SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

One-Alpha ® Injection

2.    Qualitative and Quantitative Composition

Alfacalcidol (1a-hydroxyvitamin D₃) 2 micrograms/ml.

3    PHARMACEUTICAL FORM

Solution for injection.

Clear, colourless liquid in 1 ml one-point-cut amber glass ampoule.

4 CLINICAL PARTICULARS

4.1    Therapeutic indications

One-Alpha^® 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

One-Alpha^® Injection should be administered intravenously as a bolus over approximately 30 seconds.

The dosage of One-Alpha® Injection is the same as for One-Alpha® in its oral presentations.

Initial dosage for all indications is:

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 20 kg bodyweight	0.05 microgram/kg/day
Children over 20 kg bodyweight	1 microgram/day

The dose of One-Alpha® 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.

Maintenance doses are generally in the range of 0.25 - 1 microgram per day.

When administered as intravenous injection to patients undergoing haemodialysis the initial dosage for adults is 1 microgram per dialysis. The maximum dose recommended is 6 micrograms per dialysis and not more than 12 micrograms per week. The injection should be administered into the return line from the haemodialysis machine at the end of each dialysis.

(a)    Renal bone disease:

Patients with relatively high initial plasma calcium levels may have autonomous hyperparathyroidism, often unresponsive to One-Alpha^®. Other therapeutic measures may be indicated.

Before and during treatment with One-Alpha^®, 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, pre-operative treatment with One-Alpha® for 2-3 weeks alleviates bone pain and myopathy without aggravating pre-operative hypercalcaemia. In order to decrease post-operative hypocalcaemia, One-Alpha 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 One-Alpha®. Severe hypocalcaemia is corrected more rapidly with higher doses of One-Alpha® (eg 3-5 micrograms) together with calcium supplements.

(d)    Neonatal hypocalcaemia:

Although the normal starting dose of One-Alpha® 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.

(e)    Nutritional and malabsorptive rickets and osteomalacia:

Nutritional rickets and osteomalacia can be cured rapidly with One-Alpha^®. Malabsorptive osteomalacia (responding to large doses of IM or IV parent vitamin D) will respond to small doses of One-Alpha®.

(f)    Pseudo-deficiency (D-dependent) rickets and osteomalacia:

Although large doses of parent vitamin D would be required, effective doses of One-Alpha® 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 One-Alpha® at normal dosage rapidly relieves myopathy when present and increases calcium and phosphate retention. Phosphate supplements may also be required in some patients.

4.3 Contraindications

Hypercalcaemia, metastatic calcification.

Hypersensitivity to alfacalcidol or any of the other ingredients.

4.4 Special warnings and precautions for use

One-Alpha® 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 One-Alpha^® serum calcium and serum phosphate should be monitored regularly especially in children, 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 One-Alpha®, 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). One-Alpha^® treatment may then be restarted at a reduced dose (half the previous dose).

4.5    Interaction with other medicinal products and other forms of interaction

Patients taking barbiturates or anticonvulsants may require larger doses of One-Alpha® to produce the desired effect due to the induction of hepatic detoxification enzymes.

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

4.6    Pregnancy and lactation

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.

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 One-Alpha^®. This may influence calcium metabolism in the infant.

4.7    Effects on ability to drive and use machines

One-Alpha® 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. Hypercalcaemia can be rapidly corrected by stopping treatment until plasma calcium levels return to normal (about 1 week). One-Alpha^® treatment may then be re-started at half the previous dose.

Based on data from post-market use the total undesirable effect ‘reporting rate’ is rare or very rare being approximately 1:10,000 patients treated.

•    Metabolism and Nutrition Disorders

Hypercalcaemia

Hyperphosphataemia

•    Skin and Subcutaneous Tissue Disorders

Pruritus

Rash

Urticaria

• Renal and Urinary Disorders Nephrocalcinosis Renal impairment

4.9    Overdose

Hypercalcaemia is treated by suspending the administration of One-Alpha®.

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.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

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 One-Alpha® and 1,25 dihydroxyvitamin D are very similar.

Impaired 1 a-hydroxylation reduces 1,25 dihydroxyvitamin D 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.

5.2    Pharmacokinetic Properties

In patients on regular haemodialysis administration of doses between 1 - 4 micrograms of intravenous 1 a-hydroxyvitamin D₃ resulted in increased levels of 1,25 dihydroxyvitamin D. Formation of 1,25 dihydroxyvitamin D₃ occurred within 1 hour after intravenous 1 a -hydroxyvitamin D₃ and peak concentrations were reached between 2 and 5 hours. Elimination half life of the formed 1,25 dihydroxyvitamin D was between 14 and 30 hours.

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

Citric acid, ethanol, sodium citrate, propylene glycol and water for injection.

6.2    Incompatibilities

None known.

6.3    Shelf Life

3 years.

6.4. Special precautions for storage

Store at 2-8°C.

Keep the ampoule in the outer carton in order to protect it from light.

6.5    Nature and Contents of Container

10 x 0.5m1 amber glass ampoules.

10 x 1.0ml amber glass ampoules.

6.6    Instructions for Use/Handling

None.

7 MARKETING AUTHORISATION HOLDER

LEO Laboratories Limited

Horizon

Honey Lane

Hurley

Maidenhead

Berkshire

SL6 6RJ

UK

8. MARKETING AUTHORISATION NUMBER

PL 00043/0183

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

11/11/2005

10    DATE OF REVISION OF THE TEXT

02/12/2013