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  • CLASSES

    Antidotes, Systemic
    Chelating Agents

    BOXED WARNING

    Children, encephalopathy, increased intracranial pressure, intravenous administration

    Calcium disodium versenate (also known as edetate calcium disodium, calcium EDTA) is capable of producing toxic effects during the treatment of lead toxicity, and these effects can be fatal. Lead encephalopathy is relatively rare in adults, but occurs more often in children in whom it may be incipient and thus overlooked. The mortality rate in pediatric patients has been high. Intravenous administration of calcium EDTA can result in increased intracranial pressure and patients with lead encephalopathy and cerebral edema may experience a lethal increase in intracranial pressure following intravenous infusion. The intramuscular route is preferred for these patients. In cases where the intravenous route is necessary, avoid rapid infusion. The dosage schedule should be followed and at no time should the recommended daily dose be exceeded.

    DEA CLASS

    Rx

    DESCRIPTION

    Chelating agent; reduces blood concentrations and depot stores of lead.

    COMMON BRAND NAMES

    Calcium Disodium Versenate

    HOW SUPPLIED

    Calcium Disodium Versenate Intramuscular Inj Sol: 1mL, 200mg
    Calcium Disodium Versenate Intravenous Inj Sol: 1mL, 200mg

    DOSAGE & INDICATIONS

    For the treatment of lead toxicity.
    For the diagnosis of lead toxicity in patients with a blood lead concentration of 25 to 45 mcg/dL (i.e., the calcium EDTA mobilization test).
    NOTE: Appropriate therapy should not be delayed for performance of a mobilization test, especially in patients who are symptomatic or whose blood lead concentration is > 45 mcg/dL. The American Academy of Pediatrics considers use of the mobilization test obsolete because of factors such as inconsistent prediction of the total body burden of lead, technical difficulties in administering the test, cost, and the potential for increased lead toxicity associated with administration of calcium EDTA alone.
    Intramuscular or Intravenous dosage
    Adults and Adolescents

    500 mg/m2 IV (infused over 1 hour) or by IM injection. Urine is collected for 24 hours following administration of edetate calcium disodium. The mobilization test is considered positive if the ratio of mcg of lead excreted in urine to mg of calcium EDTA administered is greater than 1.

    Children

    500 mg/m2 (Max: 1 g) IV over 1 hour, or by IM injection given as a single dose or 2 divided doses given 12 hours apart. Urine is collected for 24 hours following administration of edetate calcium disodium. If the ratio of mcg of lead excreted in urine to mg of calcium EDTA administered is greater than 1, the mobilization test is considered positive. Some experts recommend an 8-hour mobilization test using a single dose of 500 mg/m2 IV over 1 hour, or by IM injection. The test is positive if the ratio of mcg of lead excreted in urine to mg of calcium EDTA administered is greater than 0.5 to 0.6. Alternatively, a dose of 50 mg/kg (Max: 1 g) IM may be administered, with urine collected for 6 to 8 hours following administration of the dose. If the ratio of mcg of lead excreted in urine to mg of calcium EDTA administered is greater than 0.5 or urine lead concentration is greater than 1 mg/L, the test is considered positive.

    For the treatment of severe lead toxicity (i.e., encephalopathy or blood lead concentrations greater than 70 mcg/dL) in combination with dimercaprol.
    Intravenous or Intramuscular dosage

    NOTE: Lead encephalopathy occurs more frequently in children than adults. Lethal increases in intracranial pressure have been reported in patients with lead encephalopathy and cerebral edema following the intravenous administration of edetate calcium disodium. The intramuscular route is preferred for these patients. However, intramuscular administration is painful at the site of injection. If the intravenous route is necessary, infuse slowly and monitor the patient carefully. Do not exceed the recommended dose.

    Adults, Adolescents, Children, and Infants

    The first dose of edetate calcium disodium should be given 4 or more hours after the initial dimercaprol injection, when urine flow has been established. Administer calcium EDTA 1,500 mg/m2 as an IV infusion, preferably over 12 to 24 hours, in combination with IM dimercaprol. If fluid restriction is desired (e.g., patients with encephalopathy or cerebral edema), the total dose can be given IM in equally divided doses at 8 to 12 hour intervals. Continue with calcium EDTA 1,500 mg/m2/day for 5 days, in combination with dimercaprol for at least the first 3 days of therapy. A second 5-day course of therapy (after at least 2 days without treatment) is recommended in patients with severe poisoning. Patients with a residual blood lead concentration greater than 70 mcg/dL should receive combined therapy with calcium EDTA plus dimercaprol. Patients with residual concentrations of 45 to 69 mcg/dL should receive calcium EDTA alone. A third course of therapy with calcium EDTA alone is required only if blood lead concentration rebounds to greater than 45 mcg/dL within 48 hours after the second treatment course. Wait at least 5 to 7 days before beginning a third course (if indicated), unless clinical status dictates earlier treatment.

    For the treatment of asymptomatic patients with blood lead concentrations of 45 to 69 mcg/dL.
    Intramuscular or Intravenous dosage
    Adults, Adolescents, Children, and Infants

    The calcium EDTA dosage is 1,000 mg/m2/day by IV infusion, administered over 8 to 24 hours (NOTE: The American Academy of Pediatrics suggests that therapy with oral succimer is preferred in patients with blood lead concentrations of 45 to 69 mcg/dL who do not have symptoms of lead encephalopathy). An alternative calcium EDTA regimen is 25 mg/kg/day by IV infusion over 8 to 24 hours. Therapy is generally continued for 5 days. Although the IV route is preferred, calcium EDTA may also be given IM in divided doses at 8 to 12 hour intervals. A second course of therapy may be required if the blood lead concentration rebounds to 45 mcg/dL or higher within 7 to 14 days after treatment. Allow 5 to 7 days without treatment before beginning a second course of calcium EDTA.

    For the treatment of adults with lead nephropathy.
    Intramuscular or Intravenous dosage
    Adults with SrCr less than 2 mg/dL

    1 g/m2/day IV over 8 to 24 hours (or by IM injection) for 5 days. May repeat monthly until lead excretion is reduced toward normal.

    Adults with SCr 2 to 3 mg/dL

    500 mg/m2/day IV over 8 to 24 hours (or by IM injection) for 5 days. May repeat monthly until lead excretion is reduced toward normal.

    Adults with SCr 3.1 to 4 mg/dL

    500 mg/m2 IV over 8 to 24 hours (or by IM injection), given every 48 hours for 3 doses. May repeat monthly until lead excretion is reduced toward normal.

    Adults with SCr higher than 4 mg/dL

    500 mg/m2 IV over 8 to 24 hours (or by IM injection), given once per week. May repeat monthly until lead excretion is reduced toward normal.

    MAXIMUM DOSAGE

    Adults

    1500 mg/m2/day IV or IM.

    Elderly

    1500 mg/m2/day IV or IM.

    Adolescents

    1500 mg/m2/day IV or IM.

    Children

    1500 mg/m2/day IV or IM.

    Infants

    1500 mg/m2/day IV or IM.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific dosage guidelines have not been established; however calcium EDTA is contraindicated in patients with hepatitis.

    Renal Impairment

    Specific dosage guidelines have not been established; however, dosage guidelines based on serum creatinine have been suggested for patients with lead nephropathy. These guidelines may also be useful for patients with preexisting renal impairment. The manufacturer states that edetate calcium disodium is contraindicated in patients with active renal disease.

    ADMINISTRATION

     
    NOTE: Edetate calcium disodium (i.e., calcium EDTA) may aggravate symptoms associated with toxic lead levels in patients with blood lead levels > 70 mcg/dL. In these patients, calcium EDTA should be used in conjunction with dimercaprol. Patients may be severely dehydrated and urine flow should be established before the first dose is given, although excessive fluid intake should be avoided in patients with encephalopathy. The allowable upper limit of blood lead levels is 20 mcg/mL according to the World Health Organization.

    Injectable Administration

    Edetate calcium disodium is administered intramuscularly or intravenously.
    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    NOTE: Lethal increases in intracranial pressure have been reported in patients with lead encephalopathy and cerebral edema following intravenous administration. The intramuscular route is preferred for these patients. If the intravenous route is necessary, infuse slowly and monitor the patient carefully.
    Dilute the total daily dose of edetate calcium disodium injection in 250—500 mL of 5% Dextrose injection or 0.9% Sodium Chloride injection to a final concentration of 2—4 mg/mL.
    Intermittent infusion: Using an infusion pump, administer the diluted injection over 1 hour. NOTE: For the treatment of lead toxicity, the manufacturer recommends that the total daily dose be administered as a single infusion over 8—12 hours.
    Continuous infusion: Infuse over 8—24 hours. The infusion should be interrupted for 1 hour before a blood lead concentration is measured to avoid a falsely elevated value.

    Intramuscular Administration

    Intramuscular injection is the preferred route of administration for patients at high risk for cerebral edema. Lethal increases in intracranial pressure have been reported in patients with lead encephalopathy and cerebral edema following the intravenous administration.
    Intramuscular administration of calcium EDTA is painful. To minimize pain at the injection site, lidocaine or procaine may be added to edetate calcium disodium injection. A final lidocaine or procaine concentration of 0.5% (5 mg/mL) can be obtained as follows: 0.25 mL of 10% lidocaine solution per 5 mL of edetate calcium disodium; or 1 mL of 1% lidocaine or 1% procaine solution per ml of edetate calcium disodium.
    Inject deeply into a well developed muscle. Aspirate prior to injection to avoid injection into a blood vessel. Massage injection site well following administration. Injection sites should be rotated.

    STORAGE

    Calcium Disodium Versenate:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Anuria, oliguria, renal disease

    Calcium EDTA is contraindicated for use in patients with anuria (or severe oliguria). The drug should not be administered to patients with active renal disease because this can reduce the excretion of the chelate and increase the possibility of nephrotoxicity. The EDTA-lead complex is highly nephrotoxic. In patients with anuria or oliguria, urine flow should be restored before reinstituting calcium EDTA therapy. Calcium EDTA should be used with caution in patients with dehydration secondary to vomiting or diarrhea, and urine flow should be reestablished before administration of the first dose of calcium EDTA. Once urine flow is reestablished, IV fluids must be restricted to basal water and electrolyte requirements.

    Children, encephalopathy, increased intracranial pressure, intravenous administration

    Calcium disodium versenate (also known as edetate calcium disodium, calcium EDTA) is capable of producing toxic effects during the treatment of lead toxicity, and these effects can be fatal. Lead encephalopathy is relatively rare in adults, but occurs more often in children in whom it may be incipient and thus overlooked. The mortality rate in pediatric patients has been high. Intravenous administration of calcium EDTA can result in increased intracranial pressure and patients with lead encephalopathy and cerebral edema may experience a lethal increase in intracranial pressure following intravenous infusion. The intramuscular route is preferred for these patients. In cases where the intravenous route is necessary, avoid rapid infusion. The dosage schedule should be followed and at no time should the recommended daily dose be exceeded.

    Hepatitis

    Calcium EDTA is contraindicated in patients with hepatitis.

    Pregnancy

    Calcium EDTA is classified as FDA pregnancy risk category B. No adequate human studies have examined the effects of this drug on the human fetus; however, animal studies have revealed no adverse fetal or reproductive effects. Consider the benefits of the drug to the mother, the potential risks to the fetus, and the potential adverse effects to both resulting from untreated lead poisoning. The manufacturer advises use during pregnancy only if clearly needed.

    Breast-feeding

    Advise patients requiring calcium EDTA for treatment of lead poisoning to avoid breast-feeding; lead is excreted in breast milk and is toxic to nursing infants. Data are limited regarding use of calcium EDTA in lactating women and its excretion in human milk is unknown. Although the drugs low molecular weight (374) suggests excretion in breast milk, its short half-life (20—60 minutes) and poor oral bioavailability may limit the potential exposure in a nursing infant.

    ADVERSE REACTIONS

    Severe

    anuria / Delayed / Incidence not known
    proteinuria / Delayed / Incidence not known
    renal tubular necrosis / Delayed / Incidence not known
    oliguria / Early / Incidence not known
    increased intracranial pressure / Early / Incidence not known

    Moderate

    hematuria / Delayed / Incidence not known
    glycosuria / Early / Incidence not known
    hypotension / Rapid / Incidence not known
    zinc deficiency / Delayed / Incidence not known
    anemia / Delayed / Incidence not known
    hypercalcemia / Delayed / Incidence not known

    Mild

    malaise / Early / Incidence not known
    fatigue / Early / Incidence not known
    chills / Rapid / Incidence not known
    fever / Early / Incidence not known
    myalgia / Early / Incidence not known
    headache / Early / Incidence not known
    tremor / Early / Incidence not known
    polydipsia / Early / Incidence not known
    nausea / Early / Incidence not known
    vomiting / Early / Incidence not known
    anorexia / Delayed / Incidence not known
    cheilitis / Delayed / Incidence not known
    rash (unspecified) / Early / Incidence not known
    sneezing / Early / Incidence not known
    nasal congestion / Early / Incidence not known
    lacrimation / Early / Incidence not known

    DRUG INTERACTIONS

    Azelaic Acid; Copper; Folic Acid; Nicotinamide; Pyridoxine; Zinc: (Major) Concomitant use of zinc supplements with calcium EDTA can decrease the effectiveness of both agents due to chelation. Zinc salts should not be administered until edetate calcium therapy is completed.
    Calcium Carbonate: (Major) Because edetate disodium chelates and lowers serum calcium, oral or parenteral calcium salts should not be administered concomitantly.
    Calcium Carbonate; Magnesium Hydroxide: (Major) Because edetate disodium chelates and lowers serum calcium, oral or parenteral calcium salts should not be administered concomitantly.
    Calcium Carbonate; Risedronate: (Major) Because edetate disodium chelates and lowers serum calcium, oral or parenteral calcium salts should not be administered concomitantly.
    Calcium Salts: (Major) Because edetate disodium chelates and lowers serum calcium, oral or parenteral calcium salts should not be administered concomitantly.
    Calcium: (Major) Because edetate disodium chelates and lowers serum calcium, oral or parenteral calcium salts should not be administered concomitantly.
    Calcium; Vitamin D: (Major) Because edetate disodium chelates and lowers serum calcium, oral or parenteral calcium salts should not be administered concomitantly.
    Carbetapentane; Guaifenesin; Phenylephrine: (Major) Concomitant use of zinc supplements with calcium EDTA can decrease the effectiveness of both agents due to chelation. Zinc salts should not be administered until edetate calcium therapy is completed.
    Carbetapentane; Phenylephrine: (Major) Concomitant use of zinc supplements with calcium EDTA can decrease the effectiveness of both agents due to chelation. Zinc salts should not be administered until edetate calcium therapy is completed.
    Cardiac glycosides: (Major) The pharmacodynamic actions of edetate disodium oppose those of the cardiac glycosides.
    Chlorpheniramine; Pseudoephedrine: (Major) Concomitant use of zinc supplements with calcium EDTA can decrease the effectiveness of both agents due to chelation. Zinc salts should not be administered until edetate calcium therapy is completed.
    Chromium: (Major) Because edetate disodium chelates and lowers serum calcium, oral or parenteral calcium salts should not be administered concomitantly.
    Collagenase: (Major) Because edetate disodium chelates and lowers serum calcium, oral or parenteral calcium salts should not be administered concomitantly.
    Cyanocobalamin, Vitamin B12: (Major) Because edetate disodium chelates and lowers serum calcium, oral or parenteral calcium salts should not be administered concomitantly.
    Digitoxin: (Major) The pharmacodynamic actions of edetate disodium oppose those of the cardiac glycosides.
    Digoxin: (Major) The pharmacodynamic actions of edetate disodium oppose those of the cardiac glycosides.
    Hetastarch; Dextrose; Electrolytes: (Major) Administration of oral magnesium with edetate disodium, disodium EDTA may result in binding of magnesium. Do not administer oral magnesium salts within 1 hour of edetate disodium, EDTA (Major) Because edetate disodium chelates and lowers serum calcium, oral or parenteral calcium salts should not be administered concomitantly.
    Insulins: (Minor) Use caution in administration of calcium EDTA to patients with diabetes mellitus who are receiving insulin therapy. Calcium EDTA chelates the zinc in selected exogenous insulins, thereby increasing the amount of insulin available to the body and decreasing the duration of the insulin dose. Alterations in blood glucose control may result. Diabetic patients receiving calcium EDTA may require adjustments in their insulin dosage.
    Iron Salts: (Major) Because edetate disodium chelates and lowers serum calcium, oral or parenteral calcium salts should not be administered concomitantly.
    Magnesium Citrate: (Major) Administration of oral magnesium citrate with edetate disodium, disodium EDTA may result in binding of magnesium. Do not administer oral magnesium salts within 1 hour of edetate disodium, EDTA.
    Magnesium Salts: (Major) Administration of oral magnesium with edetate disodium, disodium EDTA may result in binding of magnesium. Do not administer oral magnesium salts within 1 hour of edetate disodium, EDTA
    Magnesium: (Major) Administration of oral magnesium with edetate disodium, disodium EDTA may result in binding of magnesium. Do not administer oral magnesium salts within 1 hour of edetate disodium, EDTA
    Pantothenic Acid, Vitamin B5: (Major) Because edetate disodium chelates and lowers serum calcium, oral or parenteral calcium salts should not be administered concomitantly.
    Pyridoxine, Vitamin B6: (Major) Because edetate disodium chelates and lowers serum calcium, oral or parenteral calcium salts should not be administered concomitantly.
    Succimer: (Moderate) Concomitant use of succimer and other chelation therapy such as edetate calcium disodium, calcium EDTA (CaNa2EDTA) with or without dimercaprol (BAL) is not recommended, as data are not available. Patients who have received CaNa2EDTA with or without dimercaprol may use succimer for subsequent treatment after an interval of 4 weeks.
    Zinc Salts: (Major) Because edetate disodium chelates and lowers serum calcium, oral or parenteral calcium salts should not be administered concomitantly. (Major) Concomitant use of zinc supplements with calcium EDTA can decrease the effectiveness of both agents due to chelation. Zinc salts should not be administered until edetate calcium therapy is completed.
    Zinc: (Major) Concomitant use of zinc supplements with calcium EDTA can decrease the effectiveness of both agents due to chelation. Zinc salts should not be administered until edetate calcium therapy is completed.

    PREGNANCY AND LACTATION

    Pregnancy

    Calcium EDTA is classified as FDA pregnancy risk category B. No adequate human studies have examined the effects of this drug on the human fetus; however, animal studies have revealed no adverse fetal or reproductive effects. Consider the benefits of the drug to the mother, the potential risks to the fetus, and the potential adverse effects to both resulting from untreated lead poisoning. The manufacturer advises use during pregnancy only if clearly needed.

    Advise patients requiring calcium EDTA for treatment of lead poisoning to avoid breast-feeding; lead is excreted in breast milk and is toxic to nursing infants. Data are limited regarding use of calcium EDTA in lactating women and its excretion in human milk is unknown. Although the drugs low molecular weight (374) suggests excretion in breast milk, its short half-life (20—60 minutes) and poor oral bioavailability may limit the potential exposure in a nursing infant.

    MECHANISM OF ACTION

    Calcium EDTA is a chelating agent with an affinity for divalent and trivalent metals. Once administered, the calcium component of calcium EDTA can be displaced by other divalent and trivalent metals, forming stable, soluble complexes that are then excreted by the kidneys. EDTA has a greater affinity for lead than for calcium and releases calcium to bind with lead. The noncalcium-containing formulation of EDTA should not be used to treat lead toxicity because it will preferentially bind calcium, and serious hypocalcemia can result.
     
    One gram of edetate calcium disodium has the potential to combine with 620 mg of lead. Typically, however, only 3—5 mg of lead are excreted in response to a 1 g dose of the drug when administered to patients with acute lead poisoning or high levels of lead in the soft tissues.
     
    Once calcium EDTA is circulating in the bloodstream and extracellular fluids, it can increase the urinary excretion of lead, but orally administered dosages of the drug increase the absorption of lead. Therefore, calcium EDTA is only administered subcutaneously, intravenously, or intramuscularly. The excretion of zinc is greatly increased following administration of calcium EDTA, and although mercury will displace calcium from its binding site on calcium EDTA, the drug is not effective in treating mercury poisoning, perhaps because mercury is too tightly bound to the ligands of the tissues or is sequestered in compartments of the body that calcium EDTA does not penetrate. Calcium EDTA is also not effective in the treatment of gold or arsenic poisoning.

    PHARMACOKINETICS

    Calcium EDTA is administered  subcutaneously, intravenously, or intramuscularly. Increased urinary lead excretion is evident 1 hour after IV administration. Peak excretion of lead is achieved within 24—48 hours. Lead poisoning-induced colic can resolve within 2 hours, tremors and weakened muscles disappear within 4—5 days, and coproporphyrinuria is reduced within 4—9 days after initiation of therapy. The drug distributes predominantly into the extracellular fluid and does not enter erythrocytes or the CNS to a significant extent. Calcium EDTA is not metabolized and is excreted primarily by the kidneys as unchanged drug or as metal chelates. The half-life is 1.5 hours for an intramuscularly administered dose and 20—60 minutes for an intravenously administered dose.

    Intravenous Route

    Calcium EDTA is rapidly absorbed following intravenous administration.

    Intramuscular Route

    Calcium EDTA is rapidly absorbed following intramuscular administration.

    Subcutaneous Route

    Calcium EDTA is rapidly absorbed following subcutaneous administration.