AHFS Class:

• Heavy Metal Antagonists 64:00

Generic Name(s):

• Edetate Calcium Disodium

Edetate calcium disodium (calcium EDTA) is a heavy metal antagonist that chelates lead.

Lead Poisoning

Parenterally administered edetate calcium disodium is used for the reduction of blood and mobile depot lead in the treatment of acute and chronic lead poisoning and lead encephalopathy. Edetate calcium disodium has been reported to be useful in poisonings caused by alkyl lead compounds (e.g., tetraethyl lead). Edetate calcium disodium administration should be accompanied by appropriate supportive measures. The drug is most effective when administered early in the course of acute poisoning. Edetate calcium disodium may also be used parenterally as an aid in the diagnosis of suspected lead poisoning (the edetate calcium disodium mobilization or provocation test). Some clinicians state that the edetate calcium disodium mobilization tests may be useful for predicting the likelihood of response to edetate calcium disodium therapy when screening tests indicate that lead toxicity is evident.100,101,103 However, the American Academy of Pediatrics (AAP) currently states that these tests are obsolete because of factors such as inconsistent prediction of the total body burden of lead, technical difficulties in administering the test, cost, lack of measurable end points of chelation therapy in children with relatively low-level exposure to lead, and the potential for increased lead toxicity associated with administration of edetate calcium disodium alone.111

Blood lead concentrations are the best index of the risks and severity of lead intoxication. Clinicians should consult specialized references for detailed information on the diagnosis and management of suspected or known lead intoxication and on the decision to employ chelation therapy.100,101,102,103,111 Although recent evidence indicates that some adverse effects (e.g., deficits in neurobehavioral development, biochemical disturbances, slowing of motor nerve conduction) are apparent at blood lead concentrations previously considered relatively nontoxic (i.e., 10 to less than 25 mcg/dL),104,105,106,112 confirmed blood lead concentrations of 25 mcg/dL or higher associated with blood erythrocyte protoporphyrin concentrations of 35 mcg/dL or higher generally are considered to indicate lead toxicity.103,106 Lead encephalopathy is usually associated with a blood lead concentration higher than 100 mcg/dL, although it has occurred at blood lead concentrations as low as 70 mcg/dL.101 Symptomatic lead poisoning without encephalopathy is usually associated with a blood lead concentration higher than 70 mcg/dL, although it occasionally may be associated with a blood lead concentration as low as 50 mcg/dL; however, all children with symptomatic lead poisoning should be considered to potentially have acute lead encephalopathy.101,111

Chelation therapy is indicated in the management of patients with acute lead encephalopathy or symptomatic lead poisoning.101,102,103,111 Chelation therapy also is indicated in patients with blood lead concentrations of 45 mcg/dL or more.101,103,111 The AAP states that if abdominal radiography performed prior to initiation of chelation therapy demonstrates evidence of enteral lead, bowel decontamination may be considered as an adjunct to chelation therapy.111 Some clinicians suggest that asymptomatic patients with blood lead concentrations of 25-44 mcg/dL and blood erythrocyte protoporphyrin concentrations of 35 mcg/dL or higher who have a positive edetate calcium disodium mobilization test should also generally receive chelation therapy;100,101,103 however, treatment regimens for patients with blood lead concentrations of 25-44 mcg/dL may vary from clinic to clinic, and treatment occasionally may be recommended for such patients even in the absence of a positive mobilization test.103 The AAP currently does not recommend use of edetate calcium disodium mobilization tests to determine the need for chelation therapy and states that chelation therapy should not be given routinely to patients with blood lead concentrations of 25-45 mcg/dL.111 However, the AAP states that if blood lead concentrations of 25-45 mcg/dL persist despite repeated attempts at lead abatement, some patients may benefit from oral chelation therapy to enhance lead excretion.111 While current evidence indicates that decrements in cognition may occur at blood lead concentrations well below 25 mcg/dL, the AAP currently states that chelation therapy is not indicated in patients with blood lead concentrations less than 25 mcg/dL.111 The US Centers for Disease Control and Prevention (CDC) states that patients with blood lead concentrations of 10-19 mcg/dL generally require only follow-up, periodic rescreening, and environmental investigation and abatement of potential sources of lead but not medical treatment.103,113 Those with blood lead concentrations of 9 mcg/dL or less generally are considered at low risk but can be considered for periodic rescreening.103

In the management of acute lead encephalopathy (which occurs most often in children) and/or in patients with severe lead poisoning (blood lead concentration exceeding 70 mcg/dL), most experts recommend that edetate calcium disodium be used in conjunction with dimercaprol since edetate calcium disodium alone may aggravate manifestations of toxicity in patients with very high blood lead concentrations.101,103,109,111 Lead encephalopathy is a life-threatening emergency that should be treated according to contemporary standards for intensive-care treatment of increased intracranial pressure, including appropriate pressure monitoring, osmotic therapy, and other drug therapy, in addition to chelation therapy.111 In addition, the AAP states that children with severe lead poisoning receiving combination chelation therapy should be monitored closely for hemodynamic changes and should receive adequate hydration to ensure renal excretion of chelating agents.111 Concomitant administration of edetate calcium disodium and dimercaprol increases the rate of excretion of lead, lowers mortality, and may lower the incidence of brain damage as compared with the use of edetate calcium disodium alone; however, such concomitant therapy does not completely eliminate the risk of permanent severe residual brain damage. Since lead encephalopathy occurs only rarely in adults, experience with the use of the combination in these patients is limited; however, use of edetate calcium disodium with dimercaprol has resulted in prompt relief of symptoms in a few adults with lead encephalopathy. Although concomitant therapy with dimercaprol and edetate calcium disodium also has been recommended in symptomatic patients with blood lead concentrations less than 70 mcg/dL,103 the AAP currently states that the toxicity of dimercaprol and the current availability of alternative drugs mandate its use only in the most serious cases of lead poisoning (i.e., blood lead concentrations exceeding 70 mcg/dL or when symptoms suggestive of encephalopathy are present).111

When chelation therapy is employed in asymptomatic patients with blood lead concentrations of 45-69 mcg/dL, the CDC and some clinicians state that such therapy generally should be limited to edetate calcium disodium therapy given alone.101,103 However, the AAP currently suggests that therapy with oral succimer is preferred in patients with blood lead concentrations of 45-70 mcg/dL who do not have symptoms of lead encephalopathy; alternatively, parenteral therapy with edetate calcium disodium alone may be used.111 The AAP states that children may need to be hospitalized during initiation of such therapy to allow monitoring for adverse effects and institution of environmental lead abatement procedures.111 Because of the potential for adverse effects (e.g., anemia, neutropenia), patient noncompliance with therapy, and/or persistence of lead exposure during outpatient chelation therapy, the AAP recommends that oral chelation therapy be initiated under close medical supervision (e.g., inpatient therapy).111,113 The CDC states that succimer also can be used as follow-up therapy (beginning 4 weeks after discontinuance of parenteral therapy) to edetate calcium disodium and/or dimercaprol therapy; however, administration of succimer with edetate calcium disodium and/or dimercaprol currently is not recommended because of a lack of data concerning safety and efficacy of such concomitant therapy.103,111

Although edetate calcium disodium was once administered orally to increase the excretion of lead, this route of administration is no longer recommended, since the drug enhances absorption of lead when lead is present in the GI tract; in addition, orally administered edetate calcium disodium is poorly absorbed from the GI tract and is considered ineffective.

Edetate calcium disodium is not a substitute for control of the lead hazard, and patients should not be treated prophylactically with any chelating agent.

Other Uses

Parenterally administered edetate calcium disodium may be useful in the treatment of poisoning by radioactive and nuclear fission products† such as plutonium, thorium, uranium, and yttrium. Edetate calcium disodium may also be beneficial in the treatment of poisoning from other heavy metals† such as chromium, manganese, nickel, zinc, and possibly vanadium. The drug is not effective in the treatment of mercury, gold, or arsenic poisoning.

The US Food and Drug Administration (FDA) states that the safety and effectiveness of edetate calcium disodium for use in removing heavy metals† (e.g., mercury) and toxins† from the body, management of coronary artery disease†, or other uses† not described in the manufacturer's labeling have not been established.114,115,117

Administration

Edetate calcium disodium may be administered by slow IV infusion or by IM injection. Daily doses of the drug are preferably administered by IV infusion over 12-24 hours. Although IM administration has been recommended by some clinicians as the preferred route of administration in young children (since IV administration of the drug has been associated with fatality in some young children) and in patients with lead encephalopathy and cerebral edema (and may be necessary in the latter patients if fluid restrictions preclude IV infusion),103,109 most experts currently recommend IV administration whenever possible.101,103,111 In addition, the American Academy of Pediatrics (AAP) states that clinical experience suggests that IV administration of edetate calcium disodium is safe and more appropriate for children than the IM route.111 If edetate calcium disodium is administered IV in patients with lead encephalopathy and cerebral edema, the drug must be infused slowly since rapid infusions may increase intracranial pressure to lethal levels.109

IV Administration

For IV infusion, edetate calcium disodium should be diluted with 5% dextrose or 0.9% sodium chloride injection to a concentration of 2-4 mg/mL (0.2-0.4%). When edetate calcium disodium is administered in divided doses daily by intermittent IV infusion, some authorities state that diluted solutions of the drug may be infused over 15-60 minutes in patients not at risk from this rate of infusion;101,103 however, the manufacturer recommends that the total daily dose not be divided but instead be given as a single infusion over 8-12 hours.109 When administered as single daily IV infusions, daily doses are usually infused over 12-24 hours;100,101,102 infusion times of at least 8 hours are preferable.102 When edetate calcium disodium is administered by continuous IV infusion, it is necessary to interrupt the infusion for 1 hour before a blood lead concentration is measured in order to avoid a falsely elevated value.101

IM Administration

Prior to IM administration of edetate calcium disodium, lidocaine hydrochloride or procaine hydrochloride should be added to edetate calcium disodium injection to minimize pain at the injection site; 0.25 mL of 10% lidocaine hydrochloride injection may be added to 5 mL of edetate calcium disodium injection or, alternatively, 1 mL of 1% lidocaine hydrochloride or 1 mL of 1% procaine hydrochloride injection may be added to each mL of edetate calcium disodium injection to obtain a final lidocaine or procaine hydrochloride concentration of 5 mg/mL (0.5%).109 The manufacturer recommends that the total daily dose be given IM in equally divided doses at 8- to 12-hour intervals.109

Dosage

Diagnosis of Lead Poisoning

Edetate calcium disodium mobilization tests may be performed in the diagnosis of suspected lead poisoning when there is uncertainty as to the adequacy of the patient's response to chelation therapy. Several methods of performing edetate calcium disodium mobilization tests have been described, and clinicians should consult published protocols and specialized references for information on specific methods. The manufacturer states that the edetate calcium disodium mobilization test may be considered for patients whose blood lead concentration is 25-55 mcg/dL.109 However, appropriate chelation therapy should not be delayed for performance of a mobilization test but instead such therapy should be given immediately to patients who are symptomatic or whose blood lead concentration is 45 mcg/dL or more.103,109,111 The AAP currently considers use of mobilization tests obsolete because of factors such as inconsistent prediction of the total body burden of lead, technical difficulties in administering the test, cost, lack of measurable end points of chelation therapy in children with relatively low-level exposure to lead, and the potential for increased lead toxicity associated with administration of edetate calcium disodium alone.111

Iron status, as assessed by serum ferritin concentrations, can have a small but important effect on lead diuresis in children with blood lead concentrations of 25-55 mcg/dL.103,110 In one study employing an edetate calcium disodium mobilization test, each 1-ng/mL increase in serum ferritin resulted in a 2.4-mcg increase in urinary lead concentration over an 8-hour collection period.110 Such changes could affect interpretation of mobilization tests, particularly those with borderline results.103,110 While some experts state that the mobilization test generally should not be performed in iron-deficient patients until iron stores have been replenished,103 others state that mobilization testing and chelation therapy should not be withheld pending treatment of iron deficiency and that lead stores simply should be reassessed following iron repletion.110

In adults, the edetate calcium disodium mobilization test may be performed by administering 500 mg/m² (maximum dose of 1 g) by IV infusion over a period of 1 hour or by IM injection. Urine is collected in special lead-free collection apparatus for 24 hours beginning with administration of the drug and is analyzed for lead content; collection periods of up to 3 or 4 days may be required in individuals with renal insufficiency.100 If the ratio of mcg of lead excreted in urine to mg of edetate calcium disodium administered is greater than 1, the mobilization test is considered positive.

In children, the edetate calcium disodium mobilization test may be performed by administering 500 mg/m² (maximum dose of 1 g) by IV infusion over a period of 1 hour or IM as a single injection, or ideally, by administering two IM doses of 500 mg/m² each at 12-hour intervals; urine is collected for 24 hours beginning with administration of the drug and is analyzed for lead content. If the ratio of mcg of lead excreted in urine to mg of edetate calcium disodium administered is greater than 1, the mobilization test is considered positive.

Alternatively, a 6- to 8-hour mobilization test may be performed and may be more convenient, particularly in young children. Collections over such periods generally appear to be as reliable as those over a 24-hour period.103 In this method, a single IM dose of edetate calcium disodium of 50 mg/kg (maximum dose of 1 g) is administered; urine is collected for 6-8 hours beginning with administration of the drug and is analyzed for lead content. If the ratio of mcg of lead excreted in urine to mg of edetate calcium disodium administered is greater than 0.5 or urine lead concentration is greater than 1 mg/L, the test is considered positive. Some experts recommend an 8-hour mobilization test using a single dose of 500 mg/m² administered preferably by IV infusion over 1 hour or, if necessary, by IM injection.101,103,107 Regardless of the dose administered, these experts consider the test positive if the ratio of mcg of lead excreted in urine to mg of edetate calcium disodium administered is greater than 0.6;101,103 however, some clinicians consider this test positive if this ratio is greater than 0.5.103,108

Lead Poisoning

When a source for lead poisoning has been identified, the patient should be removed from that source.103,109,113 Because chelation therapy can increase absorption of lead from the GI tract, such therapy should be administered only to children who reside in environments that are free of lead both during and after therapy.103,113

In the management of lead poisoning, the total dose of edetate calcium disodium depends on the severity of the lead intoxication as well as the patient's response to, and tolerance of, the drug. Various dosage regimens have been recommended. Clinicians should consult published protocols and specialized references for the dosage of edetate calcium disodium and other chelating agents, the method and sequence of administration, and specific information on precautions associated with chelation therapy. Dosage of edetate calcium disodium is the same for either IV or IM administration.109 When the drug is given IV, the daily dosage may be given in 2 equally divided doses at 12-hour intervals or as a single dose administered over 8-24 hours. The AAP suggests that the daily dosage of edetate calcium disodium may be given IV as a single dose over several hours or by continuous infusion.111 When edetate calcium disodium is used alone in children and administered IM, the daily dosage usually is given in equally divided doses at 8- to 12-hour intervals. When the drug is administered IM in conjunction with dimercaprol in children or adults, the daily dosage usually is given in equally divided doses at 4-hour intervals.

Most experts recommend that edetate calcium disodium be used in conjunction with dimercaprol for the treatment of severe lead poisoning (blood lead concentration greater than 70 mcg/dL). Adults and children with symptoms of lead encephalopathy and/or blood lead concentrations greater than 70 mcg/dL (with or without symptoms) can be given dimercaprol 4 mg/kg or 75-83 mg/m² IM initially. At least 4 hours later (but not until adequate urine flow is established) and at 4-hour intervals thereafter for a minimum of 3 days but usually for 5 days, dimercaprol 4 mg/kg or 75-83 mg/m² (i.e., 450-500 mg/m² daily) and edetate calcium disodium 250 mg/m² (i.e., 1.5 g/m² daily) both may be given by deep IM injection simultaneously at separate injection sites. The AAP and some experts recommend that edetate calcium disodium preferably should be administered IV over several hours or by continuous IV infusion (e.g., at a dosage of 50 mg/kg daily) whenever possible because of the pain associated with IM injection of the drug. The AAP states that after a minimum of 3 days of concomitant therapy with edetate calcium disodium and dimercaprol, therapy with both drugs or with edetate calcium disodium alone may be continued for a total of 5 days.111 In patients with lead encephalopathy, parenteral chelation therapy with both edetate calcium disodium and dimercaprol should be continued until the patient is clinically stable before therapy is changed.111 The US Centers for Disease Control and Prevention (CDC) state that a second course of chelation therapy, but employing edetate calcium disodium alone, may be required if blood lead concentration rebounds to 45 mcg/dL or higher within 5-7 days after the initial course.103 Alternatively, the CDC states that a second course of edetate calcium disodium alone may be administered if the blood lead concentration rebounds to greater than 35 mcg/dL beyond 3 days after the initial course.103

The AAP states that in patients receiving concomitant dimercaprol-edetate calcium disodium therapy, a minimum of 2 days without treatment should elapse before a second 5-day course of therapy with either combined dimercaprol and edetate calcium disodium or edetate calcium disodium alone is considered in patients with severe lead poisoning.111 Blood lead concentrations should be assessed 10-14 days after completion of 1-2 courses of chelation therapy; retreatment based on blood lead concentrations using regimens recommended for initial treatment is required in patients with residual blood lead concentrations greater than 45 mcg/dL.111

Asymptomatic children with blood lead concentrations of 45-69 mcg/dL generally have received edetate calcium disodium alone in a dosage of 1 g/m² daily by continuous or intermittent IV infusion.101,103,109 However, the AAP currently suggests that therapy with oral succimer 30 mg/kg daily for 5 days is preferred in patients with blood lead concentrations of 45-70 mcg/dL who do not have symptoms of lead encephalopathy (see Dosage and Administration: Dosage, in Succimer 64:00); alternatively, parenteral edetate calcium disodium alone in a dosage of 25 mg/kg daily for 5 days may be used.111 Depending on the blood lead concentration and/or rebound blood lead concentration, additional courses of chelation therapy may be necessary.101,103,111 Some experts state that a second course of edetate calcium disodium alone may be required if blood lead concentration rebounds to 45 mcg/dL within 7-14 days after the initial course.103 The AAP states that blood lead concentrations should be assessed 10-14 days after completion of chelation therapy; retreatment based on lead concentrations using regimens recommended for initial treatment is required in patients with residual blood lead concentrations greater than 45 mcg/dL.111

For children with blood lead concentrations of 25-44 mcg/dL, the efficacy of chelation therapy in decreasing the adverse cognitive effects of lead remains to be established and the use of chelation therapy is not routinely recommended.103,111 (See Uses: Lead Poisoning.)

For adults with lead nephropathy, the following edetate calcium disodium dosage regimen has been suggested. Patients with serum creatinine concentration of 2 mg/dL or less may receive 1 g daily for 5 days; 500-mg doses may be given every 24 hours for 5 days to patients with serum creatinine concentration of 2-3 mg/dL, every 48 hours for 3 doses to patients with serum creatinine concentration of 3-4 mg/dL, and once weekly to patients with serum creatinine concentration greater than 4 mg/dL. It has been suggested that these regimens be repeated at 1-month intervals until lead excretion is reduced toward normal.

Adverse Effects

The principal and most serious toxic effect of edetate calcium disodium is renal tubular necrosis, which tends to occur when the daily dose is excessive and may result in fatal nephrosis. (See Cautions: Precautions and Contraindications.) Edetate calcium disodium may produce the same signs of renal damage as lead poisoning, such as proteinuria and microscopic hematuria. Rarely, changes in distal renal tubules and glomeruli, glycosuria, presence of large renal epithelial cells in urinary sediment, increased urinary frequency, and urgency may occur. Hydropic degeneration of proximal renal tubular cells also may occur; however, recovery usually occurs following discontinuance of therapy.109

Pain may occur at the injection site following IM administration; concomitant administration of a local anesthetic can minimize such pain.109 Thrombophlebitis has occurred following IV infusion of solutions of edetate calcium disodium when the concentration exceeded 0.5%. The drug should be well diluted before IV infusion to avoid thrombophlebitis. (See Dosage and Administration: Administration.)

Anorexia, nausea, vomiting, cheilosis, tremors, headache, numbness, tingling, myalgia, arthralgia, rash, hypercalcemia, cardiac rhythm irregularities, hypotension, transient bone marrow depression, anemia, zinc deficiency, and hypercalcemia may occur following parenteral administration of edetate calcium disodium.109 Mild elevations of serum ALT (SGPT) or AST (SGOT) concentrations and decreases in serum alkaline phosphatase concentrations (possibly secondary to decreased serum zinc concentrations) occur frequently in patients receiving edetate calcium disodium; however, concentrations usually return to normal within 48 hours of discontinuance of therapy with the drug.109 Occasionally, sudden fever and chills associated with malaise, fatigue, and excessive thirst and sometimes accompanied by histamine-like reactions including sneezing, nasal congestion, and lacrimation may occur 4-8 hours after IV infusion. Three patients with chronic lead nephropathy experienced acute attacks of gout a few days after IV infusion of edetate calcium disodium.

Prolonged administration of edetate calcium disodium in high dosage may produce transient bone marrow depression and skin and mucous membrane lesions, including cheilosis, which subside when the drug is discontinued. Depletion of trace metals from the body is also a possibility (especially in undernourished patients), but intermittent administration of the drug should prevent depletion of essential metals.

Precautions and Contraindications

Because edetate calcium disodium is capable of producing toxic and potentially fatal effects, the recommended dosage regimens should be followed and the recommended daily dose should not be exceeded. When the drug is used in the management of lead encephalopathy, rapid IV infusion must be avoided because it may increase intracranial pressure to lethal levels.

Because chelation therapy can increase absorption of lead from the GI tract, such therapy should be administered only to children who reside in environments that are free of lead both during and after therapy.103,113

Fatal medication errors have occurred that involve confusion between edetate calcium disodium (calcium EDTA) and edetate disodium (no longer commercially available in the US).114,115,116,117 Children and adults have mistakenly received edetate disodium instead of edetate calcium disodium;114,115,116,117,118 at least 5 deaths have occurred as a result of inadvertent administration of edetate disodium.114,115,117,118 Although both edetate calcium disodium and edetate disodium are heavy metal antagonists, the 2 drugs were originally approved by the US Food and Drug Administration (FDA) for different uses and have different effects; edetate disodium was formerly FDA approved for use in selected patients for the emergency treatment of hypercalcemia or for the control of ventricular arrhythmias associated with cardiac glycoside toxicity.114,115,116,117 Use of edetate disodium may result in a substantial, and sometimes fatal, decrease in serum calcium concentrations.115,117 In June 2008, FDA withdrew its prior approval for edetate disodium because of safety concerns following a review of the risk-benefit profile of the drug.116 FDA stated that it was not considering additional action regarding edetate calcium disodium at that time; most of the fatalities following administration of an EDTA drug have involved medication errors in which edetate disodium was administered instead of edetate calcium disodium.115 FDA has not received reports of any fatalities resulting from the administration of edetate calcium disodium that involve a medication error.115 However, FDA states that the safety and effectiveness of edetate calcium disodium for use in removing heavy metals† (e.g., mercury) and toxins† from the body, management of coronary artery disease†, or other uses† not described in the manufacturer's labeling have not been established.114,115,117 Serious adverse reactions (e.g., hypocalcemia, cardiac arrest) that may be associated with the use of edetate calcium disodium should be reported to the FDA MedWatch program by phone (800-FDA-1088), fax (800-FDA-0178), internet ([Web]) or by mail (MedWatch, 5600 Fishers Lane, Rockville, MD 20852-9787) or to the US Centers for Disease Control and Prevention (CDC) Lead Poisoning Prevention Branch by phone (770-488-3300).114,117

Edetate calcium disodium is potentially nephrotoxic. Nephrotoxicity is dose dependent and can usually be prevented by careful dosage regulation and use of intermittent therapy. It is also important to establish urine flow by administration of IV fluids before the first dose of edetate calcium disodium is given, particularly in acutely ill patients who may be dehydrated from vomiting; however, in patients with lead encephalopathy, excess fluids must be avoided and administration of IV fluids should be restricted to basal water and electrolyte requirements after urine flow has been established. If urine flow has not been established after 3 hours of IV fluid administration, edetate calcium disodium may be administered in conjunction with hemodialysis to remove the nephrotoxic lead edetate complex. Urine flow should be monitored throughout edetate calcium disodium therapy; if anuria or severe oliguria occurs during therapy, edetate calcium disodium should be discontinued to avoid high tissue concentrations of the drug. Patients receiving edetate calcium disodium should be instructed to notify their physician if urination stops for a period of 12 hours.109 Urinary sediment and BUN determinations should be performed before and periodically during each course of therapy to detect renal impairment. Urinalyses should be performed daily during therapy; if there is increasing proteinuria, an increased number of erythrocytes, or if large renal epithelial cells are present, the drug should be discontinued immediately. Edetate calcium disodium should be used with extreme caution and in reduced dosage in patients with mild renal disease.109 (See Dosage and Administration: Dosage.) The manufacturer states that the drug is contraindicated in patients with anuria and in those with active renal disease.109 Edetate calcium disodium also is contraindicated in patients with hepatitis.109

Because the drug has produced ECG changes (e.g., inversion of the T wave), patients should be monitored for cardiac rhythm irregularities during parenteral edetate calcium disodium therapy. Determinations of serum electrolyte concentrations and liver function tests should be performed before and daily during each course of therapy in severe cases of lead poisoning and after the second and fifth day of therapy in moderate cases of lead poisoning.109

Pediatric Precautions

Edetate calcium disodium has been used in the management of lead poisoning in all age groups, including pediatric patients. Because IV administration of edetate calcium disodium has been associated with fatality in some young children, some clinicians prefer IM administration of the drug in this age group.103,109 However, most experts currently recommend IV administration whenever possible.101,103,111 (See Dosage and Administration: Administration.)

Mutagenicity and Carcinogenicity

The mutagenic and carcinogenic potentials of edetate calcium disodium have not been evaluated to date.109

Pregnancy, Fertility, and Lactation

Pregnancy

A reproduction study in rats using edetate calcium disodium dosages up to about 13 times the usual human dosage has not revealed evidence of harm to the fetus; however, dosages up to 25-40 times the usual human dosage in rats were associated with fetal malformations.109 Fetal malformations were prevented in rats receiving zinc supplementation.109 There are no adequate and controlled studies to date using edetate calcium disodium in pregnant women, and the drug should be used during pregnancy only when clearly needed.109 The effect of edetate calcium disodium on labor and delivery is not known.109

Fertility

The effects of edetate calcium disodium on fertility have not been studied to date.109

Lactation

Since it is not known whether edetate calcium disodium is distributed into human milk, the drug should be used with caution in nursing women.109

Pharmacology

The calcium in edetate calcium disodium can be displaced by divalent and trivalent metals, particularly lead, to form stable soluble complexes that can then be excreted in urine. Unlike edetate disodium (no longer commercially available in the US), edetate calcium disodium is saturated with calcium and therefore can be administered IV in relatively large quantities without causing any substantial changes in serum or total body calcium concentrations. Although 1 g of edetate calcium disodium theoretically sequesters 620 mg of lead, an average of only 3-5 mg of lead is excreted in urine following parenteral administration of 1 g of the drug to patients with symptoms of acute lead poisoning or with high concentrations of lead in soft tissues. However, orally administered edetate calcium disodium may enhance the absorption of lead and this route of administration no longer is recommended . (See Uses: Lead Poisoning.) Parenteral administration of edetate calcium disodium chelates and greatly increases the urinary excretion of zinc† and, to a much lesser extent, cadmium†, manganese†, iron†, and copper†. Excretion of uranium†, plutonium†, yttrium†, and some other heavier radioactive isotopes† can be increased to a limited extent by edetate calcium disodium chelation. Although mercury readily displaces calcium from edetate calcium disodium in vitro, patients with mercury poisoning† do not respond to the drug. The US Food and Drug Administration (FDA) states that the safety and effectiveness of edetate calcium disodium for use in removing heavy metals† (e.g., mercury) and toxins† from the body, management of coronary artery disease†, or other uses† not described in the manufacturer's labeling have not been established.114,115,117

Pharmacokinetics

Absorption

Edetate calcium disodium is well absorbed following IM or subcutaneous administration. When edetate calcium disodium is administered IV in the treatment of lead poisoning, urinary excretion of chelated lead begins within about 1 hour and peak excretion of chelated lead occurs within 24-48 hours. Colic caused by lead poisoning may disappear within 2 hours, muscular weakness and tremors disappear after 4-5 days, and coproporphyrinuria and stippled erythrocytes usually decrease within 4-9 days after therapy is initiated.

Distribution

Edetate calcium disodium is distributed mainly into extracellular fluid. The drug does not penetrate erythrocytes and does not enter CSF in any appreciable quantity.

Elimination

Edetate calcium disodium is not metabolized. Following parenteral administration, it is rapidly excreted by glomerular filtration in urine, either unchanged or as metal chelates. Following IV administration, 50% of a dose appears in urine within 1 hour and 95% within 24 hours. The plasma half-life of the drug has been reported to be 20-60 minutes following IV administration and 1.5 hours following IM administration. Changes in urine flow and/or pH do not affect the excretion rate of edetate calcium disodium, but impaired renal function with reduced glomerular filtration delays excretion of the drug and thus may increase its nephrotoxicity.

Chemistry and Stability

Chemistry

Edetate calcium disodium (calcium EDTA), the calcium chelate of edetate disodium, is a chelating agent. Edetate calcium disodium is a mixture of the dihydrate and trihydrate (predominantly the dihydrate) of calcium disodium ethylenediaminetetraacetate. The drug occurs as a white, crystalline powder or granules, is slightly hygroscopic and odorless, has a faint saline taste, and is freely soluble in water and very slightly soluble in alcohol. The commercially available injection has a pH of 6.5-8 and contains approximately 5.3 mEq of sodium per gram of edetate calcium disodium.

Stability

Edetate calcium disodium injection should be stored at controlled room temperature (15-30°C).109 The manufacturer recommends that edetate calcium disodium injection be diluted with 0.9% sodium chloride or 5% dextrose injection for IV administration. Edetate calcium disodium has been reported to be physically incompatible with 10% dextrose, 10% invert sugar, 10% invert sugar in 0.9% sodium chloride, lactated Ringer's, Ringer's, and (1/6) M sodium lactate injections and with injectable preparations of amphotericin B and hydralazine hydrochloride.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Only references cited for selected revisions after 1984 are available electronically.

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102. Pincus D, Saccar CV. Lead poisoning. Am Fam Physician . 1979; 19:120-4. [PubMed 110123]

103. US Department of Health and Human Services. Preventing lead poisoning in young children: a statement by the Centers for Disease Control October 1991. Atlanta, GA: Centers for Disease Control, Center for Environmental Health.

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