Vitamin D3 Metabolite
Action And Clinical Pharmacology: The supply of vitamin D in man depends on dietary intake and/or exposure to the ultraviolet rays of the sun for conversion of 7-dehydrocholesterol to vitamin D3 (cholecalciferol). Vitamin D3 (cholecalciferol) must be metabolized in the liver and the kidneys before it is fully active on its target tissues. The initial transformation is catalyzed by a vitamin D3-25-hydroxylase enzyme (25-OH-ase) present in the liver, and the product of this reaction is 25-hydroxy-vitamin D3 (25-OH-D3). The latter undergoes hydroxylation in the mitochondria of kidney tissue. This reaction is activated by the renal 25-hydroxy-vitamin D3-1 alphahydroxylase (alpha-OH-ase) to produce 1,25-(OH)2D3 (calcitriol).
Calcitriol’s two known sites of action are intestine and bone, but additional evidence suggests that it also acts on the kidney and the parathyroid gland.
In acutely uremic rats, calcitriol stimulates calcium absorption. It is the most active known form of vitamin D3 in stimulating intestinal calcium transport. This agent also promotes the intestinal absorption of phosphorus through stimulation of an active transport system distinct from the calcium transport process.
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.
Calcitriol’s effects on the renal transport of calcium and phosphate appear to be influenced by the presence or absence of the parathyroid glands, vitamin D status, volume expansion and the dose of vitamin D metabolite used. With the available information it is not possible to determine which vitamin D metabolite, if any, influences divalent ion transport by the renal tubule under physiologic conditions or if so, whether an interaction with parathyroid hormone is required.
The presence of a direct negative feedback effect of calcitriol on the parathyroid gland has been suspected. Some investigators have postulated that calcitriol may exert a direct influence on the parathyroids. Although inhibition of PTH secretion by calcitriol has been demonstrated in vitro, the data obtained from in vivo studies are more equivocal.
Indications And Clinical Uses: The management of hypocalcemia and osteodystrophy in patients with chronic renal failure undergoing dialysis. Hypocalcemia and its clinical manifestations associated with: postsurgical hypoparathyroidism, idiopathic hypoparathyroidism, pseudohypoparathyroidism. Vitamin D resistant rickets (familial hypophosphatemia).
Contra-Indications: Hypersensitivity to calcitriol, vitamin D or its analogues and derivatives; hypercalcemia; evidence of vitamin D overdosage.
Manufacturers’ Warnings In Clinical States: Since calcitriol 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 their derivatives.
Calcitriol therapy 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.
Chronic hypercalcemia can lead to generalized vascular calcification, nephrocalcinosis, calcifications of the cornea or other soft tissues. During calcitriol treatment, the serum total calcium (mg/dL) times serum inorganic phosphate product (CaxP) 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, use calcitriol with extreme caution.
To control serum inorganic phosphate levels and dietary phosphate absorption in patients undergoing dialysis, oral aluminum carbonate or aluminum hydroxide gel must be used. Magnesium containing antacids may contribute towards hypermagnesemia in patients on chronic renal dialysis and should be avoided during calcitriol therapy.
Pregnancy: Safety in women who are or may become pregnant has not been established; use of calcitriol in these cases may be considered only when the potential benefits have been weighed against possible hazards to mother and fetus.
Lactation: Since calcitriol may be excreted in human milk, avoid breast feeding during treatment.
Precautions: Patient selection and follow-up: Patients with renal osteodystrophy and hypocalcemia, poorly managed by conventional vitamin D therapy are likely to respond to calcitriol. The desired therapeutic margin of calcitriol is narrow; therefore, determine the optimal daily dose carefully for each patient by dose titration to obtain satisfactory response in the biochemical parameters and clinical manifestations (see Dosage).
Excessive dosage of calcitriol induces hypercalcemia and hypercalciuria; therefore, early in treatment during dosage adjustment determine serum calcium at least twice weekly. A fall in serum alkaline phosphatase values may indicate impending hypercalcemia. Should hypercalcemia develop, discontinue the drug immediately until the serum calcium has normalized. This may take several days to a week.
In patients with normal renal function, chronic hypercalcemia may be associated with an increase in serum creatinine. While the elevation of serum creatinine is usually reversible, it is important in such patients to pay careful attention to those factors which may lead to hypercalcemia. Therapy should always be started at the lowest possible dose and increased with careful monitoring of serum calcium concentrations. An estimate of daily dietary calcium intake should be made and the intake adjusted when indicated.
Patients with normal renal function should avoid dehydration. Adequate fluid intake should be maintained.
Patients with vitamin D resistant rickets (familial hypophosphatemia) should pursue their oral phosphate therapy. However, the possible stimulation of intestinal phosphate absorption should be taken into account since this effect may modify the requirement for phosphate supplements.
Essential laboratory tests: Serum calcium, inorganic phosphorus, magnesium, alkaline phosphatase as well as 24 hour urinary calcium and phosphorus should be determined periodically during calcitriol maintenance therapy. During the initial phase of the medication, determine serum calcium more frequently (at least twice weekly). Periodic ophthalmological examinations and radiological evaluation of suspected anatomical regions for early detection of ectopic calcifications are advisable.
Drug Interactions: Hypercalcemia in patients on digitalis may precipitate cardiac arrhythmias. Intestinal absorption of calcitriol may be impaired by resins such as cholestyramine and by use of mineral oil as a laxative. Although the precise mechanism involved is unknown, long-term anticonvulsant treatment, particularly with phenytoin and barbiturates, may interfere with the actions of vitamin D. Patients under concurrent treatment with such agents may require slightly higher doses of calcitriol.
Information for the Patient: Inform the patient and his or her immediate relatives about the need for compliance with dosage instructions, strict adherence to prescribed calcium intake, dietary and supplementary, and avoidance of unapproved nonprescription 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 Effects).
Adverse Reactions: Most frequent: hypercalcemia (20 to 30%).
Less frequent: headache, nausea, vomiting, constipation, abdominal cramps, pruritus, conjunctivitis, agitation, extremity pain, apprehension, polyuria, insomnia, elevated AST and/or ALT, elevated alkaline phosphatase, hypercalciuria, hypermagnesemia, hyperphosphatemia, elevated lymphocytes, elevated hematocrit, elevated neutrophils, elevated hemoglobin.
The adverse effects of calcitriol 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:
a. Early: weakness, headache, somnolence, nausea, cardiac arrhythmias, excessive thirst, vomiting, dry mouth, constipation, muscle pain, bone pain, metallic taste.
b. Late: polyuria, polydipsia, anorexia, weight loss, nocturia, conjunctivitis (calcific), pancreatitis, photophobia, rhinorrhea, pruritus, hyperthermia, decreased libido, elevated BUN, albuminuria, hypercholesterolemia, elevated AST and ALT, ectopic calcification, hypertension, cardiac arrhythmias, and rarely, overt psychosis.
Symptoms And Treatment Of Overdose: Symptoms: Calcitriol administration to patients in excess of their daily requirements can cause hypercalcemia, hypercalciuria and hyperphosphatemia. Conversely, high calcium and phosphate intake concomitantly with therapeutic doses of calcitriol may cause similar abnormalities. In dialysis patients, high levels of calcium in the dialysis bath may contribute to hypercalcemia.
Treatment: Accidental Overdosage: Employ general supportive measures. If drug ingestion is discovered within a relatively short time, induction of emesis or gastric lavage may be of benefit in preventing further absorption. If the drug has passed through the stomach, mineral oil administration may promote fecal elimination. Obtain serial serum electrolyte determinations (especially calcium ion), rate of urinary calcium excretion and assessment of ECG abnormalities due to hypercalcemia. 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 concentrations occur, a variety of therapeutic alternatives may be considered, depending on the patient’s underlying condition. These include the use of drugs such as phosphates and corticosteroids as well as measures to induce an appropriate forced diuresis. Peritoneal dialysis has been used against a calcium-free dialysate.
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. Determine serum calcium concentrations daily until normocalcemia ensues. Hypercalcemia frequently resolves in 2 to 7 days. When serum calcium concentrations have returned to within normal limits, calcitriol therapy may be reinstituted at a dose of 0.25 Âµg/day less than prior therapy. Monitor serum calcium concentrations carefully (at least twice weekly) during this period of dosage adjustment and subsequent dosage titration. Correct persistent or markedly elevated serum calcium concentrations by dialysis against a calcium-free dialysate.
Dosage And Administration: Determine the optimum daily dose carefully for each patient. The effectiveness of calcitriol therapy is predicated on the assumption that each patient is receiving an adequate daily calcium intake. The recommended daily intake for calcium is in the order of 800 mg for adults and 350 mg for infants during the first 6 months of life.
To ensure an adequate daily calcium intake, instruct patients regarding appropriate dietary measures or prescribe a calcium supplement. 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.
Dialysis Patients: Adults: Titration: Initial calcitriol dose is 0.25 g/day. If a satisfactory response in the biochemical parameters and clinical manifestations of the disease state is not observed, dosage may be increased by 0.25 g/day at 2 to 4 week intervals. During this titration period, obtain serum calcium levels at least twice weekly, and if hypercalcemia is noted, discontinue the drug immediately until normocalcemia ensues.
Maintenance: Patients with normal or only slightly reduced serum calcium levels may respond to calcitriol at doses of 0.25 g every other day. Most patients undergoing hemodialysis respond to between 0.5 and 1 g/day.
In order to decrease the risk of hypercalcemic episodes, a downward adjustment of the calcitriol dose may be advisable once a reduction in serum alkaline phosphatase has been achieved.
Hypoparathyroidism and Vitamin D Resistant Rickets:
Adults: Initial dose: 0.25 g/day. If a satisfactory response in the biochemical parameters and clinical manifestations of the disease are not observed, the dose may be increased by 0.25 g/day at 2 to 4 week intervals. During the dosage titration period, serum calcium levels should be measured at least twice weekly and, if hypercalcemia is present, calcitriol should be immediately discontinued until normocalcemia ensues. Consideration should also be given to lowering the calcium intake.
Malabsorption is occasionally noted in patients with hypoparathyroidism; hence, larger doses may be needed.
Children: Initiation of Treatment: x-linked hypophosphatemic rickets: 0.01 to 0.02 g/kg/day (mean 0.018 g/kg/day).
Vitamin D dependency rickets type 1: 0.010 to 0.025 g/kg/day (mean 0.017 g/kg/day).
Hypoparathyroidism: 0.03 to 0.05 g/kg/day (mean 0.04 g/kg/day).
Response is checked after 2 weeks to ascertain that the dose has not produced hypercalcemia. Biochemical evaluation should include serum calcium (total and ionized if available), phosphate, alkaline phosphatase, and creatinine. If satisfactory biochemical improvement has not occurred, the dose is increased by about 25% and the effect re-evaluated in 2 weeks. Until the desired response to treatment is achieved, the dose is gradually increased or decreased in this manner. Improvement in the radiographic lesions of rickets takes several weeks to become apparent.
For severely hypocalcemic or symptomatic patients, an initial dose as high as 0.05 g/kg/day may be used to treat the hypocalcemia. In this situation, the serum calcium concentration should be monitored very closely (hospitalization recommended), and as soon as the patient is out of danger from hypocalcemia, the dose reduced.
Maintenance: x-linked hypophosphatemic rickets=0.01 to 0.05 g/kg/day (mean 0.022 g/kg/day).
Vitamin D dependency rickets type 1=0.0046 to 0.015 g/kg/day.
Hypoparathyroidism=0.014 to 0.040 g/kg/day (mean 0.025 g/kg/day).
Assessment of serum calcium (total and ionized), phosphate, alkaline phosphatase and creatinine should be made at 3 to 4 month intervals once treatment has been established and for as long as the medication is administered.
Hypercalcemia can occur at any time while the patient is treated with Calcitriol (even if the dose has not been changed). Patients with rachitic or osteomalacic bone changes may become hypercalcemic as the bones become remineralized and therefore take up less calcium from the blood. To decrease the risk of hypercalcemia, a downward adjustment of the calcitriol dose may be advisable once a reduction in serum alkaline phosphatase has been achieved.
The single most important indicator of calcitriol overdose appears to be hypercalcemia as determined by accurate and frequent measurement of the serum calcium concentration. Signs of hypercalcemia such as polyuria, nocturia, polydipsia, nausea, vomiting, anorexia, weight loss, and constipation should be watched for but are less sensitive indicators of toxicity. Most hypercalcemic patients are asymptomatic.
If hypercalcemia occurs, calcitriol is discontinued for 1 to 2 weeks or until hypercalcemia disappears. Hypercalcemia frequently resolves in 2 to 7 days. Therapy is then resumed with a dose about 25% lower than that which caused intoxication. If the dose has been increased or decreased for any reason, the calcium level should be re-evaluated at 2-week intervals.
Fasting urine samples for measurement of calcium/creatinine ratio may be used to monitor the development of hypercalciuria.
Kidney ultrasounds may be indicated yearly during calcitriol therapy. However, the clinical significance of the finding of nephrocalcinosis is not known.
Calcitriol solution must be measured accurately and can be administered directly into the mouth of the infant. The bottle should be closed tightly each time after use, and when stored between 15 and 30°C and protected from light, the solution is stable for 6 weeks after opening.
Availability And Storage: Capsules: 0.25 g: Each white/brownish-red oval soft gelatin capsule contains: calcitriol 0.25 g. Energy: 6.5 kJ (1.5 kcal). Nonmedicinal ingredients: butylated hydroxyanisole, butylated hydroxytoluene, canthaxanthin, fractionated coconut oil, gelatin, glycerin hydrogenated partially hydrolyzed starch and titanium dioxide. Alcohol-, gluten-, lactose-, sulfite- and tartrazine-free. Bottles of 100.
0.50 g: Each brownish-red oval soft gelatin capsule contains: calcitriol 0.50 g. Energy: 6.5 kJ (1.5 kcal). Nonmedicinal ingredients: butylated hydroxyanisole, butylated hydroxytoluene, canthaxanthin, fractionated coconut oil, gelatin, glycerin hydrogenated partially hydrolyzed starch and titanium dioxide. Alcohol-, gluten-, lactose-, sulfite- and tartrazine-free. Bottles of 100.
Solution: Each mL of clear, colorless, oily solution contains: calcitriol 1.0 g. Nonmedicinal ingredients: butylated hydroxyanisole, butylated hydroxytoluene and fractionated coconut oil. Bottles of 10 mL, boxes of 5.
Store capsules and solution at 15 to 30°C and protect from light. Discard solution 6 weeks after first opening the bottle.
ROCALTROL® Roche Calcitriol Vitamin D3 Metabolite