Alfacalcidol 0.5 Microgram Capsules
Out of date information, search anotherSUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Alfacalcidol 0.5microgram Capsules
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each capsule contains 0.5 microgram alfacalcidol.
Excipient: Sorbitol (E420) 21.54mg/capsule.
For full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Capsules, soft
Clear colourless, oily liquid filled in oval, red opaque, soft gelatine capsules.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Alfacalcidol is indicated in all conditions where there is a disturbance of calcium metabolism due to impaired 1-a hydroxylation such as when there is reduced renal function. The main indications are:
a) Renal osteodystrophy
b) Hyperparathyroidism (with bone disease)
c) Hypoparathyroidism
d) Neonatal hypocalcaemia
e) Nutritional and malabsorptive rickets and osteomalacia
f) Pseudo-deficiency (D-dependent) rickets and osteomalacia
g) Hypophosphataemic vitamin D resistant rickets and osteomalacia
4.2 Posology and method of administration
Route of administration: oral
The capsules should be swallowed whole with a drink of water.
Initial dose for all indications:
Adults: 1 microgram/day
Dosage in the elderly: 0.5 microgram/day
Neonates and premature infants: 0.05 - 0.1 microgram/kg/day
Children under 20kg bodyweight: 0.05 microgram/kg/day
Children over 20kg bodyweight: 1 microgram/day
The dose of Alfacalcidol should be adjusted thereafter to avoid hypercalcaemia according to the biochemical response. Indices of response include plasma levels of calcium (ideally corrected for protein binding), alkaline phosphatase, parathyroid hormone, as well as radiographic and histological investigations.
Plasma levels should initially be measured at weekly intervals. The daily dose of Alfacalcidol may be increased by increments of 0.25 - 0.5 microgram. When the dose is stabilised, measurements may be taken every 2 - 4 weeks.
Most adult patients respond to doses between 1 and 3 micrograms per day. When there is biochemical or radiographic evidence of bone healing, (and in hypoparathyroid patients when normal plasma calcium levels have been attained), the dose generally decreases. Maintenance doses are generally in the range of 0.25 to 1 microgram per day. If hypercalcaemia occurs, Alfacalcidol should be stopped until plasma calcium returns to normal (approximately 1 week) then restarted at half the previous dose.
a) Renal bone disease:
Patients with relatively high initial plasma calcium levels may have autonomous hyperparathyroidism, often unresponsive to Alfacalcidol. Other therapeutic measures may be indicated.
Before and during treatment with Alfacalcidol, phosphate binding agents should be considered to prevent hyperphosphataemia. It is particularly important to make frequent plasma calcium measurements in patients with chronic renal failure because prolonged hypercalcaemia may aggravate the decline of renal function.
(b) Hyperparathyroidism:
In patients with primary or tertiary hyperparathyroidism about to undergo parathyroidectomy, preoperative treatment with Alfacalcidol for 2-3 weeks alleviates bone pain and myopathy without aggravating pre-operative hypercalcaemia. In order to decrease post-operative hypocalcaemia, Alfacalcidol should be continued until plasma alkaline phosphatase levels fall to normal or hypercalcaemia occurs.
c) Hypoparathyroidism:
In contrast to the response to parent vitamin D, low plasma calcium levels are restored to normal relatively quickly with Alfacalcidol. Severe hypocalcaemia is corrected more rapidly with higher doses of Alfacalcidol (e.g. 3-5 micrograms) together with calcium supplements.
d) Neonatal hypocalcaemia:
Although the normal starting dose of Alfacalcidol is 0.05-0.1 microgram/kg/day (followed by careful titration) in severe cases doses of up to 2 microgram/kg/day may be required. Whilst ionised serum calcium levels may provide a guide to response, measurement of plasma alkaline phosphatase activity may be more useful. Levels of alkaline phosphatase approximately 7.5 times above the adult range indicates active disease.
A dose of 0.1 microgram/kg/day of Alfacalcidol has proven effective as prophylaxis against early neonatal hypocalcaemia in premature infants.
e) Nutritional and malabsorptive rickets and osteomalacia:
Nutritional rickets and osteomalacia can be cured rapidly with Alfacalcidol. Malabsorptive osteomalacia (responding to large doses of IM or IV parent vitamin D) will respond to small doses of Alfacalcidol.
f) Pseudo-deficiency (D-dependent) rickets and osteomalacia:
Although large doses of parent vitamin D would be required, effective doses of Alfacalcidol are similar to those required to heal nutritional vitamin D deficiency rickets and osteomalacia.
g) Hypophosphataemic vitamin D-resistant rickets and osteomalacia:
Neither large doses of parent vitamin D nor phosphate supplements are entirely satisfactory. Treatment with Alfacalcidol at normal dosage rapidly relieves myopathy when present and increases calcium and phosphate retention. Phosphate supplements may also be required in some patients.
Special populations:
Use in Elderly
The clinical manifestations of hypo- or hyper calcaemia should be considered especially in elderly patients with pre-existing renal or heart conditions.
Paediatric population
Alfacalcidol should be used with caution in infants, who may have increased sensitivity to its effects. Take care to ensure correct dose in infants.
4.3 Contraindications
Hypercalcaemia, metastatic calcification.
Hypersensitivity to Alfacalcidol or other ingredients in the preparation.
4.4 Special warnings and precautions for use
The product contains sorbitol, therefore patients with rare hereditary problems of fructose intolerance should not take this medicine.
Alfacalcidol should be used with caution for:
- patients being treated with cardioactive glycosides or digitalis as hypercalcaemia may lead to arrhythmia in such patients.
- patients with nephrolithiasis
During treatment with Alfacalcidol serum calcium and serum phosphate should be monitored regularly especially in patients with renal impairment and patients receiving high doses. To maintain serum phosphate at an acceptable level in patients with renal bone disease a phosphate binding agent may be used.
Hypercalcaemia may appear in patients treated with Alfacalcidol, the early symptoms are as follows:
- polyuria
- polydipsia
- weakness, headache, nausea, constipation
- dry mouth
- muscle and bone pain
- metallic taste
Hypercalcaemia can be rapidly corrected by stopping treatment until plasma calcium levels return to normal (in about one week). Alfacalcidol treatment may then be restarted at a reduced dose (half the previous dose).
Paediatric population
During treatment with Alfacalcidol serum calcium and serum phosphate should be monitored regularly in children.
4.5 Interaction with other medicinal products and other forms of interaction
Patients taking barbiturates or anticonvulsants may require larger doses of Alfacalcidol to produce the desired effect to the induction of hepatic detoxification enzymes.
Concomitant administration of colestyramine may interfere with the intestinal absorption of alfacalcidol.
Use with caution in patients being treated with thiazide diuretics as they may have an increased risk of developing hypercalcaemia.
Paediatric population
Drug interactions with Alfacalcidol are known to be similar in the paediatric age group and that in adults.
4.6 Fertility, pregnancy and lactation
Pregnancy
There are no adequate data from the use of alfacalcidol in pregnant women. Animal studies are insufficient with respect to effects on pregnancy. The potential risks for humans are unknown. Caution should be taken when prescribing to pregnant women as hypercalcaemia during pregnancy may produce congenital disorders in the offspring.
Breastfeeding
Although it has not been established, it is likely that increased amounts of 1,25-dihydroxyvitamin D will be found in the milk of lactating mothers treated with alfacalcidol. This may influence calcium metabolism in the infant.
Fertility
No fertility data is available for use of alfacalcidol.
4.7 Effects on ability to drive and use machines
Alfacalcidol has no or negligible influence on the ability to drive or use machines.
4.8 Undesirable effects
The most frequently reported undesirable effects are hypercalcaemia and various skin reactions. If hypercalcaemia occurs during treatment with Alfacalcidol, this can be rapidly corrected by stopping treatment until plasma calcium levels return to normal (about 1 week). Alfacalcidol may then be restarted at half the previous dose.
Based on data from post-market use the total undesirable effect 'reporting rate' is rare £1/10,000 to <1/1,000) or very rare (<1/10,000); being approximately 1:10,000 patients treated.
|
System Organ Class |
Adverse Drug Reactions |
|
Metabolism and Nutrition |
Hypercalcaemia |
|
Disorders |
Hyperphosphataemia |
|
Skin and Subcutaneous Tissue |
Pruritus |
|
Disorders |
Rash |
|
Urticaria | |
|
Renal and Urinary Disorders |
Nephrocalcinosis |
|
Renal impairment |
Paediatric population
Frequency and type of adverse reactions in children are the same as in adults.
Overdose
4.9
Hypercalcaemia is treated by stopping Alfacalcidol.
In severe cases of hypercalcaemia general supportive measures should be undertaken. Keep the patient well hydrated by i.v. infusion of saline (force diuresis), measure electrolytes, calcium and renal function indices; assess electrocardiographic abnormalities, especially in patients on digitalis. More specifically, treatment with glucocorticosteroids, loop diuretics, bisphosphonates, calcitonin and eventually haemodialysis with low calcium content should be considered.
Paediatric population
Infants and children are generally more susceptible to the toxic effects of vitamin D.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Vitamin D and analogues. ATC code:A11CC03
Alfacalcidol is converted rapidly in the liver to 1, 25-dihydroxyvitamin D. This is the metabolite of vitamin D which acts as a regulator of calcium and phosphate
metabolism. Since this conversion is rapid, the clinical effects of Alfacalcidol and 1, 25-dihydroxyvitamin D are very similar.
Impaired 1-O'hydroxylation by the kidneys reduces endogenous 1,25-dihydroxyvitamin D production. This contributes to the disturbances in mineral metabolism found in several disorders, including renal bone disease and hypoparathyoidism. These disorders, which require high doses of parent vitamin D for their correction, will respond to small doses of Alfacalcidol.
The delay in response and high dosage required in treating these disorders with parent vitamin D makes dosage adjustment difficult. This can result in
unpredictable hypercalcaemia which may take weeks or months to reverse. The major advantage of Alfacalcidol is the more rapid onset of response, which allows
a more accurate titration of dosage. Should inadvertent hypercalcaemia occur it can be reversed within days of stopping treatment.
Paediatric population
When 1-a hydroxylation by the kidneys is impaired, endogenous 1,25-dihydroxyvitamin D production is reduced. Disorders in which this can occur include neonatal hypocalcaemia and Vitamin D-dependent rickets. Such conditions require high doses of Vitamin D for their correction but will respond to small doses of Alfacalcidol, which does not depend on the renal 1-a hydroxylation process.
5.2 Pharmacokinetic properties
Absorption
In patients with renal failure, 1-5 pg/day of 1 a- hydroxyvitamin D (1 a-OHD3) increased intestinal calcium and phosphorus absorption in a dose-related manner. This effect was observed within 3 days of starting the drug and conversely, it was reversed within 3 days of its discontinuation.
In patients with nutritional osteomalacia, increases in calcium absorption were noted within 6 hours of giving 1 pg 1a-OHD3 orally and usually peaked at 24 hours. 1a-OHD3 also produced increases in plasma inorganic phosphorus due to
increased intestinal absorption and renal tubular re-absorption. This latter effect is a result of PTH suppression by 1 a-OHD3. The effect of the drug on calcium was about double its effect on phosphorus absorption.
Patients with chronic renal failure have shown increased serum calcium levels within 5 days of receiving 1a-OHD3 in a dose of 0.5 - 1.0 pg/day. As serum calcium rose, PTH levels and alkaline phosphatase decreased toward normal.
Distribution
Vitamin D and its metabolites circulate in the blood bound to a specific a-globulin. Alfacalcidol has a more rapid action and shorter half-life.
Biotransformation:
Alfacalcidol undergoes rapid hepatic conversion to 1,25-dihydroxyvitamin D, the Vitamin D metabolite which acts as a regulator of calcium and phosphate metabolism.
Elimination
Vitamin D compounds and their metabolites are excreted mainly in the bile and faeces with only small amounts appearing in urine; there is some enterohepatic recycling but it is considered to have a negligible contribution to vitamin D status.
Paediatric population
Limited data is available in children
5.3 Preclinical safety data
There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Capsule fill Butylhydroxyanisole Butylhydroxytoluene Triglycerides, medium chain
Capsule shell
Gelatin
Glycerol
Sorbitol 70% solution Allura Red AC Brilliant Blue FCF Yellow iron oxide Titanium dioxide Purified water
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
36 months
6.4 Special precautions for storage
Do not store above 25°C.
Keep blisters in the outer carton in order to protect from light.
6.5 Nature and contents of container
PVC/PVDC/Aluminium blister pack
Pack size: 30 capsules
Each PVC/PVDC/Aluminium pack contains 3 strips, each containing 10 capsules.
6.6 Special precautions for disposal
No special requirements.
5. MARKETING AUTHORISATION HOLDER
Mercury Pharmaceuticals Ltd Capital House, 85 King William Street,
London EC4N 7BL, UK
8 MARKETING AUTHORISATION NUMBER(S)
PL 12762/0474
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
18/04/2013
10 DATE OF REVISION OF THE TEXT
11/11/2014