Calcitriol

INDICATIONS AND USAGE Predialysis Patients Calcitriol capsules re 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 capsules are indicated in the management of hypocalcemia and the resultant metabolic bone disease in patients undergoing chronic renal dialysis. In these patients, calcitriol capsules 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 capsules are also indicated in the management of hypocalcemia and its clinical manifestations in patients with postsurgical hypoparathyroidism, idiopathic hypoparathyroidism, and pseudohypoparathyroidism.

DOSAGE AND ADMINISTRATION The optimal daily dose of calcitriol capsules must be carefully determined for each patient. Calcitriol capsules are administered orally as a capsule (0.25 mcg or 0.50 mcg). Calcitriol capsules 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 capsules 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 capsules 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 capsules, serum calcium levels should be checked at least twice weekly. When the optimal dosage of calcitriol capsules 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 capsules 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 capsules doses of 0.25 mcg every other day. Most patients undergoing hemodialysis respond to doses between 0.5 and 1 mcg/day. Oral calcitriol capsules may normalize plasma-ionized calcium in some uremic patients, yet fail to suppress parathyroid hyperfunction. In these individuals with autonomous parathyroid hyperfunction, oral calcitriol capsules may be useful to maintain normocalcemia, but has not been shown to be adequate treatment for hyperparathyroidism. Hypoparathyroidism The recommended initial dosage of calcitriol capsules 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 capsules 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 capsules may be needed. Predialysis Patients The recommended initial dosage of calcitriol capsules is 0.25 mcg/day in adults and pediatric patients 3 years of age and older. This dosag …

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

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, 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 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. Call your doctor for medical advice about side effects. You may report side effects to Strides Pharma Inc. at 1-877-244-9825 or go to www.stridesshasun.com

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 ). 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 (e.g., antacids) may cause hypermagnesemia and should therefore not be taken during therapy with calcitriol by patients on chronic renal dialysis.

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 capsules are available containing 0.25 mcg of calcitriol, USP. Calcitriol capsules contain butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) as antioxidants. The capsules contain a fractionated triglyceride of coconut oil. Gelatin capsule shells contain gelatin, glycerin (anhydrous), and titanium dioxide, with the following dyes: FD&C Yellow No. 5 and FD&C Yellow No. 6. In addition to the ingredients listed above, each capsule contains Opacode (Black) monogramming ink. Opacode (Black) contains ammonium hydroxide, iron oxide black, isopropyl alcohol, macrogol, polyvinyl acetate phthalate, propylene glycol, purified water and SDA 35A alcohol. Calcitriol, USP is a white to almost white crystal which occurs naturally in humans. It has a calculated molecular weight of 416.6 and is soluble in organic solvents but practically insoluble in water. Chemically, calcitriol, USP is 9,10-seco(5Z,7E)-5,7,10(19)-cholestatriene-1α, 3β, 25-triol and has the following structural formula: C 27 H 44 O 3 The other names frequently used for calcitriol, USP are 1α, 25-dihydroxycholecalciferol, 1,25-dihydroxyvitamin D 3 ,1,25-DHCC, 1,25(OH) 2 D 3 and 1,25-diOHC. chem-structure.jpg

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 (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 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 cal …

HOW SUPPLIED Calcitriol Capsules 0.25 mcg are supplied as opaque orange color, oval shaped capsules, imprinted with “A19”. They are available as follows: Bottles of 30: NDC 65162-519-03 Bottles of 100: NDC 65162-519-10 Bottles of 250: NDC 65162-519-25 Calcitriol Capsules 0.5 mcg are supplied as opaque orange color, oblong capsules, imprinted with “A76”. They are available as follows: Bottles of 30: NDC 65162-576-03 Bottles of 100: NDC 65162-576-10 Bottles of 250: NDC 65162-576-25 Calcitriol Capsules should be protected from light. Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. REFERENCE 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. Distributed by: Amneal Pharmaceuticals Bridgewater, NJ 08807 Rev. 11-2015-00