Edetate calcium disodium is capable of producing toxic effects that can be fatal. Lead encephalopathy is relatively rare in adults, but occurs more often in pediatric patients in whom it may be incipient and thus overlooked. The mortality rate in pediatric patients has been high. Patients with lead encephalopathy and cerebral edema may experience a lethal increase in intracranial pressure following, intravenous (IV) infusion; the intramuscular (IM) route is preferred for these patients. In cases where the IV route is necessary, avoid rapid infusion. The dosage schedule should be followed and at no time should the recommended daily dose be exceeded.
Note: Consultation with a clinical toxicologist or an expert in the treatment of heavy metal poisoning is highly recommended.
Lead poisoning: Note: Available guidelines recommend chelation therapy with blood lead levels (BLLs) >50 mcg/dL and significant symptoms; chelation therapy may also be indicated for most patients with BLLs >80 mcg/dL and all patients with BLLs ≥100 mcg/dL and/or symptoms (CSTE 2013; Kosnett 2007). Selection of chelating regimen should be made in consultation with a clinical toxicologist or expert in the treatment of heavy metal poisoning.
Symptoms suggestive of encephalopathy or BLLs >100 mcg/dL:
IM, IV: 1,500 mg/m2/day or 50 to 75 mg/kg/day for 5 days (maximum: 3,000 mg per day [Howland 2018]); administer as a continuous infusion or in 2 to 4 divided doses (Calello 2018).
Note: In patients who are also receiving dimercaprol, begin treatment with edetate CALCIUM disodium 4 hours after initiation of dimercaprol (ie, with the second dimercaprol dose) (Calello 2018).
Encephalopathy:
IM, IV: 1,000 to 1,500 mg/m2/day or 25 to 75 mg/kg/day for 5 days (maximum: 3,000 mg per day [Howland 2018]); administer as a continuous infusion or in 2 to 4 divided doses (Calello 2018).
Note: In patients who are also receiving dimercaprol, begin treatment with edetate CALCIUM disodium 4 hours after initiation of dimercaprol (ie, with the second dimercaprol dose) (Calello 2018).
Note: Treatment courses may be repeated, but 2-week intervals between courses is generally recommended because lead re-equilibrates between the extravascular storage sites (eg, bone) and the vascular compartment. High initial BLLs (eg, >100 mcg/dL) or presence of lead encephalopathy may indicate the need for more prompt retreatment (Howland 2018); consultation with a clinical toxicologist or expert in the treatment of heavy metal poisoning is highly recommended.
Lead nephropathy: An alternative dosing regimen that reflects the reduction in renal clearance and is based upon the serum creatinine is provided by the manufacturer; however, the decision to use chelation therapy in patients without elevated BLLs and symptoms should only be made in consultation with a clinical toxicologist or an expert in the treatment of heavy metal poisoning. Note: The manufacturer recommends repeating the regimen monthly until BLLs are reduced to an acceptable level: IM, IV:
Scr 2 to 3 mg/dL: 500 mg/m2 every 24 hours for 5 days.
Scr 3 to 4 mg/dL: 500 mg/m2 every 48 hours for 3 doses.
Scr >4 mg/dL: 500 mg/m2 once weekly.
Dose should be reduced with preexisting mild renal disease. Limiting the daily dose to 2 g in adults may decrease risk of nephrotoxicity, although larger doses may be needed in the treatment of lead encephalopathy (Howland 2018).
There are no dosage adjustments provided in the manufacturer's labeling.
Refer to adult dosing.
(For additional information see "Edetate calcium disodium (calcium EDTA): Pediatric drug information")
Note: Consultation with a clinical toxicologist, poison control center, or an expert in the treatment of heavy metal poisoning is highly recommended.
Lead poisoning, treatment:
Note: For the treatment of high blood lead levels (BLLs) in children, the CDC recommends chelation treatment when BLL >45 mcg/dL (CDC 2002). The AAP recommends succimer for initial management in asymptomatic children when BLL >45 mcg/dL and <70 mcg/dL. Edetate CALCIUM disodium can be used in children allergic to succimer (AAP 2005; Chandran 2010). Combination therapy with edetate CALCIUM disodium and dimercaprol is recommended for use in children whose BLL ≥70 mcg/dL or in pediatric patients with lead encephalopathy (AAP 2005; AAP [Shenoi 2020]; Calello 2018). Depending upon the BLL, additional courses may be necessary; at least 2 to 4 days should elapse before repeat treatment is initiated.
Blood lead levels 45 to <70 mcg/dL and asymptomatic:
Infants, Children, and Adolescents: IM, IV: 1,000 mg/m2/day (~25 to 50 mg/kg/day) as either a once-daily continuous IV infusion (preferred) or as equally divided intermittent doses every 6 to 12 hours; treatment duration: 5 days; maximum daily dose: 1,000 mg/day (Calello 2018; Chandran 2010). Note: Although intermittent IV doses are an option, single dose infusion time (over 8 to 12 hours) and admixture volumes for each dose may preclude use in some patients.
Note: Treatment courses may be repeated, but a 2-week interval between courses is generally recommended because lead re-equilibrates between the extravascular storage sites (eg, bone) and the vascular compartment. High initial BLL (eg, >100 mcg/dL) or presence of lead encephalopathy may indicate the need for more prompt retreatment (Calello 2018).
Blood lead levels ≥70 mcg/dL or symptomatic lead poisoning (without encephalopathy):
Infants, Children, and Adolescents: IM, IV: 1,000 to 1,500 mg/m2/day or 25 to 75 mg/kg/day as either a once-daily continuous IV infusion (preferred) or as equally divided intermittent doses every 6 to 12 hours; begin treatment 4 hours after the first dimercaprol dose; treatment duration: 5 days; maximum daily dose: 1,000 mg/day in children; in adults, the maximum daily dose is 3,000 mg/day (AAP [Shenoi 2020]; Calello 2018; Chandran 2010; Howland 2018). Note: Although intermittent IV doses are an option, single dose infusion time (over 8 to 12 hours) and admixture volumes for each dose may preclude use in some patients.
Note: Treatment courses may be repeated; for lower BLL (eg, <70 mcg/dL), a 2-week interval between courses is generally recommended because lead re-equilibrates between the extravascular storage sites (eg, bone) and the vascular compartment. High initial BLL (eg, >100 mcg/dL) or presence of lead encephalopathy may indicate the need for more prompt retreatment (Calello 2018).
Lead encephalopathy:
Infants, Children, and Adolescents: IM, IV: 1,500 mg/m2/day or 50 to 75 mg/kg/day as either a once-daily continuous IV infusion (preferred) or as equally divided intermittent doses every 6 to 12 hours; treatment duration: 5 days; maximum daily dose: 1,000 mg/day in children; in adults, the maximum daily dose is 3,000 mg/day; treatment courses may be repeated (AAP [Shenoi 2020]; Calello 2018; Chandran 2010; Howland 2018). Note: Although intermittent IV doses are an option, single dose infusion time (over 8 to 12 hours) and admixture volumes for each dose may preclude use in some patients.
Infants, Children, and Adolescents: Dose should be reduced with preexisting mild renal disease. Limiting the daily dose to 1,000 mg in children and 2,000 mg in adults may decrease risk of nephrotoxicity, although larger doses may be needed in the treatment of lead encephalopathy (Howland 2018).
There are no dosage adjustments provided in the manufacturer's labeling.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Frequency not defined.
Cardiovascular: Cardiac arrhythmia, ECG changes, hypotension, local thrombophlebitis (IV infusion when concentration >5 mg/mL)
Central nervous system: Chills, fatigue, headache, malaise, numbness, paresthesia
Dermatologic: Cheilosis, dermatitis, skin rash
Endocrine & metabolic: Glycosuria, hypercalcemia, hypokalemia, iron deficiency (with chronic therapy), magnesium deficiency (with chronic therapy), polydipsia, zinc deficiency (with chronic therapy)
Gastrointestinal: Anorexia, gastrointestinal irritation, nausea, vomiting
Genitourinary: Nephrosis, nephrotoxicity, occult blood in urine, proteinuria, urinary frequency, urinary urgency
Hematologic & oncologic: Anemia, bone marrow depression (transient)
Hepatic: Decreased serum alkaline phosphatase, increased liver enzymes (mild)
Local: Pain at injection site (intramuscular)
Neuromuscular & skeletal: Arthralgia, myalgia, tremor
Ophthalmic: Lacrimation
Renal: Renal tubular necrosis
Respiratory: Nasal congestion, sneezing
Miscellaneous: Fever
Active renal disease or anuria; hepatitis
Concerns related to adverse effects:
• Arrhythmias: Monitor for arrhythmias and ECG changes during IV therapy
• Nephrotoxicity: Edetate CALCIUM disodium is potentially nephrotoxic. Renal tubular acidosis and fatal nephrosis may occur, especially with high doses; do not exceed the recommended daily dose. If anuria, increasing proteinuria, or hematuria occurs during therapy, discontinue use. Minimize nephrotoxicity by providing adequate hydration, establishment of good urine output, avoidance of excessive doses, and limit continuous administration to ≤5 days.
Disease-related concerns:
• Cerebral edema: [US Boxed Warning]: Use with extreme caution in patients with lead encephalopathy and cerebral edema. In these patients, IV infusion has been associated with a lethal increase in intracranial pressure; IM injection is preferred.
• Lead poisoning: Investigate, identify, and remove sources of lead exposure prior to treatment. Consultation with a clinical toxicologist or an expert in the treatment of heavy metal poisoning is highly recommended before initiating chelation therapy. Do not permit patients to re-enter the contaminated environment until lead abatement has been completed.
• Renal impairment: Use with caution in patients with renal impairment; reduced dose recommended.
Other warnings/precautions:
• Potential for name confusion: Exercise caution in the ordering, dispensing, and administration of this drug. Edetate CALCIUM disodium (CaEDTA) may be confused with edetate disodium (Na2EDTA) (not commercially available in the US or Canada). Fatal hypocalcemia may result if edetate disodium is used for the treatment of lead poisoning instead of edetate CALCIUM disodium (Baxter 2008). The CDC and FDA recommend that edetate disodium should never be used for chelation therapy (especially in children) (Mitka 2008). Death has occurred following the use of edetate disodium for chelation therapy in pediatric patients with autism (Baxter 2008).
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Injection:
Generic: 1 g/5 mL (5 mL)
Yes
Solution (Edetate Calcium Disodium Injection)
1 g/5 mL (per mL): $1,558.71
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For IM or IV use; IV is generally preferred, however, the IM route is preferred when cerebral edema is present.
IV infusion: Administer the daily dose as a diluted solution over 8 to 12 hours or continuously over 24 hours (Howland 2018).
For IM injection: Daily dose should be divided into 2 to 4 equal doses (Calello 2018). Procaine hydrochloride or lidocaine may be added to the edetate CALCIUM disodium to minimize pain at injection site. Administer by deep IM injection. When used in conjunction with dimercaprol, inject into a separate site.
Parenteral: For IM or IV use; IV is generally preferred; however, the IM route is preferred when cerebral edema is present.
IV infusion: Administer the daily dose as a diluted solution over 8 to 12 hours or continuously over 24 hours (Howland 2018). Avoid rapid infusion.
IM injection: Daily dose should be divided into 2 to 4 equal doses spaced 6 to 12 hours apart. Procaine hydrochloride or lidocaine may be added to the edetate CALCIUM disodium to minimize pain at injection site. Administer by deep IM injection. When used in conjunction with dimercaprol, inject into a separate site.
Lead poisoning: Treatment of symptomatic acute and chronic lead poisoning.
To avoid potentially serious errors, the abbreviation “EDTA” should never be used.
Edetate CALCIUM disodium (CaEDTA) may be confused with edetate disodium (Na2EDTA) (not commercially available in the U.S. or Canada). CDC recommends that edetate disodium should never be used for chelation therapy in children. Fatal hypocalcemia may result if edetate disodium is used for chelation therapy instead of edetate calcium disodium. ISMP recommends confirming the diagnosis to help distinguish between the two drugs prior to dispensing and/or administering either drug.
Edetate CALCIUM disodium may be confused with etomidate
None known.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
5-Aminosalicylic Acid Derivatives: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy
BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Risk X: Avoid combination
Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Risk C: Monitor therapy
Chloramphenicol (Systemic): Myelosuppressive Agents may enhance the myelosuppressive effect of Chloramphenicol (Systemic). Risk X: Avoid combination
Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk X: Avoid combination
CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Risk C: Monitor therapy
Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Risk D: Consider therapy modification
Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Risk X: Avoid combination
Fexinidazole: Myelosuppressive Agents may enhance the myelosuppressive effect of Fexinidazole. Risk X: Avoid combination
Insulins: Edetate CALCIUM Disodium may enhance the hypoglycemic effect of Insulins. Risk C: Monitor therapy
Olaparib: Myelosuppressive Agents may enhance the myelosuppressive effect of Olaparib. Risk C: Monitor therapy
Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Risk C: Monitor therapy
Ropeginterferon Alfa-2b: Myelosuppressive Agents may enhance the myelosuppressive effect of Ropeginterferon Alfa-2b. Management: Avoid coadministration of ropeginterferon alfa-2b and other myelosuppressive agents. If this combination cannot be avoided, monitor patients for excessive myelosuppressive effects. Risk D: Consider therapy modification
Adverse events were observed in some animal reproduction studies; there are no well controlled studies of edetate CALCIUM disodium in pregnant women. Lead is known to cross the placenta in amounts related to maternal plasma levels. Prenatal lead exposure may be associated with adverse events such as spontaneous abortion, preterm delivery, decreased birth weight, and impaired neurodevelopment. Some adverse outcomes may occur with maternal blood lead levels <10 mcg/dL. In addition, pregnant women exposed to lead may have an increased risk of gestational hypertension. Consider chelation therapy in pregnant women with confirmed blood lead levels ≥45 mcg/dL (pregnant women with blood lead levels ≥70 mcg/dL should be considered for chelation regardless of trimester). Alternatives to edetate CALCIUM disodium may be indicated and consultation with experts in lead poisoning and high-risk pregnancy is recommended. Encephalopathic pregnant women should be chelated regardless of trimester (CDC 2010).
The oral absorption of edetate CALCIUM disodium is poor (<5%) which would limit exposure to a nursing infant. However, edetate CALCIUM disodium is not used orally because it may increase lead absorption from the GI tract. The amount of lead in breast milk may range from 0.6% to 3% of the maternal serum concentration. Women with confirmed blood lead levels ≥40 mcg/dL should not initiate breast-feeding; pumping and discarding breast milk is recommended until blood lead levels are <40 mcg/dL, at which point breast-feeding may resume (CDC 2010). Calcium supplementation may reduce the amount of lead in breast milk.
Urinary output; urinalysis; renal function, hepatic function, serum electrolytes (baseline and daily [severe lead poisoning] or at days 2 and 5 [less severe lead poisoning]); ECG (with IV therapy); blood lead levels (baseline and 7-21 days after completing chelation therapy); hemoglobin or hematocrit; iron status; free erythrocyte protoporphyrin or zinc protoporphyrin; neurodevelopmental changes
Calcium is displaced by divalent and trivalent heavy metals, forming a nonionizing soluble complex with lead that is excreted in the urine.
Onset of action: Chelation of lead: IV: 1 hour
Maximum excretion of chelated lead with IV administration: 24 to 48 hours
Absorption: IM, SubQ: Well absorbed; Oral: <5%
Distribution: Into extracellular fluid; minimal CSF penetration (~5%)
Metabolism: Almost none of the drug is metabolized
Half-life elimination: 20 to 60 minutes
Excretion: Urine (as metal chelates or unchanged drug); decreased GFR decreases elimination
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