Vitamin D3 Metabolite
Action And Clinical Pharmacology: 1a-hydroxyvitamin D3(1a-OHD3) 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 vitamin D deficiency, vitamin D must undergo two metabolic conversions, first in the liver to 25-hydroxyvitamin D and then in the kidney to the physiologically active metabolite, 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3). In patients with chronic renal failure, progressive nephron destruction blocks the production of 1,25-(OH)2D3 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)2D3 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 3 hours in the presence of renal insufficiency. However, serum levels of 1,25-(OH)2D3 peak approximately 12 hours after a single dose of alfacalcidol and remain measurable for at least 48 hours. The effect of 1 Âµg of alfacalcidol on intestinal calcium absorption has been observed within 6 hours of ingestion and was maximal at 24 hours.
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 of 1,25-(OH)2D3. Because calcium metabolism and production of 1,25-(OH)2D3 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 2 weeks to 3 months of the start of therapy. Malabsorption of calcium is rapidly corrected. Plasma alkaline phosphatase and PTH levels generally begin to fall within 3 months, 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.
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 3 to 6 months 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 alfacalcidol (maximum dose of 1 g/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 mmol/L) was uncommon (4.5% of patients) and readily responded to decreases in drug dosage.
Indications And Clinical Uses: Management of hypocalcemia and osteodystrophy in patients with chronic renal failure.
Contra-Indications: Known hypersensitivity to 1a-hydroxyvitamin D3, vitamin D or any of its analogues and derivatives. Evidence of hypercalcemia, hyperphosphatemia or of vitamin D overdose.
Manufacturers’ Warnings In Clinical States: 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 vitamin D products or derivatives.
As with all vitamin D 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 7.0 mg/dL (1.75 mmol/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 2 mmol/L in the study that demonstrated the benefits of 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. Use alfacalcidol with extreme caution in these patients.
Pregnancy and Lactation: Safety in pregnancy has not been established; use of alfacalcidol in pregnancy may be considered only when the potential benefits have been weighed against possible hazards to mother and fetus. Alfacalcidol may be excreted in human milk, therefore, breast-feeding during treatment should be avoided.
Precautions: 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. 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.
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 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 vitamin D.
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 nonprescription drugs or medications.
Patients should be made aware of symptoms of hypercalcemia and should be instructed to seek medical attention if such symptoms appear (see Adverse Effects).
Children: The safety and efficacy of alfacalcidol in children have not been established.
Adverse Reactions: In general, the adverse effects of alfacalcidol are similar to those encountered with excessive vitamin D intake. a) Early symptoms: Pruritus, weakness, headache, “red-eyes”, somnolence, nausea, cardiac arrhythmia, vomiting, excessive thirst, dry mouth, constipation, muscle pain, bone pain and metallic taste. b) Late symptoms: 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.
Symptoms And Treatment Of Overdose: Symptoms and Treatment: Hypercalcemia, hypercalciuria and hyperphosphatemia. 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 hypercalcemia (more than 1 mg/dL or 0.25 mmol/L above the upper limit of the normal range (usually 8.0-10.4 mg/dL or 2.2-2.6 mmol/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 2 to 7 days. When serum calcium levels have returned to within normal limits, alfacalcidol therapy can be reinstituted at half the previous dose. 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 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.
Dosage And Administration: 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 800 to 1 000 mg (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: A dose of alfacalcidol that maintains serum calcium (adjusted for albumin concentration) within the normal range should be selected. An initial dose of 0.25 g/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 1 g/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 0.25 g/day should be administered for 2 months, unless hypercalcemia develops. If hypercalcemia occurs then the dose should be reduced to 0.25 g on alternate days. If serum calcium is below the desired range, the dose may be adjusted in increments of 0.25 g/day every 2 months. Most patients will be maintained on a dose of 0.5 g/day. However, doses up to 1 g/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 500 mg of elemental calcium per day.
Dose Titration for Hemodialysis Patients: The recommended initial dose is 1 g daily. If a satisfactory response in the biochemical parameters and clinical manifestations is not observed within 4 weeks, the daily dose may be increased by 0.5 g every 2 to 4 weeks. Most patients respond eventually to a dose of between 1 and 2 g/day. Exceptionally, a dose of 3 g is required.
Maintenance Therapy: Once serum calcium levels are normalized or only slightly reduced, the dose requirement of alfacalcidol generally decreases. Maintenance doses usually range from 0.25 to 1.0 g/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.
Availability And Storage: Capsules: 0.25 g: Each white capsule contains: alfacalcidol 0.25 g. Nonmedicinal ingredients: sesame oil and a-tocopherol; in the shell: gelatin, glycerol (85%), potassium sorbate and titanium dioxide. Amber bottles of 100. Protect from direct sunlight.
1 g: Each dark brown capsule contains: alfacalcidol 1 g. Nonmedicinal ingredients: sesame oil and a-tocopherol; in the shell: gelatin, glycerol (85%), potassium sorbate, red iron oxide E172 and black iron oxide E172. Amber bottles of 100. Protect from direct sunlight.
Oral Solution: Each mL of solution contains: alfacalcidol 0.2 g. Nonmedicinal ingredients: citric acid monohydrate, ethanol, methyl parahydroxybenzoate, polyoxyl 40 hydrogenated castor oil, purified water, sodium citrate, sorbitol and a-tocopherol. Amber bottles of 60 mL. Protect from direct sunlight.
ONE-ALPHA® Leo Alfacalcidol Vitamin D3 Metabolite