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4.3 Contraindications
Rocaltrol should not be given to patients with is contraindicated in all diseases associated with hypercalcaemia or and in patients with evidence of metastatic calcification. The use of Rocaltrol in patients with known hypersensitivity to calcitriol (or drugs of the same class) and any of the constituent excipients is contraindicated.
Rocaltrol is contraindicated if there is evidence of vitamin D toxicity.
Owing to the presence of sorbitol, patients with rare hereditary problems of fructose intolerance should not take this medicine.
4.4 Special warnings and precautions for use
There is a close correlation between treatment with calcitriol and the development of hypercalcaemia.
All other vitamin D compounds and their derivatives, including proprietary compounds or foodstuffs which may be “fortified” with vitamin D, should be withheld during treatment with Rocaltrol.
If the patient is switched from a long acting vitamin D preparation (e.g. ergocalciferol or colecalciferol) to calcitriol, it may take several months for the level in the blood to return to the baseline value, thereby increasing the risk of hypercalcaemia.
As soon as serum calcium levels rise to 1mg/100ml (250µmol/l) above normal (9-11 mg/100ml or 2250-2750 µmol/l), or serum creatinine rises to >120 µmol/l, treatment with Rocaltrol should be stopped immediately until normocalcaemia ensues (see section 4.2 Posology and method of administration)
An abrupt increase in calcium intake as a result of changes in diet (e.g. increased consumption of dairy products) or uncontrolled intake of calcium preparations may trigger hypercalcaemia. Patients and families should be advised that strict adherence to prescribed diets is mandatory and they should be instructed on how to recognise the symptoms of hypercalcaemia.
In patients with end-stage renal failure, treatment does not obviate the need to control plasma phosphate with phosphate-binding agents. Since Rocaltrol affects phosphate transport in the gut and bone, the dose of phosphate-binding agent may need to be modified. The value for serum calcium multiplied by phosphorus (Ca x P) should not be allowed to exceed 70 mg2/dl2 or 5.6 mmol2/l2.
Calcitriol increases inorganic phosphate levels in serum. While this is desirable in patients with hypophosphatemia, caution is called for in patients with renal failure because of the danger of ectopic calcification. In such cases, the plasma phosphate level should be maintained at the normal level (2-5mg/100ml or 0.65-1.62 mmol/l) by the oral administration of appropriate phosphate-binding agents and low phosphate diet.
The serum calcium times phosphate (Ca x P) product should not be allowed to exceed 70mg2 /dl2 .
Patients with vitamin D-resistant rickets (familial hypophosphatemia) who are being treated with Rocaltrol must continue their oral phosphate therapy.
However, possible stimulation of intestinal absorption of phosphate by Rocaltrol should be taken into account since this effect may modify the need for phosphate supplementation.
Since calcitriol is the most effective vitamin D metabolite available, no other vitamin D preparation should be prescribed during treatment with Rocaltrol, thereby ensuring that the development of hypervitaminosis D is avoided.
If the patient is switched from ergocalciferol (vitamin D2) to calcitriol, it may take several months for the ergocalciferol level in the blood to return to the baseline value (see section 4.9 Overdose).
Immobilised patients, e.g. those who have undergone surgery, are particularly exposed to the risk of hypercalcaemia.
Patients with normal renal function who are taking Rocaltrol should avoid dehydration. Adequate fluid intake should be maintained.
‘In patients with normal renal function, chronic hypercalcemia may be associated with an increase in serum creatinine’.
Rocaltrol capsules contain sorbitol. Patients with rare hereditary problems of fructose intolerance should not take Rocaltrol capsules.
4.5 Interaction with other medicinal products and other forms of interaction
Since calcitriol is the most effective vitamin D metabolite available, no other vitamin D
preparation should be prescribed during treatment with calcitriol, thereby ensuring that
the development of hypervitaminosis D is avoided. If the patient is switched from
ergocalciferol (vitamin D2) to calcitriol, it may take several months for the ergocalciferol
level in the blood to return to the baseline value’.
Pharmacological doses of vitamin D and its derivatives should be withheld during treatment with Rocaltrol to avoid possible additive effects and hypercalcemia.
Dietary instructions, especially concerning calcium supplements, should be strictly observed, and uncontrolled intake of additional calcium-containing preparations avoided.
Concomitant treatment with a thiazide diuretic increases the risk of hypercalcaemia. Calcitriol dosage must be determined with care in patients undergoing treatment with digitalis, as hypercalcaemia in such patients may precipitate cardiac arrhythmias.
Vitamin D derivatives can increase magnesium absorption, although magnesium balance is generally not affected, owing to a compensatory increase in urinary excretion. It is therefore recommended that magnesium-containing drugs (e.g. antacids) are not taken by patients with chronic renal failure on dialysis during therapy with Rocaltrol since, under these circumstances, hypermagnesaemia could occur.
Magnesium-containing drugs (e.g. antacids) may cause hypermagnesemia and should therefore not be taken during therapy with Rocaltrol by patients on chronic renal dialysis.
Since Rocaltrol also has an effect on phosphate transport in the intestine, kidneys and bones, the dosage of phosphate-binding agents must be adjusted in accordance with the serum phosphate concentration (normal values: 2-5 mg/100 ml, or 0.65-1.62 mmol/l).
Patients with vitamin D-resistant rickets (familial hypophosphatemia) should continue their oral phosphate therapy. However, possible stimulation of intestinal phosphate absorption by calcitriol should be taken into account since this effect may modify the requirement for phosphate supplements.
Administration of enzyme inducers such as phenytoin or phenobarbital may lead to increased metabolism and hence reduced serum concentrations of calcitriol. Therefore higher doses of calcitriol may be necessary if these drugs are administered simultaneously.
A relationship of functional antagonism exists between vitamin D analogues, which promote calcium absorption, and corticosteroids, which inhibit it.
Colestyramine can reduce intestinal absorption of fat-soluble vitamins and therefore may impair intestinal absorption of calcitriol.
4.6 Pregnancy and lactation
The safety of Rocaltrol during pregnancy has not been established. Studies of reproductive toxicology in animals have not yielded unequivocal findings, and no controlled studies on the effect of exogenous calcitriol on pregnancy and foetal development have been performed in human subjects. Consequently Rocaltrol should be given only when the potential benefit has been weighed against the possible hazard to the foetus. The usual caution in prescribing any drug for women of childbearing age should be observed.
Supravalvular aortic stenosis has been produced in fetuses by near-fatal oral doses of vitamin D in pregnant rabbits. There is no evidence to suggest that vitamin D is teratogenic in humans even at very high doses. Rocaltrol should be used during pregnancy only if the benefits outweigh the potential risk to the foetus.
It should be assumed that exogenous calcitriol passes into breast milk. Mothers may breastfeed while taking Rocaltrol, provided that the serum calcium levels of the mother and infant are monitored.
4.7 Effects on ability to drive and use machines
Not relevant
On the basis of the pharmacodynamic profile of reported adverse events, this product is presumed to be safe or unlikely to adversely affect such activities.
4.8 Undesirable effects
The number of adverse effects reported from clinical use of Rocaltrol over a period of 15 years in all indications is very low with each individual effect, including hypercalcaemia, occurring rarely (≤ 0.001%).
Since calcitriol exerts vitamin D activity, adverse effects may occur which are similar to those found when an excessive dose of vitamin D is taken, i.e. hypercalcemia syndrome or calcium intoxication (depending on the severity and duration of hypercalcemia). (See section 4.2 Posology and method of administration, and section 4.4 Special warnings and precautions for use).
Hypercalcaemia and hypercalcuria are the major side effects of Rocaltrol and indicate excessive dosage. Patients with tertiary hyperparathyroidism, renal failure, or on regular haemodialysis are particularly prone to develop hypercalcaemia. The clinical features of hypercalcaemia include anorexia, constipation, nausea, vomiting, headache, weakness, apathy and somnolence. More severe manifestations may include fever, thirst/polydipsia, dehydration, polyuria, nocturia, abdominal pain, paralytic ileus, cardiac arrhythmias and psychiatric disturbances. Rarely, overt psychosis and metastatic calcification (particularly nephrocalcinosis and renal stones) may occur. The relatively short biological half-life of Rocaltrol permits rapid elimination of the compound when treatment is stopped and hypercalcaemia will recede within 2 - 7 days. This rate of reversal of biological effects is more rapid than when other vitamin D derivatives are used.
In patients with normal renal function, chronic hypercalcaemia may be associated with an increase in serum creatinine.
Because of the short biological half-life of calcitriol, pharmacokinetic investigations have shown normalization of elevated serum calcium within a few days of treatment withdrawal, i.e. much faster than in treatment with vitamin D3 preparations.
Mild, non-progressive and reversible elevations in levels of liver enzymes (SGOT, SGPT) have been noted in a few patients treated with Rocaltrol, but no pathological changes in the liver have been reported.
In concurrent hypercalcemia and hyperphosphatemia of > 6 mg/100 ml or > 1.9 mmol/l, soft-tissue calcification may occur; this can be seen radiographically.
Hypersensitivity reactions (pruritus, rash, urticaria and, very rarely, severe erythematous skin disorders) may occur in susceptible individuals.
4.9 Overdose
Treatment of asymptomatic hypercalcemia: (See section 4.2 Posology and method of administration).
Since calcitriol is a derivative of vitamin D, the symptoms of overdose are the same as for an overdose of vitamin D. Intake of high doses of calcium and phosphate together with Rocaltrol may give rise to similar symptoms. The serum calcium times phosphate (Ca x P) product should not be allowed to exceed 70 mg2 / dl2. A high calcium level in the dialysate may contribute to the development of hypercalcemia.
Acute symptoms of vitamin D intoxication: anorexia, headache, vomiting, constipation.
Chronic symptoms: dystrophy (weakness, loss of weight), sensory disturbances, possibly fever with thirst, polyuria, dehydration, apathy, arrested growth and urinary tract infections. Hypercalcemia ensues, with metastatic calcification of the renal cortex, myocardium, lungs and pancreas.
The following measures should be considered in treatment of accidental overdosage: immediate gastric lavage or induction of vomiting to prevent further absorption. Administration of liquid paraffin to promote fecal excretion. Repeated serum calcium determinations are advisable. If elevated calcium levels persist in the serum, phosphates and corticosteroids may be administered and measures instituted to bring about adequate diuresis.
Hypercalemia at higher levels (>3.2 mmol/L) may lead to renal insufficiency particularly if blood phosphate levels are normal or elevated due to impaired renal function.
In acute overdosage, toxic features are unlikely to arise, and the recommended treatment is liberal fluids only.
Should hypercalcaemia occur following prolonged treatment, Rocaltrol should be discontinued until plasma calcium levels have returned to normal. A low-calcium diet will speed this reversal. Rocaltrol can then be restarted at a lower dose or given in the same dose but at less frequent intervals than previously. Severe or persistent hypercalcaemia may be treated by administering corticosteroids, ensuring adequate hydration, inducing a diuresis where practicable and by general supportive measures. Calcitonin may increase the rate of fall of serum calcium when bone resorption is increased.
In patients treated by intermittent haemodialysis, a low concentration of calcium in the dialysate may also be used. However, a high concentration of calcium in the dialysate may contribute to the development of hypercalcaemia.
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