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Product
Anti-asthmatic Products (Aerocort Inhaler)
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Alfacip(Alfacalcidol Capsules)
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Alfacip
Alfacalcidol Capsules
COMPOSITION
Each soft gelatin capsule of ALFACIP contains
Alfacalcidol (1-alpha hydroxyvitamin D3)…0.25mcg
(green capsule)
DOSAGE FORM
Tablets for oral use.
PHARMACOLOGY
Pharmacodynamics
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 alfacalcidol and 1,25-dihydroxyvitamin D are very similar.
Impaired 1-α hydroxylation by the kidneys reduces endogenous 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 alfacalcidol.
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 alfacalcidol 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.
Pharmacokinetics
In patients with renal failure, 1-5 μg/day of 1α-hydroxyvitamin D (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 μg 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 re-absorption. 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 1α-OHD3 in a dose of 0.5 - 1.0 μg/day. As serum calcium rose, PTH levels and alkaline phosphatase decreased toward normal.
INDICATIONS
Alfacalcidol is indicated in all conditions where there is a disturbance of calcium metabolism due to impaired 1-α hydroxylation such as when there is reduced renal function. The main indications are:
» » Renal osteodystrophy
» » Hyperparathyroidism (with bone disease)
» » Hypoparathyroidism
» » Neonatal hypocalcaemia
» » Nutritional and malabsorptive rickets and osteomalacia
» » Pseudo-deficiency (D-dependent) rickets and osteomalacia
» » Hypophosphataemic vitamin D resistant rickets and osteomalacia
» » Osteoporosis
DOSAGE AND ADMINISTRATION
Initial dose for all indications:
The dose of ALFACIP 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.
Plasma levels should initially be measured at weekly intervals. The daily dose of ALFACIP may be increased by increments of 0.25 - 0.5 microgram. When the dose is stabilised, measurements may be taken every 2 - 4 weeks.
Most adult patients respond to doses between 1 and 3 micrograms per day. When there is biochemical or radiographic evidence of bone healing, (and in hypoparathyroid patients when normal plasma calcium levels have been attained), the dose generally decreases. Maintenance doses are generally in the range of 0.25 to 1 microgram per day. If hypercalcaemia occurs, ALFACIP should be stopped until plasma calcium returns to normal (approximately 1 week) then restarted at half the previous dose.
• Renal bone disease:
Patients with relatively high initial plasma calcium levels may have autonomous hyperparathyroidism, often unresponsive to ALFACIP . Other therapeutic measures may be indicated.
Before and during treatment with ALFACIP , 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.
• Hyperparathyroidism:
In patients with primary or tertiary hyperparathyroidism about to undergo parathyroidectomy, pre-operative treatment with alfacalcidol for 2-3 weeks alleviates bone pain and myopathy without aggravating pre-operative hypercalcaemia. In order to decrease post-operative hypocalcaemia, ALFACIP should be continued until plasma alkaline phosphatase levels fall to normal or hypercalcaemia occurs.
• Hypoparathyroidism:
In contrast to the response to parent vitamin D, low plasma calcium levels are restored to normal relatively quickly with alfacalcidol. Severe hypocalcaemia is corrected more rapidly with higher doses of ALFACIP (e.g. 3-5 micrograms) together with calcium supplements.
• Neonatal hypocalcaemia:
Although the normal starting dose of ALFACIP 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.
A dose of 0.1 microgram/kg/day of alfacalcidol has proven effective as prophylaxis against early neonatal hypocalcaemia in premature infants.
• Nutritional and malabsorptive rickets and osteomalacia:
Nutritional rickets and osteomalacia can be cured rapidly with ALFACIP . Malabsorptive osteomalacia (responding to large doses of IM or IV parent vitamin D) will respond to small doses of ALFACIP .
• Pseudo-deficiency (D-dependent) rickets and osteomalacia:
Although large doses of parent vitamin D would be required, effective doses of ALFACIP are similar to those required to heal nutritional vitamin D deficiency rickets and osteomalacia.
• Hypophosphataemic vitamin D-resistant rickets and osteomalacia:
Neither large doses of parent vitamin D nor phosphate supplements are entirely satisfactory. Treatment with alfacalcidol at normal dosage rapidly relieves myopathy when present and increases calcium and phosphate retention. Phosphate supplements may also be required in some patients.
• Osteoporosis:
The dose is 0.5mcg/day.
CONTRAINDICATIONS
Alfacalcidol should not be administered in the presence of hypercalcaemia, metastatic calcification, hyperphosphataemia (except when occurring with hypoparathyroidism) or hypermagnesaemia. Alfacalcidol should not be used in patients with evidence of Vitamin D toxicity or known hypersensitivity to the effects of Vitamin D or any of its analogues.
WARNINGS AND PRECAUTIONS
ALFACIP 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 ALFACIP serum calcium and serum phosphate should be monitored regularly especially in children, patients with renal impairment and patients receiving high doses. Throughout treatment with Alfacalcidol regular plasma and urinary (24-hour collection) calcium levels should be determined at least once every three months. 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 alfacalcidol, the early symptoms are as follows:
• polyuria
• polydipsia
• weakness, headache, nausea, constipation
• dry mouth
• muscle and bone pain
• metallic taste
Alfacalcidol therapy requires regular monitoring of calcium phosphate, alkaline phosphate, magnesium and creatinine levels as well as other appropriate biochemical parameters and should only be prescribed when suitable facilities are available. If there is biochemical evidence of bone healing (e.g. return towards normal serum alkaline phosphate levels), hypercalcaemia may develop if the dose of alfacalcidol is not decreased appropriately; if hypercalcaemia or hypercalcuria occur, this can be corrected rapidly by stopping treatment with Alfacalcidol and any calcium supplements until plasma calcium levels return to normal, usually in about a week. ALFACIP treatment may then be restarted at a reduced dose (half the previous dose).
Alfacalcidol should be administered with caution to patients with hypercalcaemia especially those with a history of renal calculi.
Drug interactions
Alfacalcidol/Digitalis/Glycosides - Hypercalcaemia in patients taking digitalis preparations may precipitate cardiac arrhythmias. Patients taking digitalis concurrently with alfacalcidol must therefore be closely monitored.
Alfacalcidol/Barbiturates/Enzyme-inducing Anticonvulsant Drugs - Patients on barbiturates or other enzyme-inducing anticonvulsants may require an increased dose of alfacalcidol to produce the desired effect.
Alfacalcidol/Drugs affecting intestinal absorption - Absorption of alfacalcidol may be impaired by concurrent use of mineral oil (prolonged use), cholestyramine, colestipol, sucralfate or large amounts of aluminium-based antacids.
Alfacalcidol/Magnesium - Caution should be exercised in the use of magnesium-based antacids or laxatives for patients taking alfacalcidol who are on chronic renal dialysis. Hypermagnesaemia may occur.
Alfacalcidol/Calcium/Thiazides - The risk of hypercalcaemia is increased in patients taking calcium-containing preparations or thiazide diuretics concurrently with alfacalcidol.
Alfacalcidol/Vitamin D and Derivatives - Alfacalcidol is a potent derivative of Vitamin D. Pharmacological doses of vitamin D and its derivatives should not be given during alfacalcidol treatment because of the possibility of additive effects and an increased risk of hypercalcaemia.
Pregnancy
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.
Lactation
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 alfacalcidol. This may influence calcium metabolism in the infant.
UNDESIRABLE EFFECTS
Adverse effects generally relate to hypercalcaemia and in the case of renal impairment, hyperphosphataemia which may be induced by alfacalcidol therapy.
Hypercalcaemia may manifest as malaise, fatigue, weakness, dizziness, headache, nausea, dry mouth, constipation, diarrhoea, heartburn, vomiting, abdominal pain or other gastrointestinal discomfort, muscle pain, bone pain, joint pain, pruritus or palpitations. In hypercalcaemic dialysis patients, the possibility of calcium influx from the dialysate should be considered. No other side effects associated directly with alfacalcidol therapy have been noted.
Hypercalcaemia can be rapidly corrected by stopping treatment until plasma calcium levels return to normal (about 1 week). ALFACIP 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 – Pruritis, Rash, Urticaria
Renal and Urinary Disorders – Nephrocalcinosis, Renal impairment
OVERDOSAGE
Hypercalcaemia is treated by suspending the administration of ALFACIP .
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, biphosphonates, calcitonin and eventually haemodialysis with low calcium content should be considered.
PACKAGING INFORMATION
ALFACIP is available in a blister strip of 10 capsules.
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