Rocaltrol 0.25 microgram Capsules.

Rocaltrol 0.5 microgram Capsules.

Each capsule contains either 0.25 or 0.5 microgram of calcitriol.

For excipients, see 6.1.

Soft capsules.

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

0.5 microgram: Both lengths brown-orange to red-orange opaque.

Rocaltrol is indicated for the correction of the abnormalities of calcium and phosphate metabolism in patients with renal osteodystrophy.

Rocaltrol is also indicated for the treatment of established post-menopausal osteoporosis.

The dose of Rocaltrol should be carefully adjusted for each patient according to the biological response so as to avoid hypercalcaemia.

The effectiveness of treatment depends in part on an adequate daily intake of calcium, which should be augmented by dietary changes or supplements if necessary. The capsules should be swallowed with a little water.

Adults

Renal Osteodystrophy

The initial daily dose is 0.25 mcg of Rocaltrol. In patients with normal or only slightly reduced calcium levels, doses of 0.25 mcg every other day are sufficient. If no satisfactory response in the biochemical parameters and clinical manifestations of the disease is observed within 2 - 4 weeks, the daily dosage may be increased by 0.25 mcg at 2 - 4 week intervals. During this period, serum calcium levels should be determined at least twice weekly. Should the serum calcium levels rise to 1 mg/ 100ml (250 µmol/l) above normal (9 to 11 mg/100 ml or 2250 – 2750 µmol/l), or serum creatinine rises to> 120 µmol/l, treatment with Rocaltrol should be stopped immediately until normocalcaemia ensues. Most patients respond to between 0.5 mcg and 1.0 mcg daily. See section 4.5 for details of dose adjustments related to drug interactions.

An oral Rocaltrol pulse therapy with an initial dosage of 0.1 mcg/kg/week split into two or three equal doses given at the end of the dialysis has been shown to be effective in patients with osteodystrophy refractory to continuous therapy. A maximum total cumulative dosage of 12 mcg per week should not be exceeded.

Post-menopausal Osteoporosis

The recommended dose of Rocaltrol is 0.25 mcg twice daily.

Serum calcium and creatinine levels should be determined at 1, 3 and 6 months and at 6 monthly intervals thereafter.

Elderly

Clinical experience with Rocaltrol in elderly patients indicates that the dosage recommended for use in younger adults may be given without apparent ill-consequence.

Children

Dosage in children has not been established.

Rocaltrol capsules are for oral administration only.

Rocaltrol is contraindicated in all diseases associated with hypercalcaemia 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.

.

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.

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.

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.

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.

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.

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.

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.

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.

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..

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.

Calcitriol has the greatest biological activity of the known vitamin D metabolites and is normally formed in the kidneys from its immediate precursor, 25-hydroxycholecalciferol. In physiological amounts it augments the intestinal absorption of calcium and phosphate and plays a significant part in the regulation of bone mineralisation. The defective production of calcitriol in chronic renal failure contributes to the abnormalities of mineral metabolism found in that disorder.

Rocaltrol is a synthetic preparation of calcitriol. Oral administration of Rocaltrol to patients with chronic renal failure compensates for impaired endogenous production of calcitriol which is decreased when the glomerular filtration rate falls below 30 ml/min. Consequently, intestinal malabsorption of calcium and phosphate and the resulting hypocalcaemia are improved, thereby reversing the signs and symptoms of bone disease.

In patients with established post-menopausal osteoporosis, Rocaltrol increases calcium absorption, elevates circulating levels of calcitriol and reduces vertebral fracture frequency.

The onset and reversal of the effects of Rocaltrol are more rapid than those of other compounds with vitamin D activity and adjustment of the dose can be achieved sooner and more precisely. The effects of inadvertent overdosage can also be reversed more readily.

Absorption

Calcitriol is rapidly absorbed from the intestine. Peak serum concentrations following a single oral dose of 0.25-0.75 mcg Rocaltrol were found within 2-4 hours in healthy subjects.

After a single oral dose of 0.5 mcg Rocaltrol in healthy subjects, the average serum concentrations of calcitriol rose from a baseline value of 40.0 ± 4.4 pg/ml to 60.0 ± 4.4 pg/ml after two hours, and then fell to 53.0 ± 6.9 after four hours, to 50.0 ± 7.0 after eight hours, to 44 ± 4.6 after twelve hours and to 41.5 ± 5.1 pg/ml after 24 hours.

Distribution

During transport in the blood at physiological concentrations, calcitriol is mostly bound to a specific vitamin D binding protein (DBP), but also, to a lesser degree, to lipoproteins and albumin. At higher blood calcitriol concentrations, DBP appears to become saturated, and increased binding to lipoproteins and albumin occurs.

Metabolism

Calcitriol is inactivated in both the kidney and the intestine, through the formation of a number of intermediates.

Elimination

The reported elimination half-life of calcitriol in serum is between 5 and 17 hours in normal subjects, but may extend to between 18 and 44 hours in patients with severe chronic renal failure. However, the pharmacological effect of a single dose of calcitriol lasts at least 4 days. Calcitriol is excreted in the bile and is subject to enterohepatic circulation.

Acute toxicity studies of calcitriol in mice and rats indicated oral approximate median lethal doses of 3.9 and 3.2 mg/kg, respectively. These values are several orders of magnitude higher than the proposed clinical dose of 0.25 mcg twice daily (approximately 8-10 ng/kg/day).

Subchronic toxicity studies in rats and dogs indicated that calcitriol at an oral dose of 20 ng/kg/day (twice the usual human dosage) for up to 6 months produced no or minimal adverse effects. A dose of 80 ng/kg/day (8 times the usual human dosage) for up to 6 months produced moderate adverse effects; changes seen appeared to be primarily the result of prolonged hypercalcaemia.

Reproductive toxicity studies in rats indicated that oral doses up to 300 ng/kg/day (30 times the usual human dose) did not adversely affect reproduction. In rabbits, multiple foetal abnormalities were observed in one litter from each group at oral doses of 300 ng/kg/day and 80 ng/kg/day, but not at 20 ng/kg/day (twice the usual human dose). Although there were no statistically significant differences between treated groups and controls in the numbers of litters or foetuses showing abnormalities, the possibility that these findings were due to calcitriol administration could not be discounted.

Content

Butylhydroxyanisole

Butylhydroxytoluene

Medium-chain triglycerides

Shell

Gelatin

Glycerol

Karion 83 (Sorbitol, Mannitol, Hydrogenated hydrolysed starch)

Titanium dioxide E171

Iron oxide red E172

Iron oxide yellow E172

None.

3 years.

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.

PVC opaque blisters containing 100 capsules (5 strips of 20 capsules).

Not applicable.

Roche Products Limited, 6 Falcon Way, Shire Park, Welwyn Garden City, AL7 1TW, United Kingdom.

Rocaltrol 0.25 microgram Capsules: PL 00031/0122

Rocaltrol 0.5 microgram Capsules: PL 00031/0123

13 January 2003

June 2010

Rocaltrol is a registered trade mark