ONE-ALPHA® Capsules - 1 µg and 0,25 µg: Soft gelatin capsules containing either 1 microgram or 0,25 micrograms of alphacalcidol (1alpha-hydroxyvitamin D3).
PHARMACOLOGICAL CLASSIFICATION: A 22.1.4 Vitamins: Other
PHARMACOLOGICAL ACTION: 1alpha-hydroxyvitamin D3 (1alpha-OHD3) is converted rapidly in the liver to 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3), the metabolite through which vitamin D is considered to express most of its effects on calcium and phosphorus metabolism. Impaired endogenous production of 1,25-(OH)2D3 by the kidney appears to contribute to the disturbance in mineral metabolism found in several disorders including renal bone disease, hypoparathyroidism and pseudo-deficiency rickets. These disorders, termed vitamin D resistant since they usually require high doses of vitamin D for their correction, respond to small physiological doses of 1alpha-OHD3.
Renal Bone Disease: Most patients with osteitis fibrosa and osteomalacia show a symptomatic and gradual biochemical, radiographic and histological improvement. Hypoparathyroidism: Low plasma calcium levels are restored to normal relatively quickly with 1alpha-OHD3. Severe hypocalcaemia (eg. after extensive neck surgery) may decline with higher doses of 1alpha-OHD3, (eg. 3 -5 micrograms) and calcium supplements. Normocalcaemia may be maintained with smaller doses within a relatively narrow dose range. Secondary 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 1alpha-OHD3 for two to three 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. Hypophosphataemic Vitamin D resistant rickets and osteomalacia: This is characterised by hypophosphataemia due to defective renal tubular reabsorption and intestinal absorption of phosphorus. Neither large doses of vitamin D nor phosphate supplements are entirely satisfactory, the latter tending to produce hypocalcaemia and hypoparathyroidism. 1alpha-OHD3 relieves myopathy when present, increases calcium and phosphorus retention and promotes bone healing. Phosphate supplements may also be required in some patients. Pseudo-deficiency (D-dependent) rickets: This requires large doses of vitamin D probably because of an inherited defect in the production of 1,25-(OH)2D3. 1alpha-OHD3 reverses this condition. Nutritional and malabsorptive rickets and osteomalacia: Nutritional rickets and osteomalacia can be cured with physiological doses of 1alpha-OHD3. Patients with malabsorptive osteomalacia responding to large doses of vitamin D will respond to small doses of 1alpha-OHD3.
CONTRA-INDICATIONS: ONE-ALPHA® should not be given to patients with hypercalcaemia or evidence of vitamin D intoxication. ONE-ALPHA® should only be used during pregnancy and lactation when the expected therapeutic benefits clearly outweigh the possible adverse effects.
WARNINGS: Not to be used in the first trimester of pregnancy.
DOSAGE AND DIRECTIONS FOR USE:
Initial dose for all indications: Adults: 1 microgram daily
Children over 20 kg bodymass: 1 microgram daily
Children under 20 kg bodymass: 0,05 micrograms/kg daily
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 investigations. Patients with marked bone disease 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 dose 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 0,25 - 1 micrograms daily.
For neonatal hypocalcaemia the normal starting dose of 1alpha-OHD3 is 0,05 - 0,1 micrograms/kg/day. Adjustment of the dose thereafter is by careful titration (but 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 plasma alkaline phosphatase may be markedly raised in the pre-term low birthweight infant. Whilst levels of five 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 1alpha-OHD3 of 0,1 micrograms/kg/day has proved effective as prophylaxis against early neonatal hypocalcaemia in premature neonates.
SIDE-EFFECTS AND SPECIAL PRECAUTIONS: 1alpha-OHD3 should be given with care to patients with impaired renal function. If hypercalcaemia is induced by 1alpha-OHD3 it can be rapidly corrected by stopping treatment. Throughout treatment, regular plasma calcium determinations are essential. Facilities for monitoring plasma calcium and other appropriate biochemical parameters should be available when 1alpha-OHD3 is used. If hypercalcaemia occurs, 1alpha-OHD3 should be stopped until the plasma calcium returns to normal (about one week) and then restarted at half the dose.
The risk of hypercalcaemia depends on such factors as the degree of any mineralisation defect, renal function and the dose of 1alpha-OHD3 that is used. Thus hypercalcaemia is less likely in osteomalacia and more likely in renal failure. Hypercalcaemia will occur when there is biochemical evidence of bone healing (eg. a return towards normal in the level of plasma alkaline phosphatase) and the dose of 1alpha-OHD3 is not reduced appropriately. Prolonged hypercalcaemia should be avoided, particularly in chronic renal failure. Plasma calcium levels should be measured at weekly to monthly intervals depending on the progress of the patient. Frequent estimations are necessary in the early stages of treatment and later when there is evidence of bone healing. Plasma calcium levels should also be estimated regularly during the initial treatment of disorders without significant bone involvement, eg. hypoparathyroidism.
Patients concurrently taking barbiturates and other anticonvulsant drugs may require larger doses of 1alpha-OHD3 to produce the desired effect, as these substances may interfere with the hepatic conversion of 1alpha-OHD3 to 1,25 (OH)2D3. 1alpha-OHD3 should only be used during pregnancy and lactation if considered essential by the physician.
KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT: The initial signs and symptoms of vitamin D intoxication associated with hypercalcaemia include weakness, fatigue, somnolence, headache, anorexia, nausea, vomiting, diarrhoea and pruritus. If hypercalcaemia is allowed to persist, the following may also develop, conjunctivitis, a shortened Q-T interval and cardiac arrhythmias, as well as manifestations of impaired renal function consisting of polyuria, polydipsia, nocturia, hyposthenuria, dehydration and mild proteinuria.
Agitation, apprehension, pain in the extremities, paralytic ileus, abdominal pain and, rarely, overt psychosis have also been reported with hypercalcaemia. Some mild elevations in SGOT and SGPT have been reported in a small percentage of patients treated with ONE-ALPHA®. Treatment of hypercalcaemia and overdosage in patients on hemodialysis General treatment of hypercalcaemia (greater than 0,25 mmol/L above the upper limit of the normal range) consists of immediate discontinuation of therapy, institution of a low calcium diet and withdrawal of calcium supplements. Serum calcium levels should be determined daily until normocalcaemia ensues. Hypercalcaemia frequently resolves in two to seven days. When serum calcium levels have returned to within normal limits, therapy may be reinstituted at a dose of 0,25 micrograms/day less than prior therapy. Serum calcium levels should be obtained at least twice weekly after all dosage changes and subsequent dosage titration. Persistent or markedly elevated serum calcium levels may be corrected by dialysis against a calcium-free dialysate.