One-Alpha soft capsules contain 0.25, 0.5 or 1 microgram alfacalcidol per capsule. For a full list of excipients, see section 6.1. Capsules, soft.

Transcription

1 1. NAME OF THE MEDICINAL PRODUCT One-Alpha (in NL: Etalpha LEO) 0.25 microgram soft capsules One-Alpha (in NL: Etalpha LEO) 0.5 microgram soft capsules One-Alpha (in NL: Etalpha LEO) 1 microgram soft capsules 2. QUALITATIVE AND QUANTITATIVE COMPOSITION One-Alpha soft capsules contain 0.25, 0.5 or 1 microgram alfacalcidol per capsule. For a full list of excipients, see section PHARMACEUTICAL FORM Capsules, soft. One-Alpha 0.25 microgram soft capsules are cream coloured and egg-shaped soft gelatin capsules. One-Alpha 0.5 microgram soft capsules are red and egg-shaped soft gelatin capsules. One-Alpha 1 microgram soft capsules are brown and egg-shaped soft gelatin capsules. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications One-Alpha capsules are indicated for prevention and treatment of renal osteodystrophy and treatment of secondary hyperparathyroidism in patients with chronic kidney disease stage Posology and method of administration One-Alpha capsules should be taken orally as whole capsules and should not be divided. One-Alpha capsules can be taken with food. The dose of One-Alpha must be carefully determined for each patient by monitoring of serum levels of parathyroid hormone (PTH), calcium, phosphate, calcium x phosphate product and alkaline phosphatase, and the dose adjusted until clinical target ranges of these parameters are achieved, cf. current treatment guidelines. Pre-dialysis patients (chronic kidney disease stage 3 and stage 4): Initiation of treatment with One-Alpha capsules is indicated when serum levels of 25(OH)-vitamin D are >30 ng/ml (75 nmol/l), and plasma levels of intact PTH are above the target range for the CKD stage (intact PTH >70 pg/ml for stage 3; intact PTH >110 pg/ml for stage 4) or in accordance with current guidelines. Adults: Recommended initial oral dose is 0.25 microgram per day and the oral maintenance dose is normally 0.5 microgram. The maximum recommended dose is not more than 12 microgram per week. CORREO ELECTRÓNICO sugerencias_ft@aemps.es Se atenderán exclusivamente incidencias informáticas sobre la aplicación CIMA ( C/ CAMPEZO, 1 EDIFICIO MADRID

2 Elderly: Clinical experience with One-Alpha in pre-dialysis patients aged 65 years or more supports that the dosage recommended for use in non-elderly adults can be given also to elderly. Children and adolescents: In clinical practice, alfacalcidol has been widely used in pre-dialysis patients at the age of 1 month to 18 years at dosages of ng/kg/day (equivalent to microgram/kg/day) with an average dose of ng/kg/day (equivalent to microgram/kg/day). Dialysis patients (chronic kidney disease stage 5): It is recommended to initiate One-Alpha treatment in patients with haemodialysis or peritoneal dialysis when the serum levels of intact parathyroid hormone (PTH) are >300 pg/ml (33.0 pmol/l), to reduce the serum levels of PTH to a target range of pg/ml (16.5 to 33.0 pmol/l) or in accordance with current guidelines. Adults: The recommended initial dose is 0.50 microgram per day. Dose increases of 0.25 microgram or 0.50 microgram can be performed at intervals of at least one week until monitored levels of laboratory parameters are within the target range. The oral maintenance dose is likely to be 1 microgram per day. The maximum recommended dose is 6 microgram per dialysis and not more than 12 microgram per week. Elderly: Clinical experience with One-Alpha in dialysis patients aged 65 years or more supports that the dosage recommended for use in non-elderly adults can be given also to elderly. Children and adolescents: In clinical practice, alfacalcidol has been given orally to children undergoing haemodialysis or continuous ambulatory peritoneal dialysis (CAPD). The dose ranges described in literature were ng/kg/day (equivalent to microgram/kg/day) given orally in infants, children and adolescents up to and including the age of 17 years. Hepatic impairment: The efficacy of alfacalcidol is in general retained in patients with reduced liver function. In cases of severe hepatic dysfunction, the effect of alfacalcidol may be decreased due to decreased hydroxylation of alfacalcidol to calcitriol or due to decreased absorption, e.g. due to decreased enterohepatic circulation, and a higher dose may be necessary. If a dose has been missed do not administer a double dose the next time. Continue the prescribed dosing schedule. 4.3 Contraindications Hypercalcaemia. Known hypersensitivity to alfacalcidol or to any of the excipients.

3 4.4 Special warnings and precautions for use During treatment with One-Alpha, serum calcium, serum phosphate, the calcium x phosphate product, serum PTH levels and alkaline phosphatase should be monitored regularly. Hypercalcaemia might appear in patients treated with One-Alpha. For this reason, patients should be informed about the clinical symptoms connected with hypercalcaemia. Early symptoms and signs of hypercalcaemia are: weakness, fatigue, asthenia, malaise, myalgia, arthralgia, bone pain, anorexia, nausea, vomiting, diarrhoea, constipation, dry mouth, dysgeusia, metallic taste, headache, dizziness. In case of hypercalcaemia or a persistent elevated calcium x phosphate product exceeding the clinical targets, treatment should be stopped for at least one week until the clinical target ranges have been reestablished. Treatment with One-Alpha may then be restarted at a reduced dose (half the previous dose). To maintain serum phosphate at an acceptable level in patients with renal bone disease a phosphate binding agent may be used. Over-suppression of PTH should be avoided. For dialysis patients, the serum levels of PTH should not be lower than 2-3 times above the normal range. Caution should be exercised in patients under treatment with cardiac glycosides as hypercalcaemia may lead to arrhythmia in such patients. Caution should be paid to patients with nephrolithiasis, cardiac dysrhythmias or arteriosclerosis as these conditions may be aggravated by hypercalcaemia. Caution should be paid to patients with sarcoidosis, tuberculosis or other granulomatous diseases as these conditions have a potential for enhanced sensitivity to vitamin D. Caution should be paid to patients under treatment with thiazid diuretics as they may have an increased risk of developing hypercalcaemia. Excipient warning: One-Alpha capsules contain sesame oil which may rarely cause severe allergic reactions. 4.5 Interaction with other medicinal products and other forms of interaction Patients taking anticonvulsants (barbiturates or phenytoin) or other drugs that induce the liver enzymes (such as rifampicin) may require larger doses of One-Alpha to produce the desired effect. Concomitant administration of cholestyramine may impair the intestinal absorption of One-Alpha. In order to decrease the possibility of interference, alfacalcidol should be administered at least 1 hour prior to, or 4-6 hours after the intake of cholestyramin. Concurrent use of thiazide diuretics, calcium containing preparations or other vitamin D containing preparations may enhance the risk of hypercalcaemia. Concurrent use of cardiac glycosides increases the potential for cardiac arrhythmias.

4 Concurrent use of magnesium-containing antacids may enhance the risk of hypermagnesaemia. 4.6 Pregnancy and lactation Pregnancy: There are no adequate data from the use of alfacalcidol in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. One-Alpha should not be used during pregnancy unless clearly necessary. Lactation: Alfacalcidol is suspected to be excreted into breast milk. At high doses, hypercalcaemia in the infant cannot be excluded. Because of inadequate data, lactation is advised against during treatment with alfacalcidol. 4.7 Effects on ability to drive and use machines One-Alpha has no or negligible influence on the ability to drive and use machines. 4.8 Undesirable effects In the clinical development program more than 500 patients received treatment with One-Alpha and hereof 174 received treatment with One-Alpha for at least 6 months approximately. Based on the clinical data for One-Alpha, 16% of the patients can be expected to experience an undesirable effect, mainly non-serious and dose-dependent. The most frequently reported undesirable effects for One-Alpha are hypercalcaemia and hypercalciuria and are linked to vitamin D toxicity. Early symptoms and signs of hypercalcaemia are: weakness, fatigue, asthenia, malaise, myalgia, arthralgia, bone pain, anorexia, nausea, vomiting, diarrhoea, constipation, dry mouth, dysgeusia, metallic taste, headache, dizziness. More severe cases of hypercalcaemia could manifest with: cardiac arrhythmias, confusional state, drowsiness, obnubilation, insomnia, restlessness, polydipsia, polyuria, dehydration. Prolonged hypercalcaemia can result in calcifications in the blood vessels, especially arteries and other soft tissues (myocardium, heart valves, brain, pancreas, skin, periarticular) which may further lead to organ damages of various severities. Prolonged hypercalcaemia can result in nephrocalcinosis/nephrolithiasis and further in renal impairment or aggravation of the pre-existing one. The severity and prognosis of these adverse reactions depend on the dose of One Alpha and duration of exposure to the high calcium levels. The table below shows the adverse reactions reported from clinical trials. The adverse reactions, other than manifestations of hypercalcaemia, from spontaneous reports are also included. For these reactions headings of frequency cannot be given. 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

5 Very rare < 1/10,000 Not known (cannot be estimated from the available data) Metabolism and Nutrition Disorders Very common: Hypercalcaemia Uncommon: Metastatic calcifications, Hyperphosphataemia, High calcium phosphate product, Anorexia Not known (cannot be estimated from the available data): Hypermagnesaemia, Decreased appetite Immune system disorders Not known (cannot be estimated from the available data): Hypersensitivity reactions with symptoms and signs such as fever, chills, urticaria, and tongue oedema. Nervous system disorders Uncommon: Headache, Dysaesthesia, and Dysgeusia Cardiac disorders Uncommon: Tachycardia Vascular disorders Uncommon: Hypertension Gastrointestinal disorders Uncommon: Nausea, Vomiting, Abdominal pain, Constipation, Diarrhoea, Dyspepsia Skin and Subcutaneous Tissue Disorders Common: Pruritus Not known (cannot be estimated from the available data): Rash (erythematous, maculopapular, pustular), Dermatitis exfoliative Renal and Urinary Disorders Common: Hypercalciuria Not known (cannot be estimated from the available data): Renal insufficiency, nephrocalcinosis General disorders and administration site conditions Uncommon: Calcinosis, Asthenia, and Fatigue 4.9 Overdose The overdose is expressed by hypercalcaemia and hypercalciuria, as described in section 4.8. Hypercalcaemia is treated by suspending the administration of alfacalcidol, institution of a low-calcium diet and withdrawal of calcium supplements. In severe cases of acute accidental overdosage and persistent hypercalcaemia general supportive measures should be undertaken. Depending on the patient s condition, glucocorticosteroids, loop diuretics, bisphosphonates, calcitonin, peritoneal dialysis or haemodialysis against calcium-free dialysate can be considered. Monitoring of serum electrolytes (especially calcium) renal function, assessment of electrocardiographic abnormalities, especially in patients on digitalis, is mandatory.

6 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Vitamin D and analogues. ATC Code: A11C C03. Alfacalcidol (1α-hydroxy vitamin D 3, 1α(OH)D 3 ), the active substance in One-Alpha, is a synthetic vitamin D analogue. Alfacalcidol is a pro-drug that exerts its action after it has been metabolised to calcitriol (1α,25(OH) 2 D 3 ), mainly in the liver. Calcitriol is the physiologically active form of vitamin D hormone, and under normal circumstances calcitriol is formed primarily in the kidney by a 1αhydroxylase-mediated enzymatic hydroxylation of calcifediol (25(OH)D 3 ). As a consequence of the presence of the 1α-hydroxyl group, alfacalcidol only requires hydroxylation at the 25 position in the liver to yield calcitriol and therefore acts independently of renal function. In patients with chronic kidney disease, impaired 1 -hydroxylation by the kidneys reduces endogenous calcitriol production. This contributes to the disturbances in bone and mineral metabolism including secondary hyperparathyroidism and renal bone disease. Calcitriol has direct effects on the parathyroid gland to prevent parathyroid gland hyperplasia and also has additive effect with calcium to suppress PTH production. Calcitriol also increases gastrointestinal absorption of calcium to correct hypocalcaemia. Calcitriol directly affects osteoblasts in bone and may lead to improved bone formation and mineralization. In pre-dialysis patients, use of alfacalcidol is associated with lowering of PTH levels, improvement of renal bone disease and increase in bone mineral density. In chronic dialysis patients, alfacalcidol is effective in suppressing secondary hyperparathyroidism. 5.2 Pharmacokinetic properties Alfacalcidol is a prodrug that is metabolised in the liver to the biologically active 1-alpha,25- dihydroxyvitamin D 3 (calcitriol). Therefore it is appropriate to base the assessment of the bioavailability of alfacalcidol on the measurement of serum concentrations of calcitriol after administration of alfacalcidol. When comparing the fasted AUC inf value (a measure of concentration over time) of calcitriol after a single dose of 10 microgram alfacalcidol given as capsules with the corresponding AUC inf value for 10 microgram alfacalcidol given as i.v. injection the relative bioavailability was 87%. Following a single oral dose of 10 microgram One-Alpha given as capsules in the fasted state in healthy volunteers, the maximum serum concentration was reached in 6.4 hours for alfacalcidol (75 pg/ml) and in 7.6 hours for calcitriol (93 pg/ml). When One-Alpha capsules were given as repeated doses of 1.5 microgram three times a week in haemodialysis patients with chronic kidney disease, mean serum concentration versus time profiles of calcitriol were characterised by two absorption peaks at 9 hours and 12 hours, respectively. Repeated doses of 1.5 microgram three times a week for two weeks resulted in mean serum concentrations of calcitriol in the range of 25 to 49 pg/ml over the first 48 hours which were consistent with the normal range for healthy subjects. In healthy subjects, administration of One-Alpha capsules under fed conditions resulted in approximately 30% higher mean serum concentrations of alfacalcidol as compared to administration

7 under fasted conditions while the mean serum concentration of calcitriol was slightly lower in the fed state than in the fasted state. Following a single oral dose of 10 microgram One-Alpha given as 0.25 microgram capsules in healthy volunteers, the time of maximum concentration (t max ) of alfacalcidol was one hour less in the fed state (5.5 hours) than in the fasted state (6.4 hours) while for calcitriol t max was 13.7 hours in the fed state compared to 7.6 hours in fasted state. Alfacalcidol is essentially metabolised in the liver. Alfacalcidol is converted to the biologically active form calcitriol, predominantly in the liver, by 25-hydroxylation catalysed mainly by mitochondrial CYP27A1 and microsomal CYP3A4. A slight concentration-related induction (<2-fold) of CYP3A4 was observed in human hepatocyte cultures at alfacalcidol concentrations up to 200 nm. However, the maximal serum concentrations of alfacalcidol (<50 pg/ml) and calcitriol ( pg/ml) observed clinically are not likely to result in liver accumulation of alfacalcidol or calcitriol. Studies showed that neither alfacalcidol nor calcitriol is likely to inhibit cytochrome P450. In healthy volunteers, the half-life of alfacalcidol after oral administration (fed state) was 5.0 hours. The half-life of calcitriol was 8.7 hours when One-Alpha was administered as capsules in the fasted state and 10.5 hours for capsules in the fed state. The elimination half-life of calcitriol was 19 hours when One- Alpha was given at repeated doses in haemodialysis patients. 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-fetal development, fetal 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. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Capsules, 0.25 microgram: Capsules, 0.5 microgram: Capsule content: Sesame oil, refined all-rac-α-tocopherol (E307) Capsule shell: Gelatin Glycerol (E422) Potassium sorbate (E202) Titanium dioxide (E171) Capsule content:

8 Sesame oil, refined all-rac-α-tocopherol (E307) Capsule shell: Gelatin Glycerol (E422) Potassium sorbate (E202) Titanium dioxide (E171) Red iron oxide (E172). Capsules, 1 microgram: Capsule content: Sesame oil, refined all-rac-α-tocopherol (E307) Capsule shell: Gelatin Glycerol (E422) Potassium sorbate (E202) Red iron oxide (E172) Black iron oxide (E172) 6.2 Incompatibilities Not applicable. 6.3 Shelf-life 2 years 6.4 Special precautions for storage Do not store above 25ºC. 6.5 Nature and contents of container Blister packaging consisting of a white non-transparent aluminium push-through foil and a PVC blister film, covered with a non-transparent aluminium laminate lidding. Pack sizes of 10, 30, 50 or 100 capsules. Not all pack-sizes may be marketed. 6.6 Special precautions for disposal No special requirements. 7. MARKETING AUTHORISATION HOLDER <To be completed nationally>

9 8. MARKETING AUTHORISATION NUMBER(S) <To be completed nationally> 9. DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION <To be completed nationally> 10. DATE OF REVISION OF THE TEXT <To be completed nationally>