Calcitriol Injection - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology
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Calcitriol Injection - Scientific Information

Manufacture: Fresenius Kabi USA, LLC
Country: Canada
Condition: Hypocalcemia
Class: Vitamins
Form: Liquid solution, Intravenous (IV)
Ingredients: calcitriol, edetate disodium (stabilizer), polysorbate 20, sodium chloride (tonicity), sodium ascorbate (stabilizer)

Pharmaceutical Information

Drug Substance

Proper Name: Calcitriol
Chemical Name: 9,10-Secocholesta-5,7,10(19)-triene-1,3-25-triol, (1α,3β, 5Ζ,-7E)-;
Structural Formula:
Molecular Formula: C27H44O3
Molecular Weight: 416.64

Description

Calcitriol is a white crystalline powder, slightly soluble in methanol, ethanol, ethyl acetate and relatively insoluble in water. The melting point is 111 – 115°C.

Composition

Calcitriol is available as a sterile, isotonic, clear, aqueous solution for intravenous injection.

Each 1 mL Calcitriol Injection ampoule contains:
Calcitriol 1 or 2 µg
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. Preservative-Free.

Stability and Storage Recommendations

Store at room temperature between 15 and 30°C. 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.

Availability of Dosage Forms

Calcitriol Injection is supplied in 1 mL amber ampoules containing 1 µg or 2 µg of calcitriol.

C730101 1 µg/mL, 1 mL amber ampoule in boxes of 10 ampoules.
C730201 2 µg/mL, 1 mL amber ampoule in boxes of 10 ampoules.

Pharmacology

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.

Toxicology

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
Acute Toxicity of Calcitriol Injection in Mice and Rats
Median Lethal Dosages
Species Route LD50 µg/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 µg/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 µg/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 µg/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 µg/kg/day for 14 days. Dosage groups consisted of 10 males and 10 females. There were six deaths at 0.64 µg/kg/day during the study. Apparent signs of toxicity observed at 0.13 and 0.64 µg/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 µg/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 µg/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 µg/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 µg/kg/day, no evidence of toxicity attributable to calcitriol administration was noted. The "no-effect" level was determined to be 0.20 µg/kg/day in these animals.

Dogs (3/sex/dose) were injected intramuscularly with calcitriol at dosage levels of 0, 0.02, 0.06 and 0.21 µg/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 µg/kg/day. Significantly elevated serum calcium levels were noted at the two higher dosage levels (0.06 and 0.21 µg/kg/day). Calcium deposition was not evident in the tissues at any dosage level. Therefore, a dosage of 0.02 µg/kg/day was considered to be the maximum-tolerated dose in this study.

Special Studies

Vein-irritation Study

Calcitriol was given i.v. into an ear vein in rabbits at doses of 5 µg/kg which is ten times the proposed maximum dosage. Calcitriol was found not to be irritating to veins.

Reproductive Studies

Fertility and General Reproductive Performance

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 µg/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 µg/kg/day of calcitriol.

Teratology

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 µg/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 µg/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 µg/kg/day for 31, 16, 15 and 16 rabbits respectively. Numbers of live or dead pups, 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 µg/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.

Perinatal and Postnatal Studies

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 µg/kg/day. Hypercalcemia and hypophosphatemia were noted in dams receiving 0.08 and 0.30 µg/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.

Mutagenicity

There was no evidence of mutagenicity as studied by the Ames Method. Concentrations as high as 1000 µg were found to be non mutagenic to Salmonella strain.