4.1. Therapeutic indications

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

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

4.2. Posology and method of administration

The dose of Calcitriol 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.

Posology

Adults

Renal Osteodystrophy

The initial daily dose is 0.25 mcg of Calcitriol. 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 Calcitriol 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 Calcitriol 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 Calcitriol 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 Calcitriol in elderly patients indicates that the dosage recommended for use in younger adults may be given without apparent ill-consequence.

Paediatric Population

The safety and efficacy of calcitriol capsules in children have not been sufficiently investigated to enable dosing recommendations. Limited data are available for the use of calcitriol capsules in paediatric patients.

Method of administration

Calcitriol capsules are for oral administration only.

4.3. Contraindications

Calcitriol is contraindicated:

• in patients with known hypersensitivity to calcitriol (or drugs of the same class) and any of the excipients listed in section 6.1

• in all diseases associated with hypercalcaemia

• in patients with evidence of metastatic calcification

• 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 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 Calcitriol.

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 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 hypercalcaemia.

As soon as the serum calcium levels rise to 1 mg/100 ml (250 µmol/l) above normal (9-11 mg/100 ml or 2250-2750 µmol/l), or serum creatinine rises to >120 µmol/l, treatment with Calcitriol should be stopped immediately until normocalcaemia ensues (see section 4.2).

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

Calcitriol increases inorganic phosphate levels in serum. While this is desirable in patients with hypophosphataemia, 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 hypophosphataemia) 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 a long acting vitamin D preparation (e.g. ergocalciferol (vitamin D2) or colecalciferol) to calcitriol, it may take several months for the ergocalciferol level in the blood to return to the baseline value, thereby increasing the risk of hypercalcaemia (see section 4.9).

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 hypercalcaemia may be associated with an increase in serum creatinine.

Calcitriol capsules contain sorbitol

Calcitriol contains 2.87 – 4.37 mg sorbitol in each 0.25 microgram capsule.

The additive effect of concomitantly administered products containing sorbitol (or fructose) and dietary intake of sorbitol (or fructose) should be considered.

The content of sorbitol in medicinal products for oral use may affect the bioavailability of other medicinal products for oral use administered concomitantly.

4.5. Interaction with other medicinal products and other forms of interaction

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).

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 hypermagnesaemia 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 hypophosphataemia) 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.

Bile acid sequestrants including cholestyramine and sevelamer can reduce intestinal absorption of fat-soluble vitamins and therefore may impair intestinal absorption of calcitriol.

4.6. Fertility, pregnancy and lactation

Pregnancy

The safety of Calcitriol during pregnancy has not been established.

Supravalvular aortic stenosis has been produced in foetuses 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.

Breast-feeding

It should be assumed that exogenous calcitriol passes into breast milk. In view of the potential for hypercalcaemia 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

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 adverse reactions listed below reflect the experience from investigational studies of Calcitriol, and the post-marketing experience.

The most commonly reported adverse reaction 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 Calcitriol

System Organ Class

Very common

Common

Uncommon

Not known

Immune System Disorders

Hypersensitivity, Urticaria

Metabolism and Nutrition Disorders

Hypercalcaemia

Decreased appetite

Polydipsia, Dehydration, Weight decreased

Psychiatric Disorders

Apathy, Psychiatric disturbances

Nervous System Disorders

Headache

Muscular weakness, Sensory disturbance, Somnolence

Cardiac Disorders

Cardiac arrhythmias

Gastrointestinal Disorders

Abdominal pain, Nausea

Vomiting

Constipation, Abdominal pain upper, Paralytic ileus

Skin and subcutaneous tissue disorders

Rash

Erythema, Pruritus

Musculoskeletal and Connective Tissue Disorders

Growth retardation

Renal and Urinary Disorders

Urinary tract infection

Polyuria, Nocturia

General disorders and administration site conditions

Calcinosis, Pyrexia, Thirst

Investigations

Blood creatinine increased

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 sections 4.2 and 4.4). Occasional acute symptoms include decreased appetite, headache, nausea, vomiting, abdominal pain or abdominal pain upper and constipation.

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, i.e. much faster than in treatment with vitamin D3 preparations.

Chronic effects may include muscular weakness, weight decreased, sensory disturbances, pyrexia, thirst, polydipsia, polyuria, dehydration, apathy, growth retardation and urinary tract infections.

In concurrent hypercalcaemia and hyperphosphataemia of > 6 mg/100 ml or > 1.9 mmol/l, calcinosis may occur; this can be seen radiographically.

Hypersensitivity reactions including rash, erythema, pruritus and urticaria may occur in susceptible individuals.

Laboratory Abnormalities

In patients with normal renal function, chronic hypercalcaemia may be associated with a blood creatinine increase.

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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Treatment of asymptomatic hypercalcaemia (see section 4.2).

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 exceed 70 mg2 / dl2. A high calcium level in the dialysate may contribute to the development of hypercalcaemia.

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. Hypercalcaemia 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 faecal 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.

Hypercalcaemia 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.