One Alpha
Россия
  • Россия
  • Украина

One Alpha - Scientific Information

Manufacture: LEO Pharma
Country: Great Britain
Condition: Hypocalcemia, Secondary Hyperparathyroidism
Class: Vitamins
Form: Capsules
Ingredients: alfacalcidol, titanium dioxide

Pharmaceutical Information

Drug Substance

Alfacalcidol (1α-hydroxycholecalciferol)

Molecular Formula: C27H44O2
Molecular Weight: 400.65
Chemical Name: (5Z, 7E)-9,10-secocholesta-5,7,10(19)-triene-1α, 3β-diol
Description: Alfacalcidol is a colorless crystalline compound with a melting range of 136o-144oC. It is sensitive to light and very soluble in methanol, ethanol and chloroform, soluble in ether, sparingly soluble in methylformate and acetronitrile.
Composition
1 mcg soft gel Capsules: Non-medicinal ingredients: sesame oil and α-tocopherol; shell composition: gelatin, glycerol, potassium sorbate, red iron oxide E172 and black iron oxide E172.
0.25 mcg soft gel Capsules: Non-medicinal ingredients: sesame oil and α-tocopherol; shell composition: gelatin, glycerol, potassium sorbate and titanium dioxide.
2 mcg/mL Oral Drops: Non-medicinal ingredients: citric acid monohydrate, ethanol, methyl parahydroxybenzoate, polyoxyl 40 hydrogenated castor oil, purified water, sodium citrate, sorbitol and α-tocopherol.
2 mcg/mL Injection: Non-medicinal ingredients: citric acid monohydrate 0.16 mg/ml, ethanol 80 mg/ml, sodium citrate 6.8 mg/ml, propylene glycol 415 mg/ml and water up to 1 ml.
Stability and Storage Recommendations
1 mcg soft gel Capsules: Protect from direct sunlight. Store at 15-25oC.
0.25 mcg soft gel Capsules: Protect from direct sunlight. Store at 15-25oC.
2 mcg/mL Oral Drops: Protect from direct sunlight. Keep refrigerated (2-8°C). Use within 28 days of first opening the bottle.
2 mcg/mL Injection: Keep ampoules in outer carton to protect from light. Keep refrigerated (2-8oC). Shake well before use. Single use ampoules - discard unused portion.
AVAILABILITY OF DOSAGE FORMS
1 mcg soft gel Capsules: Each brown, egg-shaped soft gelatin capsule contains 1 mcg alfacalcidol. Available in tropical blisters of 100 (10x10 blisters).
0.25 mcg soft gel Capsules: Each cream-coloured, egg-shaped soft gelatin capsule contains 0.25 mcg alfacalcidol. Available in tropical blisters of 100 (10x10 blisters).
2 mcg/mL Oral Drops: A clear or slightly opalescent colourless solution containing 2 mcg alfacalcidol per mL. Available in amber glass bottles of 10 mL fitted with a polyethylene dropping device.
Drop size: 1 drop equals 0.1 mcg alfacalcidol.
2 mcg/mL Injection: A sterile aqueous solution intended for intravenous injection containing 2 mcg alfacalcidol per mL. Available in cartons of 10 ampoules. Each amber glass ampoule contains a unit dose of 1 mcg/0.5 mL or 2 mcg/1 mL. Shake well before use.

Information for the Consumer

One-Alpha (alfacalcidol)

Capsules (0.25mcg and 1 mcg) and Oral Drops (2 mcg/mL)

This leaflet is intended to give you some important information about using One-Alpha. If you have any questions please talk to your doctor or pharmacist.

What is One-Alpha?

One-Alpha is a medication used to help your body absorb calcium from your diet. Calcium is needed for good bone development and muscular activity. One-Alpha is available as an oral preparation (capsules and liquid drops) and as an intravenous injection.

Before using One-Alpha

Tell your doctor or pharmacist:

  • about all other medicines or vitamins you may be taking. Do not use any prescription or non-prescription medications (including antacids and calcium supplements) without first checking with your doctor or pharmacist.
  • if you are pregnant or breast feeding or if you become pregnant during your treatment.

How should I take One-Alpha?

The amount of One-Alpha will be tailored exactly for your body’s needs. FOLLOW YOUR DOCTOR’S INSTRUCTIONS PRECISELY ABOUT WHEN AND HOW TO USE THIS MEDICINE. READ THE LABEL CAREFULLY. Your doctor will send you for blood tests to determine if a dosage adjustment of One-Alpha is needed.

Do not stop taking One-Alpha without first checking with your doctor. If a dose is forgotten, take it as soon as possible. If it is almost time for the next dose, do not double the dose. One-Alpha Capsules and Oral Drops may be taken with water or milk.

Your doctor may also prescribe other medications and a special diet in order to help improve your medical condition. It is very important to follow your doctors’ instructions carefully.

When using the One-Alpha Oral Drops, remove the protective cap but not the plastic dropper which is inserted into the bottle. To use the dropper, hold the bottle upside down. The liquid should flow immediately, but if it does not, tap the bottle gently. Do not shake the bottle.

One-Alpha Injection is to be given only by a doctor or nurse during haemodialysis in patients with chronic renal failure.

Side-effects

One-Alpha is generally safe, but side-effects can occur. Your doctor should be notified if any of the following symptoms occur:

More common: Itching, headache.

Less common: Nausea, vomiting, constipation, loss of appetite, dry mouth, muscle or bone pain, drowsiness, irregular heart beat, red eyes, increased urination.

Rare: Weight loss.

Side-effects can be reduced by following your doctors’ instructions carefully.

Storing your One-Alpha

Oral Drops should be stored in its carton in your refrigerator (2-8°C) preferably on a lower shelf. Protect from direct sunlight. Use within 28 days of first opening the bottle.

Oral Capsules should be stored at room temperature (15-25°C) and protected from direct sunlight.

Keep away from children. One-Alpha contains enough medication to seriously harm a child.

Do not use One-Alpha after the expiry date indicated on the label.

Pharmacology

In normal and anephric rats given 6.25 - 62500 pmol 1α-OHD3 and in the chick treated with 0.3-0.6 nmol 1α-OHD3 , the stimulation of intestinal calcium transport and bone mobilization was between one-half and equal to that of 1,25-(OH)2D3 . In both species, the conversion of 1α-OHD3 to 1,25-(OH)2D3 has been demonstrated by the isolation of radioactive 1,25-(OH)2D3 after administration of labelled 1α-OHD3 . Further studies on the transformation have demonstrated 25-hydroxylation in the liver homogenates from both the rat and the chick and also in intestinal mucosa from the chick. Whereas the hepatic 25-hydroxylation of vitamin D3 is feedback regulated, the corresponding conversion of 1α-OHD3 to 1,25-(OH)2D3 seems to be quantitative.

The 25-hydroxylation of 1α-OHD3 in the liver occurs very rapidly. Vitamin D-deficient rats were dosed with the radio-labelled compound (a single dose of 0.125 mcg 1α-OH(6-3H)D3 orally or i.v.). The intestinal calcium transport in orally dosed animals was noted after 4 hours and reached a maximum at 12 hours; in animals receiving the i.v. dose, there was insignificant intestinal calcium transport at 4 hours, but a maximal response was attained at 6 hours. Following both routes, a high level of transport was maintained for up to 96 hours. Intestinal tissue concentrations of 1,25-(OH)2 (6-3H)D3 appeared rapidly, within 2 hours of either the i.v. or oral dose of 1α-OH(6-3H)D3. These concentrations maximized by 4 hours at 310 and 250 pg/g following the oral and i.v. dose, respectively. Although intestinal levels of 1α-25(OH)2D3 are similar following a single oral or i.v. dose of 1α-OHD3 , blood and bone concentrations are much lower in the orally dosed animals than in animals dosed parenterally.

Blood levels and intestinal absorption of both 1α-OHD3 and 1,25-(OH)2D3 have also been determined in chicks following the oral or i.v. administration of 0.125 mcg 1α-OH(6-3H)D3 . As early as 1 hour after the i.v. injection, intestinal concentrations of 1,25-(OH)2 (6-3H)D3 were noted, which maximized at 6 hours. In orally dosed animals, no 1,25-(OH)2 (6-3H)D3 was measured at 1 hour, but at 4 hours the maximum concentration of 1.5 ng/g was reached which was 1.5 times higher than that reached after the i.v. dose. However, the i.v. dose yielded higher bone and blood concentrations than the oral dose.

These studies demonstrate that the transformation of 1α-OHD3 to 1,25-(OH)2D3 occurs rapidly enough to account for the biological response to 1α-OHD3. Although it cannot be excluded that 1 α -OHD3 may have a direct effect on the intestine when present at a relatively high concentration immediately after oral administration, it seems reasonable to conclude that it functions mainly after conversion to 1,25-(OH)2D3.

Apart from these effects, 1α-OHD appears devoid of pharmacological action.

Clinical Pharmacology

Metabolism of Vitamin D and Its Therapeutic Implications

It is now generally agreed that vitamin D is itself biologically inactive and only expresses its physiological effects after undergoing two metabolic conversions. Before any physiological action can take place, vitamin D must first be hydroxylated at the 25 position in the liver to the metabolic intermediary 25-OHD3. Secondly, 25-OHD3 undergoes a 1α-hydroxylation in the kidney to the physiologically active metabolite, 1,25-dihydroxy-vitamin D3 [1,25-(OH)2D3].

This final critical conversion in the kidney becomes impaired or blocked in patients with renal failure or disorders of calcium and phosphorus metabolism. Therefore, these patients respond poorly to even high doses of vitamin D.

In man, ONE-ALPHA (alfacalcidol) is converted directly and rapidly to 1,25-(OH)2D3 in the liver, thereby totally bypassing the critical renal conversion. Impairment of the hepatic conversion of 1α-OHD3 to 1,25-(OH)2D3 is rare, even in the presence of liver abnormalities.

Pharmacodynamic Effects of 1α-OHD3

In patients with renal failure, 1-5 mcg/day of 1α-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 mcg 1α-OHD3 orally and usually peaked at 24 hours. 1α-OHD3 also produced increases in plasma inorganic phosphorus due to increased intestinal absorption and renal tubular reabsorption. This latter effect is a result of PTH suppression by 1α-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 oral 1α-OHD3 in a dose of 0.5 - 1.0 mcg/day. Serum calcium levels also increase during the first 4 weeks of treatment with intermittent (2-3 times weekly) intravenous 1α-OHD3 in a dose of 2.7-8.5 mcg/week. As serum calcium rose, PTH levels and alkaline phosphatase decreased toward normal.

Hypercalcemia has usually been observed with dosages exceeding 4 mcg/day. The appearance of hypercalcemia is predicated on the ease with which calcium is utilized for bone mineralization and on renal excretion. Thus, chronic renal failure is a condition which would dispose patients toward hypercalcemia; conversely, changes induced by 1α-OHD3 on the Ca X P product and on PTH secretion may also alter renal function, but in most patients with chronic renal failure, 1α-OHD3 has not adversely affected renal function.

A rise in plasma creatinine (or a fall in glomerular filtration rate) has been reported in children with renal failure who are treated with ONE-ALPHA. However, it is still unclear whether this response was due to the action of the drug or to increased creatinine production during growth.

The beneficial effects of ONE-ALPHA on the development of renal bone disease in pre-dialysis patients have been demonstrated in a large, randomized, placebo controlled study. Long-term administration of ONE-ALPHA (maximum dose of 1 mcg/day for up to 2 years) improved bone histology and halted the progression of changes in serum alkaline phosphatase activity and parathyroid hormone levels compared to placebo. Long-term administration of alfacalcidol proved to be well tolerated and had no adverse effect on renal function in patients for whom the dose was titrated to prevent persistent hypercalcemia. Although elevation of serum calcium was observed, marked hypercalcemia (> 3.00 mmol/L) was uncommon (4.5% of patients) and readily responded to decreases in drug dosage.

Toxicology

Acute Toxicity

Studies performed in mice and rats have revealed that 1α-OHD3 has an acute toxicity which is relatively low as compared to therapeutic doses. The following table illustrates the LD50 values obtained with both species: the discrepancy in the LD50 values reported by two centres are probably attributable to differences in the procedures followed in the two laboratories.

Mice died from 3 to 7 days after dosing by both routes of administration as a result of general calcification.

Rats treated orally with the drug showed progressive general deterioration and were highly emaciated at death. Autopsy revealed general calcification which was most pronounced in the kidneys.

LD Values Obtained with 1α-Hydroxyvitamin D3
SPECIES ROUTE OF
ADMINISTRATION
LD50 (mcg/kg)
Mice Oral 490
Mice (Male) Oral 476
Mice (Female) Oral 440
Mice I.V. 290
Mice (Male) I.V. 71
Mice (Female) I.V. 56
Rats Oral 510
Rats (Male Oral 340
Rats (Female) Oral 720

Oral Subacute Toxicity

One study in rats showed that repeated dosing with up to 2.5 mcg/kg/day for 30 days did not cause any untoward effects. Higher doses resulted in hypercalcemia and metastatic calcification.

In another study, rats were dosed with 0.4, 2.0 and 10 mcg/kg/day of the drug for 7-8 weeks. From week 3 onwards, the animals showed signs of general deterioration, apathy and weight loss. Post-mortem examinations revealed a lighter colour and calcinosis in the kidneys in the highest dose group. In the other groups, there was a slight but dose-related calcinosis in the kidneys which was more pronounced in the females than in the males.

Dogs were treated orally for 3 to 8 weeks with 1α-OHD3 in doses of 0.1, 0.4 and 3.2 mcg/kg/day. After 3 and 7 weeks respectively, dogs on the 3.2 mcg dose and dogs on the 0.4 mcg dose showed considerable deterioration with loss of appetite and weight, apathy and subnormal temperature. Post-mortems revealed slight muscular dehydration and reduced fat deposition. Females on 0.4 mcg/kg/day had scattered small foci of calcium deposits and groups of dilated tubules in the cortex and medulla; the male animals, however, showed only traces of calcium deposition. In all 4 dogs on the highest dose, focal groups of dilated tubules with flattened epithelium and interstitial fibrosis in the cortex and medulla of the kidney were observed. Scattered calcium deposits were present in the fundus of the stomach (mucosa and submucosa) and in the bronchi and alveoli and corresponding vessels. In the group of dogs (2 male and 2 female) treated with 0.1 mcg/kg, histopathology showed one case of calcium deposits in the renal medulla. No other untoward effects were noted in the low dose group.

Intravenous Subacute Toxicity

In a 6 week study in rats dosed with 0.1, 0.3 and 0.9 mcg/kg/d of 1α-OHD3, the only dose-effect relationship observed was for hemoglobinurea. Animals in the highest dose group exhibited cessation of growth followed by slight weight loss, languid behaviour, moderate reductions in food consumption, hypothermia, and pale mucous membranes. Pigmented corneal granulations were evident and post-mortem examinations showed weight reductions for the pituitary, ovaries and uterus. Renal tubule casts were also present and there was an increase in the intensity of renal microcalculi in females. In the control group receiving vehicle injections, there was slight hyperuremia and small increases in hemoglobinuria.

Sensitivity to vehicle injections was also noted in a 14 day tolerance study in beagle dogs. Dogs receiving high doses of vehicle (0.4 ml/kg) showed a slight degree of hemolysis immediately after injection which disappeared within 4 hours. In a 6 week study in dogs dosed with 0.01, 0.03, 0.09, and 0.18 mcg/kg/day of 1α-OHD3, effects were noted only in the highest dose group. Aside from increases in monocyte number, post-mortem examinations showed vascular calcification and dystrophic mineralization in the aorta and stomach. Kidneys had a firmer texture, the kidney cortex zone had a paler colour, tubules were dilated and had chronic inflammatory cell infiltration.

Chronic Toxicity

Rats were dosed orally with 0.2, 0.8 and 3.2 mcg/kg/day with 1α-OHD3 for 6 months. Increased serum levels of calcium were recorded in all groups from week 9 onwards; phosphate levels were increased in week 26 and there was a decrease in total protein with the two highest dose levels at the end of the study. Autopsy revealed soft tissue calcification in the kidneys, stomach and aorta with the intermediate and high dose levels. A slight increase in the incidence of calcinosis of the kidney was observed in the low dose group.

In a 6-month study in dogs, the initial oral doses of 1α-OHD3 were 0.05, 0.1 and 0.2 mcg/kg/day, but because of adverse effects on bodyweight and food consumption, dosing with 0.2 mcg/kg/day was stopped after 72 days. In some of these animals, dosing continued at 0.025 mcg/kg/day which allowed the animals to recover. Apart from the effects with the 0.2 mcg dose, there were no untoward clinical signs or effects on bodyweight or food consumption. The only macroscopic abnormality noted was enlarged spleens in the treated dogs. Two dogs which were sacrificed after the 0.2 mcg/kg dose and 2 other dogs on 0.1 mcg/kg showed areas of dilated basophilic tubules in the kidneys. One dog on 0.2 mcg/kg had numerous calcified foci in the lamina propria of the fundus and excessive muscle stiffness due to soft tissue calcification. Soft tissue calcification was also noted in a dog treated with 0.1 mcg/kg/day.

Teratogenic Studies

Studies were performed in rats and rabbits using daily doses of 0.1, 0.3 and 0.9 mcg/kg of 1α-OHD3. Parent animals dosed with the drug had a lower weight gain than undosed animals. Reduced litter size and lower weights of fetuses were recorded in rabbits at the intermediate and high dose levels, but no significant increase in the incidence of fetal malformations were noted.

The effect of 1α-OHD3 on the reproductive function in the rats was investigated using the same doses. At the highest dose level, the pregnancy rate, litter size and birth weights were significantly lower than in control animals, in both the original parent animals and offspring of the first generation. No other parameters were affected and no late effects of the drug were observed in any of the progeny.