Calcitriolo Mylan Generics

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.

Calcitriolo Mylan Generics is indicated in topical treatment of mild to moderately severe plaque psoriasis (psoriasis vulgaris) with up to 35% of body surface area involvement.

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.

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.

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.

Rocaltrol capsules are for oral administration only.

Posology

Calcitriolo Mylan Generics Ointment should be applied to the psoriasis affected areas twice per day, once in the morning and once in the evening before retiring and after washing. It is recommended that not more than 35% of the body surface be exposed to daily treatment. Not more than 30 g of ointment should be used per day. There is limited clinical experience available for the use of this dosage regimen of more than 6 weeks.

Paediatric population

There is no experience of the use of Calcitriolo Mylan Generics in children (see 4.4. Special Warnings and Precautions for Use).

Special population

Patients with kidney or liver dysfunction should not use Calcitriolo Mylan Generics (see also 4.3. Contraindications).

Rocaltrol is contraindicated:

- in all diseases associated with hypercalcaemia

- in patients with evidence of metastatic calcification

- in patients with known hypersensitivity to calcitriol (or drugs of the same class) and any of the constituent excipients

- if there is evidence of vitamin D toxicity.

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- Patients on systemic treatment of calcium homeostasis.

- Patients with kidney or liver dysfunction.

- Patients with hypercalcaemia and patients known to suffer from abnormal calcium metabolism.

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.

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 Rocaltrol should be stopped immediately until normocalcaemia ensues.

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 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 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.

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 hypercalcaemia 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.

Special population

Patients with kidney or liver dysfunction should not use Calcitriolo Mylan Generics (see also 4.3. Contraindications).

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- Patients on systemic treatment of calcium homeostasis.

- Patients with kidney or liver dysfunction.

- Patients with hypercalcaemia and patients known to suffer from abnormal calcium metabolism.

The ointment can be applied to the face with caution, as there is an increased risk of irritation in this area. Contact with the eyes should be avoided. The hands should be washed after applying the ointment in order to avoid unintentional application to non lesional areas. Not more than 35% of the body surface should be exposed to daily treatment. Not more than 30g of ointment should be used per day.

Due to potential effects on calcium metabolism, substances which stimulate absorption must not be added to the ointment, and the ointment must not be covered with an occlusive dressing.

In case of severe irritation or contact allergy, the treatment with Calcitriolo Mylan Generics should be discontinued and the patient should obtain medical advice. If contact allergy is demonstrated this discontinuation is definitive.

Although no clinically significant hypercalcaemia was observed in clinical studies with a dosage under 30 g/day of Calcitriolo Mylan Generics ointment, some absorption of calcitriol through the skin does occur and excessive use of the ointment can lead to systemic side-effects, such as an increase in urine and serum calcium levels, which is a known class effect for calcitriol.

There is no information about the use of Calcitriolo Mylan Generics in other clinical forms of psoriasis (other than plaque psoriasis) i.e. Psoriasis guttata acuta, pustular psoriasis, psoriasis erythrodermica and rapid progressive plaque psoriasis.

Paediatric population

In view of the particular sensitivity of neonates versus adult rodents to the toxic effects of calcitriol, exposure of children to calcitriol ointment should be avoided (see also 4.2. Posology and Method of administration).

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.

Calcitriolo Mylan Generics has no or negligible influence on the ability to drive and use machines.

The adverse reactions listed below reflect the experience from investigational studies of Rocaltrol, 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 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) . 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 Rocaltrol 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.

Between 10% and 20% of patients can be expected to experience adverse reactions. Adverse reactions are usually localised to the application site and mild to moderate in nature.

*Adverse reactions reported from post marketing surveillance

In case of severe irritation or contact allergy, the treatment with Calcitriolo Mylan Generics should be discontinued and the patient should obtain medical advice. If contact allergy is demonstrated this discontinuation is definitive.

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 Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

Treatment of asymptomatic hypercalcaemia.

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 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, 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.

The most common symptoms which may occur after accidental administration are anorexia, nausea, vomiting, constipation, hypotonia and depression. Lethargy and coma are occasionally observed. If hypercalcaemia or hypercalciuria occurs, the use of Calcitriolo Mylan Generics should be discontinued until the serum or urinary calcium levels have returned to normal.

If the medication is applied excessively no more rapid or better results will be obtained and marked redness, peeling or discomfort may occur.

Calcitriol is the most active known form of vitamin D₃ in stimulating intestinal calcium transport. It 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.

The biological effects of calcitriol are mediated by the vitamin D receptor, a nuclear hormone receptor expressed in most cell types and functioning as a ligand-activated transcription factor that binds to DNA sites to modify the expression of target genes.

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.

Pharmacotherapeutic group: Other antipsoriatics for topical use, ATC code: D 05AX03

Mechanism of action

Calcitriol inhibits the proliferation and stimulates differentiation of keratinocytes. Calcitriol inhibits proliferation of T-cells and normalises the production of various inflammation factors.

Pharmacodynamic effects

Topical administration of Calcitriolo Mylan Generics Ointment to patients with plaque psoriasis results in an improvement of the skin lesions. This effect is noted from 4 weeks after the start of treatment.

Absorption

Calcitriol is rapidly absorbed from the intestine. Peak serum concentrations following a single oral dose of 0.25-1µg Rocaltrol in healthy subjects were found within 2-6 hours.

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 hydroxylated and oxidised in the kidney and in the liver by a specific cytochrome P450 enzyme: CYP24A1.

Several metabolites with different degrees of vitamin D activity have been identified.

Elimination

The elimination half-life of calcitriol in plasma ranges between 5 to 8 hours. However, the pharmacological effect of a single dose of calcitriol lasts at least 4 days. The elimination and absorption kinetics of calcitriol remain linear in a very broad dose range and up to 165 µg single oral dose. Calcitriol is excreted in the bile and may undergo an enterohepatic circulation.

Absorption

The mean absorption of calcitriol is estimated at around 10%. Following absorption, both unchanged calcitriol and metabolites have been demonstrated in plasma. The effect of the metabolites on calcium homeostasis is negligible. In most patients, circulating levels of exogenous calcitriol are below the level of detection (2pg/ml).

Distribution

In clinical trials, no relevant increase in plasma calcitriol levels after treatment of large body surface areas of up to 6000 cm² (35% body surface area) was noted.

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 two litters at an oral maternally toxic dose of 300 ng/kg/day and one litter at 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.

Animal studies show that repeated excessive exposure to calcitriol leads to renal failure and tissue calcification due to hypervitaminosis D associated with hypercalciuria, hypercalcaemia, and hyperphosphataemia.

No indication of teratogenicity was observed in embryofoetal toxicity studies designed to assess the teratogenic potential of calcitriol. Some evidence of developmental toxicity was obtained in a cutaneous rabbit study at doses which caused maternal toxicity. No such effect was found in rats.

Local toxicity studies in animals with Calcitriol showed slight skin and eye irritation.

None.

There are no relevant data on the compatibility of Calcitriolo Mylan Generics with other medicinal products.).

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

Not applicable.

No special requirements.