcitriol

ADVERSE REACTIONS 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, ie, 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, ie, much faster than in treatment with vitamin D 3 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 Chartwell RX, LLC. at 1-845-232-1683 or FDA at 1800-FDA-1088 or www.fda.gov/medwatch.

CONTRAINDICATIONS 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.

DESCRIPTION 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 All dosage forms contain butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) as antioxidants. The capsules contain medium chain triglycerides. Gelatin capsule shells contain glycerin, sorbitol, with the following dye systems: 0.25 mcg FD&C Yellow No. 6, FD&C red No.3 and titanium dioxide; 0.5 mcg- FD&C Yellow No. 6, FD&C red No.3 and titanium dioxide. The imprinting ink contains propylene glycol, shellac, black iron oxide, isopropyl alcohol, N-butyl alcohol and ammonium hydroxide. 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 lα,25-dihydroxycholecalciferol, 1, 25-dihydroxyvitamin D3, 1,25-DHCC, 1,25(OH) 2 D 3 and 1,25-diOHC. image description

DOSAGE AND ADMINISTRATION The optimal daily dose of calcitriol capsules must be carefully determined for each patient. Calcitriol capsule can be administered orally as a capsule (0.25 mcg or 0.50 mcg). Calcitriol capsule 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 capsule 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 capsule 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.

INDICATIONS AND USAGE Predialysis Patients Calcitriol capsule 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 capsule 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 capsule is also indicated in the management of hypocalcemia and its clinical manifestations in patients with postsurgical hypoparathyroidism, idiopathic hypoparathyroidism, and pseudohypoparathyroidism.

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 calcification, 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. 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 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.

OVERDOSAGE 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 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 capsule 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 capsule therapy from 0.5 mcg to 0.25 mcg daily. If the patient is receiving a therapy of 0.25 mcg daily, discontinue calcitriol capsule 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 capsule 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 capsule therapy was previously administered at a dosage of 0.25 mcg/day, calcitriol capsule 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 capsule 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 capsules 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.

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 3 (cholecalciferol). Vitamin D 3 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 3 is catalyzed by a vitamin D 3 -25-hydroxylase enzyme (25-OHase) present in the liver, and the product of this reaction is 25-hydroxyvitamin D 3 [25-(OH) D 3 ]. Hydroxylation of 25-(OH) D 3 occurs in the mitochondria of kidney tissue, activated by the renal 25-hydroxyvitamin D 3 -1 alpha-hydroxylase (alpha-OHase), to produce 1,25-(OH) 2 D 3 (calcitriol), the active form of vitamin D 3 . 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).

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Calcitriol Calcitriol BUTYLATED HYDROXYANISOLE BUTYLATED HYDROXYTOLUENE MEDIUM-CHAIN TRIGLYCERIDES GLYCERIN SORBITOL FD&C YELLOW NO. 6 FD&C RED NO. 3 TITANIUM DIOXIDE CALCITRIOL CALCITRIOL 673 Calcitriol Calcitriol BUTYLATED HYDROXYANISOLE BUTYLATED HYDROXYTOLUENE MEDIUM-CHAIN TRIGLYCERIDES GLYCERIN SORBITOL FD&C YELLOW NO. 6 FD&C RED NO. 3 TITANIUM DIOXIDE CALCITRIOL CALCITRIOL Oblong 674

ANDA091356

Calcitriol

Calcitriol

62135-611

HUMAN PRESCRIPTION DRUG

ORAL

PACKAGE LABEL-PRINCIPAL DISPLAY PANEL Calcitriol Capsules, 0.25 mcg - NDC 62135-610-90- 90's Bottle Label Calcitriol Capsules, 0.5 mcg - NDC 62135-611-90- 90's Bottle Label "Image Description" "Image Description"

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 D 3 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 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.

REFERENCES 1. Jones CL, et al. Comparisons between oral and intraperitoneal 1, 25-dihydroxyvitamin D 3 therapy in children treated with peritoneal dialysis. Clin Nephrol. 1994; 42:44-49. Manufactured by: Strides Pharma Science Limited Bengaluru - 562106, India Manufactured for: Chartwell RX, LLC . Congers, NY 10920 L71474 Revised 06/2023

HOW SUPPLIED Capsules: 0.25 mcg calcitriol in soft gelatin, orange, oval capsules, imprinted with 673; bottles of 90 (NDC 62135-610-90). Capsules : 0.5 mcg calcitriol in soft gelatin, orange, oblong capsules, imprinted with 674; bottles of 90 (NDC 62135-611-90). Calcitriol Capsules should be protected from light. Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]

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. 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. 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.

PRECAUTIONS