One Alpha: Indications, Dosage, Precautions, Adverse Effects
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One Alpha - Product Information

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

Vitamin D Analogue

Action and Clinical Pharmacology

1α-hydroxyvitamin D3(1α-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-dihydroxy vitamin D3 (1,25-(OH)2D3). In patients with chronic renal failure, progressive nephron destruction blocks the production of 1,25-(OH)2 D3 by the kidneys resulting in diminished serum levels of this metabolite.

When ONE-ALPHA (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 ONE-ALPHA is accomplished very rapidly, before any stimulation of the intestine or bone occurs.

The biological half-life of ONE-ALPHA 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 oral ONE-ALPHA and approximately 4 hours after a single dose of intravenous ONE-ALPHA. Levels of 1,25(OH)2D3 remain measurable for at least 48 hours. The effect of 1 mcg of oral ONE-ALPHA on intestinal calcium absorption has been observed within 6 hours of ingestion and was maximal at 24 hours. There is evidence that vitamin D, its 1α-hydroxylated metabolites and analogues are extensively bound to a serum binding protein of the α -globulin fraction. 1,25-(OH)2D3 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 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 ONE-ALPHA therapy are those characterized by abnormally low plasma calcium levels, elevated alkaline phosphatase and PTH levels, and histological evidence of osteitis fibrosa and osteomalacia.

In the majority of patients treated with ONE-ALPHA, 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. In patients on daily oral therapy, 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. The decrease in PTH levels may be more rapid in patients on intermittent intravenous therapy, with significant reductions being achieved within 3 months 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, ONE-ALPHAmay 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 effects 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 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.

Indications and Clinical Use

Management of hypocalcemia, secondary hyperparathyroidism, and osteodystrophy in patients with chronic renal failure.

Contraindications

Known hypersensitivity to 1α-hydroxyvitamin D3, vitamin D or any of its analogues and derivatives.

ONE-ALPHA (alfacalcidol) is contraindicated when there is biochemical evidence of hypercalcemia, hyperphosphatemia, or evidence of vitamin D overdose.

Warnings

ONE-ALPHA (alfacalcidol) is a potent cholecalciferol derivative with a profound positive effect on intestinal absorption of dietary calcium. The effect of ONE-ALPHA 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.

ONE-ALPHA 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 ONE-ALPHA. Regular monitoring of plasma calcium is essential. Indeed, ONE-ALPHA should only be used when adequate facilities are available for monitoring of blood and urine chemistries on a regular basis.

During treatment with ONE-ALPHA, progressive hypercalcemia either due to hyper-responsiveness 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 ONE-ALPHA, the TOTAL SERUM CALCIUM (mg/dL) TIMES SERUM INORGANIC PHOSPHATE (mg/dL) PRODUCT (Ca x P) SHOULD BE MAINTAINED AT ACCEPTED LEVELS. A dialysate calcium level of 1.75 mmoles/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 2.0 mmol/L in the study that demonstrated the benefits of daily oral ONE-ALPHA 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 ONE-ALPHA should be used with extreme caution.

The safety of ONE-ALPHA in women who are or may become pregnant has not been established; use of ONE-ALPHA in these cases may be considered only when the potential benefits have been weighed against possible hazards to mother and fetus.

ONE-ALPHA may be excreted in human milk, therefore, breast feeding during treatment should be avoided.

Precautions

Patient Selection and Follow-up

The therapeutic margin with ONE-ALPHA (alfacalcidol) is narrow, therefore, the optimal daily dose must be carefully titrated for each individual patient (See DOSAGE AND ADMINISTRATION).

The occurrence of hypercalcemia depends on such factors as the degree of bone mineralization, the state of renal function and the dose of ONE-ALPHA. Excessive doses of the drug induce hypercalcemia and hypercalciuria.

Pre-Dialysis Administration of ONE-ALPHA

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 ONE-ALPHA 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, ONE-ALPHA 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 re-checked in another week and if still at normal levels, ONE-ALPHAmay be re-instituted 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 to 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 ONE-ALPHA, 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 ONE-ALPHA, 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

ONE-ALPHA 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 ONE-ALPHA.

Patients concurrently treated with barbiturates and other anticonvulsant drugs may require higher doses of ONE-ALPHA, as these drugs may interfere with the action of vitamin D.

Information for 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. (See ADVERSE REACTIONS).

Pediatric Use

The safety and efficacy of ONE-ALPHA in children has not been established.

Adverse Reactions

In general, the adverse effects of ONE-ALPHA (alfacalcidol) are similar to those encountered with excessive vitamin D intake.

The early and late signs and symptoms associated with vitamin D intoxication and hypercalcemia may include:

Early:Pruritus, weakness, headache, "red-eyes", somnolence, nausea, cardiac arrhythmia, vomiting, excessive thirst, dry mouth, constipation, muscle pain, bone pain and metallic taste.
Late:Polyuria, polydipsia, anorexia, weight loss, nocturia, conjunctivitis, corneal calcification, photophobia, rhinorrhea, pancreatitis, pruritus, hyperthermia, decreased libido, elevated BUN, albuminuria, hypercholesterolemia, elevated SGOT and SGPT, ectopic calcification, hypertension, cardiac arrhythmias and, rarely, overt psychosis.

Hypercalcemia and possibly an exacerbation of hyperphosphatemia are the more frequent adverse reactions that have been reported with ONE-ALPHA 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 Overdosage

Dosages of ONE-ALPHA (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 ONE-ALPHA may cause similar abnormalities.

Treatment of Hypercalcemia Due to Overdose

General treatment of serum calcium levels 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 ONE-ALPHA, 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. ONE-ALPHA therapy can be re-instituted 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

The treatment of acute accidental overdosage with ONE-ALPHA should consist of 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 ONE-ALPHA, 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 of ONE-ALPHA (alfacalcidol) 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 ONE-ALPHA 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 800-1000 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.

Pre-Dialysis Patients on Daily Oral Therapy

Dose Titration

A dose of ONE-ALPHA that maintains serum calcium (adjusted for albumin concentration) within the normal range should be selected. An initial dose of 0.25 mcg/day is recommended, followed by dose adjustment until an appropriate dose is achieved. ONE-ALPHA has been shown to be safe and effective in the prevention of renal bone disease when doses were maintained at or below 1 mcg/day. ONE-ALPHA 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 mcg/day should be administered for 2 months, unless hypercalcemia develops. If hypercalcemia occurs then the dose should be reduced to 0.25 mcg on alternate days. If serum calcium is below the desired range, the dose may be adjusted in increments of 0.25 mcg/day every 2 months. Most patients will be maintained on a dose of 0.5 mcg/day. However, doses up to 1 mcg/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.

Dialysis Patients on Daily Oral Therapy

Dose Titration

The recommended initial dose of ONE-ALPHA is 1 mcg 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 mcg every 2 to 4 weeks. Most patients respond eventually to a dose of between 1 and 2 mcg per day. Only exceptionally, a dose of 3 mcg 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

Once serum calcium levels are normalized or only slightly reduced, the dose requirement of ONE-ALPHA generally decreases. Maintenance doses usually range from 0.25 - 1.0 mcg per day. If this small maintenance dose still proves too high, adequate control can usually be achieved by giving the dose on alternative days or even less frequently.

Dialysis Patients on Intermittent Intravenous Therapy

Dose Titration

A dose of ONE-ALPHA 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 ONE-ALPHA is 1 mcg per dialysis (2-3 times weekly). If a satisfactory response in biochemical parameters is not observed within 1 week, the dose may be increased in weekly increments of 1 mcg per dialysis to a maximum of 12 mcg per week. The total dose titration period should not exceed 6 weeks. If hypercalcemia is noted, the drug should be discontinued immediately until serum calcium levels normalize. Once calcium levels return to the normal range, ONE-ALPHA should be re-introduced at lower doses.

Maintenance Doses

Doses required to maintain serum calcium levels in the upper half of the normal range are usually around 6 mcg per week but can range from 1.5 to 12 mcg per 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, ONE-ALPHA should be re-introduced at lower doses.