SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Calcitriol 0.5 microgram Capsules

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains 0.5 micrograms of calcitriol.

For excipients, see 6.1.

3 PHARMACEUTICAL FORM

Capsule, soft.

Opaque, green, oblong, soft gelatine capsules imprinted 0.5.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Calcitriol capsules are indicated for the treatment of patients with renal osteodystrophy to correct abnormal calcium and phosphate metabolism.

4.2 Posology and method of administration

For oral use.

To avoid hypercalcaemia, the dose of calcitriol should be based on the patients physiological response to calcitriol and should be adjusted for the individual. An adequate daily calcium intake should be observed for treatment to be effective, including changes to the diet or calcium supplements, if necessary.

The capsules should be taken with a drink of water.

Adults

Initially 0.25 ^g of calcitriol per day. A dose of 0.25 ^g on alternate days should be sufficient for patients with normal or just below normal calcium levels.

Doses may be increased by 0.25 ^g at 2 - 4 week intervals if a satisfactory biochemical or clinical response has not been achieved. Serum calcium levels should be monitored at least twice a week during this period. Should serum calcium levels rise by 1 mg / 100 ml (250 pmol/l) above the accepted normal range of 9 - 11 mg / 100 ml (2250 - 2750 pmol/l) or serum creatinine levels rise above 120 pmol/l, treatment with calcitriol should be stopped immediately. Treatment should recommence only when serum calcium levels are within their accepted normal range.

For the initial treatment and the increase of the dose, as mentioned before, the dosage form 0.25 pg should be used.

Generally a dose of 0.5 - 1.0 pg per day elicits the appropriate response. However, higher doses may be required if barbiturates or anticonvulsant medicinal products are used concurrently.

Children

Calcitriol is not recommended for use in children.

The Elderly

The recommended adult dosage is appropriate.

4.3 Contraindications

Calcitriol is contraindicated:

•    In patients with known hypersensitivity to calcitriol (or drugs of the same class) and any of the excipients

•    In all diseases associated with hypercalcemia

•    If there is evidence of vitamin D toxicity

4.4 Special warnings and precautions for use

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

All other vitamin D compounds and their derivative, including proprietary compounds or foodstuffs which may be “fortified” with vitamin D, should be withheld during treatment with calcitriol.

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 hypercalaemia.

As soon as the serum calcium levels rise to 1 mg/100 ml (250 qmol/l) above normal (9-11 mg/100 ml, or 2250-2750 qmol/l), or serum creatinine rises to > 120 qmol/l, treatment with calcitriol 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 hypercalcemia. Patients and their families should be advised that strict adherence to the prescribed diet is mandatory and they should be instructed on how to recognise the symptoms of hypercalcemia.

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 (2-5 mg/100 ml 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 70 mg²/dl².

Patients with vitamin D-resistant rickets (familial hypophosphatemia) who are being treated with calcitriol must continue their oral phosphate therapy.

However, possible stimulation of intestinal absorption of phosphate by calcitriol 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 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 (see section 4.9 Overdose).

Immobilized patients, e.g. those who have undergone surgery, are particularly exposed to the risk of hypercalcemia.

Patients with normal renal function who are taking calcitriol 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.

Patients with rare hereditary problems of fructose intolerance should not take this medicine.

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 calcitriol 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 hypercalcemia. Calcitriol dosage must be determined with care in patients undergoing treatment with digitalis, as hypercalcemia in such patients may precipitate cardiac arrhythmias.(See section 4.4 Special warnings and precautions for use)

Magnesium-containing drugs (e.g. antacids) may cause hypermagnesemia and should therefore not be taken during therapy with calcitriol by patients on chronic renal dialysis.

Since calcitriol 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.

Cholestyramine can reduce intestinal absorption of fat-soluble vitamins and therefore may impair intestinal absorption of calcitriol.

4.6 Pregnancy and lactation

Pregnancy

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. Calcitriol should be used during pregnancy only if the benefits outweigh the potential risk to the foetus.

Breastfeeding

It should be assumed that exogenous calcitriol passes into breast milk. In view of the potential for hypercalcemia in the mother and for adverse reactions from calcitriol in nursing infants, mothers may breastfeed while taking calcitriol, provided that the serum calcium levels of the mother and infant are monitored.

4.7 Effects on ability to drive and use machines

No effects on the ability to drive or use machines have been observed.

4.8 Undesirable effects

Clinical Trials

List of adverse reactions

Immune system disorders

Hypersensitivity reactions (pruritus, rash, urticaria, and very rarely severe erythematous skin disorders) may occur in susceptible individuals.

Metabolism and nutrition disorders

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 „Special warnings and precautions for use“).

Occasional acute symptoms include anorexia, headache, nausea, vomiting, abdominal pain or stomach ache and constipation.

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.

Chronic effects may include dystrophy, sensory disturbances, fever with thirst, thirst/polydipsia, polyuria, dehydration, apathy, arrested growth and urinary tract infections.

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.

Investigations

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

Post Marketing

The number of adverse effects reported from clinical use of calcitriol over a period of 15 years in all indications is very low with each individual effect, including hypercalcaemia, occurring at a rate of 0.001% or less.

The major side effects of calcitriol are hypercalcuria and hypercalcaemia and indicate excessive dosage. Hypercalcaemia is more likely in patients who have renal failure, hyperparathyroidism or regular haemodialysis. The symptoms of hypercalcaemia include nausea, vomiting, constipation, anorexia, weakness, headache, somnolence and apathy. More serious symptoms are dehydration, thirst, nocturia, polyuria, cardiac arrhythmias, paralytic ileus and abdominal pain. Rarely, metastatic calcification and overt psychosis may occur.

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

There have been a few reports of a mild non-progressive rise in levels of liver enzymes (SGOT, SGPT). This rise is reversible and no pathological changes to the liver has occurred.

In susceptible individuals hypersensitivity reactions (pruritus, rash, urticaria and very rarely, severe erythematous skin disorders) may occur.

The following table lists the adverse reactions and laboratory investigations observed from spontaneous reporting and in clinical trials. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. The frequency terms listed are defined as follows: Very common (>1/10), common (> 1/100 to < 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).

Very common1 Common	Uncommon	Rare	Very Rare Not known2
Immune system disorders
			Allergic reaction2
Metabolism and nutrition disorders
		Metastatic calcification Hypercalciuria Hypercalcaemia
Nervous system disorders
		Overt psychosis
Investigations
			Elevations of liver enzymes (SGOT, SGPT)

¹    These side effects are grouped under frequency “Very Common”

²    These side effects are grouped under frequency “Not Known”

4.9 Overdose

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 calcitriol may give rise to similar symptoms. The

serum calcium times phosphate (Ca x P) product should not be allowed to

2 2

exceed 70 mg /dl . 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.

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 following prolonged treatment, calcitriol should be discontinued until plasma calcium levels have returned to normal. A low calcium diet will speed this reversal. Calcitriol 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.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: Vitamin D and analogues ATC code: A11CC04

Calcitriol is usually formed, in the kidneys from the precursor 25-hydroxycholecalciferol and of all the known vitamin D metabolites, it has the greatest biological activity.

Calcitriol enhances the absorption of calcium and phosphate from the intestine and is also significantly involved in regulating bone mineralisation. In chronic renal failure when the GFR falls below 30m1/min, there is a reduction in endogenous calcitriol production leading to abnormal mineral metabolism.

The hypocalcaemia which results can be improved by taking calcitriol, therefore reversing bone disease. In patients with established postmenopausal osteoporosis calcitriol increases calcium absorption and circulating levels of calcitriol, thereby decreasing vertebral fracture frequency.

The action of calcitriol is more rapid than other vitamin D metabolites and the effects can also be reversed quickly. The advantage of this is that the dose can be adjusted earlier and more accurately. In cases of inadvertent overdose, the effects can also be reversed more easily.

5.2 Pharmacokinetic properties

Peak serum levels of calcitriol are reached 4 - 6 hours after an oral dose. The half life of calcitriol is 3 - 6 hours but it is pharmacologically active for 3 - 5 days. When a 1 mcg oral dose of radiolabelled calcitriol is given to normal individuals, 10% of the total radioactivity is detected in the urine in 24 hours. Enterohepatic recirculation also occurs, the biliary system providing the main route of excretion.

5.3 Preclinical safety data

Increases in foetal absorption/abnormalities, maternal toxicity and neonatal mortality in rabbits have been reported at doses of 0.3 mcg/kg of calcitriol per day. (See section 4.6.)

6 PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Capsule content:

Butylated Hydroxyanisole (E320) Butylated Hydroxytoluene (E321) Fractionated Coconut Oil

Capsule shell:

Gelatin

Glycerol (E422)

Sorbitol (E420)

Titanium Dioxide (El71) Quinoline Yellow (E104)

Patent Blue (E131)

Printing ink:

Shellac (E904) Glaze Black iron oxide (El72)

6.2    Incompatibilities

Not applicable.

6.3 Shelf life

2 years

6.4 Special precautions for storage

Do not store above 30°C. Store in the original package.

Nature and contents of container