Edetate Disodium Injection

Overview of Edetate Disodium (EDTA) Injection

Dosage Strength of Edetate Disodium Injection

150 mg/mL Preservative Free 30 mL Vial

General Information

Edetate disodium, a chelating agent with affinity for divalent and trivalent metals, is indicated in the treatment of hypercalcemia. Because the drug can decrease blood calcium levels too rapidly (causing tetany, cardiac arrhythmias, and respiratory arrest), it now is only rarely used. Due to its pharmacodynamic actions that oppose those of the cardiac glycosides, edetate disodium was once used to treat arrhythmias associated with digitalis toxicity, but digoxin immune Fab is now the preferred agent for this condition. Edetate disodium should not be confused with its calcium salt (calcium EDTA), which is used to treat lead toxicity. In the 1950s and 1960s, edetate disodium was used for atherosclerotic vascular disease despite a lack of clinical data to support its efficacy. Only 1 large, placebo-controlled, randomized, double-blind study has been conducted to evaluate this use of edetate disodium and this study showed no significant symptomatic or angiographic improvement in the EDTA group relative to placebo.1 Nevertheless, there continues to be sustained interest in using this drug for the treatment of atherosclerosis. Based on a recent clinical trial (PATCH), there is no evidence to support a benefit (evaluated exercise time to ischemia, exercise capacity, and quality of life measurements) of chelation therapy (Endrate®) in patients with ischemic heart disease including stable angina.2 Because of the possibility of potentially lethal adverse effects, edetate disodium should not be used for the treatment of generalized arteriosclerosis due to advancing age. Edetate disodium was approved by the FDA for clinical use in 1956.

Mechanism of Action

Edetate disodium preferentially binds calcium ions, forming a stable, soluble complex that is then excreted by the kidneys. Serum calcium levels decrease quickly following intravenous administration of edetate disodium, and 1 gm of edetate disodium has the potential to combine with 120 mg of calcium. The decrease in calcium precipitated by administration of the drug antagonizes the inotropic and chronotropic effects that digitalis glycosides exert on the ventricles of the heart, thereby helping to control digitalis-induced ventricular arrhythmias. In addition, edetate disodium exhibits negative cardiac inotropic activity. A too rapid decrease in serum calcium induced by edetate disodium can precipitate hypocalcemic tetany, seizures, severe cardiac arrhythmias, and respiratory arrest, but these effects are usually related to high doses or rapid infusion rates. Slow IV infusion allows time for calcium in bone to be mobilized to replenish the serum calcium pool, thereby lowering the risk of developing these adverse effects. The concentration of calcium ions in the cerebrospinal fluid is not affected by edetate disodium administration.

Edetate disodium also chelates and enhances the excretion of other trace metals including magnesium and zinc, and although the drug does not chelate potassium, the administration of edetate disodium can increase renal excretion and decrease serum concentration of this mineral, possibly producing hypokalemia. At one time, it was thought the calcium-lowering actions of edetate disodium could be utilized in the management of atherosclerosis but this use has been refuted.1 Edetate disodium is still advocated as a treatment for this condition and now its proponents claim that the drug works by chelating iron and copper, thereby impairing the generation of free radicals.3 This mechanism has not been verified. The use and mechanism of action of edetate disodium for this condition remains speculative.

Pharmacokinetics

Edetate disodium is administered intravenously, and although the distribution of the drug has not been established, it does not appear to cross the blood-brain barrier to a significant extent. No metabolism of the drug occurs, and an intravenous dose is excreted primarily as the calcium chelate. Approximately 95% of a dose is excreted in the urine within 24 hours.

Special Populations:

Renal Impairment: Impaired renal function can reduce the excretion of edetate disodium, possibly leading to nephrotoxicity.

Indications

For the treatment of hypercalcemia, or, for treatment of cardiac glycoside-induced arrhythmias (i.e., ventricular arrhythmias associated with digitalis toxicity):

Intravenous dosage:

Adults: 50 mg/kg/day (up to 3 g/day) administered by slow IV infusion. Frequency and duration of administration are quite variable, and should be determined based on the patient's serum calcium. Five consecutive daily doses may be administered, followed by 2 days without medication, repeating these courses as necessary to a total of 15 doses.

Maximum Dosage Limits:

Adults: 50 mg/kg/day IV, not to exceed 3 g/day.
Elderly: 50 mg/kg/day IV, not to exceed 3 g/day.
Adolescents: Safety and efficacy have not been established, although doses up to 70 mg/kg/day IV (not to exceed 3 g/day IV) have been used.
Children: Safety and efficacy have not been established, although doses up to 70 mg/kg/day IV have been used.

Patients with Hepatic Impairment Dosing:

Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Patients with Renal Impairment Dosing:

Specific guidelines for dosage adjustments in renal impairment are not available; edetate disodium is contraindicated in anuric patients. Patients with renal impairment may be at higher risk for adverse effects.

General Administration Information

For storage information, see the specific product information within the How Supplied section.

NOTE: Because of the possibility of potentially lethal adverse effects, edetate disodium should not be used for the treatment of generalized arteriosclerosis due to advancing age. There is no acceptable scientific evidence to support the use of edetate disodium in treating atherosclerotic, coronary, or peripheral vascular disease.

Route-Specific Administration

Injectable Administration

Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

Intravenous infusion

Do not administer rapidly; rapid administration or high serum concentrations of edetate disodium may cause a sudden drop in serum calcium concentrations which may produce hypocalcemic tetany, convulsions, severe cardiac arrhythmias, and death from respiratory arrest. Infuse diluted solution slowly IV over 3 hours or more, preferably over 4—6 hours. Care should be taken to avoid extravasation because the drug is very irritating to extravascular tissue. Following infusion, the patient should remain in bed for a few minutes to avoid postural hypotension.

Dilution

Adults: Dilute calculated dose in 500 mL of 5% Dextrose or sodium chloride injection. Children: Dilute calculated dose in a sufficient amount of 5% Dextrose or sodium chloride injection to make an infusion solution of concentration no greater than 3%.

Intravenous Administration

Edetate disodium (EDTA) is administered by IV infusion.

Contraindications/Precautions

The cardiac status of the patient should be determined before administering edetate disodium. The drug's negative inotropic effects could adversely affect a patient with cardiac disease (incipient congestive heart failure or limited cardiac reserve), so the drug should be used cautiously in such patients. Because of the high sodium content of the drug, edetate disodium also should be used cautiously in patients who require sodium restriction.

Rapid intravenous administration may cause a precipitous fall in the serum calcium concentration, which could result in death; toxicity has been directly related to the total dose and rate of infusion. Because edetate disodium chelates and reduces serum calcium, it should not be used in patients with hypocalcemia or in patients with normal serum calcium values. Edetate disodium should be used with caution in patients with a seizure disorder or intracranial lesions because the drug-induced hypocalcemia can precipitate seizures.

Although the drug does not chelate potassium, the administration of edetate disodium can increase renal excretion and decrease serum concentration of this mineral, possibly producing hypokalemia. Therefore, the drug should be used with caution in patients with a potassium deficiency. In addition, hypomagnesemia may occur after prolonged administration; monitor serum electrolytes carefully during therapy.

Edetate disodium is contraindicated in patients with anuria. Use with caution in those with renal failure or renal impairment; edetate disodium may contribute to decreased renal function. Perform assessments of renal function during edetate disodium treatment. To the extent that geriatric patients may be more likely to have renal function impairment, caution should be used upon administration to elderly patients.

Because edetate disodium may cause postural hypotension, patients should remain in bed for a short time after the infusion.

Edetate disodium should not be used in patients with calcified tubercular lesions that have healed or in patients with active tuberculosis.

Edetate disodium may cause hypoglycemia and a reduction in insulin requirements in patients with diabetes mellitus; monitor blood glucose carefully during treatment.

Edetate disodium is classified as FDA pregnancy risk category C. No adequate and well-controlled studies have been conducted in pregnant women, and its ability to cause fetal harm or affect reproductive capacity is unknown. Therefore, the manufacturer recommends use during pregnancy only if clearly needed.4

Data are limited regarding use of edetate disodium during breast-feeding and its excretion in human milk is unknown. Due to the drugs short elimination half-life (1 hour), significant presence in breast milk is not expected. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, health care providers are encouraged to report the adverse effect to the FDA.4

Safety and efficacy of edetate disodium have not been established in children.

Pregnancy

Edetate disodium is classified as FDA pregnancy risk category C. No adequate and well-controlled studies have been conducted in pregnant women, and its ability to cause fetal harm or affect reproductive capacity is unknown. Therefore, the manufacturer recommends use during pregnancy only if clearly needed.4

Breast-Feeding

Data are limited regarding use of edetate disodium during breast-feeding and its excretion in human milk is unknown. Due to the drugs short elimination half-life (1 hour), significant presence in breast milk is not expected. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, health care providers are encouraged to report the adverse effect to the FDA.4

Interactions

Azelaic Acid; Copper; Folic Acid; Nicotinamide; Pyridoxine; Zinc: 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.5

Calcium Carbonate: Because edetate disodium chelates and lowers serum calcium, oral or parenteral calcium salts should not be administered concomitantly.6

Calcium Carbonate; Magnesium Hydroxide: Because edetate disodium chelates and lowers serum calcium, oral or parenteral calcium salts should not be administered concomitantly.6

Calcium Carbonate; Risedronate: Because edetate disodium chelates and lowers serum calcium, oral or parenteral calcium salts should not be administered concomitantly.6

Calcium Salts: Because edetate disodium chelates and lowers serum calcium, oral or parenteral calcium salts should not be administered concomitantly.6

Calcium: Because edetate disodium chelates and lowers serum calcium, oral or parenteral calcium salts should not be administered concomitantly.6

Calcium; Vitamin D: Because edetate disodium chelates and lowers serum calcium, oral or parenteral calcium salts should not be administered concomitantly.6

Carbetapentane; Guaifenesin; Phenylephrine: 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.5

Carbetapentane; Phenylephrine: 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.5

Cardiac glycosides: The pharmacodynamic actions of edetate disodium oppose those of the cardiac glycosides.7

Chlorpheniramine; Pseudoephedrine: 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.5

Chromium: Because edetate disodium chelates and lowers serum calcium, oral or parenteral calcium salts should not be administered concomitantly.6

Collagenase: Because edetate disodium chelates and lowers serum calcium, oral or parenteral calcium salts should not be administered concomitantly.6

Cyanocobalamin, Vitamin B12: Because edetate disodium chelates and lowers serum calcium, oral or parenteral calcium salts should not be administered concomitantly.6

Digitoxin: The pharmacodynamic actions of edetate disodium oppose those of the cardiac glycosides.7

Digoxin: The pharmacodynamic actions of edetate disodium oppose those of the cardiac glycosides.7

Guaifenesin; Phenylephrine: 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.5

Hetastarch; Dextrose; Electrolytes: 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 5 Because edetate disodium chelates and lowers serum calcium, oral or parenteral calcium salts should not be administered concomitantly.6

Insulins: 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.5

Iron Salts: Because edetate disodium chelates and lowers serum calcium, oral or parenteral calcium salts should not be administered concomitantly.6

Magnesium Citrate: 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.5

Magnesium Salts: 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,8 Because edetate disodium chelates and lowers serum calcium, oral or parenteral calcium salts should not be administered concomitantly.6

Magnesium Sulfate; Potassium Sulfate; Sodium Sulfate: 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 5

Magnesium: 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 5

Melatonin: Because edetate disodium chelates and lowers serum calcium, oral or parenteral calcium salts should not be administered concomitantly.6

Pantothenic Acid, Vitamin B5: Because edetate disodium chelates and lowers serum calcium, oral or parenteral calcium salts should not be administered concomitantly.6

Succimer: 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.9

Thiamine, Vitamin B1: Because edetate disodium chelates and lowers serum calcium, oral or parenteral calcium salts should not be administered concomitantly.6

Zinc Salts: Because edetate disodium chelates and lowers serum calcium, oral or parenteral calcium salts should not be administered concomitantly.6 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.5

Zinc: 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.5

Adverse Reactions/Side Effects

Chronic administration of edetate disodium can cause dermatitis resulting in lesions similar to those seen with vitamin B6 deficiency, which may be due to zinc depletion.

Edetate disodium administration may induce laboratory abnormalities, including certain electrolyte imbalance, hepatic enzyme changes, hyperuricemia, and anemia. Hypocalcemia and hypokalemia could be seen soon after drug administration. Appropriate monitoring of blood labs and cardiac function should be performed throughout treatment as clinically indicated, particularly in patients with ventricular arrhythmia, seizure disorder, or intracranial lesions. Intravenous calcium replacement (e.g., calcium gluconate) may also be necessary. Hypomagnesemia is possible with prolonged therapy. If clinical evidence suggests any disturbance of liver function during treatment, appropriate laboratory determinations should be performed and withdrawal of the drug may be required.4

Thrombo-phlebitis, febrile reactions (fever), exfoliative dermatitis, and other toxic skin and mucous membrane reactions have been reported with edetate disodium administration. Irritation of the tissues resulting in an injection site reaction may be seen if appropriate dilution has not occurred prior to administration.4

Adverse GI symptoms often occur during edetate disodium administration and can include diarrhea, nausea, and vomiting.4

Following administration of edetate disodium, disodium EDTA, transient symptoms such as circumoral paresthesias, numbness, and headache may occur. Orthostatic hypotension may also occur; having the patient remain in bed for a short time after the infusion should alleviate this.4

High doses of edetate disodium can result in hemorrhagic damage to the reticuloendothelial system and in nephrotoxicity. Nephrotoxicity is manifested as nocturia, urinary urgency, polyuria, dysuria, oliguria, proteinuria, renal failure, or (rarely) acute renal tubular necrosis. It usually is related to excessive doses and typically is reversible within a few days of drug discontinuation.4

Storage

Store this medication at 68°F to 77°F (20°C to 25°C) and away from heat, moisture and light. Keep all medicine out of the reach of children. Throw away any unused medicine after the beyond use date. Do not flush unused medications or pour down a sink or drain.

  • 1. a. b. Sloth-Nielsen J, Guldager B, Mouritzen C, et al. Arteriographic findings in EDTA chelation therapy on peripheral arteriosclerosis. Am J Surg 1991;162:122-5.
  • 2. Knudtson ML, Wyse DG, Galbraith PD, et al. Chelation therapy for ischemic heart disease: a randomized controlled trial. JAMA 2002;287:481-6.
  • 3. Babu AN, Gonzalez-Pena H. Iron chelating agents are not useful in treating atherosclerosis. Ann Intern Med 1994;121:384.
  • 4. a. b. c. d. e. f. g. h. i. Endrate (edetate disodium, anhydrous injection) package insert. Lake Forest, IL: Hospira, INC.; 2004 May.
  • 5. a. b. c. d. e. f. g. h. i. j. k. l. Calcium Disodium Versenate® (edetate calcium disodium injection,USP) package insert. North Chicago, IL: Abbott Laboratories; 2000 Jan.
  • 6. a. b. c. d. e. f. g. h. i. j. k. l. m. n. o. p. Waters RS, Bryden NA, Patterson KY, et al. EDTA chelation effects on urinary losses of cadmium, calcium, chromium, cobalt, copper, lead, magnesium, and zinc. Biol Trace Elem Res 2001;83:207—21.
  • 7. a. b. c. Lanoxin® (digoxin) package insert. Research Triangle Park, NC: Glaxo Smith Kline; 2001 Aug.
  • 8. EDTA Calcium Disodium Versenate® (edetate calcium disodium injection,USP) package insert. North Chicago, IL: Abbott Laboratories; 2000 Jan.
  • 9. Chemet (succimer) package insert. Seymour, IN: Schwarz Pharma Mfg, Inc.; 2009 May.

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