Calcium Disodium Versenate

Generic Name: Edetate Calcium Disodium
Class: Heavy Metal Antagonists
ATC Class: V03AB03
VA Class: AD300
CAS Number: 23411-34-9

Warning(s)

  • Fatality Risk
  • Risk of potentially fatal toxic effects.b (See Fatality Risk and also see Renal Effects under Cautions.)

  • Possible lethal increase in intracranial pressure following IV infusion in patients with lead encephalopathy and cerebral edema.b Manufacturer recommends IM administration in this patient population.b If administered IV, avoid rapid infusion.b (See Administration under Dosage and Administration and see Fatality Risk under Cautions.)

  • Follow dosage schedule; do not exceed recommended daily dose.b

  • Encephalopathy Risk
  • Lead encephalopathy occurs rarely in adults; occurs more often in pediatric patients, in whom encephalopathy may be incipient and overlooked and results in high mortality rate.b

Introduction

Heavy metal antagonist; used to chelates lead, but also chelates zinc and other heavy metals.a b d

Uses for Calcium Disodium Versenate

Lead Poisoning

Used for the reduction of blood and mobile depot lead in the treatment of acute and chronic lead poisoning and lead encephalopathy.a b c d f g h

Management of acute lead encephalopathy or symptoms suggestive of encephalopathy and symptomatic lead poisoning in patients with severe lead poisoning (blood lead concentration >100 mcg/dL in adults or >70 mcg/dL in pediatric patients).a f g h Used in conjunction with dimercaprol since edetate calcium disodium alone may aggravate manifestations of toxicity in patients with very high blood lead concentrations.101 103 111 b

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AAP considers edetate calcium disodium an alternative to succimer in asymptomatic pediatric patients with blood lead concentrations of 45–70 mcg/dL and who are intolerant or allergic to succimer or noncompliant with oral therapy.111 a f h

CDC and AAP do not recommend routine chelation therapy in pediatric patients with blood lead concentrations 25–45 mcg/dL.111 h

Chelation therapy not indicated in pediatric or adult patients with blood lead concentrations <25 mcg/dL or <70 mcg/dL, respectively.111 h

May be most effective when administered early in the course of acute poisoning; administration should be accompanied by appropriate supportive measures.a

Not a substitute for control of the lead hazard,a including effective measures to eliminate or reduce further lead exposure.b Patients should not be treated prophylactically with any chelating agent.a

Consult most recent AAP and CDC recommendations for information regarding chelation therapy.a

Has been reported to be useful in poisonings caused by alkyl lead compounds (e.g., tetraethyl lead).a However, chelation therapy has not been found to be clinically efficacious and experts recommend supportive therapy, with sedation, as necessary, for treatment of tetraethyl lead toxicity.h

Has been used parenterally as an aid in the diagnosis of suspected lead poisoning (the edetate calcium disodium mobilization or provocation test)a b when adequacy of patient’s response to chelation therapy is uncertain.a However, AAP and other experts state these tests are obsolete and have the potential for increased lead toxicity associated with administration of edetate calcium disodium alone, unreliability of the test, and expense.111 g

Calcium Disodium Versenate Dosage and Administration

General

  • Chelation therapy can increase lead absorption from the GI tract; therefore, remove patient from lead poisoning source once it has been identified.103 113 b Ensure that patient resides in lead-free environment during and after therapy.103 113

  • Various dosage regimens have been recommended in lead poisoning management;a total dose of edetate calcium disodium depends on patient’s response to, and tolerance of the selected agent,a as well as severity of lead toxicity.h

  • Subsequent course(s) of therapy may be required based on clinical symptoms and blood lead concentrations.h

  • Consult published protocols and specialized references for dosages of chelating agents, the method and sequence of administration, and specific information on precautions associated with chelation therapy.a

  • Maintain adequate hydration to ensure renal excretion of chelating agents.111

  • Prior to initiating therapy, ensure that adequate urine flow is established.b g

Administration

Administer by slow IV infusion or by IM injection.a b Should not be given orally since edetate calcium disodium enhances absorption of lead present in the GI tract; in addition, orally administered drug is poorly absorbed from the GI tract and is considered ineffective.a

Manufacturer states that IM injection is preferred route of administration for patients with lead encephalopathy and cerebral edema and may be preferred in young children.b However, most experts, including AAP and CDC, recommend administration by slow IV infusion whenever possible,101 103 111 g h and AAP states that clinical experience suggests slow IV infusion is safe and more appropriate for children than IM injection.111

IV Infusion

For solution and drug compatibility information, see Compatibility under Stability.

Administer by slow IV infusion as a single daily dose or in divided-dose infusions.a h

When administered by continuous IV infusion, interrupt infusion for 1 hour before obtaining a blood lead concentration to avoid falsely elevated blood lead concentrations.101

Dilution

Prior to administration, dilute with 250–500 mLb of 0.9% sodium chloride or 5% dextrose injectiona b to provide a final concentration of <0.5%.111 g h

Rate of Administration

Rapid IV infusions may increase risk of severe and potentially fatal adverse effects (e.g., increased intracranial pressure and cerebral edema).109 111

Administer slowly over several hours (e.g., 4 hours);111 manufacturer recommends slow IV infusion over 8–12 hours.b 111 May also be administered as a continuous infusion over 24 hours.g

IM Administration

When administered alone, daily dosage usually given in equally divided doses at 8–12 hour intervals.a b

When administered in conjunction with dimercaprol, daily dosage usually given in equally divided doses at 4-hour intervals.a

Dilution

To minimize pain at the injection site, add 0.25 mL of 10% lidocaine hydrochloride injection to 5 mL of edetate calcium disodium injection or, alternatively, add 1 mL of 1% lidocaine hydrochloride or 1 mL of 1% procaine hydrochloride injection to each mL of edetate calcium disodium injection to provide a final lidocaine or procaine hydrochloride concentration of 5 mg/mL (0.5%).a b (See Local Effects under Cautions.)

Dosage

Dosage same for IV and IM administration.109 (See Possible Prescribing and Dispensing Errors under Cautions.)

Pediatric Patients

Lead Poisoning

Consult most recent published protocols, including those from AAP and CDC, and specialized references for combination therapy dosage recommendations.a b

Encephalopathy, Symptoms Suggestive of Encephalopathy, or Blood Lead Concentration >70 mcg/dL
IV or IM

1500 mg/m2 or 50–75 mg/kg daily for 5 days; initiate administration 4 hours after initial IM administration of dimercaprol and immediately after second IM dose of dimercaprol.111 h Other experts recommend 1–1.5 g/m2 or 25–75 mg/kg daily for 5 days.g h Decision to repeat therapy should be based on clinical symptoms and blood lead concentrations.h If additional chelation therapy required, allow >2–4 days without treatment to elapse to allow redistribution of lead and to prevent depletion of essential metals before initiating a second 5-day course of therapy.111 a b g

Asymptomatic Patients with Blood Lead Concentration 45–70 mcg/dL
IV or IM

1 g/m2 or 25 mg/kg daily for 5 days.111 b g Decision to repeat therapy should be based on clinical symptoms and blood lead concentrations.111 h Allow 10–14 days without treatment to elapse to allow reequilibration before assessing blood lead concentrations and restarting therapy.h

Adults

Lead Poisoning

Consult most recent published protocols, including those from AAP and CDC, and specialized references for combination therapy dosage recommendations.a b

Encephalopathy, Symptoms Suggestive of Encephalopathy, or Blood Lead Concentration >100 mcg/dL
IV or IM

1.5 g/m2 or 50–75 mg/kg daily for 5 days; initiate administration 4 hours after initial IM administration of dimercaprol and immediately after second IM dose of dimercaprol.h Other experts recommend 1–1.5 g/m2 or 25–75 mg/kg daily for 5 days.g h

Asymptomatic Patients with Blood Lead Concentration <70 mcg/dL
IV or IM

Manufacturer recommends 1 g/m2 daily for 5 days.b However, most experts do not recommend chelation therapy in adult, asymptomatic patients with blood lead concentration <70 mcg/dL.h

Prescribing Limits

Pediatric Patients

Lead Poisoning
Encephalopathy, Symptoms Suggestive of Encephalopathy, or Blood Lead Concentration >70 mcg/dL
IV or IM

Maximum 1.5 g/m2 or 75 mg/kg daily.g h

Asymptomatic Patients with Blood Lead Concentration 45–70 mcg/dL
IV or IM

Maximum 1 g/m2 or 25–50 mg/kg daily.111 h

Adults

Lead Poisoning
Encephalopathy, Symptoms Suggestive of Encephalopathy, or Blood Lead Concentration >100 mcg/dL
IV or IM

Maximum 1.5 g/m2 or 75 mg/kg daily.g h

Asymptomatic Patients with Blood Lead Concentration <70 mcg/dL
IV or IM

Maximum 1 g/m2 daily.b

Special Populations

Hepatic Impairment

No specific dosage recommendations for hepatic impairment.b

Renal Impairment

Reduce dosage in patients with pre-existing mild renal disease;b some experts recommend maximum 50 mg/kg daily in patients with renal impairment.g Immediately discontinue administration if urine flow stops during therapy.b

Lead Poisoning
Lead Nephropathy
IV or IM

Dosage regimens may be repeated at monthly intervals until lead excretion is reduced toward normal.b

Table 1. Dosage for Treatment of Lead Poisoning in Adults with Lead Nephropathyb

Scr

Recommended Dosage

≤2

1 g daily for 5 days

2–3

500 mg every 24 hours for 5 days

3–4

500 mg every 48 hours for 3 doses

>4

500 mg once weekly

Geriatric Patients

No specific geriatric dosage recommendations.b

Cautions for Calcium Disodium Versenate

Contraindications

  • Anuria.b

  • Active renal disease.b

  • Hepatitis.b

Warnings/Precautions

Warnings

Possible Prescribing and Dispensing Errors

Ensure accuracy of prescription.c d Similarity in names of edetate calcium disodium (Versenate) and edetate disodium (Endrate; no longer commercially available in the US) has resulted in errors and adverse reactions, including fatalities.c d

Fatalities reported when edetate disodium has been administered instead of edetate calcium disodium (calcium disodium versenate) or when edetate disodium was used for “chelation therapies” or other nonapproved uses.c

When prescribing, use full product name; do not use the abbreviation “EDTA” when prescribing, dispensing, or administering edetate calcium disodium.c

Fatality Risk

Risk of potentially fatal toxic effects, including renal tubular necrosis, which may result in fatal nephrosis; follow recommended dosage schedule and do not exceed recommended daily dosage.a b (See Prescribing Limits under Dosage and Administration and see Renal Effects under Cautions.)

Potentially fatal increase in intracranial pressure with rapid IV infusion in patients with lead encephalopathy; administer by slow IV infusion or IM injection.a b

Major Toxicities

Renal Effects

Potential for dose-dependent nephrotoxicity,a b including renal tubular necrosis, proteinuria, and microscopic hematuria.b (See Fatality Risk under Cautions.) 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.a

Immediately discontinue therapy at first sign of renal toxicity (i.e., increasing proteinuria, increased number of erythrocytes, or if large renal epithelial cells are present).b

Hydropic degeneration of proximal renal tubular cells may occur; cells usually recover following discontinuance of therapy.109 b

Adequate diuresis prior to initiation of therapy may reduce drug-induced renal damage; monitor urine flow throughout therapy and stop therapy if anuria or severe oliguria develops.a b Administer IV fluids prior to first dose to establish urine flow, particularly in acutely ill patients at risk of dehydration from vomiting;a b however, avoid excess fluid in patients with concurrent encephalopathy.b

Drug may produce same signs of renal damage as lead poisoning (e.g., proteinuria, microscopic hematuria).a

General Precautions

Cardiovascular Effects

Possible ECG changes (e.g., inversion of the T wave); monitor for cardiac rhythm irregularities and ECG changes during therapy.a b

Other Therapeutic Measures

Chelation therapy should not be a substitute for effective measures to eliminate or reduce further lead exposure.b (See Lead Poisoning under Uses.)

Parenteral chelation therapy may increase absorption of lead in the GI tract; consider bowel decontamination as an adjunct to chelation therapy.111 h

Laboratory Monitoring

Monitor serum electrolyte concentrations and hepatic function 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.b

Monitor renal function (e.g., BUN determinations) before and periodically during each course of therapy to detect renal impairment.a Perform urinalyses and urinary sediment determinations daily during therapy in severe cases of lead poisoning and after the second and fifth day of therapy in moderate cases of lead poisoning.b Discontinue therapy immediately at the first sign of renal toxicity, including increasing proteinuria, an increased number of erythrocytes, or presence of large renal epithelial cells.a b

Hepatic Effects

Potential for reduced alkaline phosphatase levels (possibly due to reduced serum zinc levels and increased serum AST and ALT concentrations); usually return to normal within 48 hours after cessation of therapy.b

Metabolic Effects

Possible zinc deficiencyb or hypercalcemia.b

Local Effects

Possible thrombophlebitis with IV infusion of concentrations >0.5%; dilute drug before IV infusion to avoid thrombophlebitis.a

Possible injection site pain following IM administration; concomitant administration of a local anesthetic may minimize pain.b

Specific Populations

Pregnancy

Category B.b e If drug is indicated, maternal benefit appears to outweigh fetal risk;e however, only use drug during pregnancy if clearly needed.b

Lactation

Not known whether edetate calcium disodium is distributed into human milk;b however, breastfeeding is contraindicated in women receiving edetate calcium disodium because maternal lead poisoning itself creates a risk of exposing nursing infant to the toxic lead.e

Pediatric Use

Edetate calcium disodium has been used in the management of lead poisoning in all age groups, including pediatric patients.a

Lead encephalopathy occurs more often in pediatric patients, in whom encephalopathy may be incipient and overlooked and results in high mortality rate.b

Hepatic Impairment

Contraindicated in patients with hepatitis.b (See Contraindications.)

Renal Impairment

Contraindicated in patients with active renal disease.b (See Contraindications.) Use with extreme caution and in reduced dosage in patients with mild renal disease.109 b

Common Adverse Effects

Injection site pain.b

Interactions for Calcium Disodium Versenate

Specific Drugs

Drug

Interaction

Insulin, zinc-containing preparations

Interference with action of insulin due to chelation of zincb

Steroids

Potential increased renal toxicityb

Calcium Disodium Versenate Pharmacokinetics

Absorption

Bioavailability

Poorly absorbed from the GI tract.b

Well absorbed following IM or sub-Q administration.a

Onset

Following IV administration, urinary excretion of chelated lead begins within about 1 hour; peak excretion of chelated lead occurs within 24–48 hours.a

Distribution

Extent

Distributed primarily into the extracellular fluid;a b in blood, all drug found in plasma.b Does not appear to penetrate erythrocytes.a b

Does not enter CSF in any appreciable quantity;a approximately 5% of the plasma concentration is found in spinal fluid.b g

Elimination

Metabolism

Does not undergo metabolism.a b

Elimination Route

Rapidly excreted by glomerular filtration into the urine unchanged or as metal chelates.a Within 1 hour following IV administration, approximately 50% of drug is excreted; over 95% is excreted within 24 hours.a b

Half-life

IV administration: 20–60 minutes.a b

IM administration: 1.5 hours.a

Special Populations

Excretion rate not affected by changes in urine flow and/or pH; however, impaired renal function with reduced glomerular filtration delays drug excretion and may increase nephrotoxicity.a

Stability

Storage

Parenteral

Injection

15–30°C.a b

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Incompatible with dextrose 10%, invert sugar 10% in water, invert sugar 10% in sodium chloride 0.9%, Ringer’s injection, lactated Ringer’s injection, and sodium lactate (1/6) M.HID

Drug CompatibilityHID
Admixture Compatibility

Incompatible

Amphotericin B

Hydralazine HCl

Actions

  • Forms a stable chelate with divalent and trivalent metals (e.g., lead, zinc, cadmium, manganese, iron, mercury) that can displace calcium in the edetate calcium disodium molecule;b the chelate then can be excreted in urine.a

  • Does not cause substantial changes in serum or total body calcium concentrations following IV administration of large doses because edetate calcium disodium is saturated with calcium.a

  • Theoretically, 1 g of edetate calcium disodium sequesters 620 mg of lead; however, an average of only 3–5 mg of lead is excreted in urine following parenteral administration of 1 g in patients with acute lead poisoning or high concentrations of lead in soft tissues.a

  • Orally administered edetate calcium disodium increases excretion of lead in urine and may enhance absorption of lead.a

  • Parenterally administered edetate calcium disodium chelates and greatly increases urinary excretion of zinc and, to a much lesser extent, cadmium, manganese, iron, and copper.a b Increases excretion of uranium, plutonium, yttrium, and some other heavier radioactive isotopes to a limited extent.a

  • Mercury readily displaces calcium from edetate calcium disodium in vitro; however, patients with mercury poisoning do not respond to the drug.a

Advice to Patients

  • Importance of identifying source of lead poisoning and then removing patient from that source.111 a b h Importance of patient residing in an environment that is lead-free during and after therapy.103 113

  • Importance of patients notifying physician immediately if urine output stops for a period of 12 hours.b

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.b

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.b

  • Importance of informing patients of other important precautionary information. b (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Edetate Calcium Disodium

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection

200 mg/mL

Calcium Disodium Versenate

Graceway

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions June 1, 2009. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

100. Centers for Disease Control. Preventing lead poisoning in young children: a statement by the Centers for Disease Control. J Pediatr. 1978; 93:709-20. [PubMed 212543]

101. Piomelli S, Rosen JF, Chisolm JJ Jr et al. Management of childhood lead poisoning. J Pediatr. 1984; 105:523-32. [IDIS 190925] [PubMed 6481529]

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.

104. Agency for Toxic Substances and Disease Registry and CDC Center for Environmental Health and Injury Control. Childhood lead poisoning—United States: report to Congress by the Agency for Toxic Substances and Disease Registry. MMWR Morb Mortal Wkly Rep. 1988; 37:481-5. [IDIS 244783] [PubMed 3135478]

105. Agency for Toxic Substances and Disease Registry. The nature and extent of lead poisoning in children in the United States: a report to Congress. Atlanta, GA: US Department of Health and Human Services, Public Health Service; 1988 Jul.

106. American Academy of Pediatrics Committee on Environmental Hazards and Committee on Accident and Poison Prevention. Statement on childhood lead poisoning. Pediatrics. 1987; 79:457-65. [IDIS 227025] [PubMed 3822655]

107. Markowitz ME, Rosen JF. Assessment of lead stores in children: validation of an 8-hour CaNa2EDTA provocative test. J Pediatrics. 1984; 104:337-2.

108. Weinberger HL, Post EM, Schneider T et al. An analysis of 248 initial mobilization tests performed on an ambulatory basis. Am J Dis Child. 1987; 141:1266-70. [PubMed 3120575]

109. 3M Pharmaceuticals. Calcium disodium Versenate (edetate calcium disodium injection) prescribing information. Northridge, CA; 1997 Aug.

110. Markowitz ME, Rosen JF, Bijur PE. Effects of iron deficiency on lead excretion in children with moderate lead intoxication. J Pediatr. 1990; 116:360-4. [IDIS 298045] [PubMed 2106578]

111. Committee on Drugs, American Academy of Pediatrics. Treatment guidelines for lead exposure in children. Pediatrics. 1995; 96:155-60. [IDIS 349805] [PubMed 7596706]

112. Schwartz J, Landrigan PJ, Feldman RG et al. Threshold effect in lead-induced peripheral neuropathy. J Pediatr. 1988; 112:12-17. [IDIS 237788] [PubMed 2826742]

113. Committee on Environmental Health, American Academy of Pediatrics. Lead poisoning: from screening to primary prevention. Pediatrics. 1993; 92:176-83. [PubMed 8516071]

a. AHFS Drug Information 2007. McEvoy GK, ed. Edetate Calcium Disodium. Bethesda, MD: American Society of Health-System Pharmacists; 2007. From AHFS Drug Information website.

b. Graceway Pharmaceuticals. Calcium disodium Versenate (edetate calcium disodium injection) prescribing information. Lake Forest, IL; July 2004.

c. FDA Public Health Advisory: Edetate disodium (marketed as Endrate and generic products); 2008. From FDA website.

d. MMWR. Deaths associated with hypocalcemia from chelation therapy - Texas, Pennsylvania, and Oregon, 2003-2005. March 2006: 55(08): 204-207. Centers for Disease Control. From CDC website.

e. Briggs GC, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005: 536-538.

f. . American Academy of Pediatrics, Committee on Environmental Health. Lead exposure in children: prevention, detection, and management. Pediatrics. 2005; 116:1036-46.

g. Howland, MA. Edetate Calcium Disodium (CaNa2 EDTA). In: Flomenbaum NE, Goldfrank LR, Hoffman RS et al, eds. Goldfrank’s toxicologic ermergencies. 8th ed. New York: McGraw-Hill; 2006:1331-3.

h. Henretig FM. Lead. In: Flomenbaum NE, Goldfrank LR, Hoffman RS et al, eds. Goldfrank’s toxicologic emergencies. 8th ed. New York: McGraw-Hill; 2006:1308-24.

HID. Trissel LA. Handbook on injectable drugs. 14th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2007:608.

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