PRINCIPIOS DE FARMACOLOGIA

Description: Calcitriol, or 1,25-dihydroxycholecalciferol, is a vitamin D3 analog available for oral and intravenous use. Calcitriol is structurally similar to calcifediol; however, calcitriol has more than twice the vitamin D activity of calcifediol. Vitamin D occurs in two primary forms: cholecalciferol (vitamin D3), which is synthesized in the skin after exposure to ultraviolet light, and ergocalciferol (vitamin D2), which is produced from plant sterols and is the primary dietary source of vitamin D. Many vitamin D analogs are commercially available, but the responsiveness of various conditions differs based on the pharmacologic properties of each vitamin D analog. Calcitriol may be preferable to ergocalciferol in the acute treatment of hypocalcemia because of its faster onset of action. Calcitriol is also preferable to calcifediol in the management of hypocalcemia in dialysis-dependent renal failure patients because calcifediol must be activated by healthy kidneys to be effective. Calcitriol is also indicated for the treatment of secondary hyperparathyroidism and the resultant metabolic bone disease in chronic renal failure patients who are not receiving dialysis. Calcitriol also has been used in hypoparathyroidism, familial hypophosphatemia, and vitamin D-dependent rickets. Calcitriol was approved by the FDA in 1978. Its patent expires on January 28, 2001. Mechanism of Action: In the body, active vitamin D (1,25-(OH)2D3), also known as calcitriol, plays an important role in maintaining calcium balance and in the regulation of parathyroid hormone (PTH). Calcitriol promotes renal reabsorption of calcium, increases intestinal absorption of calcium and phosphorus, and increases calcium and phosphorus mobilization from bone to plasma. Calcitriol appears to promote intestinal absorption of calcium through binding to a specific receptor in the mucosal cytoplasm of the intestine. Subsequently, calcium is absorbed through formation of a calcium-binding protein. Some evidence suggests that calcitriol acts at the level of the cell nucleus to increase plasma calcium and phosphorus. Once plasma saturation of these electrolytes occurs, bone mineralization takes place. Calcitriol decreases PTH levels through several mechanisms. Calcitriol suppresses PTH, first, by a negative feedback mechanism due to increased calcium levels and, second, by suppressing the synthesis and release of PTH by inhibiting PTH gene transcription in specific target cells. Calcitriol is synthesized from calcifediol in the kidneys. The synthesis of calcitriol is stimulated by PTH activating renal alpha-hydroxylase enzymes and low plasma phosphorus levels. Hypocalcemia stimulates the release of PTH. Patients with uremia are unable to synthesize calcitriol in response to hypocalcemia, which perpetuates the hypocalcemia and leads to secondary hyperparathyroidism. This may be a contributory factor to renal osteodystrophy, characteristic of renal failure. The beneficial effect of calcitriol in renal osteodystrophy is due to the correction of hypocalcemia and secondary hyperparathyroidism. It is not certain if calcitriol produces other independent beneficial effects. Pharmacokinetics: Calcitriol is administered orally and by intravenous injection. Following an oral dose, calcitriol is readily absorbed from the intestine. Absorption can be delayed in patients with hepatic, biliary, or GI disease. Increased calcium absorption occurs in 2—6 hours. Peak hypercalcemic effects are attained in about 10 hours. Calcitriol has a duration of action of 3—5 days. Response to vitamin D can be monitored through serum calcium levels, which should be maintained at 9—10 mg/dl. This vitamin is widely distributed. Vitamin D is excreted into breast milk in small amounts (see Contraindications). Calcitriol is metabolized in the liver to hydroxy metabolites. When circulating concentrations of the metabolites are adequate, further hydroxylation in the kidneys occurs. Metabolism is influenced by parathyroid hormone, serum calcium and phosphate concentrations, and other hormones. The plasma half-life is 3—6 hours. Calcitriol and its metabolites are excreted primarily via the bile, with some renal elimination. The elimination half-life of calcitriol increased 2-fold in chronic renal failure patients and hemodialysis patients as compared to healthy volunteers. In patients with nephrotic syndrome the Tmax was 4 hours and the calcitriol half-life was 16.2 hours. Hemodialysis patients had a calcitriol Tmax of 8—12 hours with a half-life of 21.9 hours. In pediatric peritoneal dialysis patients receiving calcitriol, the average half-life was 27.4 hours.

Indications...Dosage For the treatment of secondary hyperparathyroidism and resultant metabolic bone disease (renal osteodystrophy) in patients with moderate to severe chronic renal failure not yet on dialysis (CrCl 15—55 ml/min/1.73 m2): Oral dosage: Adults and children >= 3 years: 0.25 µg/day PO initially. This dosage may be incresed to 0.5 µg/day PO if necessary. Children < 3 years: Initially, 0.01—0.015 µg/kg/day PO. For the management of hypocalcemia: •for patients undergoing chronic hemodialysis: Oral dosage: Adults and children >= 6 years: Initially, 0.25 µg PO once daily. The dosage may be increased by 0.25 µg daily at 4—8 week intervals. Patients with normal or only slightly reduced seum calcium levels may respond to doses of 0.25 µg every other day. Most patients undergoing dialysis repond to 0.5—1.0 µg once daily. Children age 1—5 years: 0.25—2 µg PO once daily. Intravenous dosage: Adults: 1 µg (0.02 µg/kg) to 2 µg IV three times weekly, approximately every other day. Doses as small as 0.5 µg and as large as 4 µg three times weekly have been used as an initial dose. The dosage may be increased by 0.5—1 µg at 2—4 week intervals. If hypercalcemia or a serum calcium-phosphorus product (Ca x PO4) greater than 70 is noted, hold calcitriol therapy until these parameters normalize. Then calcitriol may be restarted at a lower dose. Doses may need to be reduced as parathyroid hormone (PTH) levels decrease in response to therapy. Thus incremental dosing must be individualized and commensurate with serum PTH, calcium, and phophorus levels. The following dosage titration is recommended based on serum PTH levels: For PTH level the same or increasing versus baseline: Increase calcitriol dose. For PTH level decreasing < 30% from baseline: Increase calcitriol dose. For PTH level decreasing > 30% or < 60% from baseline: Maintain calcitriol dose. For PTH level decreasing > 60% from baseline: Decrease calcitriol dose. For PTH level 1.5- to 3-times the upper limit of normal: Maintain calcitriol dose. Children†: 0.01—0.05 µg/kg three times a week. •for hypocalcemia in premature infants: Oral dosage: Infants: 1 µg PO once daily for 5 days. •for hypocalcemia tetany in premature infants: Intravenous dosage: Infants: 0.05 µg/kg IV once daily for 5—12 days. For the treatment of patients with postsurgical hypoparathyroidism, idiopathic hypoparathyroidism and pseudohypoparathyroidism manifesting as hypocalcemia: Oral dosage: Adults and children >= 6 years: Initially 0.25 µg PO once daily in the morning. Dosage may be increased at 2—4 week intervals. Maintenance dose is usually 0.5—2.0 µg once daily. Children age 1—5 years: 0.25—0.75 µg PO once daily. Infants < 1 year: 0.04—0.08 µg/kg PO once daily. For the treatment of vitamin D-dependent rickets†: Oral dosage: Adults and children: 1 µg PO once daily. For the treatment of familial hypophosphatemia†: Oral dosage: Adults: 2 µg PO once daily. Children: Initially, 0.015—0.02 µg/kg PO once daily. Maintenance doses range from 0.03—0.06 µg/kg PO once daily. Maximum dose is 2 µg PO once daily. For the treatment of osteoporosis†: •For the treatment of postmenopausal osteoporosis†: Oral dosage: Adults: 0.25 µg PO twice daily. Modify dose according to serum calcium concentration. •For osteoporosis prophylaxis† in recipients of chronic corticosteroid therapy: Oral dosage: Adults: Calcitriol 0.5—1.0 µg/day PO was beneficial in preventing bone loss in patients receiving corticosteroid therapy for 2 years, although benefit was seen only in lumbar spine. In this study, the mean daily dose of prednisone was 13.5 mg/day.[1334] For the treatment of osteopetrosis†: Oral dosage: Children: High dose calcitriol 1—2 µg/kg/day PO, administered in 4—6 divided doses has been shown to stimulate osteoclast activity and bone resorption in some but not all patients. Treatment with calcitriol only seems to be effective for as long as therapy is continued; indicators of bone resorption fall rapidly when calcitriol therapy is stopped.[2750] Patients with renal impairment: Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed. †non-FDA-approved indication

Administration NOTE: Patients must receive an adequate amount of calcium while taking calcitriol. Patients are advised to have a dietary intake of calcium of at least 600 mg/day. The US RDA for calcium in adults is 1000—1500 mg/day. Oral Administration •Calcitriol may be administered without regard to meals. •Calcitriol capsules and oral solution should be protected from light. •During titration of calcitriol serum calcium should be monitored twice weekly. If hypercalcemia develops, discontinue calcitriol until normocalcemia is noted. •Store at room temperature 59°—86°F (15°—30°C). Intravenous Administration •During titration period, serum calcium and phosphorus levels should be monitored twice weekly. •Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. •Store at room temperature 59°—86°F (15°—30°C). Intravenous injection: •No dilution necessary. •Administer by rapid IV injection through the catheter at the end of a hemodialysis session.

Contraindications Calcitriol is a potent vitamin D analog and should not be given to patients with hypercalcemia or hypervitaminosis D. Chronic hypercalcemia can lead to soft tissue calcification, nephrocalcinosis, and other toxicities. The serum calcium times phosphate (Ca x P) product should not exceed 70. Radiographic evalution of suspect areas may be useful in the early detection of soft tissue calcification. Patients with renal failure may be at increased risk for vitamin D-induced hypercalcemia even with usual dosages. During titration of calcitriol dose, serum calcium levels should be monitored twice weekly. If hypercalcemia develops or if the calcium-phosphorus product (Ca x PO4) is greater than 70, discontinue calcitriol until these parameters normalize (see Dosage). Calcitriol should be used cautiously in patients with hyperphosphatemia due to the risk of metastatic calcification. Treatment with calcitriol may be initiated after stabilization of phosphorus levels. Calcitriol should be administered with caution to patients with cardiac disease, arteriosclerosis, or those receiving digoxin because hypercalcemia and/or cardiac arrhythmias can result. Clinical experience has not identified differences in responses between elderly and younger patients. However, dose selection for an elderly patient should start at the lower end of the dosage range, reflecting the greater frequency of decreased cardiac, hepatic, or renal function and concomitant disease or other drug therapy in this patient poplulation. Patients who are taking calcitriol should avoid dehydration. Adequate fluid intake should be maintained. Although vitamin D analogs have different potencies, all have similar effects on the mother and fetus during pregnancy. Calcitriol injection is classified as a FDA pregnancy category C drug. There are no adequate and well-controlled studies of calcitriol in pregnant women. Calcitriol injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Oral calcitriol administered at 17 to 36 mcg/day during pregnancy resulted in mild hypercalcemia in the neonate during first 2 days of life which returned to normal on the third day. Problems in humans from normal daily intake of vitamin D have not been documented; however, hypercalcemia during pregnancy has been associated with suppression of parathyroid hormone in the neonate, resulting in mental retardation and congenital aortic stenosis. The risks to benefits of untreated hypoparathyroidism or hypophosphatemia in the mother should be considered before using vitamin D analogs such as calcitriol. Vitamin D and its metabolites, including calitriol, are distributed in small amounts into breast milk. A committee of the American Academy of Pediatrics considers maternal consumption of vitamin D compatible with breast-feeding. However, serum calcium concentrations in the infant should be monitored when using vitamin D in a nursing mother. Patients with sarcoidosis, and possibly other granulomatuous diseases, may have increased sensitivity to the effects of vitamin D. Patients must receive an adequate amount of calcium while taking calcitriol. Patients are advised to have a dietary intake of calcium of at least 600 mg/day. The US RDA for calcium in adults is 1000-1500 mg/day.

Interactions

The use of other vitamin D analogs with calcitriol is not recommended because of the increased potential for additive effects and toxicity. In addition, due to calcitriol-induced increased serum phosphorus levels, concurrent administration of phosphorus salts may increase the toxicity of calcitriol. Magnesium-containing antacids and supplemental magnesium salts should be used cautiously in patients receiving calcitriol. Because vitamin D analogs can increase serum magnesium concentrations, the combined use of calcitriol and magnesium-containing antacids should be avoided, if possible, in patients with chronic renal failure. The concurrent use of vitamin D with calcium-containing antacids or other calcium salts can cause hypercalcemia; in some patients, however, this combination may be beneficial. The chronic use of aluminum-containing antacids for hyperphosphatemia in conjunction with vitamin D can lead to increased aluminum concentrations and toxicity. This is of primary significance in patients with renal failure. Anticonvulsants, such as phenobarbital, phenytoin, and primidone, can increase the metabolism of vitamin D, thereby decreasing its activity. In rare cases, this has caused anticonvulsant-induced rickets and osteomalacia. Vitamin D supplementation may be required in patients with inadequate dietary intake of vitamin D who are receiving chronic treatment with anticonvulsants. Calcitriol should be administered with caution to patients with cardiac disease or those receiving cardiac glycosides. Vitamin D may cause hypercalcemia which may affect the actions of the cardiac glycoside and/or lead to cardiac arrhythmias. Cholestyramine, colestipol, or mineral oil can decrease the intestinal absorption of oral calcitriol. If used concurrently, administration times of these agents should be staggered for the longest interval possible. Orlistat decreases the body's absorption of dietary fat, which also affects the absorption of fat soluble vitamins. Concomitant use of thiazide diuretics and calcitriol in patients with hypoparathyroidism can result in hypercalcemia, which is likely due to increased release of calcium from the bone. This condition may be transient or require discontinuation of the vitamin D analog. Ketoconazole may inhibit both synthetic and catabolic enzymes of calcitriol. Reductions in endogenous serum calcitriol concentrations have been observed following the the administration of ketoconazole 300—1200 mg/day.

Adverse Reactions Hypervitaminosis D can occur during therapy with calcitriol and manifests as hypercalcemia. Early signs of hypercalcemia include fatigue, somnolence, headache, anorexia, xerostomia, metallic taste, nausea/vomiting, abdominal cramps, constipation, diarrhea, vertigo, tinnitus, ataxia, exanthema, myalgia, arthralgia, and irritability. Polyuria, photophobia, anorexia, rhinorrhea, hyperthermia, cardiac arrhythmias, and hypertension are all late symptoms of hypercalcemia. Hypercalcemia has been reported in at least one-third of patients receiving calcitriol. Hypercalciuria has been noted in about 14% of patients. Calcitriol should be discontinued if symptoms become severe. Mild pain at the injection site has been noted occasionally as an injection site reaction. Since vitamin D increases the absorption of phosphorus, calcitriol can cause hyperphosphatemia, especially in patients with renal failure. Elevated serum creatinine levels have been observed in about 17% of patients. Calcitriol dosage adjustments may be required for patients receiving aluminum-containing antacids for the treatment of hyperphosphatemia. One case each of erythema multiforme and an allergic reation consisiting of urticaria and swelling of the lips have been confirmed during treatment and rechallenge of calcitriol.

Rocaltrol®, Calcijex®