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 paediatric patients in whom it may be incipient and thus overlooked. The mortality rate in paediatric patients has been high. Patients with lead encephalopathy and cerebral oedema 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.
Edetate calcium disodium
Calcium Disodium Versenate (edetate calcium disodium injection, USP) is a sterile, injectable, chelating agent in concentrated solution for intravenous infusion or intramuscular injection. Each 5 ml ampoule 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',ON,ON']-,disodium, hydrate, (OC-6-21)-Calciate(2-).
C10H10CaN2Na2O8 . xH2O Molecular weight 374.27 (anhydrous)
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 mobilised are not significant. Copper is not mobilised 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. Edetate calcium disodium is poorly absorbed from the gastrointestinal tract. In blood, all the active substance 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. Almost none of the compound is metabolised. 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. 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. (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.
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 paediatric populations and adults. Chelation therapy should not replace effective measures to eliminate or reduce further exposure to lead.
Edetate calcium disodium should not be given during periods of anuria, nor to patients with active renal disease or hepatitis.
See boxed warning. Edetate calcium disodium may produce the same renal damage as lead poisoning, such as proteinuria and microscopic haematuria. 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.
Patients should be instructed to immediately inform their physician if urine output stops for a period of 12 hours.
Since lead poisoning occurs in paediatric populations and adults but is frequently more severe in paediatric patients, Calcium Disodium Versenate is used in patients of all ages. The intramuscular route is preferred by some for young paediatric patients. In cases where the intravenous route is necessary, avoid rapid infusion (see Warnings). Urine flow must be monitored throughout therapy; Calcium Disodium Versenate therapy must be stopped if anuria or severe oliguria develops. (See Precautions) At no time should the recommended daily dosage be exceeded. (See Dosage and Administration)
Long term animal studies have not been conducted with edetate calcium disodium to evaluate its carcinogenic potential, mutagenic potential or its effect on fertility.
One reproduction study was performed in rats at doses up to 13 times the human dose and revealed no evidence of impaired fertility or harm to the foetus due to Calcium Disodium Versenate. Another reproduction study performed in rats at doses up to about 25 to 40 times the human dose revealed evidence of foetal malformations due to Calcium Disodium Versenate, which were prevented by simultaneous supplementation of dietary zinc. There are however, no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this medicine should be used during pregnancy only if clearly needed.
Calcium Disodium Versenate has no recognised use during labour and delivery, and its effects during these processes are unknown.
It is not known whether this medicine is secreted in human milk. Because many medicines are secreted in human milk, caution should be exercised when Calcium Disodium Versenate is administered to a nursing woman.
There is no known interference with standard clinical laboratory tests. Steroids enhance the renal toxicity of edetate calcium disodium in animals. Edetate calcium disodium interferes with the action of zinc insulin preparations by chelating the zinc.
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 mobilisation test can be considered. (See Diagnostic Test) An elevation of urinary coproporphyrin (adults: >250 mcg/day; paediatric patients under 36 Kg >75 mcg/day) and elevation of urinary delta aminolevulinic acid (ALA) (adults: >4 mg/day; paediatric patients: >3 mg/m2/day) are associated with blood lead levels >40 mcg/dl. Urinary coproporphyrin may be falsely negative in terminal patients and in severely iron-depleted paediatric patients who are not regenerating haeme. In growing paediatric patients long bone x-rays showing lead lines and abdominal x-rays showing radio-opaque material in the abdomen may be of help in estimating the level of exposure to lead.
The following adverse effects have been associated with the use of edetate calcium disodium:
Body as a Whole:
pain at intramuscular injection site, fever, chills, malaise, fatigue, myalgia, arthralgia.
Cardiovascular:
hypotension, cardiac rhythm irregularities.
Renal:
acute necrosis of proximal tubules (which may result in fatal nephrosis), infrequent changes in distal tubules and glomeruli.
Urinary:
glycosuria, proteinuria, microscopic hematuria and large epithelial cells in urinary sediment.
Nervous System:
tremors, headache, numbness, tingling.
Gastrointestinal: Hepatic:
cheilosis, nausea, vomiting, anorexia, excessive thirst.
mild increases in SGOT and SGPT are common, and return to normal within 48 hours after cessation of therapy.
Immunogenic:
histamine-like reactions (sneezing, nasal congestion, lacrimation), rash..
Hematopoietic:
transient bone marrow depression, anaemia.
Metabolic:
zinc deficiency, hypercalcemia.
When a source for the lead intoxication has been identified, the patient should be removed from the source, if possible. The recommended dose of Calcium Disodium Versenate for asymptomatic adults and paediatric patients whose blood lead level is <70 mcg/dl but >20 mcg/dl (World Health Organisation recommended upper allowable level) is 1000 mg/m2/day whether given intravenously or intramuscularly. (See Surface Area Nomogram)
Surface Area Nomogram
For adults with lead nephropathy, the following dosing regimen has been suggested: 500 mg/m2 every 24 hours for 5 days for patients with serum creatinine levels of 2-3 mg/dl, every 48 hours for 3 doses for patients with creatinine levels of 3-4 mg/dl, and once weekly for patients with creatinine levels above 4 mg/dl. These regimens may be repeated at one month intervals. Calcium Disodium Versenate, used alone, may aggravate symptoms in patients with very high blood lead levels. When the blood lead level is >70 mcg/dl or clinical symptoms consistent with lead poisoning are present, it is recommended that Calcium Disodium Versenate be used in conjunction with BAL (dimercaprol). Please consult published protocols and specialized references for dosage recommendations of combination therapy. Therapy of lead poisoning in adults and paediatric patients with Calcium Disodium Versenate is continued over a period of five days. Therapy is then interrupted for 2 to 4 days to allow redistribution of the lead and to prevent severe depletion of zinc and other essential metals. Two courses of treatment are usually employed; however, it depends on severity of the lead toxicity and the patient's tolerance of the medicine. Calcium Disodium Versenate is equally effective whether administered intravenously or intramuscularly. The intramuscular route is used for all patients with overt lead encephalopathy and this route is preferred by some for young paediatric patients. Acutely ill individuals may be dehydrated from vomiting. Since edetate calcium disodium is excreted almost exclusively in the urine, it is very important to establish urine flow with intravenous fluid administration before the first dose of the chelating agent is given; however, excessive fluid must be avoided in patients with encephalopathy. Once urine flow is established, further intravenous fluid is restricted to basal water and electrolyte requirements. Administration of Calcium Disodium Versenate should be stopped whenever there is cessation of urine flow in order to avoid unduly high tissue levels of the substance. Edetate calcium disodium must be used in reduced doses in patients with pre-existing mild renal disease.
Intravenous Administration:
Add the total daily dose of Calcium Disodium Versenate (1000 mg/m2/day) to 250-500 ml of 5% glucose or 0.9% sodium chloride injection. The total daily dose should be infused over a period of 8-12 hours. Calcium Disodium Versenate injection is incompatible with 10% glucose, 10% invert sugar in 0.9% sodium chloride, lactate Ringer's, Ringer's, one-sixth molar sodium lactate injections, and with injectable amphotericin B and hydralazine hydrochloride.
Intramuscular Administration:
The total daily dosage (1000 mg/m2/day) should be divided into equal doses spaced 8-12 hours apart. Lignocaine or procaine should be added to the Calcium Disodium Versenate injection to minimise pain at the injection site. The final lignocaine or procaine concentration of 5 mg/ml (0.5%) can be obtained as follows: 0.25 ml of 10% lignocaine solution per 5 ml (entire content of ampoule) concentrated Calcium Disodium Versenate; 1 ml of 1% lignocaine or procaine solution per ml of concentrated Calcium Disodium Versenate. When used alone, regardless of method of administration, Calcium Disodium Versenate should not be given at doses larger than those recommended.
Diagnostic Test:
Several methods have been described for lead mobilisation tests using edetate calcium disodium to assess body stores. These procedures have advantages and disadvantages that should be reviewed in current references. Edetate calcium disodium mobilisation tests should not be performed in symptomatic patients and in patients with blood lead levels above 55 mcg/dl for whom appropriate therapy is indicated. Parenteral medicines should be inspected visually for particulate matter and discolouration prior to administration, whenever solution and container permit.
Symptoms:
Inadvertent administration of 5 times the recommended dose, infused intravenously over a 24 hour period, to an asymptomatic 16 month old patient with a blood lead content of 56 mcg/dl did not cause any ill effects. Edetate calcium disodium can aggravate the symptoms of severe lead poisoning; therefore, most toxic effects (cerebral oedema, renal tubular necrosis) appear to be associated with lead poisoning. Because of cerebral oedema, a therapeutic dose may be lethal to an adult or a paediatric patient with lead encephalopathy. Higher dosage of edetate calcium disodium may produce a more severe zinc deficiency.
Treatment:
Cerebral oedema should be treated with repeated doses of mannitol. Steroids enhance the renal toxicity of edetate calcium disodium in animals and therefore, are no longer recommended. Zinc levels must be monitored. Good urinary output must be maintained because diuresis will enhance elimination. It is not known if edetate calcium disodium is dialysable.
Calcium Disodium Versenate injection, 5 ml ampoule containing 200 mg of edetate calcium disodium per ml (1 g per ampoule), in boxes containing 6 ampoules. Store at controlled room temperature 15deg-30degC.
Prescription Medicine
INova Pharmaceuticals (New Zealand) Limited C/o Simpson Grierson 88 Shortland Street Auckland Distributed by: Douglas Pharmaceuticals Limited, Auckland Telephone: (09) 835 0660 Facsimile: (09) 835 0685
16 July 2007