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One-Alpha (Alfacalcidol)
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Pharmacology
1a-hydroxyvitaminD 3(1a-OHD 3) stimulates intestinal calcium and phosphorus absorption, the reabsorption of calcium from bone and possibly the renal reabsorption of calcium.
To be effective in disorders resulting from vitaminD deficiency, vitaminD must undergo 2metabolic conversions, first in the liver to 25-hydroxyvitaminD and then in the kidney to the physiologically active metabolite, 1,25-dihydroxyvitaminD 3 (1,25-(OH) 2D 3). In patients with chronic renal failure, progressive nephron destruction blocks the production of 1,25-(OH) 2D 3 by the kidneys resulting in diminished serum levels of this metabolite.
When alfacalcidol is administered in this clinical situation, it is rapidly converted to 1,25-(OH) 2D 3 in the liver, effectively bypassing the critical renal metabolic conversion. This hepatic conversion of alfacalcidol is accomplished very rapidly, before any stimulation of the intestine or bone occurs.
The biological half-life of alfacalcidol has been shown to be approximately 3hours in the presence of renal insufficiency. However, serum levels of1,25-(OH) 2D 3 peak approximately 12hours after a single dose of oral alfacalcidol and approximately 4hours after a single dose of i.v. alfacalcidol. Levels of 1,25-(OH) 2D 3 remain measurable for at least 48hours. The effect of 1µg of oral alfacalcidol on intestinal calcium absorption has been observed within 6hours of ingestion and was maximal at 24hours. There is evidence that vitaminD, its 1a-hydroxylated metabolites and analogues are extensively bound to a serum binding protein of the a-globulin fraction. 1,25-(OH) 2D 3 appears to function in the intestine and bone by a receptor-nuclear activation mechanism.
One of the first abnormalities to be observed in patients with chronic renal failure is the disturbance of calcium metabolism due to increased phosphate retention and impaired production of1,25-(OH) 2D 3. Because calcium metabolism and production of1,25-(OH) 2D 3 is at least partially mediated by the parathyroid glands, hypocalcemia leads to increased parathyroid hormone (PTH) secretion and high plasma PTH levels. Therefore, the patients with renal bone disease most likely to benefit from alfacalcidol therapy are those characterized by abnormally low plasma calcium levels, elevated alkaline phosphatase and PTH levels and histological evidence of osteitic fibrosa and osteomalacia.
In the majority of patients treated with alfacalcidol, clinical symptoms of bone pain and muscle weakness begin to remit promptly, within 2weeks to 3months of the start of therapy. Malabsorption of calcium is rapidly corrected. In patients on daily oral therapy, plasma alkaline phosphatase and PTH levels generally begin to fall within 3months, but plasma calcium levels may not normalize for several months. This delay should not necessarily be construed as a poor response but may indicate that calcium is being utilized for bone mineralization. The decrease in PTH levels may be more rapid in patients on intermittent i.v. therapy, with significant reductions being achieved within 3months of therapy.
By contrast, hypercalcemia may occur at any stage of treatment, the risk being higher just after treatment is started and later when the plasma alkaline phosphatase level falls towards normal (see Precautions).
Because of a modest action on intestinal phosphorus absorption, alfacalcidol may elevate plasma phosphorus levels even further in patients with renal osteodystrophy and this may require increasing the dose of phosphate binding agents.
Normalization of plasma PTH levels frequently correlates well with healing of osteitis fibrosa, but radiographic improvement can occur without significant changes in plasma PTH concentrations. After 3to 6months of treatment, radiological evidence of healing is generally apparent. Histological responses, such as a decrease in the surface of bone undergoing resorption and a decrease in the volume of osteoid, are often much slower.
The beneficial effect of alfacalcidol on the development of renal bone disease in patients with renal failure not yet undergoing dialysis has been demonstrated in a large, randomized, placebo controlled study. Long-term administration of oral alfacalcidol (maximum dose of 1µg/day for up to 2years) 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 (>3mmol/L) was uncommon (4.5% of patients) and readily responded to decreases in drug dosage.
1a-hydroxyvitaminD 3(1a-OHD 3) stimulates intestinal calcium and phosphorus absorption, the reabsorption of calcium from bone and possibly the renal reabsorption of calcium.
To be effective in disorders resulting from vitaminD deficiency, vitaminD must undergo 2metabolic conversions, first in the liver to 25-hydroxyvitaminD and then in the kidney to the physiologically active metabolite, 1,25-dihydroxyvitaminD 3 (1,25-(OH) 2D 3). In patients with chronic renal failure, progressive nephron destruction blocks the production of 1,25-(OH) 2D 3 by the kidneys resulting in diminished serum levels of this metabolite.
When alfacalcidol is administered in this clinical situation, it is rapidly converted to 1,25-(OH) 2D 3 in the liver, effectively bypassing the critical renal metabolic conversion. This hepatic conversion of alfacalcidol is accomplished very rapidly, before any stimulation of the intestine or bone occurs.
The biological half-life of alfacalcidol has been shown to be approximately 3hours in the presence of renal insufficiency. However, serum levels of1,25-(OH) 2D 3 peak approximately 12hours after a single dose of oral alfacalcidol and approximately 4hours after a single dose of i.v. alfacalcidol. Levels of 1,25-(OH) 2D 3 remain measurable for at least 48hours. The effect of 1µg of oral alfacalcidol on intestinal calcium absorption has been observed within 6hours of ingestion and was maximal at 24hours. There is evidence that vitaminD, its 1a-hydroxylated metabolites and analogues are extensively bound to a serum binding protein of the a-globulin fraction. 1,25-(OH) 2D 3 appears to function in the intestine and bone by a receptor-nuclear activation mechanism.
One of the first abnormalities to be observed in patients with chronic renal failure is the disturbance of calcium metabolism due to increased phosphate retention and impaired production of1,25-(OH) 2D 3. Because calcium metabolism and production of1,25-(OH) 2D 3 is at least partially mediated by the parathyroid glands, hypocalcemia leads to increased parathyroid hormone (PTH) secretion and high plasma PTH levels. Therefore, the patients with renal bone disease most likely to benefit from alfacalcidol therapy are those characterized by abnormally low plasma calcium levels, elevated alkaline phosphatase and PTH levels and histological evidence of osteitic fibrosa and osteomalacia.
In the majority of patients treated with alfacalcidol, clinical symptoms of bone pain and muscle weakness begin to remit promptly, within 2weeks to 3months of the start of therapy. Malabsorption of calcium is rapidly corrected. In patients on daily oral therapy, plasma alkaline phosphatase and PTH levels generally begin to fall within 3months, but plasma calcium levels may not normalize for several months. This delay should not necessarily be construed as a poor response but may indicate that calcium is being utilized for bone mineralization. The decrease in PTH levels may be more rapid in patients on intermittent i.v. therapy, with significant reductions being achieved within 3months of therapy.
By contrast, hypercalcemia may occur at any stage of treatment, the risk being higher just after treatment is started and later when the plasma alkaline phosphatase level falls towards normal (see Precautions).
Because of a modest action on intestinal phosphorus absorption, alfacalcidol may elevate plasma phosphorus levels even further in patients with renal osteodystrophy and this may require increasing the dose of phosphate binding agents.
Normalization of plasma PTH levels frequently correlates well with healing of osteitis fibrosa, but radiographic improvement can occur without significant changes in plasma PTH concentrations. After 3to 6months of treatment, radiological evidence of healing is generally apparent. Histological responses, such as a decrease in the surface of bone undergoing resorption and a decrease in the volume of osteoid, are often much slower.
The beneficial effect of alfacalcidol on the development of renal bone disease in patients with renal failure not yet undergoing dialysis has been demonstrated in a large, randomized, placebo controlled study. Long-term administration of oral alfacalcidol (maximum dose of 1µg/day for up to 2years) 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 (>3mmol/L) was uncommon (4.5% of patients) and readily responded to decreases in drug dosage.
Indications
1a-hydroxyvitaminD 3(1a-OHD 3) Stimulates Intestinal Calcium And Phosphorus Absorption, The Reabsorption Of Calcium From Bone And Possibly The Renal Reabsorption Of Calcium.
To Be Effective In Disorders Resulting From VitaminD Deficiency, VitaminD Must Undergo 2metabolic Conversions, First In The Liver To 25-hydroxyvitaminD And Then In The Kidney To The Physiologically Active Metabolite, 1,25-dihydroxyvitaminD 3 (1,25-(OH) 2D 3). In Patients With Chronic Renal Failure, Progressive Nephron Destruction Blocks The Production Of 1,25-(OH) 2D 3 By The Kidneys Resulting In Diminished Serum Levels Of This Metabolite.
When Alfacalcidol Is Administered In This Clinical Situation, It Is Rapidly Converted To 1,25-(OH) 2D 3 In The Liver, Effectively Bypassing The Critical Renal Metabolic Conversion. This Hepatic Conversion Of Alfacalcidol Is Accomplished Very Rapidly, Before Any Stimulation Of The Intestine Or Bone Occurs.
The Biological Half-life Of Alfacalcidol Has Been Shown To Be Approximately 3hours In The Presence Of Renal Insufficiency. However, Serum Levels Of1,25-(OH) 2D 3 Peak Approximately 12hours After A Single Dose Of Oral Alfacalcidol And Approximately 4hours After A Single Dose Of I.v. Alfacalcidol. Levels Of 1,25-(OH) 2D 3 Remain Measurable For At Least 48hours. The Effect Of 1µg Of Oral Alfacalcidol On Intestinal Calcium Absorption Has Been Observed Within 6hours Of Ingestion And Was Maximal At 24hours. There Is Evidence That VitaminD, Its 1a-hydroxylated Metabolites And Analogues Are Extensively Bound To A Serum Binding Protein Of The A-globulin Fraction. 1,25-(OH) 2D 3 Appears To Function In The Intestine And Bone By A Receptor-nuclear Activation Mechanism.
One Of The First Abnormalities To Be Observed In Patients With Chronic Renal Failure Is The Disturbance Of Calcium Metabolism Due To Increased Phosphate Retention And Impaired Production Of1,25-(OH) 2D 3. Because Calcium Metabolism And Production Of1,25-(OH) 2D 3 Is At Least Partially Mediated By The Parathyroid Glands, Hypocalcemia Leads To Increased Parathyroid Hormone (PTH) Secretion And High Plasma PTH Levels. Therefore, The Patients With Renal Bone Disease Most Likely To Benefit From Alfacalcidol Therapy Are Those Characterized By Abnormally Low Plasma Calcium Levels, Elevated Alkaline Phosphatase And PTH Levels And Histological Evidence Of Osteitic Fibrosa And Osteomalacia.
In The Majority Of Patients Treated With Alfacalcidol, Clinical Symptoms Of Bone Pain And Muscle Weakness Begin To Remit Promptly, Within 2weeks To 3months Of The Start Of Therapy. Malabsorption Of Calcium Is Rapidly Corrected. In Patients On Daily Oral Therapy, Plasma Alkaline Phosphatase And PTH Levels Generally Begin To Fall Within 3months, But Plasma Calcium Levels May Not Normalize For Several Months. This Delay Should Not Necessarily Be Construed As A Poor Response But May Indicate That Calcium Is Being Utilized For Bone Mineralization. The Decrease In PTH Levels May Be More Rapid In Patients On Intermittent I.v. Therapy, With Significant Reductions Being Achieved Within 3months Of Therapy.
By Contrast, Hypercalcemia May Occur At Any Stage Of Treatment, The Risk Being Higher Just After Treatment Is Started And Later When The Plasma Alkaline Phosphatase Level Falls Towards Normal (see Precautions).
Because Of A Modest Action On Intestinal Phosphorus Absorption, Alfacalcidol May Elevate Plasma Phosphorus Levels Even Further In Patients With Renal Osteodystrophy And This May Require Increasing The Dose Of Phosphate Binding Agents.
Normalization Of Plasma PTH Levels Frequently Correlates Well With Healing Of Osteitis Fibrosa, But Radiographic Improvement Can Occur Without Significant Changes In Plasma PTH Concentrations. After 3to 6months Of Treatment, Radiological Evidence Of Healing Is Generally Apparent. Histological Responses, Such As A Decrease In The Surface Of Bone Undergoing Resorption And A Decrease In The Volume Of Osteoid, Are Often Much Slower.
The Beneficial Effect Of Alfacalcidol On The Development Of Renal Bone Disease In Patients With Renal Failure Not Yet Undergoing Dialysis Has Been Demonstrated In A Large, Randomized, Placebo Controlled Study. Long-term Administration Of Oral Alfacalcidol (maximum Dose Of 1µg/day For Up To 2years) 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 (>3mmol/L) Was Uncommon (4.5% Of Patients) And Readily Responded To Decreases In Drug Dosage.
1a-hydroxyvitaminD 3(1a-OHD 3) Stimulates Intestinal Calcium And Phosphorus Absorption, The Reabsorption Of Calcium From Bone And Possibly The Renal Reabsorption Of Calcium.
To Be Effective In Disorders Resulting From VitaminD Deficiency, VitaminD Must Undergo 2metabolic Conversions, First In The Liver To 25-hydroxyvitaminD And Then In The Kidney To The Physiologically Active Metabolite, 1,25-dihydroxyvitaminD 3 (1,25-(OH) 2D 3). In Patients With Chronic Renal Failure, Progressive Nephron Destruction Blocks The Production Of 1,25-(OH) 2D 3 By The Kidneys Resulting In Diminished Serum Levels Of This Metabolite.
When Alfacalcidol Is Administered In This Clinical Situation, It Is Rapidly Converted To 1,25-(OH) 2D 3 In The Liver, Effectively Bypassing The Critical Renal Metabolic Conversion. This Hepatic Conversion Of Alfacalcidol Is Accomplished Very Rapidly, Before Any Stimulation Of The Intestine Or Bone Occurs.
The Biological Half-life Of Alfacalcidol Has Been Shown To Be Approximately 3hours In The Presence Of Renal Insufficiency. However, Serum Levels Of1,25-(OH) 2D 3 Peak Approximately 12hours After A Single Dose Of Oral Alfacalcidol And Approximately 4hours After A Single Dose Of I.v. Alfacalcidol. Levels Of 1,25-(OH) 2D 3 Remain Measurable For At Least 48hours. The Effect Of 1µg Of Oral Alfacalcidol On Intestinal Calcium Absorption Has Been Observed Within 6hours Of Ingestion And Was Maximal At 24hours. There Is Evidence That VitaminD, Its 1a-hydroxylated Metabolites And Analogues Are Extensively Bound To A Serum Binding Protein Of The A-globulin Fraction. 1,25-(OH) 2D 3 Appears To Function In The Intestine And Bone By A Receptor-nuclear Activation Mechanism.
One Of The First Abnormalities To Be Observed In Patients With Chronic Renal Failure Is The Disturbance Of Calcium Metabolism Due To Increased Phosphate Retention And Impaired Production Of1,25-(OH) 2D 3. Because Calcium Metabolism And Production Of1,25-(OH) 2D 3 Is At Least Partially Mediated By The Parathyroid Glands, Hypocalcemia Leads To Increased Parathyroid Hormone (PTH) Secretion And High Plasma PTH Levels. Therefore, The Patients With Renal Bone Disease Most Likely To Benefit From Alfacalcidol Therapy Are Those Characterized By Abnormally Low Plasma Calcium Levels, Elevated Alkaline Phosphatase And PTH Levels And Histological Evidence Of Osteitic Fibrosa And Osteomalacia.
In The Majority Of Patients Treated With Alfacalcidol, Clinical Symptoms Of Bone Pain And Muscle Weakness Begin To Remit Promptly, Within 2weeks To 3months Of The Start Of Therapy. Malabsorption Of Calcium Is Rapidly Corrected. In Patients On Daily Oral Therapy, Plasma Alkaline Phosphatase And PTH Levels Generally Begin To Fall Within 3months, But Plasma Calcium Levels May Not Normalize For Several Months. This Delay Should Not Necessarily Be Construed As A Poor Response But May Indicate That Calcium Is Being Utilized For Bone Mineralization. The Decrease In PTH Levels May Be More Rapid In Patients On Intermittent I.v. Therapy, With Significant Reductions Being Achieved Within 3months Of Therapy.
By Contrast, Hypercalcemia May Occur At Any Stage Of Treatment, The Risk Being Higher Just After Treatment Is Started And Later When The Plasma Alkaline Phosphatase Level Falls Towards Normal (see Precautions).
Because Of A Modest Action On Intestinal Phosphorus Absorption, Alfacalcidol May Elevate Plasma Phosphorus Levels Even Further In Patients With Renal Osteodystrophy And This May Require Increasing The Dose Of Phosphate Binding Agents.
Normalization Of Plasma PTH Levels Frequently Correlates Well With Healing Of Osteitis Fibrosa, But Radiographic Improvement Can Occur Without Significant Changes In Plasma PTH Concentrations. After 3to 6months Of Treatment, Radiological Evidence Of Healing Is Generally Apparent. Histological Responses, Such As A Decrease In The Surface Of Bone Undergoing Resorption And A Decrease In The Volume Of Osteoid, Are Often Much Slower.
The Beneficial Effect Of Alfacalcidol On The Development Of Renal Bone Disease In Patients With Renal Failure Not Yet Undergoing Dialysis Has Been Demonstrated In A Large, Randomized, Placebo Controlled Study. Long-term Administration Of Oral Alfacalcidol (maximum Dose Of 1µg/day For Up To 2years) 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 (>3mmol/L) Was Uncommon (4.5% Of Patients) And Readily Responded To Decreases In Drug Dosage.
Contraindications
Known hypersensitivity to 1a-hydroxyvitaminD 3, vitaminD or any of its analogues and derivatives. Biochemical evidence of hypercalcemia, hyperphosphatemia or of vitaminD overdose.
Known hypersensitivity to 1a-hydroxyvitaminD 3, vitaminD or any of its analogues and derivatives. Biochemical evidence of hypercalcemia, hyperphosphatemia or of vitaminD overdose.
Safety Information / Warning
Alfacalcidol is a potent cholecalciferol derivative with a profound positive effect on intestinal absorption of dietary calcium. The effect of alfacalcidol on inorganic phosphorus absorption is less marked, although it is important to recognize that the drug may increase plasma phosphorus concentrations, which may increase the requirements for phosphate binding agents.
Alfacalcidol should not be used concomitantly with other vitaminD products or derivatives.
As with all vitaminD preparations and metabolites, hypercalcemia must be anticipated when using alfacalcidol. Regular monitoring of plasma calcium is essential. Indeed, alfacalcidol should only be used when adequate facilities are available for monitoring of blood and urine chemistries on a regular basis.
During treatment with alfacalcidol, progressive hypercalcemia either due to hyperresponsiveness or overdose may become so severe as to require emergency treatment.
Chronic hypercalcemia can lead to generalized vascular calcification, nephrocalcinosis or calcifications of the cornea or other soft tissues. During treatment with alfacalcidol, the total serum calcium (mg/dL) times serum inorganic phosphate (mg/dL) product (Ca´P) should be maintained at accepted levels. A dialysate calcium level of 1.75mmol/L or above, in addition to excess dietary calcium supplements may lead to frequent episodes of hypercalcemia.
To control serum inorganic phosphate levels and dietary phosphate absorption, appropriate oral phosphate binding agents in association with a low phosphate diet may be necessary to prevent hyperphosphatemia and extra-skeletal calcifications. Serum phosphate levels were maintained below 2mmol/L in the study that demonstrated the benefits of daily oral alfacalcidol on the development of bone disease in pre-dialysis patients.
Antacids containing magnesium should be avoided as they may contribute towards hypermagnesemia.
In patients on digitalis, hypercalcemia may precipitate cardiac arrhythmias. In such patients alfacalcidol should be used with extreme caution.
Pregnancy: The safety of alfacalcidol in women who are or may become pregnant has not been established; use of the alfacalcidol in these cases may be considered only when the potential benefits have been weighed against possible hazards to mother and fetus.
Lactation: Alfacalcidol may be excreted in human milk, therefore, breast-feeding during treatment should be avoided.
Alfacalcidol is a potent cholecalciferol derivative with a profound positive effect on intestinal absorption of dietary calcium. The effect of alfacalcidol on inorganic phosphorus absorption is less marked, although it is important to recognize that the drug may increase plasma phosphorus concentrations, which may increase the requirements for phosphate binding agents.
Alfacalcidol should not be used concomitantly with other vitaminD products or derivatives.
As with all vitaminD preparations and metabolites, hypercalcemia must be anticipated when using alfacalcidol. Regular monitoring of plasma calcium is essential. Indeed, alfacalcidol should only be used when adequate facilities are available for monitoring of blood and urine chemistries on a regular basis.
During treatment with alfacalcidol, progressive hypercalcemia either due to hyperresponsiveness or overdose may become so severe as to require emergency treatment.
Chronic hypercalcemia can lead to generalized vascular calcification, nephrocalcinosis or calcifications of the cornea or other soft tissues. During treatment with alfacalcidol, the total serum calcium (mg/dL) times serum inorganic phosphate (mg/dL) product (Ca´P) should be maintained at accepted levels. A dialysate calcium level of 1.75mmol/L or above, in addition to excess dietary calcium supplements may lead to frequent episodes of hypercalcemia.
To control serum inorganic phosphate levels and dietary phosphate absorption, appropriate oral phosphate binding agents in association with a low phosphate diet may be necessary to prevent hyperphosphatemia and extra-skeletal calcifications. Serum phosphate levels were maintained below 2mmol/L in the study that demonstrated the benefits of daily oral alfacalcidol on the development of bone disease in pre-dialysis patients.
Antacids containing magnesium should be avoided as they may contribute towards hypermagnesemia.
In patients on digitalis, hypercalcemia may precipitate cardiac arrhythmias. In such patients alfacalcidol should be used with extreme caution.
Pregnancy: The safety of alfacalcidol in women who are or may become pregnant has not been established; use of the alfacalcidol in these cases may be considered only when the potential benefits have been weighed against possible hazards to mother and fetus.
Lactation: Alfacalcidol may be excreted in human milk, therefore, breast-feeding during treatment should be avoided.
Precautions
Patient Selection and Follow-up: The therapeutic margin with alfacalcidol is narrow; the optimal daily dose must be carefully titrated for each individual patient (see Dosage).
The occurrence of hypercalcemia depends on such factors as the degree of bone mineralization, the state of renal function and the dose of alfacalcidol. Excessive doses of the drug induce hypercalcemia and hypercalciuria.
Pre-Dialysis Administration of Alfacalcidol: Serum calcium and phosphate levels should be monitored at monthly intervals or as is considered necessary if hypercalcemia develops.
If hypercalcemia develops at any time during treatment then the dose of alfacalcidol should be reduced by 50% and all calcium supplements stopped until calcium levels return to normal.
Administration of Alfacalcidol to Patients Undergoing Dialysis: Plasma calcium should be measured at weekly intervals depending on the progress of the patient. In early treatment during dosage adjustment, serum calcium should be determined at least twice weekly. In the later stages of treatment when there is evidence of bone healing (e.g., when the plasma alkaline phosphatase level falls toward normal), weekly estimations are recommended.
If hypercalcemia occurs, alfacalcidol should be discontinued immediately. Upon discontinuation of the drug, serum calcium levels generally normalize within a few days to a week. Calcium levels should be rechecked in another week and if still at normal levels, alfacalcidol may be reinstituted at half the previous dose.
Patients with renal bone disease and a relatively high initial plasma calcium and “autonomous” hyperparathyroidism are liable to early hypercalcemia, as are the minority of dialysis patients with low plasma alkaline phosphatase.
Essential Laboratory Tests: Laboratory tests considered essential for adequate patient monitoring include: serum calcium, inorganic phosphorus, magnesium, alkaline phosphatase, creatinine, BUN and protein (for correction of plasma calcium in instances of hypercalcemia). For pre-dialysis patients treated with alfacalcidol, serum calcium and phosphate levels should be monitored at monthly intervals or as is considered necessary if hypercalcemia develops. For patients undergoing dialysis serum calcium should be determined at least twice weekly during dose titration. During maintenance therapy with alfacalcidol, 24-hour urinary calcium and phosphorus should be determined periodically.
Periodic ophthalmological examinations and radiological evaluation of suspected anatomical regions for early detection of ectopic calcifications are advisable.
Drug Interactions : Alfacalcidol should be used with extreme caution in patients on digitalis, as hypercalcemia may trigger cardiac arrhythmias.
Resins such as cholestyramine and mineral oil used as a laxative may interfere with the intestinal absorption of alfacalcidol.
Patients concurrently treated with barbiturates and other anticonvulsant drugs may require higher doses of alfacalcidol, as these drugs may interefere with the action of vitaminD.
Information to Be Provided to the Patient: Patients and their immediate relatives should be informed about the need for compliance with the dosage instructions, strict adherence to prescribed calcium intake (dietary and supplementary) and avoidance of unapproved non-prescription drugs or medications.
Patients should be made aware of symptoms of hypercalcemia and should be instructed to seek medical attention if such symptoms appear.
Children: The safety and efficacy of alfacalcidol in children have not been established.
Patient Selection and Follow-up: The therapeutic margin with alfacalcidol is narrow; the optimal daily dose must be carefully titrated for each individual patient (see Dosage).
The occurrence of hypercalcemia depends on such factors as the degree of bone mineralization, the state of renal function and the dose of alfacalcidol. Excessive doses of the drug induce hypercalcemia and hypercalciuria.
Pre-Dialysis Administration of Alfacalcidol: Serum calcium and phosphate levels should be monitored at monthly intervals or as is considered necessary if hypercalcemia develops.
If hypercalcemia develops at any time during treatment then the dose of alfacalcidol should be reduced by 50% and all calcium supplements stopped until calcium levels return to normal.
Administration of Alfacalcidol to Patients Undergoing Dialysis: Plasma calcium should be measured at weekly intervals depending on the progress of the patient. In early treatment during dosage adjustment, serum calcium should be determined at least twice weekly. In the later stages of treatment when there is evidence of bone healing (e.g., when the plasma alkaline phosphatase level falls toward normal), weekly estimations are recommended.
If hypercalcemia occurs, alfacalcidol should be discontinued immediately. Upon discontinuation of the drug, serum calcium levels generally normalize within a few days to a week. Calcium levels should be rechecked in another week and if still at normal levels, alfacalcidol may be reinstituted at half the previous dose.
Patients with renal bone disease and a relatively high initial plasma calcium and “autonomous” hyperparathyroidism are liable to early hypercalcemia, as are the minority of dialysis patients with low plasma alkaline phosphatase.
Essential Laboratory Tests: Laboratory tests considered essential for adequate patient monitoring include: serum calcium, inorganic phosphorus, magnesium, alkaline phosphatase, creatinine, BUN and protein (for correction of plasma calcium in instances of hypercalcemia). For pre-dialysis patients treated with alfacalcidol, serum calcium and phosphate levels should be monitored at monthly intervals or as is considered necessary if hypercalcemia develops. For patients undergoing dialysis serum calcium should be determined at least twice weekly during dose titration. During maintenance therapy with alfacalcidol, 24-hour urinary calcium and phosphorus should be determined periodically.
Periodic ophthalmological examinations and radiological evaluation of suspected anatomical regions for early detection of ectopic calcifications are advisable.
Drug Interactions : Alfacalcidol should be used with extreme caution in patients on digitalis, as hypercalcemia may trigger cardiac arrhythmias.
Resins such as cholestyramine and mineral oil used as a laxative may interfere with the intestinal absorption of alfacalcidol.
Patients concurrently treated with barbiturates and other anticonvulsant drugs may require higher doses of alfacalcidol, as these drugs may interefere with the action of vitaminD.
Information to Be Provided to the Patient: Patients and their immediate relatives should be informed about the need for compliance with the dosage instructions, strict adherence to prescribed calcium intake (dietary and supplementary) and avoidance of unapproved non-prescription drugs or medications.
Patients should be made aware of symptoms of hypercalcemia and should be instructed to seek medical attention if such symptoms appear.
Children: The safety and efficacy of alfacalcidol in children have not been established.
Side Effects / Adverse Effects
In general, the adverse effects of alfacalcidol are similar to those encountered with excessive vitaminD intake.
The early and late signs and symptoms associated with vitaminD intoxication and hypercalcemia may include: a)Early: pruritus, weakness, headache, “red-eyes”, somnolence, nausea, cardiac arrhythmia, vomiting, excessive thirst, dry mouth, constipation, muscle pain, bone pain and metallic taste. b)Late: polyuria, polydipsia, anorexia, weight loss, nocturia, conjunctivitis, corneal calcification, photophobia, rhinorrhea, pancreatitis, pruritus, hyperthermia, decreased libido, elevated BUN, albuminuria, hypercholesterolemia, elevated AST and ALT, ectopic calcification, hypertension, cardiac arrhythmias and, rarely, overt psychosis.
Hypercalcemia and possibly an exacerbation of hyperphosphatemia are the most frequent adverse reactions that have been reported with alfacalcidol in patients with renal osteodystrophy. Elevated levels of calcium and phosphorus increase the risk of metastatic calcification and may accelerate the decline in renal function in some patients with chronic renal failure.
In general, the adverse effects of alfacalcidol are similar to those encountered with excessive vitaminD intake.
The early and late signs and symptoms associated with vitaminD intoxication and hypercalcemia may include: a)Early: pruritus, weakness, headache, “red-eyes”, somnolence, nausea, cardiac arrhythmia, vomiting, excessive thirst, dry mouth, constipation, muscle pain, bone pain and metallic taste. b)Late: polyuria, polydipsia, anorexia, weight loss, nocturia, conjunctivitis, corneal calcification, photophobia, rhinorrhea, pancreatitis, pruritus, hyperthermia, decreased libido, elevated BUN, albuminuria, hypercholesterolemia, elevated AST and ALT, ectopic calcification, hypertension, cardiac arrhythmias and, rarely, overt psychosis.
Hypercalcemia and possibly an exacerbation of hyperphosphatemia are the most frequent adverse reactions that have been reported with alfacalcidol in patients with renal osteodystrophy. Elevated levels of calcium and phosphorus increase the risk of metastatic calcification and may accelerate the decline in renal function in some patients with chronic renal failure.
Overdose
Symptoms and Treatment: Dosages of alfacalcidol in excess of daily requirements can cause hypercalcemia, hypercalciuria and hyperphosphatemia. Conversely, a high intake of calcium and phosphate concomitantly with therapeutic doses of alfacalcidol may cause similar abnormalities.
Treatment of Hypercalcemia Due to Overdose: General treatment of serum calcium levles more than 1mg/dL or 0.25mmol/L above the upper limit of the normal range (usually 8.0to 10.4mg/dL or 2.2to 2.6mmol/L)) consists of immediate discontinuation of alfacalcidol, institution of a low calcium diet and withdrawal of calcium supplements. Serum calcium levels should be determined daily until the patient achieves normocalcemia. Hypercalcemia frequently resolves in 2to 7days. Alfacalcidol therapy can be reinstituted at half the previous dose when serum calcium levels have returned to within normal limits. Serum calcium levels should be carefully monitored (at least twice weekly) during this period of dosage adjustment and subsequent dosage titration. Persistent or markedly elevated serum calcium levels in hemodialysis patients may be corrected by dialysis against a calcium free dialysate.
Treatment of Accidental Overdosage: General supportive measures. If drug ingestion is discovered within a relatively short time, induction of emesis or gastric lavage may be of benefit in preventing further absorption. If the drug has passed through the stomach, the administration of mineral oil may promote its fecal elimination. Serial serum electrolyte determinations (especially calcium ion), rate of urinary calcium excretion and assessment of electrocardiographic abnormalities due to hypercalcemia should be obtained. Such monitoring is critical in patients receiving digitalis. Discontinuation of supplemental calcium and low calcium diet are also indicated in accidental overdosage. Due to the relatively short pharmacological action of alfacalcidol, further measures are probably unnecessary. However, if persistent and markedly elevated serum calcium levels occur, there are a variety of therapeutic alternatives which may be considered depending on the underlying condition of the patient. These include the use of drugs such as phosphates and corticosteroids as well as measures to induce an appropriate forced diuresis. The use of dialysis against a calcium free dialysate has also been reported.
Symptoms and Treatment: Dosages of alfacalcidol in excess of daily requirements can cause hypercalcemia, hypercalciuria and hyperphosphatemia. Conversely, a high intake of calcium and phosphate concomitantly with therapeutic doses of alfacalcidol may cause similar abnormalities.
Treatment of Hypercalcemia Due to Overdose: General treatment of serum calcium levles more than 1mg/dL or 0.25mmol/L above the upper limit of the normal range (usually 8.0to 10.4mg/dL or 2.2to 2.6mmol/L)) consists of immediate discontinuation of alfacalcidol, institution of a low calcium diet and withdrawal of calcium supplements. Serum calcium levels should be determined daily until the patient achieves normocalcemia. Hypercalcemia frequently resolves in 2to 7days. Alfacalcidol therapy can be reinstituted at half the previous dose when serum calcium levels have returned to within normal limits. Serum calcium levels should be carefully monitored (at least twice weekly) during this period of dosage adjustment and subsequent dosage titration. Persistent or markedly elevated serum calcium levels in hemodialysis patients may be corrected by dialysis against a calcium free dialysate.
Treatment of Accidental Overdosage: General supportive measures. If drug ingestion is discovered within a relatively short time, induction of emesis or gastric lavage may be of benefit in preventing further absorption. If the drug has passed through the stomach, the administration of mineral oil may promote its fecal elimination. Serial serum electrolyte determinations (especially calcium ion), rate of urinary calcium excretion and assessment of electrocardiographic abnormalities due to hypercalcemia should be obtained. Such monitoring is critical in patients receiving digitalis. Discontinuation of supplemental calcium and low calcium diet are also indicated in accidental overdosage. Due to the relatively short pharmacological action of alfacalcidol, further measures are probably unnecessary. However, if persistent and markedly elevated serum calcium levels occur, there are a variety of therapeutic alternatives which may be considered depending on the underlying condition of the patient. These include the use of drugs such as phosphates and corticosteroids as well as measures to induce an appropriate forced diuresis. The use of dialysis against a calcium free dialysate has also been reported.
Recommended Dosage
The daily dose must be carefully individualized and titrated according to such factors as the state of renal function, degree of bone mineralization and initial plasma calcium and alkaline phosphatase concentrations. Other factors which may be taken into account are urinary calcium excretion, plasma PTH and phosphorus.
The success of alfacalcidol is also based on the assumption that the patient is receiving an adequate daily intake of calcium during treatment. The recommended daily allowance of calcium in adults is about 800to 1000mg (from all sources such as dialysate, diet and calcium supplements). The physician should ensure that each patient receives an adequate daily intake of calcium by prescribing a calcium supplement or instructing the patients in appropriate dietary measures.
Dose Titration: Pre-Dialysis Patients on Daily Oral Therapy: A dose of alfacalcidol that maintains serum calcium (adjusted for albumin concentration) within the normal range should be selected. An initial dose of 0.25µg/day is recommended, followed by dose adjustment until an appropriate dose is achieved. Alfacalcidol has been shown to be safe and effective in the prevention of renal bone disease when doses were maintained at or below 1µg/day. Alfacalcidol is usually administered as a single dose each day taken with food.
The following protocol for dosage adjustment is suggested: An initial dose of 0.25µg/day should be administered for 2months, unless hypercalcemia develops. If hypercalcemia occurs then the dose should be reduced to 0.25µg on alternate days. If serum calcium is below the desired range, the dose may be adjusted in increments of 0.25µg/day every 2months. Most patients will be maintained on a dose of 0.5µg/day. However, doses up to 1µg/day may be necessary to maintain serum calcium within the desired range. If hypercalcemia develops at any time during treatment then the dose of alfacalcidol should be reduced by 50% and all calcium supplements stopped until calcium levels return to normal.
Serum calcium and phosphate levels should be monitored at monthly intervals or as is considered necessary if hypercalcemia develops. Calcium supplements should not exceed 500mg of elemental calcium per day.
Dose Titration: Dialysis Patients on Daily Oral Therapy: The recommended initial dose is 1µg daily. If a satisfactory response in the biochemical parameters and clinical manifestations is not observed within 4weeks, the daily dose may be increased by 0.5µg every 2to 4weeks. Most patients respond eventually to a dose of between 1and 2µg/day. Exceptionally, a dose of3µg is required. During this titration period, serum calcium levels should be obtained at least twice weekly and, if hypercalcemia is noted, the drug should be discontinued immediately until serum calcium levels normalize
Maintenance Doses: Dialysis Patients on Daily Oral Therapy: Once serum calcium levels are normalized or only slightly reduced, the dose requirement of alfacalcidol generally decreases. Maintenance doses usually range from 0.25to 1.0µg/day. If this small maintenance dose still proves too high, adequate control can usually be achieved by giving the dose on alternate days or even less frequently.
Dose Titration: Dialysis Patients on Intermittent I.V. Therapy: A dose of alfacalcidol that maintains total serum calcium in the upper half of the normal range should be selected. Calcium levels should be measured weekly during the dose titration period. The recommended initial dose of alfacalcidol is 1µg per dialysis (2to 3 times a weekly). If a satisfactory response in biochemical parameters is not observed within 1week, the dose may be increased in weekly increments of 1µg per dialysis to a maximum of 12µg/week. The total dose titration period should not exceed 6weeks. If hypercalcemia is noted, the drug should be discontinued immediately until serum calcium levels normalize. Once calcium levels return to the normal range, alfacalcidol should be reintroduced at lower doses.
Maintenance Doses: Dialysis Patients on Intermittent I.V. Therapy: Doses required to maintain serum calcium levels in the upper half of the normal range are usually around 6µg/week but can range from 1.5 to 12µg/week. Serum calcium and phosphate levels should be monitored every other week or as is considered necessary if hypercalcemia is noted. If hypercalcemia develops, adequate control can usually be achieved by temporarily stopping treatment. Once calcium levels normalize, alfacalcidol should be reintroduced at lower doses.
Information for the Patient: See Blue Section--Information for the Patient “One-Alpha”.
The daily dose must be carefully individualized and titrated according to such factors as the state of renal function, degree of bone mineralization and initial plasma calcium and alkaline phosphatase concentrations. Other factors which may be taken into account are urinary calcium excretion, plasma PTH and phosphorus.
The success of alfacalcidol is also based on the assumption that the patient is receiving an adequate daily intake of calcium during treatment. The recommended daily allowance of calcium in adults is about 800to 1000mg (from all sources such as dialysate, diet and calcium supplements). The physician should ensure that each patient receives an adequate daily intake of calcium by prescribing a calcium supplement or instructing the patients in appropriate dietary measures.
Dose Titration: Pre-Dialysis Patients on Daily Oral Therapy: A dose of alfacalcidol that maintains serum calcium (adjusted for albumin concentration) within the normal range should be selected. An initial dose of 0.25µg/day is recommended, followed by dose adjustment until an appropriate dose is achieved. Alfacalcidol has been shown to be safe and effective in the prevention of renal bone disease when doses were maintained at or below 1µg/day. Alfacalcidol is usually administered as a single dose each day taken with food.
The following protocol for dosage adjustment is suggested: An initial dose of 0.25µg/day should be administered for 2months, unless hypercalcemia develops. If hypercalcemia occurs then the dose should be reduced to 0.25µg on alternate days. If serum calcium is below the desired range, the dose may be adjusted in increments of 0.25µg/day every 2months. Most patients will be maintained on a dose of 0.5µg/day. However, doses up to 1µg/day may be necessary to maintain serum calcium within the desired range. If hypercalcemia develops at any time during treatment then the dose of alfacalcidol should be reduced by 50% and all calcium supplements stopped until calcium levels return to normal.
Serum calcium and phosphate levels should be monitored at monthly intervals or as is considered necessary if hypercalcemia develops. Calcium supplements should not exceed 500mg of elemental calcium per day.
Dose Titration: Dialysis Patients on Daily Oral Therapy: The recommended initial dose is 1µg daily. If a satisfactory response in the biochemical parameters and clinical manifestations is not observed within 4weeks, the daily dose may be increased by 0.5µg every 2to 4weeks. Most patients respond eventually to a dose of between 1and 2µg/day. Exceptionally, a dose of3µg is required. During this titration period, serum calcium levels should be obtained at least twice weekly and, if hypercalcemia is noted, the drug should be discontinued immediately until serum calcium levels normalize
Maintenance Doses: Dialysis Patients on Daily Oral Therapy: Once serum calcium levels are normalized or only slightly reduced, the dose requirement of alfacalcidol generally decreases. Maintenance doses usually range from 0.25to 1.0µg/day. If this small maintenance dose still proves too high, adequate control can usually be achieved by giving the dose on alternate days or even less frequently.
Dose Titration: Dialysis Patients on Intermittent I.V. Therapy: A dose of alfacalcidol that maintains total serum calcium in the upper half of the normal range should be selected. Calcium levels should be measured weekly during the dose titration period. The recommended initial dose of alfacalcidol is 1µg per dialysis (2to 3 times a weekly). If a satisfactory response in biochemical parameters is not observed within 1week, the dose may be increased in weekly increments of 1µg per dialysis to a maximum of 12µg/week. The total dose titration period should not exceed 6weeks. If hypercalcemia is noted, the drug should be discontinued immediately until serum calcium levels normalize. Once calcium levels return to the normal range, alfacalcidol should be reintroduced at lower doses.
Maintenance Doses: Dialysis Patients on Intermittent I.V. Therapy: Doses required to maintain serum calcium levels in the upper half of the normal range are usually around 6µg/week but can range from 1.5 to 12µg/week. Serum calcium and phosphate levels should be monitored every other week or as is considered necessary if hypercalcemia is noted. If hypercalcemia develops, adequate control can usually be achieved by temporarily stopping treatment. Once calcium levels normalize, alfacalcidol should be reintroduced at lower doses.
Information for the Patient: See Blue Section--Information for the Patient “One-Alpha”.
Supplied / Packaging
Capsules: 0.25µg: Each white capsule contains: alfacalcidol 0.25µg. Nonmedicinal ingredients: sesame oil and a-tocopherol; in the shell: gelatin, glycerol (85%), potassium sorbate and titanium dioxide. Tropical blisters of 100. Protect from direct sunlight. Store at 15 to 25°C.
1µg: Each dark brown capsule contains: alfacalcidol 1µg. Nonmedicinal ingredients: sesame oil and a-tocopherol; in the shell: gelatin, glycerol (85%), potassium sorbate, red iron oxide E172 and black iron oxide E172. Tropical blisters of 100. Protect from direct sunlight. Store at 15 to 25°C.
Drops: EachmL of clear or slightly opalescent colorless solution contains: alfacalcidol 2µg. Nonmedicinal ingredients: citric acid monohydrate, ethanol, methyl parahydroxybenzoate, polyoxyl 40 hydrogenated castor oil, purified water, sodium citrate, sorbitol and a-tocopherol. Amber glass bottles of 10or 20mL fitted with a polyethylene dropping device. Protect from direct sunlight. Store in a cold place 2to 8°C. Drop size: 1drop equals 0.1µg alfacalcidol.
Injection: Each mL of i.v. injection contains: alfacalcidol 2µg. Nonmedicinal ingredients: citric acid monohydrate, ethanol, propylene glycol, sodium citrate and water. Amber glass ampuls containing unit doses of 1µg/0.5mL or 2µg/1 mL, cartons of 10. Single use ampuls-discard unused portion. Protect from direct sunlight. Keep refrigerated (2to 8°C). Protect from freezing.
Capsules: 0.25µg: Each white capsule contains: alfacalcidol 0.25µg. Nonmedicinal ingredients: sesame oil and a-tocopherol; in the shell: gelatin, glycerol (85%), potassium sorbate and titanium dioxide. Tropical blisters of 100. Protect from direct sunlight. Store at 15 to 25°C.
1µg: Each dark brown capsule contains: alfacalcidol 1µg. Nonmedicinal ingredients: sesame oil and a-tocopherol; in the shell: gelatin, glycerol (85%), potassium sorbate, red iron oxide E172 and black iron oxide E172. Tropical blisters of 100. Protect from direct sunlight. Store at 15 to 25°C.
Drops: EachmL of clear or slightly opalescent colorless solution contains: alfacalcidol 2µg. Nonmedicinal ingredients: citric acid monohydrate, ethanol, methyl parahydroxybenzoate, polyoxyl 40 hydrogenated castor oil, purified water, sodium citrate, sorbitol and a-tocopherol. Amber glass bottles of 10or 20mL fitted with a polyethylene dropping device. Protect from direct sunlight. Store in a cold place 2to 8°C. Drop size: 1drop equals 0.1µg alfacalcidol.
Injection: Each mL of i.v. injection contains: alfacalcidol 2µg. Nonmedicinal ingredients: citric acid monohydrate, ethanol, propylene glycol, sodium citrate and water. Amber glass ampuls containing unit doses of 1µg/0.5mL or 2µg/1 mL, cartons of 10. Single use ampuls-discard unused portion. Protect from direct sunlight. Keep refrigerated (2to 8°C). Protect from freezing.
