Calcitriol is the active form of vitamin D3 (cholecalciferol). The natural or endogenous supply of vitamin D in man mainly depends on ultraviolet light for conversion of 7-dehydrocholesterol to vitamin D3 in the skin. Vitamin D3 must be metabolically activated in the liver and the kidney before it is fully active on its target tissues. The initial transformation is catalyzed by a vitamin D3-25- hydroxylase enzyme present in the liver, and the product of this reaction is 25- hydroxyvitamin D3 (calcifediol). The latter undergoes hydroxylation in the mitochondria of kidney tissue, and this reaction is activated by the renal 25-hydroxyvitamin D3-1-alpha-hydroxylase to produce 1,25-dihydroxyvitamin D3 (calcitriol), the active form of vitamin D3. The known sites of action of calcitriol are intestine and bone, but additional evidence suggests that it also acts on the kidney and the parathyroid gland. Calcitriol is the most active known form of vitamin D3 in stimulating intestinal calcium transport. Calcitriol when administered by bolus injection is rapidly available in the blood stream. Vitamin D metabolites are known to be transported in blood, bound to specific alpha2 globulins. The pharmacologic activity of an administered dose of calcitriol is about 3 to 5 days. Two metabolic pathways for calcitriol have been identified; conversion to 1,24,25-(OH)3D3 and to calcitroic acid.
Calcitriol Injection is indicated in the management of hypocalcemia in patients undergoing chronic renal dialysis. It has been also shown to significantly reduce elevated parathyroid hormone levels in many of these patients. Reduction of PTH has been shown to result in an improvement in renal osteodystrophy.
Calcitriol Injection should not be given to patients with previous hypersensitivity to calcitriol or any of its excipients, Vitamin D or its analogues and derivatives, hypercalcemia or evidence of vitamin D toxicity.
Since Calcitriol Injection is a potent cholecalciferol derivative with profound effects on intestinal absorption of dietary calcium and inorganic phosphate, it should not be used concomitantly with other vitamin D products or its derivatives. Therapy with calcitriol injection should only be considered when adequate laboratory facilities for monitoring of blood and urine chemistries are available. During treatment progressive hypercalcemia either due to hyper-responsiveness or overdosage may become so severe as to require emergency treatment (see SYMPTOMS AND TREATMENT OF OVERDOSAGE). Chronic hypercalcemia can lead to generalized vascular calcification, nephrocalcinosis, calcifications of the cornea or other soft tissues. During treatment with calcitriol THE SERUM TOTAL CALCIUM (mg/dL) TIMES SERUM INORGANIC PHOSPHATE PRODUCT (Ca x P) SHOULD NOT EXCEED 70. Dialysate calcium level of 7 mg % or above in addition to excessive dietary calcium supplements may lead to frequent episodes of hypercalcemia. In patients on digitalis, hypercalcemia may precipitate cardiac arrhythmias; in such patients calcitriol should be used with extreme caution. To control serum phosphorus levels and dietary phosphate absorption in patients undergoing dialysis, a non-aluminum phosphate-binding compound should be used. Magnesium-containing antacids may contribute towards hypermagnesemia in patients on chronic renal dialysis and should be avoided during therapy with calcitriol (see Drug Interactions).
Use in pregnancy
Calcitriol given orally, has been reported to be teratogenic in rabbits when given in doses 4 and 15 times the dose recommended for human use. All 15 fetuses in 3 litters at these doses showed external and skeletal abnormalities. However, none of the other 23 litters (156 fetuses) showed significant abnormalities compared with controls. Teratology studies in rats showed no evidence of teratogenic potential. There are no adequate and well controlled studies in pregnant women. Calcitriol Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
General
Patients with renal osteodystrophy and hypocalcemia, poorly managed by conventional vitamin D therapy, are likely to respond to Calcitriol Injection. The desired therapeutic margin of calcitriol is narrow, therefore, the optimal daily dose must be carefully determined for each patient by dose titration to obtain satisfactory response in the biochemical parameters and clinical manifestations (see
).
Excessive dosage of calcitriol induces hypercalcemia. and hypercalciuria; therefore, early in treatment during dosage adjustment, serum calcium and phosphorus should be determined at least twice weekly. A fall in serum alkaline phosphatase values may indicate impending hypercalcemia. Should hypercalcemia develop, the drug should be discontinued immediately until the serum calcium level has normalized. This may take several days to a week. Calcitriol should be given cautiously to patients on digitalis, because hypercalcemia in such patients may precipitate cardiac arrhythmias (see Drug Interactions).
Use in Children
Safety and efficacy of Calcitriol Injection in children have not been established.
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from calcitriol, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Drug Interactions
Hypercalcemia in patients on digitalis may precipitate cardiac arrhythmias. Although the precise mechanism involved is unknown, there is evidence that long term anticonvulsant treatment, particularly with diphenylhydantoin and barbiturates, may interfere with the actions of vitamin D. Patients under concurrent treatment with such agents may require slightly higher doses of calcitriol. Magnesium-containing antacids and calcitriol should not be used concomitantly, since such use may lead to the development of hypermagnesemia. Corticosteroids may counteract the effects of vitamin D analogs.
Laboratory Tests
Serum calcium, inorganic phosphorus, magnesium, alkaline phosphatase as well as 24-hour urinary calcium and phosphorus should be determined periodically during maintenance therapy with calcitriol. During the initial phase of the medication, serum calcium and phosphorus should be determined more frequently (at least twice weekly). Periodic ophthalmological examinations and radiological evaluation of suspected anatomical regions for early detection of ectopic calcifications are advisable.
Carcinogenesis
Long-term studies in animals have not been performed to evaluate the carcinogenic potential of Calcitriol Injection.
Transplantation
The rate of bone loss can be excessive and may exceed 5% per year in the immediate post-transplant period. Recommendations for treating post-transplant bone loss with Calcitriol Injection have not been established.
Menopausal Osteoporosis Secondary to Decrease Estrogens
Efficacy has not been established for this patient population.
Information to be provided to the Patient
The patient and his or her immediate relatives should be informed about the need for compliance with dosage instructions, strict adherence to prescribed calcium intake, dietary and supplementary, and avoidance of unapproved non-prescription drugs or medications. Patients should also be made aware of the symptoms of hypercalcemia and should seek medical attention if such symptoms are noted (see ADVERSE REACTIONS).
The following adverse reactions have been reported in association with Calcitriol Injection treatment: The most frequently reported adverse effect is hypercalcemia (35% approx. after the 4th week of treatment). The less frequently reported adverse effects were headache, nausea, vomiting, constipation, abdominal cramp, pruritis, conjunctivitis, agitation, extremity pain, apprehension, polyuria, insomnia, elevated SGOT and/or SGPT, elevated alkaline phosphatase, hypercalciuria, hypermagnesemia, hyperphosphatemia, elevated lymphocytes, elevated hematocrit, elevated neutrophils, elevated hemoglobin. Rare cases of hypersensitivity reactions have been reported including anaphylaxis. Occasional mild pain and localized redness at injection site have been observed. The adverse effects of Calcitriol Injection are, in general, similar to those encountered with excessive vitamin D intake. The early and late signs and symptoms associated with vitamin D intoxication and hypercalcemia are:
Early : weakness, headache, somnolence, nausea, cardiac arrhythmias, excessive thirst, vomiting, dry mouth, constipation, muscle pain, bone pain, and metallic taste.
Late: polyuria, polydipsia, anorexia, weight loss, nocturia, conjunctivitis (calcific), pancreatitis, photophobia, rhinorrhea, pruritus, hyperthermia, decreased libido, elevated BUN, albuminuria, hypercholesterolemia, elevated SGOT and SGPT, ectopic calcification, hypertension, cardiac arrhythmias, and rarely, overt psychosis.
Administration of Calcitriol Injection to patients in excess of their daily requirements can cause hypercalcemia, hypercalciuria and hyperphosphatemia. Conversely, high intake of calcium and phosphate concomitantly with therapeutic doses of Calcitriol Injection may cause similar abnormalities. In dialysis patients, high levels of calcium in the dialysis bath may contribute to hypercalcemia.
Treatment of Hypercalcemia in Patients Undergoing Hemodialysis
General treatment of hypercalcemia (more than 1 mg/dL or 0.25 mmol/L above the upper limit of the normal range) consists of immediate discontinuation of Calcitriol Injection therapy, institution of a low calcium diet and withdrawal of calcium supplements. Decreasing calcium concentration in the dialysate solution may be considered. Serum calcium levels should be determined daily until normocalcemia ensues. Hypercalcemia frequently resolves in two to seven days. When serum calcium levels have returned to within normal limits, Calcitriol Injection therapy may be reinstituted at a dose of 0.5 ug less than prior therapy. Serum calcium levels should be carefully monitored (at least twice weekly) during this period of dosage adjustment and subsequent dosage titration. Persistent or markedly elevated serum calcium levels may be corrected by dialysis against a calcium-free dialysate.
Treatment of Accidental Overdosage
The treatment of acute accidental overdosage with Calcitriol Injection should consist of general supportive measures. Serial serum electrolyte determinations (especially calcium ion), 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 low calcium diet are also indicated in accidental overdosage. Due to the relatively short 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, corticosteroids, bisphosphonates, mithramycin, calcitonin, glucocorticoids, and galium nitrate as well as measures to induce an appropriate forced saline diuresis. The use of peritoneal dialysis against a calcium free dialysate has also been reported.
THE OPTIMAL DOSE OF CALCITRIOL INJECTION MUST BE CAREFULLY DETERMINED FOR EACH PATIENT. The effectiveness of Calcitriol Injection therapy is predicated on the assumption that each patient is receiving an adequate daily intake of calcium. The recommended daily allowance for calcium in adults is in the order of 1 g. 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 appropriate dietary measures. However, because of improved calcium absorption from the gastro-intestinal tract, some patients may be maintained on a lower calcium intake or no supplementation at all. The recommended initial dose of Calcitriol Injection is 0.5 ug (0.01ug/kg) administered three times weekly, every other day. Calcitriol Injection can be administered as a bolus dose intravenously through the catheter at the end of hemodialysis. If a satisfactory response in the biochemical parameters and clinical manifestations of the disease state is not observed, the dose may be increased by 0.25 to 0.50 ug at two to four week intervals. During this titration period, serum calcium and phosphorus levels should be obtained at least twice weekly, and if hypercalcemia is noted, the drug should be immediately discontinued until normocalcemia ensues. Most patients undergoing hemodialysis respond to doses between 0.5 and 3.0 ug (0.01 to 0.05 ug/kg) three times per week.
FURTHER INFORMATION:
Higher dosing regimens have been studied in the literature. These academic trials are limited with respect to sample size but suggest evidence of healing of secondary hyperparathyroidism. Clinical studies are currently in progress to further evaluate this dosing regimen.
Drug Substance
Calcitriol
9,10-Secocholesta-5,7,10(19)-triene-1,3-25-triol, (1a, 3b, 5Z,-7E)-;
Molecular Formula: C27H44O3
416.64
Calcitriol is a white crystalline powder, slightly soluble in methanol, ethanol, ethyl acetate and relatively insoluble in water. The melting point is 111-115C.
Calcitriol is available as a sterile, isotonic, clear, aqueous solution for intravenous injection. Each 1 mL Calcitriol Injection ampoule contains: Calcitriol 1 or 2 ug Edetate disodium (stabilizer) 1.1 mg Polysorbate 20 4 mg Sodium Chloride (tonicity) 1.5 mg Sodium ascorbate (stabilizer) 10 mg Dibasic sodium phosphate, anhydrous and monobasic sodium phosphate, monohydrate as buffers and water for injection qs. The pH of the solution is approximately 7. It does not contain a preservative.
Store at room temperature between 15 and 30degC. Protect from light, freezing or excessive heat. As with all parenteral drug products, intravenous admixtures should be inspected for clarity of solutions, particulate matter, precipitate, discolouration and leakage prior to administration, whenever solution and container permit. Solutions showing haziness, particulate matter, precipitate, discolouration or leakage should not be used.
Calcitriol Injection is supplied in 1 mL amber ampoules containing 1 ug or 2 ug of calcitriol. C730101 1 ug/mL, 1 mL amber ampoule in boxes of 10 ampoules. C730201 2 ug/mL, 1 mL amber ampoule in boxes of 10 ampoules.
There is evidence that calcitriol (1,25-(OH)2 D3) is the biologically active form of vitamin D, responsible in part for maintaining calcium and phosphorus homeostasis. Calcitriol stimulates the intestinal transport of calcium. The active transport of calcium occurs primarily in the duodenum. Although the exact mechanism by which this occurs is uncertain, most evidence suggest that calcitriol enhances calcium movement across the brush border into the intestinal cells. Evidence further suggests that a specific calcium-binding protein, which is stimulated by calcitriol, acts to augment the entry of calcium into the cell. In addition, calcitriol may exert a nuclear effect by directing the synthesis of messenger RNA which in turn stimulated synthesis of new proteins which are thought to be involved in the calcium transport process. Bone is the second tissue at which calcitriol acts to mobilize calcium for circulation. Whether calcitriol can directly stimulate bone mineralization or whether it leads to mineralization by increasing the levels of calcium and phosphate in the extracellular fluid surrounding bone remains unclear. Cytosolic receptor proteins for calcitriol in bone cells have been isolated. In acutely uremic rats, calcitriol has been shown to stimulate intestinal calcium absorption. In bone, calcitriol, in conjunction with parathyroid hormone, stimulates resorption of calcium; and in the kidney, calcitriol increases the tubular reabsorption of calcium. Calcitriol stimulates bone resorption which serves to mobilize calcium for the circulation, when an intestinal source of calcium is absent. This effect is related to the role of Vitamin D in maintaining the homeostasis of calcium and phosphorus in plasma. In addition, calcitriol may interact directly with osteoblasts. The mechanism whereby calcitriol acts on the kidney and parathyroid gland remains unclear. Evidence suggests that calcitriol may enhance renal tubular calcium reabsorption. Recent studies in parathyroidectomized animals suggest that calcitriol has a direct proximal tubular action to promote phosphate retention. Further studies are needed to clarify the precise role of calcitriol in regulating the secretion of PTH by the parathyroid gland. Evidence suggests that calcitriol may affect the secretion of PTH through a direct action on the parathyroid gland and may be involved in the regulation of PTH synthesis and/or its secretion.
Clinical Pharmacology
In human studies, calcitriol is rapidly absorbed from the intestine. Vitamin D metabolites are known to be transported in blood, bound to a specific alpha2 globulin. In a controlled trial with 20 patients treated with calcitriol injection, serum parathyroid hormone (PTH) also showed a significant decrease during the treatment period compared to pre-treatment levels; thirteen patients out of twenty, showed a decrease greater than 50%. By the last week of the post-treatment period mean serum PTH had increased almost to mean levels during the last week of the pre- treatment period. A vitamin D-resistant state may exist in uremic patients because of the failure of the kidney to adequately convert precursors to the active compound, calcitriol. Recent reports have indicated that vitamin D analogues may cause a deterioration of renal function in chronic renal failure patients who are not on renal dialysis. Calcitriol administered intravenously or intraperitonealy was found to be a simple and effective means to suppress secondary hyperparathyroidism in patients undergoing hemodialysis or ambulatory peritoneal dialysis.
Acute Toxicity
The acute toxicity of calcitriol administered by a variety of routes was studied in mice and rats. The lethal dosages are shown in Table 1.
Table 1
| Species | Route | LD50ug/kg |
| Mice | IP PO SC | 1900 1350 145 |
| Rat | SC | 66 |
The primary signs of toxicity included decreased lacrimation ataxia, body temperature decrease and somnolence.
Subacute Toxicity
Neonatal rats (15/sex/dose) were administered calcitriol once daily for 14-16 days at oral doses of 0, 0.06, 0.19 and 0.64 ug/kg/day. Five controls, four low-dose, two mid-dose, and fifteen high-dose pups died during the two-week treatment period. Some of the deaths were attributed to dosing accidents, but more than half of the deaths in the high-dose group were drug-related. An additional 6 high-dose pups died during a 7-week "recovery" period. Drug-related deaths resulted from metastatic calcification alone or in combination with the stress imposed by weaning. Many high-dose pups were considerably smaller than pups in the other groups, exhibited subcutaneous white patches on head and lower jaw and developed splayed limbs, and had higher serum calcium levels than controls. Gross and histologic changes reflective of metastatic calcification were seen in a number of organs including kidney and heart. Nephrocalcinosis was the most consistent histologic lesion noted. No significant signs of toxicity were noted in low-dose pups examined soon after final treatment, but 3 of 8 low-dose animals examined after the 7-week "recovery" period exhibited a minimal degree of renal calcification. The observed effects, were deemed to be entirely attributable to the induction of hypercalcemia in previously normocalcemic animals. Neonatal rats (15/sex/dose) were treated intramuscularly once daily for 14-16 consecutive days with calcitriol at doses of 0, 0.13, 0.38 and 1.28 ug/kg/day. The majority of the animals were killed following the last treatment, but a number of pups were maintained on a 7-week "recovery" period. One control, one mid-dose and two high-dose pups died during the two-week treatment period; six additional mid-dose and seven additional high-dose pups died during the "recovery" period. Drug- related deaths resulted from metastatic calcification or renal tubular necrosis. Subcutaneous white patches on the head and splayed limbs were observed at the high-dose, 1.28 ug/kg/day. Mean body weights of males in all groups were significantly less than the control mean. Serum calcium levels were elevated in all animals receiving calcitriol. Gross pathologic changes included white streaks of spots on the liver, heart and diaphragm. Metastatic calcification was the principal treatment-related histologic lesion found in all treatment groups. Nephrocalcinosis, gastric mineralization and calcium deposition in heart, aorta and respiratory system were consistently seen. Residual calcium deposits tended to be less severe in the tissues of the recovery animals. Rats (10/sex/dose) were injected intramuscularly with calcitriol at dosage levels of 0, 0.03, 0.13 and 0.64 ug/kg/day for 14 days. Dosage groups consisted of 10 males and 10 females. There were six deaths at 0.64 ug/kg/day during the study. Apparent signs of toxicity observed at 0.13 and 0.64 ug/kg/day included labored breathing, reduced motor activity, corneal opacities, decreased defecation and elevated serum calcium levels. Elevation in BUN and decreases in total serum protein and potassium, body weight and food consumption were noted at 0.64 ug/kg/day. Microscopic lesions found included calcification of the myocardial fibers, arteriosclerosis of the coronary and aortic arteries, nephrolithiasis, calcification of the stomach and the large intestine and thymus hypoplasia. The only histopathological change observed at 0.03 and 0.13 ug/kg/day was an increase in phagocytosis by the large cortical cells of the thymus. The thymus hypoplasia was considered to be attributable to a high degree of stress consequent upon debilitation and possibly severe electrolyte changes. Corneal opacities observed were not considered by the authors to be drug-related. The maximum tolerated dosage was 0.03 ug/kg/day in this study. Immature rats (10/sex/dose) were administered calcitriol once daily for a minimum of six weeks beginning on postnatal day 15. At doses of 0, 0.02, 0.06 and 0.20 ug/kg/day, no evidence of toxicity attributable to calcitriol administration was noted. The "no-effect" level was determined to be
ug/kg/day in these animals.
Dogs (3/sex/dose) were injected intramuscularly with calcitriol at dosage levels of 0, 0.02, 0.06 and ug/kg/day for 14 days. There were no deaths in the study. Thinness, dehydration, decreased activity, ocular discharge, decreased body weight and food consumption were observed at 0.06 and 0.21 ug/kg/day. Significantly elevated serum calcium levels were noted at the two higher dosage levels (0.06 and 0.21 ug/kg/day). Calcium deposition was not evident in the tissues at any dosage level. Therefore, a dosage of 0.02 ug/kg/day was considered to be the maximum-tolerated dose in this study.
Special Studies
Calcitriol was given i.v. into an ear vein in rabbits at doses of 5 ug/kg which is ten times the proposed maximum dosage. Calcitriol was found not to be irritating to veins.
Reproductive Studies:
Calcitriol was administered orally to male rats for 60 days prior to mating and to female rats (24/dosage) from 14 days prior to mating until sacrifice of the females either on gestation day 13 or on lactation day 21. Dosages tested were 0, 0.002, 0.08 and 0.30 ug/kg/day. No adverse effects on either fertility or neonatal development were noted. All Fo generation animals survived. It was concluded that under the conditions of this study there were no adverse effects observed on either reproductive parameters or the pups themselves at dosages as great as 0.30 ug/kg/day of calcitriol.
Calcitriol was orally administered to pregnant rats (20/dosage) from gestation day 7 to gestation day 15. Dosages tested were 0 (control), 0.02, 0.08 and 0.30 ug/kg/day. Numbers of fetuses, implantation sites and resorption sites were counted. Fetuses were weighed and examined for external abnormalities. One- third of the fetuses in each litter were examined for visceral abnormalities, two-thirds of the fetuses in each litter were prepared for skeletal evaluation. Maternal weight gain was significantly reduced in dams receiving 0.3 ug/kg/day. No biologically significant adverse effects on rat embryonic or fetal development were observed at any of the tested dosages. There was no evidence that calcitriol was teratogenic in rats. Calcitriol was orally administered to pregnant rabbits from gestation day 7 to gestation day 18. Dosages tested were 0, 0.02, 0.08 and 0.30 ug/kg/day for 31, 16, 15 and 16 rabbits respectively. Numbers of live or dead p0ups, resorption sites, corpora lutea and implantation sites were recorded. Fetuses were examined for external abnormalities, dissected to check for visceral abnormalities and prepared for skeletal evaluation. Marked weight loss occurred among high-dose dams; 3 high-dose animals died - 2 clearly as a result of hypervitaminosis D. The mean litter size was reduced and the resorption frequency was increased among high-dose dams. Although not statistically significant, these changes were considered to be biologically significant by the authors. The percentage of viable pups that survived 24 hours of incubation was significantly decreased at the highest dose. The average fetal body weight was slightly reduced at this dosage as well. While the overall incidence of external, visceral and skeletal anomalies was comparable among all groups, one entire litter in each of the 0.08 and 0.30 ug/kg groups exhibited multiple external malformations. These malformations included open eyelids, microphthalmia, cleft palate, reduced long bones, gnarled paws, pes caves, shortened ribs and sternebral defects in 9 mid-dose fetuses and open eyelids, reduced long bones and shortened ribs in 6 high-dose fetuses. The authors concluded that while the low incidence of litters involved, the lack of clear dose-response and the lack of statistical significance made it uncertain that these abnormalities were related to calcitriol administration this possibility could not be discounted.
Calcitriol was orally administered to pregnant rats (20/dosage) from gestation day 15 through day 21 of lactation. Dosages tested were 0, 0.02, 0.08 and 0.30 ug/kg/day. Hypercalcemia and hypophosphatemia were noted in dams receiving 0.08 and 0.30 ug/kg/day. Serum sampled from pups on postnatal day 21 was hypercalcemic in both the mid- and high-dose groups. Aside from this no adverse effects on reproduction or pup growth and survival were observed at the tested dosages.
There was no evidence of mutagenicity as studied by the Ames Method. Concentrations as high as 1000 ug were found to be non mutagenic to Salmonella strain.
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