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LEO Pharma

Cashel Road, Dublin 12,
Telephone: +353 1 490 8924
WWW: http://www.leo-pharma.ie
Medical Information Direct Line: +353 1 4908924
Medical Information e-mail: medical-info.ie@leo-pharma.com
Medical Information Facsimile: Not Applicable


Summary of Product Characteristics last updated on medicines.ie: 27/01/2014
SPC One-Alpha 0.25 mcg Capsules



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1. NAME OF THE MEDICINAL PRODUCT

One-Alpha 0.25 micrograms soft capsules


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2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains 0.25 micrograms of Alfacalcidol.

Excipient(s) with known effects: contains sesame oil.

For the full list of excipients, see section 6.1.


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3. PHARMACEUTICAL FORM

Capsule, soft (capsule)

Cream-coloured, egg-shaped soft gelatin capsule, holding 0.1 g oily solution.


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4. CLINICAL PARTICULARS

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4.1 Therapeutic indications

One-Alpha® is indicated in all conditions where there is a disturbance of calcium metabolism due to impaired 1 α-hydroxylation of vitamin D3 such as when there is reduced renal function.

The main indications are:

a) Uraemic bone disease.

b) Hyperparathyroidism (with bone disease).

c) Hypoparathyroidism.

d) Post-menopausal, senile and steroid-induced osteoporosis.

e) Nutritional and malabsorptive rickets and osteomalacia.

f) Pseudo-deficiency (D-dependent) rickets.

g) Hypophosphataemic vitamin D resistant rickets and osteomalacia.

h) Prophylactic and therapeutic use in neonatal hypocalcaemia.


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4.2 Posology and method of administration

Initial dosage for all indications is:

• Adults & children over 20 kg bodyweight

1 microgram/day

• Neonates and premature infants

0.05 -0.1 microgram/kg/day

• Children under 20 kg bodyweight

0.05 microgram/kg/day

• Elderly

0.5 microgram/day may be sufficient

Regular monitoring of response by assays of serum calcium and phosphate, parathyroid hormone and alkaline phosphatase levels and urinary calcium may be used as a guide for subsequent dosage.

Most patients respond eventually to doses between 0.5 - 6 micrograms daily. The dosage requirements generally decrease in bone disorders at a time when there is biochemical or radiographic evidence of bone healing, and in hypoparathyroid patients after normal plasma calcium levels have been attained. Maintenance doses are generally in the range of 0.25 - 2 micrograms daily.

a) Renal bone disease

Most patients with osteitis fibrosa and osteomalacia show a rapid symptomatic and a gradual biochemical, radiographic and histological improvement. In these patients, the only unwanted effects of One-Alpha® appears to be hypercalcaemia which is more likely when there is evidence of bone healing. Patients with relatively high initial calcium levels may have autonomous hyperparathyroidism which is often unresponsive to One-Alpha®. In these cases other therapeutic measures may be indicated.

Before and during treatment with One-Alpha®, phosphate-binding agents should be considered to prevent hyperphosphataemia, which is known to increase the risk of metastatic calcification, especially when associated with hypercalcaemia. 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.

Early hypercalcaemia is more likely in patients with autonomous hyperparathyroidism, those with histologically 'pure' osteomalacia related possibly to phosphate depletion or aluminium intoxication, and those dialysed against a high dialysate calcium concentration.

b) Hypoparathyroidism

In contrast to the response to parent vitamin D, low plasma calcium levels are restored to normal relatively quickly with One-Alpha®. Severe hypocalcaemia (e.g. after extensive neck surgery) is corrected and symptoms abolished even more rapidly with higher doses of One-Alpha® (e.g. 3-5 micrograms) together with calcium supplements. Normocalcaemia may be maintained with smaller doses within a relatively narrow dose range.

c) Hyperparathyroidism

Following parathyroidectomy, patients with primary or tertiary hyperparathyroidism and bone disease often require large doses of vitamin D and intravenous calcium to avoid severe hypocalcaemia. Preliminary studies suggest that pre-operative treatment with One- Alpha® for 2 to 3 weeks alleviates bone pain and myopathy when present without aggravating pre-operative hypercalcaemia. Continued post-operative treatment decreases post-operative hypocalcaemia and should be continued until the plasma alkaline phosphatase level falls to normal or hypercalcaemia occurs.

d) Hypophosphataemic vitamin D-resistant rickets and osteomalacia

These conditions are characterised by hypophosphataemia due to defective tubular reabsorption and intestinal absorption of phosphorous. Neither large doses of parent vitamin D nor phosphate supplements are entirely satisfactory, the latter tending to produce hypocalcaemia and hyperparathyroidism. Treatment of children and adults with One-Alpha® rapidly relieves myopathy when present, increases calcium and phosphorous retention and promotes bone healing. Phosphate supplements may also be required in some patients.

e) Pseudo-deficiency (D-dependent) rickets

Although large doses of parent vitamin D would be required (probably because of an inherent defect in the production of 1,25-(OH)2D3), effective doses of One-Alpha® are similar to those required to heal nutritional Vitamin D deficiency rickets.

f) Nutritional and malabsorptive rickets and osteomalacia

Nutritional rickets and osteomalacia can be cured rapidly with 'physiological' doses of One-Alpha®. Limited experience suggests that patients with malabsorptive osteomalacia (responding only to large doses of parenterally administered vitamin D) will respond to small doses of One-Alpha®.

g) Osteoporosis

Patients with post-menopausal and senile osteoporosis are said to have low levels of plasma 1,25-(OH)2D3, even though their nutritional vitamin D status is normal. This may explain why some of these patients have calcium malabsorption, which is relatively resistant to vitamin D but responsive to small doses of One-Alpha®. Many post-menopausal osteoporotic women appear to have both oestrogen deficiency and calcium malabsorption. To avoid hypercalcaemia, a daily dose of 1 microgram of One-Alpha® should not be exceeded and excessive calcium supplementation is not indicated.

h) Neonatal hypocalcaemia

Although the normal starting dose of One-Alpha® is 0.05-0.1 micrograms/kg/day (and subsequent adjustment is by careful titration), in severe cases doses of up to 2 micrograms/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 may be markedly raised in the pre-term low birthweight infant. Whilst levels of 5 times the normal adult laboratory value may be usual in this group, alkaline phosphatase levels above 7.5 times the adult range indicate active disease. A dose of 0.1 micrograms/kg/day has proved effective as prophylaxis against early neonatal hypocalcaemia in premature neonates.


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4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Hypercalcaemia.


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4.4 Special warnings and precautions for use

During treatment with One-Alpha®, serum calcium and serum phosphate levels should be monitored regularly PTH, alkaline phosphatase and the calcium x phosphate product should be monitored as clinically indicated.

Hypercalcaemia might appear in patients treated with One-Alpha®. For this reason, patients should be informed about the clinical symptoms connected with hypercalcaemia. Signs of hypercalcaemia are anorexia, fatigue, nausea and vomiting, constipation or diarrhoea, polyuria, sweating, headache, polydipsia, hypertension, somnolence and vertigo.

Hypercalcaemia can be rapidly corrected by stopping treatment until plasma calcium levels return to normal (in about one week). One-Alpha® may then be restarted at a reduced dose (half the previous dose) with monitoring of calcium (see section 4.8).

Prolonged hypercalcaemia may aggravate arteriosclerosis, cardiac valve sclerosis or nephrolithiasis and so should be avoided in patients with these conditions. Transient or even long-lasting deterioration of kidney function has been observed. One-Alpha® should also be used with caution in patients with calcification of pulmonary tissue as this may result in cardiac disease.

Concurrent use of digitalis glycosides in the presence of hypercalcaemia increases the potential for cardiac arrhythmias.

Use with caution in patients being treated with thiazide diuretics as they may have an increased risk of developing hypercalcaemia.

In patients with renal bone disease or severely reduced renal function, a phosphate binding agent could be used simultaneously with alfacalcidol to prevent increased serum phosphate and potential metastatic calcification.

One-Alpha® should be used with caution in patients with granulomatous diseases such as sarcoidosis where the sensitivity to vitamin D is increased due to increased hydroxylation activity.

One-Alpha® capsules contain sesame oil as an excipient. Sesame oil may rarely cause severe allergic reactions.


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4.5 Interaction with other medicinal products and other forms of interaction

Thiazide diuretics and calcium containing preparations

Concurrent use of thiazide diuretics or calcium containing preparations may enhance the risk of hypercalcaemia. Calcium levels should be monitored.

Vitamin D containing preparations/Other Vitamin D analogues

Concurrent use of vitamin D containing preparations with alfacalcidol may enhance the risk of hypercalcaemia. Use of multiple vitamin D analogues should also be avoided.

Anticonvulsants

Anticonvulsants (e.g. barbiturates, phenytoin, carbamazepine or primidone) have enzyme-inducing effects resulting in an increased metabolism of alfacalcidol. Patients taking anticonvulsants may require larger doses of One-Alpha®.

Cholestyramine

Concomitant oral administration of cholestyramine may impair the intestinal absorption of oral One-Alpha® formulations. One-Alpha® should be administered at least 1 hour before, or 4 to 6 hours after the intake of cholestyramine in order to minimize the potential risk of interaction.

Magnesium-containing antacids

Absorption of magnesium-containing antacids may be enhanced by One-Alpha®, increasing the risk of hypermagnesaemia.

Aluminium containing preparations

One-Alpha® may increase the serum concentration of aluminium. Patients taking aluminium containing preparations (e.g. aluminium hydroxide, sucralfate) should be monitored for signs of aluminium related toxicities.


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4.6 Pregnancy and lactation

Pregnancy

There is a limited amount of data from the use of alfacalcidol in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3).

One-Alpha® should not be used in pregnancy unless clearly necessary as hypercalcaemia during pregnancy may produce congenital disorder in the offspring. Caution should be exercised in women of childbearing potential.

Breast-feeding

One-Alpha® is excreted in human milk. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from One-Alpha® therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Breast-fed infants of women receiving alfacalcidol therapy should be monitored closely for hypercalcaemia.

Fertility

No clinical information is available regarding the effect of alfacalcidol on fertility.


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4.7 Effects on ability to drive and use machines

Alfacalcidol has no or negligible direct influence on the ability to drive and use machines. However, the patient should be informed that dizziness may occur during treatment and take this into account while driving or using machines.


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4.8 Undesirable effects

The estimation of the frequency of undesirable effects is based on a pooled analysis of data from clinical studies and spontaneous reporting.

The most frequently reported undesirable effects are various skin reactions such as pruritus and rash, hypercalcaemia, gastrointestinal pain/discomfort and hyperphosphataemia.

Symptoms and signs which may occur in association with hypercalcaemia are anorexia, fatigue, nausea and vomiting, constipation or diarrhoea, polyuria, sweating, headache, polydipsia, somnolence and vertigo.

Prolonged hypercalcaemia can result in nephrocalcinosis/nephrolithiasis and renal impairment (see section 4.4). Renal failure has been reported post-marketing.

Undesirable effects are listed by MedDRA system organ class (SOC) and the individual undesirable effects are listed starting with the most frequently reported one. Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Very common ≥1/10

Common ≥1/100 and < 1/10

Uncommon ≥1/1,000 and <1/100

Rare ≥1/10,000 and <1/1,000

Very rare <1/10,000

Metabolism and nutrition disorders

Common:

(≥1/100 and < 1/10)

Hypercalcaemia

Hyperphosphatemia

Psychiatric disorders

Uncommon:

(≥1/1,000 and <1/100)

Confusional state

Nervous system disorders

Uncommon:

(≥1/1,000 and <1/100)

Headache

Rare:

( ≥1/10,000 and <1/1,000)

Dizziness

Gastrointestinal disorders

Common:

(≥1/100 and < 1/10)

Abdominal pain and discomfort

Uncommon:

(≥1/1,000 and <1/100)

Diarrhoea

Vomiting

Constipation

Nausea

Skin and subcutaneous tissue disorders

Common:

( ≥1/100 and < 1/10)

Rash*

Pruritus

*Various types of rash reactions such as erythematous, maculo-papular and pustular have been reported

Musculoskeletal and connective tissue disorders

Uncommon:

(≥1/1,000 and <1/100)

Myalgia

Renal and urinary disorders

Common:

(≥1/100 and < 1/10)

Hypercalciuria

Uncommon:

(≥1/1,000 and <1/100)

Renal impairment (including acute renal failure)

Nephrolithiasis/ Nephrocalcinosis

General disorders and administration site conditions

Uncommon:

(≥1/1,000 and <1/100)

Fatigue/asthenia/malaise

Calcinosis

Paediatric population

The observed safety profile is similar for children and adults.

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 preferably through the online reporting option accessible from the IMB homepage. A downloadable report form is also accessible from the IMB website, which may be completed manually and submitted to the IMB via 'freepost', in addition to the traditional post-paid 'yellow card' option.

FREEPOST

Pharmacovigilance Section

Irish Medicines Board

Kevin O'Malley House

Earlsfort Centre

Earlsfort Terrace

Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.imb.ie

e-mail: imbpharmacovigilance@imb.ie


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4.9 Overdose

Excessive intake of One-Alpha® may lead to the development of hypercalcaemia, however, the effect is reversed rapidly on withdrawal. 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 functions indices, assess electrocardiographic abnormalities, especially on patients on digitalis. More specifically, treatment with glucocorticosteroids, loop diuretics, bisphosphonates, calcitonin and eventually haemodialysis with low calcium contents should be considered.


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5. PHARMACOLOGICAL PROPERTIES

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5.1 Pharmacodynamic properties

ATC code: A11C C03

Alfacalcidol is converted rapidly in the liver to 1,25 dihydroxyvitamin D3. This is the metabolite of vitamin D3 which acts as a regulator of calcium and phosphate metabolism. Since this conversion is rapid, the clinical effects of One-Alpha® and 1,25 dihydroxyvitamin D3 are very similar.

Impaired renal 1-hydroxylation reduces 1,25 dihydroxyvitamin D3 production. This contributes to the disturbances in mineral metabolism found in several disorders, including renal bone disease, hypoparathyroidism, neonatal hypocalcaemia and vitamin D dependent rickets. These disorders, which require high doses of parent vitamin D for their correction, will respond to small doses of One-Alpha®.

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 One-Alpha® 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.


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5.2 Pharmacokinetic properties

Serum levels of 1,25 dihydroxyvitamin D3 reach peak concentrations approximately 8-12 hours after a single dose of One-Alpha® with a half-life of 1,25-(OH)2 -D3 of about 35 hours.

The metabolism is similar to that of vitamin D after the 25-hydroxylation to 1,25 dihydroxyvitamin D3.


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5.3 Preclinical safety data

The non-clinical toxicity of alfacalcidol is attributed to the known vitamin D-effect of calcitriol on calcium homeostasis, which is characterised by hypercalcaemia, hypercalciuria and eventually soft tissue calcification.

Alfacalcidol is not genotoxic.

No specific effects of alfacalcidol on fertility or behaviour of the offspring were noted in rats and rabbits. In terms of embryo-foetal development, foetal toxicity (post-implantation loss, lower litter size and lower pup weight) was observed at doses high enough to cause toxicity in the dams. High doses of vitamin D are known to be teratogenic in experimental animals.


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6. PHARMACEUTICAL PARTICULARS

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6.1 List of excipient(s)

sesame oil, refined

all-rac-α-tocopherol

Capsule shell:

gelatin

glycerol (E422)

potassium sorbate (E202)

titanium dioxide (E171)


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6.2 Incompatibilities

Not applicable.


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6.3 Shelf life

Two years.


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6.4 Special precautions for storage

Do not store above 25°C.


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6.5 Nature and contents of container

Al/PVC blister foil, Polyamide/Al lid containing 30 or 100 capsules.

Not all pack sizes may be marketed.


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6.6 Special precautions for disposal and other handling

No special requirements.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.


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7. MARKETING AUTHORISATION HOLDER

LEO Laboratories Limited, 285 Cashel Road, Dublin 12


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8. MARKETING AUTHORISATION NUMBER(S)

PA 46/24/2


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9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 15th March 1978

Date of last renewal: 2nd March 2008


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10. DATE OF REVISION OF THE TEXT

December 2013



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Active Ingredients

 
   Alfacalcidol