Calcijex - Product Information
|Condition:||Hypoparathyroidism, Hypocalcemia, Renal Osteodystrophy, Rickets|
|Form:||Liquid solution, Intravenous (IV)|
|Ingredients:||calcitriol, anhydrous dibasic sodium phosphate, edentate disodium, monobasic sodium phosphate monohydrate, polysorbate 20, sodium ascorbate, sodium chloride.|
Summary Product Information
|Route of |
|Dosage Form / |
|Clinically Relevant Non-medicinal Ingredients|
|Intravenous||Injectable / 1 mcg/mL |
and 2 mcg/mL
|Anhydrous dibasic sodium phosphate, edetate|
disodium, monobasic sodium phosphate
monohydrate, polysorbate 20, sodium ascorbate,
Indications and Clinical Use
CALCIJEX (calcitriol injection) is indicated for:
- the management of hypocalcemia in patients undergoing chronic renal dialysis.
It has been also shown to significantly reduce elevated parathyroid hormone levels (PTH) in many of these patients. Reduction of PTH has been shown to result in an improvement in renal osteodystrophy.
Geriatrics (≥ 65 years of age)
Clinical studies of CALCIJEX did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects.
Pediatrics (< 18 years of age)
Safety and efficacy of CALCIJEX have not been established in the pediatric population.
- CALCIJEX (calcitriol injection) is contraindicated in patients with previous hypersensitivity to vitamin D or its analogues and derivatives
- CALCIJEX is contraindicated in patients with hypercalcemia or evidence of vitamin D toxicity
- CALCIJEX is contraindicated in patients with previous hypersensitivity to calcitriol or to any ingredient in the formulation or component of the container. For a complete listing of components/excipients, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section of the Product Monograph.
Warnings and Precautions
Since CALCIJEX (calcitriol injection) is a potent cholecalciferol derivative with profound effects on intestinal absorption of dietary calcium and inorganic phosphate, vitamin D and its derivatives should be withheld during treatment to avoid possible additive effects and hypercalcemia.
Therapy with CALCIJEX should only be considered when adequate laboratory facilities for monitoring of blood and urine chemistries are available. Overdosage of any form of vitamin D is dangerous. During treatment with CALCIJEX, progressive hypercalcemia either due to hyper-responsiveness or overdosage may become so severe as to require emergency treatment (see OVERDOSAGE). Chronic hypercalcemia can lead to generalized vascular calcification, nephrocalcinosis, and calcifications of the cornea or other soft tissues. Radiographic evaluation of suspect anatomical regions may be useful in the early detection of this condition. During treatment with calcitriol, the serum total calcium times serum inorganic phosphate product (Ca x P) should not exceed 70 mg2/dL2.
Dialysate calcium level of 7 mg % or above in addition to excessive dietary calcium supplements may lead to frequent episodes of hypercalcemia.
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).
Patient Selection and Follow-up: Patients with renal osteodystrophy and hypocalcemia, poorly managed by conventional vitamin D therapy, are likely to respond to CALCIJEX. 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 DOSAGE AND ADMINISTRATION).
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.
CALCIJEX should be used with extreme caution in patients on digitalis. Hypercalcemia in such patients may precipitate cardiac arrhythmias (see DRUG INTERACTIONS).
Carcinogenesis and Mutagenesis
See TOXICOLOGY, Mutagenicity and Carcinogenicity.
Calcitriol has been reported to be teratogenic in rabbits when given orally 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 at doses up to 0.45 mcg/kg showed no evidence of teratogenic potential.
There are no adequate and well-controlled studies in pregnant women. CALCIJEX should not be used during pregnancy unless the potential benefit to the mother justifies the potential risk to the fetus.
It is not known whether calcitriol 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.
Pediatrics (< 18 years of age)
Safety and efficacy of CALCIJEX in pediatric patients younger than eighteen years of age have not been established.
Geriatrics (≥ 65 years of age)
Clinical studies of CALCIJEX did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose 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.
Monitoring and Laboratory Tests
Serum calcium, inorganic phosphorous, magnesium, alkaline phosphatase as well as 24-hour urinary calcium and phosphorous should be determined periodically during maintenance therapy with CALCIJEX. During the initial phase of the medication, serum calcium and phosphorous should be determined more frequently (at least twice weekly). Periodic ophthalmological examinations and radiological evaluation of suspected anatomical regions for early detection of ectopic classifications are advisable.
Adynamic bone disease may develop if PTH levels are suppressed to abnormal levels. If a biopsy is not being done for other (diagnostic) reasons, PTH levels may be used to indicate the rate of bone turnover. In patients treated with CALCIJEX, if PTH levels fall below the recommended target range (1.5 to 3 times the upper limit of normal), the calcitriol dose should be reduced or therapy should be discontinued. Discontinuation of CALCIJEX therapy may result in rebound effect; therefore, appropriate titration downward to a maintenance dose is recommended.
Adverse Drug Reaction Overview
The following adverse reactions have been reported in association with CALCIJEX (calcitriol injection) treatment.
The most frequently reported adverse effect is hypercalcemia (35% approximately 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 serum glutamic oxaloacetic transaminase (SGOT) and/or serum glutamic pyruvic transaminase (SGPT), elevated alkaline phosphatase, hypercalciuria, hypermagnesemia, hyperphosphatemia, elevated lymphocytes, elevated hematocrit, elevated neutrophils, and elevated hemoglobin.
The adverse effects of CALCIJEX 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.
Asthenia, headache, somnolence, nausea, cardiac arrhythmias, excessive thirst, vomiting, dry mouth, constipation, myalgia, bone pain, dysgeusia, decreased appetite, abdominal pain, and dyspepsia.
Polyuria, polydipsia, decreased appetite, weight decreased, nocturia, conjunctival deposit, pancreatitis, photophobia, rhinorrhoea, pruritus, hyperthermia, libido decreased, blood urea increased, albuminuria, hypercholesterolemia, aspartate aminotransferase increased, alanine aminotransferase increased, calcinosis, hypertension, cardiac arrhythmias, muscular weakness, paresthesia, dehydration, apathy, urinary tract infections, and rarely, overt psychosis.
Clinical Trial Adverse Drug Reactions
Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
CALCIJEX was studied in 20 patients undergoing maintenance hemodialysis for chronic renal disease (see CLINICAL TRIALS, Study CP5691). This open-label study had no comparator; each patient served as his/her own control. Patients received CALCIJEX three times weekly, post-dialysis over a treatment period of 4 to 8 weeks. Doses were titrated for each patient based upon serum total calcium response.
Abnormal Hematologic and Clinical Chemistry Findings
The most frequently reported adverse effect is hypercalcemia (35% approximately after the 4th week of treatment).
Post-Market Adverse Drug Reactions
Hypersensitivity reactions have been commonly reported in Post-Market Clinical Trials at a frequency of 2.3%. Rare postmarketing reports of anaphylaxis have also been received. Occasional mild pain and localized redness at the injection site have been observed. The adverse drug reactions occurring in patients receiving CALCIJEX in seven Post Market Clinical Studies are summarized for a total of 485 subjects randomized to CALCIJEX (Table 1).
|System Organ Class||Very Common||Common||Uncommon||Not Known|
|Infections and Infestations||Urinary tract infection|
|Immune System Disorders||Hypersensitivity*|
|Metabolism and Nutrition Disorders||Decreased appetite|
|Psychiatric Disorders||Libido decreased|
|Nervous System Disorders||Headache||Somnolence|
|Eye Disorders||Conjuctival deposit Photophobia|
|Cardiac Disorders||Cardiac arrhythmia|
|Respiratory, Thoracic and Mediastinal Disorders||Rhinorrhoea|
Constipation Abdominal pain Dyspepsia
|Skin and Subcutaneous Tissue Disorders||Pruritus|
|Musculoskeletal and Connective Tissue Disorders||Myalgia||Bone pain|
|Renal and Urinary Disorders||Polyuria|
|General Disorders and Administration Site Conditions||Pain||Injection site pain|
|Injection site reaction|
Aspartate aminotransferase increased
|Blood urea increased|
Alanine aminotransferase increased
*Anaphylaxis has not been observed in clinical trials.
The drugs listed in Table 2 are based on potential interactions due to the expected magnitude and seriousness of the interaction.
|Proper name||Ref||Effect||Clinical comment|
(e.g. diphenylhydantoin and barbiturates)
|T||↑ calcitriol elimination and|
↓ calcitriol effect
|Patients under concurrent treatment with such agents may require slightly higher doses of calcitriol.|
|Corticosteroids||T||May counteract the effects of vitamin D analogs||May worsen bone disease and demineralization.|
|Digitalis||T||Possible increase of digitalis toxicity||Hypercalcemia in patients on digitalis may precipitate cardiac arrhythmias.|
|T||↑ intestinal absorption of magnesium||Magnesium-containing antacids and calcitriol should not be used concomitantly, since such use may lead to the development of hypermagnesemia.|
|Thiazide diuretics||T||↑ risk of hypercalcemia||Thiazide diuretics act on the distal tubule and inhibit reabsorption of sodium and potassium. This in turn stimulates the reabsorption of calcium, therefore, an increase in calcium level.|
Legend: T = Theoretical
Interactions with food have not been established.
Interactions with herbal products have not been established.
Interactions with laboratory tests have not been established.
Dosage and Administration
- CALCIJEX is for intravenous injection only.
- The optimal dose of CALCIJEX (calcitriol injection) must be carefully determined for each patient.
- The effectiveness of CALCIJEX 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 gastrointestinal tract, some patients may be maintained on a lower calcium intake or no supplementation at all.
Recommended Dose and Dosage adjustment
The recommended initial dose of CALCIJEX is 0.5 mcg (0.01 mcg/kg) administered three times weekly, every other day. 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. If hypercalcemia or a serum calcium times phosphate product greater than 70 is noted, the drug should be immediately discontinued until these parameters normalize. The CALCIJEX dose should then be reinitiated at a lower dose. Doses may need to be reduced as the PTH levels decrease and commensurate with PTH, serum calcium and phosphorous levels.
Most patients undergoing hemodialysis respond to doses between 0.5 and 3 mcg (0.01 to 0.05 mcg/kg) three times per week.
CALCIJEX can be administered as a bolus dose intravenously through the catheter at the end of hemodialysis.
|For management of a suspected drug overdose, contact your regional Poison Control Centre.|
Administration of CALCIJEX (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 CALCIJEX may cause similar abnormalities (see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS). 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 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, CALCIJEX therapy may be reinstituted at a dose of 0.5 mcg 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 CALCIJEX 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.
Action and Clinical Pharmacology
Mechanism of Action
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 phosphorous 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 suggests 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 stimulates the 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 phosphorous 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 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.
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.
Not applicable as CALCIJEX is an injectable drug.
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.
Storage and Stability
Store between 15 and 25°C; however, brief exposure up to 40°C does not adversely affect the product. Protect from light.
Special Handling Instructions
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.
Discard unused portion.
Dosage Forms, Composition and Packaging
CALCIJEX (calcitriol injection) is a sterile, isotonic, clear, aqueous solution for intravenous injection and is supplied in 1 mL ampoules available in 2 strengths: 1 mcg or 2 mcg of calcitriol.
Listing of Non-Medicinal Ingredients
Each 1 mL ampoule contains 1 or 2 mcg calcitriol, anhydrous dibasic sodium phosphate (buffer), edetate disodium, monobasic sodium phosphate monohydrate (buffer), polysorbate 20, sodium ascorbate and sodium chloride. The pH of the solution is approximately 7. It does not contain a preservative.