Calcitriol
Calcitriol is chemically designated (5Z,7E)-9,10-secocholesta-5,7,10(19)-triene-1,3,25-triol and has the following structural formula: Molecular Formula: C27H44O3 The other names frequently used for calcitriol are 1,25-dihydroxycholecalciferol, 1,25- dihydroxy-vitamin D3, 1,25-DHCC, 1,25(OH)2D3 and 1,25-diOHC.
32222-06-3
Calcijex Intravenous Injection is synthetically manufactured calcitriol and is available as a sterile, isotonic, clear, aqueous solution for intravenous injection. Each 1 mL contains calcitriol, 1 or 2 mcg; polysorbate 20, sodium chloride, sodium ascorbate, sodium phosphate- dibasic anhydrous, sodium phosphate monobasic (monohydrate), edetate sodium (dihydrate) and Water for Injections. Approximately pH 7. It does not contain a preservative. Calcitriol is a colourless, crystalline compound which occurs naturally in humans. It is soluble in organic solvents but relatively insoluble in water.
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 catalysed by a vitamin D3-25hydroxylase enzyme present in the liver, and the product of this reaction is 25- (OH)D3 (calcifediol). The latter undergoes hydroxylation in the mitochondria of kidney tissue, and this reaction is activated by the renal 25-hydroxyvitamin D3-1-hydroxylase to produce 1, 25-(OH)2D3 (calcitriol), the active form of vitamin D3. The known sites of action of calcitriol are intestine, bone, kidney and parathyroid gland. Calcitriol is the most active known form of vitamin D3 in stimulating intestinal calcium transport. In acutely uremic rats, calcitriol, in conjunction with parathyroid hormone, stimulates resorption of calcium; and in the kidney, calcitriol increases the tubular reabsorption of calcium. In-vitro and in-vivo studies have shown that calcitriol directly suppresses secretion and synthesis of PTH. Calcitriol has been shown to reduce significantly elevated parathyroid hormone concentrations, although the concentrations still remain well above the normal range in most cases. 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.
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 plasma proteins. 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.
Calcijex intravenous injection is indicated for the management of hypocalcaemia in patients undergoing chronic renal dialysis.
Calcijex intravenous injection should not be given to patients with hypercalcaemia or evidence of vitamin D toxicity. This drug is contraindicated in patients with previous hypersensitivity to calcitriol or any of its excipients.
Excessive dosage of Calcijex intravenous injection induces hypercalcaemia and in some instances hypercalciuria; therefore, early in treatment during dosage adjustment, serum calcium and phosphorous should be determined at least twice weekly. Should hypercalcaemia develop, the drug should be discontinued immediately. The patient should be informed about adherence to instructions about diet and calcium supplementation and avoidance of the use of unapproved non-prescription drugs, including magnesium-containing antacids. Patients should also be carefully informed about the symptoms of hypercalcaemia (see 'Adverse Effects'). Serum calcium, phosphorous, magnesium and alkaline phosphatase, as well as 24-hour urinary calcium and phosphorous, should be determined periodically during treatment. Calcijex should be given cautiously to patients on digitalis, because hypercalcaemia in such patients may precipitate cardiac arrhythmias. Since calcitriol is the most potent metabolite of vitamin D available, vitamin D supplementation and its derivatives should be withheld during treatment to avoid possible additive effects and hypercalcemia. A non-aluminium phosphate-binding compound should be used to control serum phosphorous levels in patients undergoing dialysis. Overdosage of any form of vitamin D is dangerous. Progressive hypercalcaemia due to overdosage of vitamin D and its metabolites may be so severe as to require emergency attention. Chronic hypercalcaemia can lead to generalised vascular calcification, nephrocalcinosis and other soft-tissue calcification. The serum calcium (albumin corrected) times phosphate (Ca x P) product should not be allowed to exceed 70 mg2/dL2 (5.6 mmol2/L2). Radiographic evaluation of suspect anatomical regions may be useful in early detection of this condition. Abnormal bone disease may develop if PTH levels are suppressed to abnormal levels. If biopsy is not being done for other (diagnostic) reasons, PTH levels may be used to indicate the rate of bone turnover. If PTH levels fall below recommended target range (1.5 to 3 times the upper limit of normal), in patients treated with calcitriol, the calcitriol dose should be reduced or therapy discontinued. Discontinuation of calcitriol may result in rebound effect, therefore, appropriate titration downward to a maintenance dose is recommended. 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 have not been established.
No significant effects of oral calcitriol on fertility were reported.
Pregnancy Category B3 Calcitriol has been considered to be teratogenic in rabbits at oral doses of 0.08 and 0.3 mcg/kg/day. Foetal abnormalities included shortened long bones, shortened ribs and open eyes. All foetuses in 3 litters showed these abnormalities, although 23 other litters showed no significant abnormalities. In rats, doses of up to 0.3 mcg/kg/day produced no evidence of foetal abnormalities. The significance of these findings for humans is not known. Teratology studies in rats showed no evidence of teratogenic potential. There are no adequate and well-controlled studies in pregnant women. Calcijex should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.
It is not known whether this drug is excreted in human milk. As there may be potential for serious adverse reactions in nursing infants from calcitriol, a decision should be made as to whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Clinical experience with Calcijex in patients under 18 years of age is limited. Animal data suggests that immature animals may be more sensitive to calcitriol. Studies in neonatal rats have also showed a clear increase in the incidence of ocular abnormalities.
D
ose selection for an elderly patient should be cautious, usually starting at the low end of the dosage range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Long-term studies in animals have not been performed to evaluate the carcinogenic potential of Calcijex.
There was no evidence of mutagenicity as studied by the Ames Method.
Magnesium-containing antacid and Calcijex should not be used concomitantly, because such use may lead to the development of hypermagnesaemia. Concurrent use of vitamin D analogues and cardiac glycosides may result in cardiac arrhythmias. The effects of vitamin D may be reduced in patients taking barbiturates or anticonvulsants. Corticosteroids may counteract the effects of vitamin D analogues. Concomitant treatment with a thiazide diuretic increases the risk of hypercalcemia.
Adverse effects of Calcijex intravenous injection are, in general, similar to those encountered with excessive vitamin D intake. The early and late signs of symptoms of vitamin D intoxication associated with hypercalcaemia include:
Early:
Weakness, headache, somnolence, nausea, vomiting, dry mouth, constipation, muscle pain, bone pain, metallic taste, anorexia, abdominal pain, and epigastric discomfort.
Late:
Polyuria, polydipsia, anorexia, weight loss, nocturia, conjunctivitis (calcific), pancreatitis, photophobia, rhinorrhoea, pruritus, hyperthermia, decreased libido, elevated urea, albuminuria, hypercholesterolaemia, elevated AST and ALT, ectopic calcification, nephrocalcinosis, hypertension, cardiac arrhythmias, dystrophy, sensory disturbance, dehydratation, apathy, urinary tract infections, and, rarely, overt psychosis. Occasional mild pain on injection has been observed. The following adverse events have been reported spontaneously post marketing of the product overseas: brown tumour, anaphylactic reactions, bleeding at the venipuncture site, seizure, chest pain, pancreatitis, haemolysis and non-malignant tumour on the ribs. Rare cases of hypersensitivity reactions have been reported including anaphylaxis and localised redness at the injection site.
The optimal dose of Calcijex intravenous injection must be carefully determined for each patient. The effectiveness Calcijex therapy is predicated on the assumption that each patient is receiving an adequate and appropriate daily intake of calcium. The Recommended Daily Intake (RDI) for calcium in adults is 800 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. The recommended initial dose of Calcijex is 0.50 mcg (approximately 0.01 mcg/kg) administered intravenously three times weekly, approximately every other day. Calcijex should be administered as a bolus dose intravenously through the catheter at the end of haemodialysis. 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 mcg at two to four week intervals. During this titration period, serum calcium and phosphorous levels should be obtained at least twice weekly, and if hypercalcaemia is noted, the drug should be immediately discontinued until normocalcaemia ensues. Most patients undergoing haemodialysis respond to doses between 0.5 and 3.0 mcg three times per week. Parenteral drug products should be inspected visually for particulate matter prior to administration. Polyvinylchloride (PVC) is incompatible with calcitriol. Therefore the use of PVC syringes is not recommended. It is acceptable for polypropylene syringes to be used. Discard any unused portion.
Administration of Calcijex intravenous injection to patients in excess of their requirements can cause hypercalcaemia, hypercalciuria and hyperphosphataemia. High intake of calcium and phosphate concomitant with Calcijex may lead to similar abnormalities (see 'Precautions' and 'Adverse Effects' sections). For information on the management of overdose, contact the Poison Information Centre on 131126.
General treatment of hypercalcaemia (greater than 1 mg/dL above the upper limit of normal range) consists of immediate discontinuation of Calcijex 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 normocalcaemia ensues. Hypercalcaemia usually resolves in two to seven days. When serum calcium levels have returned to within normal limits, Calcijex therapy may be reinstituted at a dose 0.5 mcg less than prior therapy. Serum calcium levels should be obtained at least twice weekly after all dosage changes.
The treatment of acute accidental overdosage of Calcijex should consist of general supportive measures. Serial serum electrolyte determinations (especially calcium), rate of urinary calcium excretion and assessment of electrocardiographic abnormalities due to hypercalcaemia should be obtained. Such monitoring is critical in patients receiving digitalis. Discontinuation of supplemental calcium and initiation of a low calcium diet are also indicated in hypercalcaemia after accidental overdosage of Calcijex. Should elevated serum calcium levels persist, there are a variety of therapeutic alternatives which may be considered, depending on the patient's underlying condition. Management approaches reported in the literature include: forced saline diuresis, haemodialysis against a calcium-free dialysate and the use of drugs such as biphosphonates, mithramycin, calcitonin, glucocorticoids and galium nitrate.
Calcijex intravenous injection is supplied in 1 mL ampoules containing 1 mcg and 2 mcg *. 5 ampoules are placed in a tray and 5 trays are packed into a carton, giving a presentation of 25 ampoules in a carton. * Not marketed in Australia Protect from light. Store below 25degC.
AbbVie Pty Ltd 32-34 Lord St Botany NSW 2019 Australia
Schedule 4 - Prescription Only Medicine
12 December 1995
21 August 2012 Version 07