Roche Products (Ireland) Ltd

Rocaltrol 0.25 microgram Soft Capsules

Each capsule contains 0.25 microgram of calcitriol.

Each capsule contains up to 4.37mg sorbitol

For a full list of excipients, see section 6.1.

Capsule, soft.

One length brown-orange to red-orange opaque and the other white to grey-yellow or grey-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/100 ml (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.

An oral Rocaltrol pulse therapy with an initial dosage of 0.1 mcg/kg/week split into two or three equal doses given at night 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 contra-indicated.

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

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.

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

Rocaltrol capsules contain sorbitol, patients with rare hereditary problems of fructose intolerance should not take Rocaltrol capsules .

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.

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.

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.

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 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.

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 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

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.

Hypercalcemia 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, 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.

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

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 0.25-1.0 mcg Rocaltrol were found within 3-6 hours.

Following multiple administration, serum calcitriol levels reached a steady state within 7 days, with a relationship to the dose of calcitriol administered.

Distribution

After a single oral dose of 0.5 mcg Rocaltrol, 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. During transport in the blood, calcitriol and other vitamin D metabolites are bound to specific plasma proteins.

It can be assumed that exogenous calcitriol passes from the maternal blood into the foetal bloodstream and breast milk.

Metabolism

Several metabolites of calcitriol, each exerting different vitamin D activities have been identified: 1α,25-dihydroxy-24-oxo-cholecalciferol, 1α,23,25-trihydroxy-24-oxo-cholecalciferol, 1α,24R,25-trihydroxycholecalciferol, 1α, 25R-dihydroxycholecalciferol-26, 23S-lactone, 1α,25S,26-trihydroxycholecalciferol, 1α,25-dihydroxy-23-oxo-cholecalciferol and 1α-hydroxy-23-carboxy-24,25,26,27-tetranorcholecalciferol.

Elimination

The elimination half-life of calcitriol in serum is 9-10 hours. 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.

After i.v. administration of radioactive calcitriol in healthy subjects, about 27% of the radioactivity is found in the faeces and about 7% in the urine within 24 hours.

After oral administration of 1 mcg radioactive calcitriol in healthy subjects, about 10% of the entire radioactivity was found in the urine within 24 hours. On the sixth day after i.v. administration of radioactive calcitriol, urine and faeces accounted for an average of 16% and 49% respectively of the cumulative excretion of radioactivity.

Acute toxicity studies in mice and rats indicated that the oral approximate median lethal dose of calcitriol ranged from 1.35 to 3.9 mg/kg. These values are several orders of magnitude higher than the proposed clinical dose of 0.25mcg 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, calcitriol produced some maternal and foetotoxic effects at an oral dose of 300 ng/kg/day, but did not show any adverse effect at 20 or 80 ng/kg/day (8 times the usual human dose).

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

Capsule Contents

Butylhydroxyanisole (E320)

Butylhydroxytoluene (E321)

Medium-chain triglycerides

Capsule Shell

Gelatin

Glycerol

Karion 83 (Sorbitol, Mannitol, Hydrogenated hydrolysed starch)

Titanium dioxide (E171)

Iron oxide red (E172)

Iron oxide yellow (E172)

Not applicable.

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 all pack sizes may be marketed.

No special requirements.

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

PA 50/47/1

Date of first authorisation: 18^th February 1980

Date of last renewal: February 2010

July 2010

Further information is available from Roche Products (Ireland) Limited, 3004 Lake Drive, City West, Naas Road, Dublin 24.

Rocaltrol is a registered trade mark