Package Insert for Calcium Disodium Versenate

(edetate calcium disodium injection, USP)

WARNINGS:
Calcium Disodium Versenate is capable of producing toxic effects which can be fatal. Lead encephalopathy is relatively rare in adults, but occurs more often in pediatric patients in whom it may be incipient and thus overlooked. The mortality rate in pediatric patients has been high. Patients with lead encephalopathy and cerebral edema may experience a lethal increase in intracranial pressure following, intravenous infusion; the intramuscular route is preferred for these patients. In cases where the intravenous route is necessary, avoid rapid infusion. The dosage schedule should be followed and at no time should the recommended daily dose be exceeded.

DESCRIPTION:
Calcium Disodium Versenate (edetate calcium disodium injection, USP) is a sterile, injectable, chelating agent in con-centrated solution for intravenous infusion or intramuscular injection. Each 5 ml ampul contains 1000 mg of edetate calcium disodium (equivalent to 200 mg/ml) in water for injection. Chemically, this product is called [[N,N'-1,2-ethanediyl-bis[ N-(carboxymethyl)-glycinato]](4-)-N, N',O,O',O N ,ON ']-,disodium,hydrate, (OC-6-21)- Calciate(2-).

CLINICAL PHARMACOLOGY:
The pharmacologic effects of edetate calcium disodium are due to the formation of chelates with divalent and trivalent metals. A stable chelate will form with any metal that has the ability to displace calcium from the molecule, a feature shared by lead, zinc, cadmium, manganese, iron and mercury. The amounts of manganese and iron mobilized are not significant. Copper [1] is not mobilized and mercury is unavailable for chelation because it is too tightly bound to body ligands or it is stored in inaccessible body compartments. The excretion of calcium by the body is not increased following intravenous administration of edetate calcium disodium, but the excretion of zinc is considerably increased [1] Edetate calcium disodium is poorly absorbed from the gastrointestinal tract. In blood, all the drug is found in the plasma. Edetate calcium disodium does not appear to penetrate cells; it is distributed primarily in the extracellular fluid with only about 5% of the plasma concentration found in spinal fluid. The half life of edetate calcium disodium is 20 to 60 minutes. It is excreted primarily by the kidney, with about 50% excreted in one hour and over 95% within 24 hours [2]. Almost none of the compound is metabolized. The primary source of lead chelated by Calcium Disodium Versenate is from bone; subsequently, soft-tissue lead is redistributed to bone when chelation is stopped [3,4]. There is also some reduction in kidney lead levels following chelation therapy. It has been shown in animals that following a single dose of Calcium Disodium Versenate urinary lead output increases, blood lead concentration decreases, but brain lead is significantly increased due to internal redistribution of lead [5]. (See WARNINGS.) These data are in agreement with the recent results of others in experimental animals showing that after a five day course of treatment there is no net reduction in brain lead [6].

INDICATIONS AND USAGE:
Edetate calcium disodium is indicated for the reduction of blood levels and depot stores of lead in lead poisoning (acute and chronic) and lead encephalopathy, in both pediatric populations and adults. Chelation therapy should not replace effective measures to eliminate or reduce further exposure to lead.

CONTRAINDICATIONS:
Edetate calcium disodium should not be given during periods of anuria, nor to patients with active renal disease or hepatitis.

WARNINGS:
See boxed warning.

PRECAUTIONS:
General Precautions: Edetate calcium disodium may produce the same renal damage as lead poisoning, such as proteinuria and microscopic hematuria. Treatment-induced nephrotoxicity is dose-dependent and may be reduced by assuring adequate diuresis before therapy begins. Urine flow must be monitored throughout therapy which must be stopped if anuria or severe oliguria develop. The proximal tubule hydropic degeneration usually recovers upon cessation of therapy. Edetate calcium disodium must be used in reduced doses in patients with pre-existing mild renal disease. Patients should be monitored for cardiac rhythm irregularities and other ECG changes during intravenous therapy.
Information for patients: Patients should be instructed to immediately inform their physician if urine output stops for a period of 12 hours.
Laboratory tests: Urinalysis and urine sediment, renal and hepatic function and serum electrolyte levels should be checked before each course of therapy and then be monitored daily during therapy in severe cases, and in less serious cases after the second and fifth day of therapy. Therapy must be discontinued at the first sign of renal toxicity. The presence of large renal epithelial cells or increasing number of red blood cells in urinary sediment or greater proteinuria call for immediate stopping of edetate calcium disodium administration. Alkaline phosphatase values are frequently depressed (possibly due to decreased serum zinc levels), but return to normal within 48 hours after cessation of therapy. Elevated erythrocyte protoporphyrin levels (>35 mcg/dl of whole blood) indicate the need to perform a venous blood lead determination. If the whole blood lead concentration is between 25-55 mcg/dl a mobilization test can be considered.7,8 (See Diagnostic Test.) An elevation of urinary coproporphyrin (adults: >250 mcg/day; pediatric patients under 80 lbs: >75 mcg/day) and elevation of urinary delta aminolevulinic acid (ALA) (adults: >4 mg/day; pediatric patients: >3 mg/ m 2 /day) are associated with blood lead levels >40 mcg/dl. Urinary coproporphyrin may be falsely negative in terminal patients and in severely iron-depleted pediatric patients who are not regenerating heme.9 In growing pediatric patients long bone x-rays showing lead lines and abdominal x-rays showing radioopaque material in the abdomen may be of help in estimating the level of exposure to lead.
Drug Interactions: There is no known drug interference with standard clinical laboratory tests. Steroids enhance the renal toxicity of edetate calcium disodium in animals.7 Edetate calcium disodium interferes with the action of zinc insulin preparations by chelating the zinc.7 Carcinogenesis, Mutagenesis, Impairment of Fertility: Long term animal studies have not been conducted with edetate calcium disodium to evaluate its carcinogenic potential, mutagenic potential or its effect on fertility.

This page was posted on August 25, 2004.

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