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QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains 0.25 microgram of calcitriol.

Each capsule contains upto 4.37mg sorbitol

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 contra-indicated.

Rocaltrol is contra-indicated if there is evidence of vitamin D toxicity.

Special warnings and precautions for use

There is a close correlation between treatment with calcitriol and the development of hypercalcemia.

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.

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 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)

As soon as serum levels rise to 1mg/100ml (250 µmol/l) above normal (9-11mg/100ml, or 2250-2750 µmol/l), or serum creatinine rises to >120 µmol/l, treatment with Rocaltrol should be stopped immediately until normocalcemia 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.

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 phosphate (Ca x P) should not be allowed to exceed 70 mg²/dl².

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 70mg ² / 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.

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

Owing to the presence of Rocaltrol capsules contain sorbitol, patients with rare hereditary problems of fructose intolerance should not take Rocaltrol capsules this medicine..

Patients being treated with Rocaltrol should be under regular surveillance and those being treated for renal osteodystrophy should be under the supervision of a specialist having at their disposal facilities to monitor the appropriate biochemical parameter.

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. (see section 4.4 special warnings and precautions for use).

A relationship of functional antagonism exists between vitamin D analogues, which promote calcium absorption, and corticosteroids, which inhibit it.

Magnesium-containing drugs (e.g. antacids) may cause hypomagnesaemia 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:2-5mg/100ml, or 0.65-1.62mmol/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 supplement.

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.

Pregnancy and lactation

The safety of Rocaltrol during pregnancy has not been established and it should be given only when the potential benefit has been weighed against the possible hazard. 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.In view of the potential for hypercalcemia in the mother and for adverse events for nursing infants,  mothers may breastfeed while taking Rocaltrol, provided that the serum calcium levels of the mother and infant are monitored.

Effects on ability to drive and use machines

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.

Not relevant.

Undesirable effects

The most commonly reported adverse reaction (occurring in over 5% of patients treated with Rocaltrol) was hypercalcaemia.

The ADRs listed in Table 1 are presented by system organ class and frequency categories, defined using the following convention: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 1. Summary of ADRs occurring in patients receiving Rocaltrol^® (calcitriol)

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. hypercalcaemia syndrome or calcium intoxication (depending on the severity and duration of hypercalcaemia). (See section 4.2 Posology and method of administration, and section 4.4 Special warnings and precautions for use). Occasional acute symptoms include anorexia, headache, nausea, vomiting, abdominal pain or stomach ache and constipation. 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.

Hypersensitivity reactions including Rash, Erythema, Pruritus, and Urticaria have been observed in some patients.

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%) or less..

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 Occasional acute symptoms include anorexia, headache constipation, nausea, vomiting, headacheabdominal pain or stomach ache and constipation., weakness, apathy and somnolence. 

Chronic manifestations may include dystrophy, sensory disturbances, fever with thirst, thirst/polydipsia, polyuria, dehydration, apathy, arrested growth and urinary tract infectionnocturia, abdominal pain, paralytic ileus, cardiac arrythmias fever, thirst/polydipsia, dehydration, polyuria, nocturia, abdominal pain, paralytic ileus, cardiac arrhythmias, dystrophy, arrested growth, sensory disturbances and urinary tract infections.  Rarely, overt psychosis and metastatic calcification 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.

Because of the short biological half-life of calcitriol, pharmacokinetic investigations have shown normalisation of elevated serum calcium within a few days of treatment withdrawal, ie much faster than in treatment with n vitamin D₃ preparations.

In patients with normal renal function, chronic hypercalcaemia may be associated with an increase in serum creatinine.

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 >6mg/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.

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 the overdose are the same as for an overdose of vitamin D. Intake of high doses of calcium and phosphate together with roclatrol may give rise to similar symptoms. The serum calcium times phosphate (Ca x P) product should not be allowed to exceed 70 mg²/dl²

Acute symptoms of vitamin D intoxication: anorexia, headache, vomiting, constipation.

Chronic symptoms: dystrophy, (weakness, loss of weight), sensoty 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.

Hypercalcemia at higher levels (>3.2 mmol/L) may lead to  renal insufficiency particularly if blodd phosphate levels are normal or elevated due to impaired renal function.

In acute overdosage gastric lavage or induction of vomiting should be considered as soon after ingestion as possible provided that the drug was taken within the previous 6 - 8 hours.  Liquid paraffin may be administered to promote faecal excretion.

The value for serum calcium multiplied by phosphate (Ca x P) should not be allowed to exceed 70 mg²/dl².   Repeated serum calcium determinations are advisable.

Should hypercalcaemia occur, 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 phosphates and 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.

Pharmacodynamic properties

Pharmacotherapeutic group: vitamin D and analogues; ATC code AII CC04

Preclinical safety data

Supravalvular aortic stenosis has been produced in fetuses by near-fatal oral doses of vitamin D in pregnant rabbits.

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2        QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains 0.25 microgram of calcitriol.

Each capsule contains upto 4.37mg of sorbitol.

For a full list of excipients, see section 6.1.

5.1       Pharmacodynamic properties

                        Pharmacotherapeutic group: Vitamin D and analogues; ATC Code: A11CC04

6.1       List of excipients

Capsule Contents

Butylhydroxyanisole (E320)

Butylhydroxytoluene (E321)

Medium–chain triglycerides

Capsule Shell

Gelatin

Glycerol

Karion 83 (Sorbitol (E420), Mannitol (E421), Hydrogenated hydrolysed starch)

Titanium dioxide (E171)

Iron oxide red (E172)

Iron oxide yellow (E172)

NAME OF THE MEDICINAL PRODUCT

Rocaltrol 0.25 microgram Soft cCapsules

Rocaltrol 0.5 microgram capsules

PHARMACEUTICAL FORM

Capsule, soft.

0.25 micrograms:  One length brown-redorange to red-orange-grey opaque and the other white to grey-yellow or grey-orange opaque.

0.5 micrograms:    Both lengths brown-red to orange-grey opaque.

List of excipients

Capsule Contents

Butylated hydroxyanisole (E320)

Butylated hydroxytoluene (E321)

Triglycerides, mMedium- chain triglycerides

Capsule Shell

Gelatin

Glycerol

Karion 83 (Sorbitol, Mannitol, Hydrogenated hydrolysed starch)

Titanium dioxide (E171)

Canthaxanthin (E161)Iron oxide red (E172)

Iron oxide yellow (E172)

Special precautions for storage

Glass bottles

Do not store above 30°C.

Blisters

Do not store above 25°C.   Store in the original package and keep the blisters in the outer carton in order to protect from light and moisture.

Nature and contents of container

Amber glass bottles with plastic screw caps containing 100 capsules and PVC opaque blisters containing 100 capsules (5 strips of 20 capsules).

Due to the use of a natural colouring agent, discolouration of the capsule may occur.  This does not affect the quality of the medicine.

Not all pack sizes may be marketed.

MARKETING AUTHORISATION NUMBER

Rocaltrol 0.25mcg Capsules:                         PA 50/47/1

Rocaltrol 0.5mcg Capsules:                     PA 50/47/2

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6.1       List of excipients

Capsule Shell

Gelatin

Glycerol

Karion 83 (Sorbitol, Mannitol, Hydrogenated hydrolysed starch)

Titanium dioxide (E171)

Canthaxanthin (E161)

10.       DATE OF REVISION OF THE TEXT

Updated to: February 2007