Edetate Calcium Disodium (Systemic)



INN:

Sodium calcium edetate

VA CLASSIFICATION
Primary: AD300
Secondary: DX900

Commonly used brand name(s): Calcium Disodium Versenate.

Other commonly used names are
calcium EDTA, edathamil calcium disodium, and sodium calcium edetate .
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Chelating agent—

diagnostic aid, lead mobilization—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Toxicity, lead (treatment)—Edetate calcium disodium is indicated for the treatment of acute and chronic lead poisoning (plumbism) and lead encephalopathy. {01}

—Dimercaprol complements edetate calcium disodium by rapidly removing lead from red blood cells and by assisting in mobilizing lead from skeletal stores. {13} When the combination is used, the rate of lead excretion is doubled, {13} thus decreasing the mortality rate and likelihood of permanent neurologic deficits from lead poisoning. {04} {07}
—Signs and symptoms of lead poisoning include anemia, gastrointestinal complaints (abdominal pain and vomiting), {05} nephropathy, and encephalopathy. {03} Symptoms of lead encephalopathy include headache and insomnia; persistent vomiting, sometimes projectile; visual disturbances; irritability, restlessness, delirium, hallucinations; ataxia; {05} {29} convulsions and coma; and characteristically high intracranial pressure. Recovery is slow and often incomplete, with residual neurologic deficit. {15} {28}
—Edetate calcium disodium may be used as sole therapy when blood lead levels fall between 45 and 69 mcg per deciliter, unless serious symptoms such as encephalopathy are present. {03} {28} Clinical signs and symptoms suggesting lead poisoning that should be treated with the dimercaprol, edetate calcium disodium combination include the following:    • Patient is symptomatic (with or without encephalopathy). {03}
   • Blood lead concentrations are greater than or equal to 70 mcg per deciliter. {03}


[Lead mobilization determination]1—Edetate calcium disodium may be used as a diagnostic agent to identify patients who qualify for a full course of chelation therapy by determining the magnitude of lead stores in high-risk, asymptomatic children with mild to moderate increases in lead absorption (25 {24} {25} {26} to 44 {03} mcg of lead per deciliter of whole blood). However, use of the lead mobilization test is controversial because of variable results, difficulty in collecting urine from non–toilet-trained children, possible increase in brain lead levels, and risk of iron deficiency causing a negative mobilization result. {30} {31} {32} {33}

Unaccepted
To a lesser extent, cadmium, manganese, iron, copper, chromium, and nickel are also chelated, {02} {04} {16} but the value of edetate calcium disodium in poisoning caused by these metals is questionable or unproven.

Edetate calcium disodium is not effective in arsenic, gold, or mercury {04} poisoning. {07}

Edetate calcium disodium is not effective in preventing or retarding the progression of atherosclerosis. {25}

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    374.27

Mechanism of action/Effect:

Edetate calcium disodium reduces blood concentrations and depot stores of lead. {01} {05} The calcium is replaced by divalent and trivalent metals, {08} especially any available lead, {15} to form stable, soluble complexes that are readily excreted. {07} Edetate calcium disodium is saturated with calcium but can be administered intravenously in large quantities without causing any significant changes in serum or total body calcium concentrations. {04} {08}


Other actions/effects:

Edetate calcium disodium greatly increases chelation and urinary excretion of zinc, {05} but this action is considered clinically insignificant unless therapy is continued for more than 5 {30} days or zinc stores are low prior to treatment. {23} {34} Edetate calcium disodium has been found to chelate iron, copper, calcium, and manganese. {08} {27} {35}

Absorption:

Well absorbed after parenteral administration; {04} poorly absorbed from the gastrointestinal tract. The oral route of administration is no longer used because of poor GI absorption. The absorption of any lead in the intestines may be increased upon oral administration of edetate calcium disodium because the lead chelate formed is more soluble than the lead itself. After absorption, the chelate dissociates and releases free lead ions, producing increased symptoms of lead toxicity. {07} {13}

Distribution:

Extracellular fluid (90%); edetate calcium disodium does not penetrate erythrocytes and only slowly diffuses into the cerebrospinal fluid. {13}

Biotransformation:

No metabolism occurs; after parenteral administration, edetate calcium disodium is excreted in the urine either unchanged or as the metal chelates. {04} {08} {09}

Half-life:


Plasma:

Intravenous administration: 20 to 60 minutes. {08}

Intramuscular administration: 1.5 hours. {04} {08} {09}


Elimination:
    Renal, by glomerular filtration; 50% of the chelate that is formed appears in urine within the first hour after parenteral administration; {01} {08} 70% or more during first 4 hours; {13} and 95% in 24 hours. {06} {08} Excretion is unaffected by urinary pH. {07} Theoretically, one gram of edetate calcium disodium chelates 620 mg of lead, but only 3 to 5 mg of lead is excreted in the urine after parenteral administration of one gram to patients with symptoms of acute lead poisoning or with high concentrations of lead in soft tissues. {04}


Precautions to Consider

Pregnancy/Reproduction

Pregnancy—
Studies in humans have not been done. Risk-benefit must be considered during early pregnancy or in women of child-bearing potential. {01}

One reproduction study in rats at doses up to 13 times the human dose revealed no evidence of impaired fertility or harm to the fetus. Another reproduction study performed in rats at doses up to 25 to 40 times the human dose revealed evidence of fetal malformations, which were prevented by simultaneous administration of zinc supplements. {01}

FDA Pregnancy Category B. {01}

Breast-feeding

It is not known whether edetate calcium disodium is distributed into breast milk.

Pediatrics

Because the intramuscular route is painful and there may be poor blood flow to muscle, the intravenous route is recommended for children. {03} {05} {35} In cases of lead encephalopathy, fluid restriction may necessitate giving edetate calcium disodium intramuscularly. {44} Children may require repeated courses of therapy if blood lead levels are greater than 45 mcg per deciliter. {03} {28}

The preferred treatment for children with lead encephalopathy is combined therapy with edetate calcium disodium and dimercaprol. {07}


Geriatrics


No information is available on the relationship of age to the effects of edetate calcium disodium in geriatric patients.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

Insulin    (concurrent use will decrease the duration of action of zinc insulin preparations by chelation of zinc {01} {07})


Zinc supplements    (concurrent use may decrease the effectiveness of edetate calcium disodium and zinc supplements due to chelation; zinc supplement therapy should be withheld until edetate calcium disodium therapy is completed {05} {23})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
Electrocardiogram (ECG) readings    (inversion of T-wave may occur {04} {08} {39})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problems exist:
» Anuria{01} or
» Oliguria, severe    (fatal lower nephron necrosis may result; if anuria occurs during therapy or is present before therapy, urine flow should be restored before starting edetate calcium disodium therapy {04} {29})


Risk-benefit should be considered when the following medical problems exist
» Dehydration    (when acutely ill patients are dehydrated from vomiting and/or diarrhea, urine flow must be established before administering the first dose of edetate calcium disodium; once the flow is established, intravenous fluids must be restricted to basal water and electrolyte requirements {03})


Hypercalcemia    (transitory hypercalcemia during treatment may exacerbate an existing condition {04})


» Renal function impairment    (reduced glomerular filtration may delay the excretion of the chelate and increase the risk of nephrotoxicity {01} {04} {07})



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Blood urea nitrogen (BUN) concentrations{03}{07} and
Calcium concentrations, serum{07} and
Creatinine concentrations, serum{03}{07} and
Hepatocellular enzymes{03} and
Phosphorus concentrations, serum{03}{07} and
Urine output{03}    (determinations recommended prior to treatment and on the first, third, and fifth day of each course of therapy for evidence of renal function impairment {01} {07})


Cardiac monitoring    (may be recommended periodically to find irregularities of cardiac rhythm, {01} {04} especially if edetate calcium disodium is given intravenously {40})


Fluid intake    (must be kept to a minimum if cerebral edema is present; volume of urine and flow must be adequate for elimination of lead chelate {11})


Urinalysis, routine    (recommended daily during each course of therapy; since severe, acute lead poisoning and edetate calcium disodium may both produce the same signs of renal damage, urinalyses should be performed to determine if proteinuria or hematuria is improving or if evidence of renal tubular injury is worsening; {03} edetate calcium disodium must be discontinued immediately if large renal epithelial cells or increasing numbers of red blood cells are present in urinary sediment, or if there is evidence of increased proteinuria {01})




Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Systemic febrile reaction (chills or sudden fever; fatigue; headache; increased thirst; loss of appetite; malaise){01}{08}
    
histamine-like reaction (sneezing{07}{08}; stuffy nose{04}{07}{08}; watery eyes{07}{08})—possibly occurring 4 to 8 hours after intravenous infusion{04}
    
low blood pressure {01}{07}
    
nausea or vomiting {01}{08}
    
renal damage or renal tubular necrosis (cloudy urine){01}{08}
    
thrombophlebitis (pain or swelling at site of injection){07}

Note: Febrile reaction has been observed in some patients 4 to 8 hours after infusion; {04} {08} it may accompany histamine-like reaction. {04} {07}
Renal damage or tubular necrosis may occur when daily dose is excessive. Microscopic hematuria, proteinuria, or large renal epithelial cells may be observed in urine. {01} {07}
Thrombophlebitis may be a result of inadequate dilution of injection. Concentration of solution should not exceed 0.5%. {04}


Incidence less frequent
    
Transient anemia{01}{08} or bone marrow depression{01}{04}{07} (bleeding and bruising; sore throat and fever; unusual tiredness or weakness)
    
dermatitis (cracking and dry, scaly skin, or sores in mouth and on lips){01}{07}{08}
    
hypercalcemia {01}{04}(constipation; drowsiness; dry mouth; continuing headache; loss of appetite; metallic taste)

Note: Dermatitis lesions are similar to those caused by vitamin B 6 deficiency; {08} results from prolonged administration at high doses and may be due to zinc depletion. {02} {16}
Hypercalcemia is usually transitory {08} and accompanied by a significant increase in urinary excretion of calcium from endogenous sources. {13} However, since recurring hypercalcemia may be causally related to renal tubular injury, discontinuation of edetate calcium disodium therapy is recommended when hypercalcemia occurs in susceptible patients.


Incidence rare
    
Frequent or sudden urge to urinate {08}
    
secondary gout (severe pain in feet, knees, hands, elbows)—hyperuricemia may result from renal tubular toxicity{04}





General Dosing Information
Warning: The dosage schedule should be followed and the recommended daily dose must not be exceeded because of the toxic and potentially fatal effects of edetate calcium disodium. {01}

Edetate calcium disodium is equally effective when administered intramuscularly or intravenously. However, the intravenous route is preferred because the intramuscular route is painful and children have poor blood flow to muscle. {03} {05} {35}

In patients with lead encephalopathy or cerebral edema, intravenous infusion is preferred, but rapid infusion may be lethal because of a sudden increase in intracranial pressure. {01} {41} An excess of fluids must be avoided in such patients, and the intramuscular route should be used.

If edetate calcium disodium is given intramuscularly, pain at site of intramuscular injection may be reduced by mixing a 20% solution of edetate calcium disodium with procaine or lidocaine. A final procaine or lidocaine concentration of 5 mg per mL (0.5%) can be obtained by mixing 0.25 mL of a 10% lidocaine solution per 5 mL of edetate calcium disodium or 1 mL of 1% procaine or lidocaine solution per mL of edetate calcium disodium. {22} Crystalline procaine may be used instead to maintain minimum fluid volume. {01} {04} {07}

Urine flow should be established before the first dose of edetate calcium disodium is administered to acutely ill, dehydrated patients. When urine flow has been established, further intravenous fluids should be restricted to basal water and electrolyte requirements. {01}

Each course of therapy should not exceed 5 to 7 days, with a drug-free interval of at least 2 days (preferably 2 weeks) between courses. This allows redistribution of lead from inaccessible storage sites, such as soft tissue or bone, {35} and will result in a greater amount of lead available for elimination. {01} {07} {08}

In cases of lead encephalopathy, children may require repeated courses of therapy if blood lead levels are greater than 45 mcg per deciliter. {03} {28}

Successful chelation therapy requires the administration of a sufficient molar excess of chelating agent over lead. Since the maximum safe dose of edetate calcium disodium alone may cause a shift of lead into the CNS, {28} dimercaprol is combined with edetate calcium disodium . The preferred route of administration for edetate calcium disodium is intravenous and dimercaprol is given by deep intramuscular injection in divided doses every 4 hours for 5 days. If both drugs are given by intramuscular injection, then they must be given at separate sites. Dimercaprol is given alone for the first dose 4 hours before the combination is begun. {28} Injection sites should be rotated. {45} In asymptomatic or mildly symptomatic patients, dimercaprol may be discontinued after 48 hours, with edetate calcium disodium being continued for an additional 48 to 72 hours at reduced dosage . {09} {17}

Oral penicillamine is used after initial therapy with edetate calcium disodium or combined dimercaprol and edetate calcium disodium for long-term chelation therapy, {07} {11} especially if long-bone radiographs show lead lines. {11} The oral chelating agent succimer has recently been approved for treatment of children with blood lead levels greater than 45 mcg per deciliter. Although use to date has been limited, toxicity appears to be less than with other agents. {03} {36}

For lead mobilization test
Use of the lead mobilization test is controversial because of variable results, difficulty in collecting urine from non–toilet-trained children, possible increase in brain lead levels, and risk of iron deficiency causing a negative mobilization result. {30} {31} {32} {33}
Since the blood lead (BL) concentrations may not be a sensitive indicator of the body burden of lead in asymptomatic children with BL 25 to 44 {03} mcg per dL, diagnostic tests may be performed as follows:

   • Edetate calcium disodium is given intravenously at a dose of 15 mg per kg of body weight (mg/kg) (500 mg per square meter) in 5% dextrose over 1 hour; or edetate calcium disodium given intramuscularly at a dose of 15 mg/kg (500 mg per square meter) mixed with an equivalent amount of procaine so that the final concentration of procaine is 0.5%. {03} {05}
   • An 8-hour urine sample, collected in lead-free equipment, is obtained. {03} {21}
   • The test is considered positive for increased body burden of lead when the 8-hour urinary excretion of lead is greater than 0.6 mcg {14} per mg of edetate calcium disodium administered.
   • If the diagnostic mobilization test is positive, a five-day course of therapy is administered. {03} The test may be repeated if another course of therapy is necessary.
   • The upper limit for acceptable blood lead concentrations is 10 mcg {03} {28} per deciliter of whole blood. At 20 mcg per deciliter, medical evaluation should occur. {03} {30}
   • In symptomatic patients or those with whole blood lead concentrations greater than or equal to 45 mcg per dL {03} {42}, appropriate chelation therapy should be given immediately without performing the mobilization test. {07}

For treatment of adverse effects
Recommended treatment consists of the following:

   • Cessation of urine flow during therapy—Administration of edetate calcium disodium must be stopped to avoid excessively high tissue concentrations of the chelating agent. {01}
   • Sores in mouth and on lips—Subside when edetate calcium disodium is discontinued; replacement of zinc by supplementation may be advisable during drug-free interval between courses of therapy. {04} {15}


Parenteral Dosage Forms

Note: Bracketed uses in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.

EDETATE CALCIUM DISODIUM INJECTION USP

Usual adult and adolescent dose
Lead toxicity
Intravenous or intramuscular, in conjunction with dimercaprol, 30 to 50 mg of edetate calcium disodium per kg of body weight (1 to 1.5 grams per square meter of body surface area) per day in two divided doses twelve hours apart for three to five days. {07}

Note: Patients with blood lead levels between 45 and 69 mcg per deciliter may be treated with edetate calcium disodium alone using the same dosage given above for use with dimercaprol. {38} {43}
A second course of treatment may be administered for up to five additional days after at least a two-day drug-free interval (preferably two weeks). {03}
When serum creatinine is 2 mg per deciliter or less, the dosage is 1 gram a day for 5 days. If the serum creatinine is 2 to 3 mg per deciliter, the dosage is 500 mg a day. {04} {37}
For intravenous administration, the dilution must be infused slowly over a period of at least two hours for symptomatic patients and one hour for asymptomatic patients. {01}


[Lead mobilization test]1
Intravenous, 1 gram {28} {29} over 1 hour. {03} The same dose can be mixed with procaine, so that the final concentration of procaine is 0.5%, and given intramuscularly. {03}


Usual adult prescribing limits
The maximum dose is 2 grams a day. {28} {31}

Usual pediatric dose
Lead toxicity
For blood lead levels greater than 70 mcg per deciliter or serious symptoms: Intravenous or intramuscular, in conjunction with dimercaprol, 1500 mg of edetate calcium disodium per square meter of body surface area a day, administered on a four-hour schedule for 5 days. {10}

Note: Some clinicians prefer that edetate calcium disodium be given by continuous intravenous infusion. If given by intramuscular route, it must be given at a separate site from dimercaprol.
Children with blood lead levels between 45 and 69 mcg per deciliter may be treated with edetate calcium disodium alone, using a dose of 1000 mg of edetate calcium disodium per square meter of body surface area a day for 5 days. {10}
A second course of treatment may be administered after a drug-free interval of at least two days. {10}
Children with lead encephalopathy may require additional courses of therapy. Therapy should continue if blood lead levels are greater than 45 mcg per dL.


[Lead mobilization test]1
Intravenous, 15 mg per kg of body weight (500 mg per square meter of body surface area) up to a maximum dose of 1 gram {28} over 1 hour. {03} The same dose can be mixed with procaine, so that the final concentration of procaine is 0.5%, and given intramuscularly. {03}


Strength(s) usually available
U.S.—


200 mg per mL (Rx) [Calcium Disodium Versenate]

Canada—


200 mg per mL (Rx) [Calcium Disodium Versenate]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer.

Preparation of dosage form:
Intravenous—Dilute 1 gram of edetate calcium disodium with 250 to 500 mL of 0.9% sodium chloride injection or 5% dextrose injection. {01}

Incompatibilities:
Edetate calcium disodium injection is physically incompatible with 10% dextrose injection, 10% invert sugar, 10% invert sugar in sodium chloride injection, lactated Ringer's injection, Ringer's injection, one-sixth molar sodium lactate injection, {22} and injectable preparations of amphotericin B and hydralazine hydrochloride. {04}

Additional information:
Contains 5.3 mEq of sodium per gram of edetate calcium disodium. {04}



Revised: 07/06/1992



References
  1. Calcium Disodium Versenate package insert (Riker—US), Rev 4/92, Rec 4/92.
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  1. CDC Preventing lead poisoning in young children, 1991.
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  1. Ellerhorn MJ, Barceloux DG. Medical toxicology. Diagnosis and treatment of human poisoning. New York: Elsevier, 1988.
  1. Drug facts and comparisons. St. Louis: Facts and Comparisons, Inc., 1985.
  1. AMA Drug evaluations, Annual 1991.
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  1. Graziano J, Lolacono N, Meyer P. Dose-response study of oral 2,3-dimercaptosuccinic acid in children with elevated blood lead concentrations. J Pediatr 1988; 113: 751-7.
  1. Reviewer comment, 1992.
  1. Panel comment, 1992.
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  1. Chisolm J. Mobilization of lead by calcium disodium edetate. Am J Dis Child 1987; 141: 1256-7.
  1. Markowitz M, Rosen J, Bijur P. Effects of iron deficiency on lead excretion in children with moderate lead intoxication. J Pediatr 1990; 116: 360-4.
  1. Thomas D, Chisolm J. Lead, zinc and copper decorporation during calcium disodium ethylenedeamine tetraacetate treatment of lead-poisoned children. J Pharm Exp Ther 1986; 239[3]: 829-35.
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