LEO Pharma

One-Alpha® 2 micrograms/ml oral drops

Alfacalcidol 2 micrograms/ml

Each drop (0.05 millilitre) contains 0.1 micrograms (100 nanograms) alfacalcidol.

Excipients: ethanol 113 mg/ml, sorbitol (E420), methylparahydroxybenzoate (E218), macrogolglycerol hydroxystearate.

For a full list of excipients, see 6.1

Oral drops, solution.

Clear, aqueous solution

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

The main indications are:

• Uraemic bone disease

• Hyperparathyroidism (with bone disease)

• Hypoparathyroidism

• Post-menopausal, senile and steroid-induced osteoporosis

• Nutritional and malabsorptive rickets and osteomalacia

• Pseudo-deficiency (D-dependent) rickets

• Hypophosphataemic vitamin D resistant rickets and osteomalacia

• Prophylactic and therapeutic use in neonatal hypocalcaemia

Initial dosage for all indications is:

To administer this medicine:

Hold the dropper in a vertical position, upside down. The drops should flow immediately but if they do not, tap the bottle gently. Do not shake the bottle.

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.

Dosage requirements generally decrease in patients as biochemical or radiographic evidence of healing of bone takes place, and in hypoparathyroid patients after normal serum calcium levels have been obtained.

It is important to adjust dosage thereafter according to the biochemical responses and to avoid hypercalcaemia. Indices of response include levels of plasma calcium, alkaline phosphatase, parathyroid hormone, urinary calcium excretion as well as radiographic and histological investigation. Patients with marked bone disease (other than those with renal failure) may tolerate a higher dose without developing hypercalcaemia. However, failure of the plasma calcium to rise promptly in osteomalacic patients does not necessarily mean that a higher dose is required since calcium from increased intestinal calcium absorption may be incorporated into demineralised bone.

Most patients respond eventually to doses between 1 – 3 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 - 1 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 effect 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 indicates active disease. A dose of 0.1 microgram/kg/day has proved effective as prophylaxis against early neonatal hypocalcaemia in premature neonates.

Hypercalcaemia.

Hypersensitivity to any of its constituents.

During treatment with One-Alpha^®, serum calcium and serum phosphate should be monitored regularly, especially in the early stages of treatment. Calcium supplements may also be required.

To maintain serum phosphate at an acceptable level in patients with renal bone disease a phosphate binding agent may be used.

Hypercalcaemia might appear in patients treated with One-Alpha^®. Patients with renal failure, tertiary hyper-parathyroidism, or those on regular haemodialysis (potentially phosphate depleted) are particularly prone to develop hypercalcaemia. For this reason, patients should be informed about the clinical symptoms connected with hypercalcaemia. The early signs of hypercalcaemia are polyuria, polydipsia, weakness, headache, nausea, dry mouth, constipation, muscle pain, bone pain and metallic taste.

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).

Caution in patients under treatment with cardioactive glycosides or digitalis as hypercalcaemia may lead to arrhythmia in such patients.

Caution should be paid to patients with nephrolithiasis.

Patients with rare hereditary problems of fructose intolerance should not take this medicine.

This product contains small amounts of ethanol (alcohol), less than 100 mg per 1 microgram of alfacalcidol.

Macrogolglycerol hydroxystearate may cause stomach upset and diarrhoea.

Methylparahydroxybenzoate may cause allergic reactions (possibly delayed).

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.

Concomitant administration of colestyramine may interfere with the intestinal absorption of One-Alpha^®.

There is no clinical experience.

One-Alpha^® should only be used in pregnancy if considered essential by the physician 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 D₃ will be found in the milk of lactating mothers treated with One-Alpha^®. This may influence calcium metabolism in the infant therefore, it is advised that if possible women receiving vitamin D do not breastfeed their infants as this may lead to the development of hypercalcaemia in the infant.

No or negligible influence.

The most frequently reported undesirable effects are hypercalcaemia and various skin reactions such as rash.

Symptoms and signs which may occur in association with hypercalcaemia are diarrhoea, constipation, nausea, vomiting, dry mouth, metallic taste, hypercalciuria, polyuria, polydipsia, headache, dizziness, confusional state, myalgia, bone pain, irregular heartbeat, pruritus and fatigue. Prolonged hypercalcaemia can result in nephrocalcinosis and renal impairment.

Based on post-marketing data the total undesirable effect 'reporting rate' is rare or very rare being approximately 1:10,000 patient treatment years.

Metabolism and Nutrition Disorders

Hypercalcaemia

Hyperphosphataemia

Skin and Subcutaneous Tissue Disorders

Pruritus

Rash

Urticaria

Renal and Urinary Disorders

Nephrocalcinosis

Renal impairment

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 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.

ATC code: A11C C03

Alfacalcidol is converted rapidly in the liver to 1,25 dihydroxyvitamin D₃. 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 D₃ are very similar.

Impaired renal 1α-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 D₃ 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.

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.

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

ethanol

macrogolglycerol hydroxystearate

methylparahydroxybenzoate (E218)

citric acid monohydrate (E330)

sodium citrate (E331)

sorbitol (E420)

all-rac-α-Tocopherol

water.

Not applicable.

3 years

Store in a refrigerator (2 to 8°C).

Amber glass bottles of 10 and 20 ml, fitted with a polyethylene dropping device and a polypropylene screw cap.

Not all pack sizes may be marketed.

No special requirements.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

LEO Laboratories Limited, Cashel Road, Dublin 12

PA 46/24/9

26^th July 1999/ 2^nd March 2008

June 2008

Product subject to prescription which may be renewed (B)