Edetate Disodium (Systemic)

VA CLASSIFICATION
Primary: AD300

Commonly used brand name(s): Endrate.

Other commonly used names are
disodium EDTA , edathamil disodium, and sodium edetate .
^† However, it is available by emergency drug release from the Health Protection Branch.
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

^†Not commercially available in Canada.

Category:


Chelating agent—

Indications

Accepted

Hypercalcemia (treatment)—Edetate disodium is indicated in selected patients for the emergency treatment of acute hypercalcemia, but is recommended only when the severity of the clinical condition (as when there has been a judgment of imminent death from hypercalcemic crisis ^{07}) justifies the aggressive measures associated with this therapy. ^{01}{16} Other therapies should be started simultaneously so that treatment with edetate disodium will not exceed 48 hours. ^{07} Some physicians recommend not using edetate disodium for hypercalcemia, especially when it is associated with metastatic bone disease, because of minimal and temporary beneficial effects and the great risk of renal damage. ^{04}

Toxicity, digitalis glycoside (treatment)—Edetate disodium is indicated for the control of ventricular arrhythmias associated with digitalis toxicity. ^{01}{16} Although its onset of action is rapid, the short-term effects require that alternative therapy be undertaken quickly. Edetate disodium is rarely used to treat digitalis-induced ventricular arrhythmias since other more effective agents are available. Although edetate disodium may have been useful when other medications, such as potassium or phenytoin, were contraindicated or ineffective, or when controlling arrhythmias caused by digitalis poisoning in children who had ingested massive doses, it has now been replaced by digoxin immune fab as the first-line agent for treatment of life-threatening digitalis glycoside toxicity. ^{{04} {15}}

Unaccepted
Edetate disodium is not indicated for the treatment of arteriosclerosis or atherosclerotic vascular disease involving coronary or peripheral vessels ^{15} associated with advancing age, since it has not been proven effective and severe nephrotoxicity may occur. ^{04}

Edetate disodium is not indicated for the treatment of lead poisoning because, unlike edetate calcium disodium, it causes hypocalcemia. ^{04}

Edetate disodium is not indicated for the treatment of renal calculi by retrograde irrigation. ^{15}


Pharmacology/Pharmacokinetics

Physicochemical characteristics:


pH
    6.5 to 7.5.^{01}{16}

Mechanism of action/Effect:

Hypercalcemia—Edetate disodium forms soluble complexes with calcium in the blood, which are filtered by the glomeruli and not reabsorbed by the renal tubules. ^{07} Chelation with calcium produces a lowering of serum calcium concentrations and a mobilization of extracirculatory calcium stores, especially from bone, during slow intravenous infusion. ^{01}{16} Theoretically, 1 gram of edetate disodium will chelate 120 mg of calcium. ^{04} Hypocalcemic tetany, seizures, severe cardiac arrhythmias, and respiratory arrest may occur with the rapid decrease in serum calcium concentrations. ^{04} However, the mobilization of calcium from bone may lessen the risk of hypocalcemia. ^{04} Calcium ion concentrations in cerebrospinal fluid are not affected by edetate disodium. ^{04}

Digitalis toxicity—Edetate disodium exerts a negative inotropic effect on the heart. ^{01}{16} The chronotropic and inotropic effects of digitalis glycosides on the ventricles of the heart are transiently antagonized by the hypocalcemia induced by edetate disodium. ^{04}


Other actions/effects:

Edetate disodium also forms chelates with and increases urinary excretion of other polyvalent metals, such as magnesium, zinc, and other trace elements. ^{01}{16}

Although edetate disodium does not form a chelate with potassium, the serum concentration of potassium may be decreased and the urinary excretion of potassium increased. ^{01}{16}

Biotransformation:

None. ^{04}

Elimination:
    Rapidly excreted by the kidneys, principally as the calcium chelate; 50% of the chelate appears in the urine in 1 hour and over 95% in 24 hours; changes in urine flow and pH do not affect the rate of excretion of the chelate. ^{{01} {04}{16}}


Precautions to Consider

Pregnancy/Reproduction

Pregnancy—
Edetate disodium crosses the placenta. Adequate and well-controlled studies in humans have not been done.

Studies in rats have shown that edetate disodium causes impaired reproduction and fetal malformations. Since these effects were prevented by simultaneous supplementation of dietary zinc, it is believed that zinc deficiency may be the cause. ^{{04} {13}}

FDA Pregnancy Category C. ^{01}{16}

Breast-feeding

It is not known whether edetate disodium is distributed in breast milk. However, problems in humans have not been documented.

Pediatrics

No information is available on the relationship of age to the effects of edetate disodium in pediatric patients.^{16}


Geriatrics


No information is available on the relationship of age to the effects of edetate 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):

» Digitalis glycosides    (sudden drop in serum calcium concentrations induced by edetate disodium may reverse effects of digitalis ^{01}{16})


Insulin    (concurrent use may require adjustments in dosage of insulin due to decreased serum glucose and possible chelation of zinc in insulin ^{01}{16})



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
Electrocardiograms (ECGs) ^{01}    (changes such as sagging of the S-T segment, depression of the T wave, and elevation of the U wave may occur as a result of reduced serum potassium concentrations ^{14})


Calcium determinations, serum    (the oxalate method of determining serum calcium tends to give low readings in the presence of edetate disodium; sampling just before a subsequent dose will produce the least interference; acidifying the sample or using an alternate method may be necessary ^{01}{16})

With physiology/laboratory test values
Alkaline phosphatase, serum    (concentration may be lowered because of hypomagnesemia induced by edetate disodium ^{04})


Glucose, serum    (treatment with edetate disodium may cause a lowering of blood sugar concentrations ^{01}{16})


Glucose, urine ^{01}{16}    (concentration may be increased)


Magnesium, serum ^{01}{16} or
Potassium, serum ^{01}{16}    (concentration may be decreased)


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}{16} or
» Renal function impairment    (excretion of edetate disodium may be delayed by reduced glomerular filtration, increasing the risk of nephrotoxicity ^{04})


» Hypocalcemia    (may be exacerbated)


Risk-benefit should be considered when the following medical problems exist
Diabetes mellitus    (treatment with edetate disodium may reduce blood sugar concentrations and require adjustment of insulin dosage in diabetic patients ^{{01} {04}{16}})


» Heart disease    (myocardial contractility may be affected ^{01}{16})


Hypokalemia    (edetate disodium may exacerbate hypokalemia and produce ECG changes ^{01}{16})


Intracranial lesions or
» Seizure disorders, history of    (edetate disodium may induce seizures because of hypocalcemia ^{01}{16})


Sensitivity to edetate disodium
Tuberculosis, active or with healed calcified lesions    (may be provoked ^{04})



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 pressure determinations    (recommended prior to and periodically during therapy)


Blood urea nitrogen (BUN) concentrations and
Creatinine concentrations, serum    (determinations recommended prior to and during therapy for evidence of renal function impairment ^{01}{16})


Cardiac function studies, including ECG ^{01}{16} and
Electrolyte determinations, serum and urinary, especially potassium ^{01}{16} and magnesium ^{01}{16}    (recommended prior to administration of edetate disodium and periodically, as clinically indicated, during therapy, especially in patients with ventricular arrhythmias, limited cardiac reserve, congestive heart failure, ^{04} or a history of seizure disorders or intracranial lesions; ^{01}{16} reduced serum potassium concentrations may produce ECG changes; ^{01}{16} serum magnesium determinations may be required during prolonged therapy ^{01}{16})


Liver function tests    (recommended if there is any clinical evidence of liver function impairment during treatment ^{01}{16})


Urinalysis    (recommended daily during treatment ^{01}{16})




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
    
Thrombophlebitis (pain, burning, or swelling at site of injection )^{01}{16}

Incidence less frequent
    
Anemia (unusual tiredness or weakness)^{01}{16}
    
exfoliative dermatitis ^{01}{16}(skin rash or other skin and mucous membrane lesions)
    
febrile reaction, ^{01}{16} (chills or sudden fever ^{04}; fatigue ; headache; malaise; muscle cramps ^{04}; excessive thirst; weakness ^{04})
    
gout, secondary (severe pain or inflammation in feet, knees, hands, or elbows)— hyperuricemia may result from renal tubular toxicity^{01}{04}{16}
    
hypocalcemia (convulsions; difficulty in breathing; irregular heartbeats; mood or mental changes; muscle spasms [tetany] in hands, arms, feet, legs, or face; numbness and tingling around the mouth, fingertips, or feet)— due to sudden decrease in serum calcium concentration caused by rapid intravenous infusion or high dose of edetate disodium^{{01}{04}{14}{16}}
    
hypokalemia or hypomagnesemia (drowsiness ; loss of appetite ^{04}; muscle twitching or trembling; nausea or vomiting ^{{01} {04}{16}}; unusual tiredness or weakness ^{05})—may be accompanied by hypocalcemia
    
nephrotoxicity ^{01}{15}{16}(cloudy urine; frequent or sudden urge to urinate ^{04}; large or small volume of urine ^{04}; painful or difficult urination ^{04})

Note: Prolonged use may cause lesions similar to those seen with pyridoxine deficiency, such as cracking and dry scaly skin and sores in mouth and on lips, possibly due to zinc depletion.
Nephrotoxicity may be due to damage to the reticuloendothelial system with hemorrhagic tendencies, or may indicate possible renal tubular necrosis. ^{{01} {04} {06}{16}} Microscopic hematuria, ^{{01} {04} {06}{16}} proteinuria, ^{{01} {04} {06}{16}} and/or large renal epithelial cells in urine may be observed. Nephrotoxicity is usually associated with high doses ^{{04} {06}} of edetate disodium. Signs are often reversible within a few days after discontinuation of medication. ^{04}




Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Abdominal or stomach pain or cramps ^{04}
    
diarrhea ^{01}{16}
    
hypotension, postural (dizziness or lightheadedness)^{01}{16}

Incidence less frequent
    
Headache, without other symptoms of a febrile reaction ^{01}{04}{16}
    
numbness and
paresthesia, circumoral (burning; crawling; itching; numbness; prickling ; "pins and needles" ; or tingling feelings )
^{01}{16}




Overdose
For more information on the management of overdose or unintentional ingestion, contact a poison control center (see Poison Control Center Listing).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute
    
Hypocalcemia or
hypocalcemic tetany (abdominal cramps; confusion; convulsions ; difficulty in breathing; irregular heartbeats ; mood or mental changes; muscle cramps in hands, arms, feet, legs, or face; numbness and tingling around the mouth, fingertips, or feet; shortness of breath ; tremor)
^{01}{16}

Treatment of overdose


Specific treatment:
Intravenous calcium replacement, such as calcium gluconate^{01}{16}



Monitoring:
Serum calcium level^{01}{16}



General Dosing Information
Because of its irritant effect on the tissues ^{01}{16} and the danger of hypocalcemia, ^{07} edetate disodium must be diluted before infusion.

Dilute solution must be infused slowly over three hours or more, ^{01}{16} preferably four to six hours, ^{07} and the cardiac reserve of the patient not exceeded. ^{01}{16} Rapid intravenous infusion or high serum concentrations of edetate disodium may cause a sudden drop in serum calcium concentration, resulting in hypocalcemic tetany, convulsions, severe cardiac arrhythmias, and death from respiratory arrest. ^{{01} {04}{16}}

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

   • Hypocalcemia—A parenteral calcium salt, such as calcium gluconate, should be immediately available before administration of edetate disodium for calcium ion replacement. ^{01}{16} However, intravenous calcium should be administered with caution in the treatment of tetany , especially in patients who are digitalized, since a reversal of digitalis effects may occur. ^{01}{16}
   • Nephrotoxicity—Edetate disodium must be discontinued; maximum hydration compatible with patient"s cardiovascular reserve may be necessary. ^{15}
   • Postural hypotension—Patient should remain in bed for a short time after infusion. ^{01}{16}


Parenteral Dosage Forms

EDETATE DISODIUM INJECTION USP

Usual adult dose
Hypercalcemia or
Digitalis toxicity
Intravenous, 50 mg ^{01}{16} per kg of body weight in twenty-four hours. The dosage may be repeated for 4 more consecutive daily doses followed by a two-day drug-free interval, with repeated courses, as necessary, up to fifteen doses. ^{01}{16}


Usual adult prescribing limits
3 grams in twenty-four hours. ^{01}{16}

Usual pediatric dose
Hypercalcemia or
Digitalis toxicity
Intravenous, 40 mg per kg of body weight in twenty-four hours. ^{01}


Usual pediatric prescribing limits
70 mg per kg in twenty-four hours
^{01}
Strength(s) usually available
U.S.—


150 mg per mL ^{01} (Rx) [Endrate (preservative free )^{16}][Generic]

Canada—
Edetate disodium injection is not commercially available in Canada; however, it is available by emergency drug release from the Health Protection Branch.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Avoid excessive heat. Protect from freezing. ^{01}{16}

Preparation of dosage form:
Adult use—The calculated dose is dissolved in 500 mL of 5% dextrose injection or 0.9% sodium chloride injection.^{01}{16}

Pediatric use—The calculated dose is dissolved in a sufficient volume of 5% dextrose injection or 0.9% sodium chloride injection to make a final concentration of not more than 3% (30 mg per mL). ^{01}

Additional information:
Injection contains 5.4 mEq of sodium per gram of edetate disodium. ^{04}

Revised: 02/09/2000

References

1. Product Information: Edetate Disodium Injection, USP. Steris Labs, Phoenix, AZ, (PI revised 4/90), reviewed 1/2000.
   

2. Fleeger CA, editor. USP dictionary of USAN and international drug names 1996. Rockville, MD: The United States Pharmacopeial Convention, Inc., 1995: 254.
   

3. The United States pharmacopeia. The national formulary. USP 21st revision (January 1, 1985). NF 16th ed. (January 1, 1985). Rockville, MD: The United States Pharmacopeial Convention, Inc., 1985: 368, 1453.
   

4. AHFS Drug information 86. Bethesda, MD: American Society of Hospital Pharmacists, 1986: 1490.
   

5. Cellulose Sodium Phosphate monograph, USP DI 1986.
   

6. Edetate Calcium Disodium monograph, USP DI 1987, draft.
   

7. AMA Drug evaluations. 6th ed. Chicago: American Medical Association, September 1986.
   

8. Payne BA. EDTA-induced pseudothrombocytopenia. Recognizing a laboratory artifact. Postgrad Med 1985; 77(8): 75-6.
   

9. Payne BA, Pierre RV. Pseudothrombocytopenia: a laboratory artifact with potentially serious consequences. Mayo Clin Proc 1984; 59(2): 123-5.
   

10. Savage RA. Pseudoleukocytosis due to EDTA-induced platelet clumping. Am J Clin Pathol 1984; 81(3): 317-22.
    

11. Reynolds JEF, editor. Martindale, the extra pharmacopeia. 28th ed. London: The Pharmaceutical Press, 1982.
    

12. Pentel P, Jorgensen C, Somerville J. Chelation therapy for the treatment of atherosclerosis. Minnesota Med 1984 Feb.
    

13. Swenerton H, Hurley LS. Teratogenic effects of a chelating agent and their prevention by zinc. Science 1971: 173: 62.
    

14. Cecil textbook of medicine. 17th ed. Philadelphia: W. B. Saunders Company.
    

15. Panel comment, 1988.
    

16. Product Information: Endrate®, edetate disodium injection. Abbott Labs, North Chicago, IL, (PI revised 12/97), reviewed 2/2000.