Edetate Calcium

INDICATIONS AND USAGE Edetate calcium disodium is indicated for the reduction of blood levels and depot stores of lead in lead poisoning (acute and chronic) and lead encephalopathy, in both pediatric populations and adults. Chelation therapy should not replace effective measures to eliminate or reduce further exposure to lead.

DOSAGE AND ADMINISTRATION When a source for the lead intoxication has been identified, the patient should be removed from the source, if possible. The recommended dose of edetate calcium disodium for asymptomatic adults and pediatric patients whose blood lead level is < 70 mcg/dL but > 20 mcg/dL (World Health Organization recommended upper allowable level) is 1,000 mg/m 2 /day whether given via intravenous infusion or intramuscularly (see Surface Area Nomogram). For adults with lead nephropathy, the following dosing regimen has been suggested: 500 mg/m 2 every 24 hours for 5 days for patients with serum creatinine levels of 2 to 3 mg/dL, every 48 hours for 3 doses for patients with creatinine levels of 3 to 4 mg/dL, and once weekly for patients with creatinine levels above 4 mg/dL. These regimens may be repeated at one month intervals. 12 Edetate calcium disodium, used alone, may aggravate symptoms in patients with very high blood lead levels. When the blood lead level is > 70 mcg/dL or clinical symptoms consistent with lead poisoning are present, it is recommended that edetate calcium disodium be used in conjunction with BAL (dimercaprol). Please consult published protocols and specialized references for dosage recommendations of combination therapy. 14-18 Therapy of lead poisoning in adults and pediatric patients with edetate calcium disodium is continued over a period of five days. Therapy is then interrupted for 2 to 4 days to allow redistribution of the lead and to prevent severe depletion of zinc and other essential metals. Two courses of treatment are usually employed; however, it depends on the severity of the lead toxicity and the patient's tolerance of the drug. Edetate calcium disodium is equally effective whether administered intravenously or intramuscularly. The intramuscular route is used for all patients with overt lead encephalopathy and this route is preferred by some for young pediatric patients. Acutely ill individuals may be dehydrated from vomiting. Since edetate calcium disodium is excreted almost exclusively in the urine, it is very important to establish urine flow with intravenous fluid administration before the first dose of the chelating agent is given; however, excessive fluid must be avoided in patients with encephalopathy. Once urine flow is established, further intravenous fluid is restricted to basal water and electrolyte requirements. Administration of edetate calcium disodium should be stopped whenever there is cessation of urine flow in order to avoid unduly high tissue levels of the drug. Edetate calcium disodium must be used in reduced doses in patients with pre-existing mild renal disease. Intravenous Administration Add the total daily dose of edetate calcium disodium (1,000 mg/m 2 /day) to 250 to 500 mL of 5% dextrose or 0.9% sodium chloride injection. The total daily dose should be infused over a period of 8 to 12 hours. Discard unused portion. Edetate calcium disodium injection is incompatible with 10% dextrose, 10% invert sugar in 0.9% sodium chloride, lactate Ringer's, Ringer's, one-sixth molar sodium lactate injections, and with injectable amphotericin B and hydralazine hydrochloride. Intramuscular Administration The total daily dosage (1,000 mg/m 2 /day) should be divided into equal doses spaced 8 to 12 hours apart. Discard unused portion. Lidocaine or procaine should be added to the edetate calcium disodium injection to minimize pain at the injection site. The final lidocaine or procaine concentration of 5 mg/mL (0.5%) can be obtained as follows: 0.25 mL of 10% lidocaine solution per 5 mL concentrated edetate calcium disodium; 1 mL of 1% lidocaine or procaine solution per mL of concentrated edetate calcium disodium. When used alone, regardless of method of administration, edetate calcium disodium should not be given at doses larger than those recommended. Diagnostic Test Several methods have been described for lead mobilization tests using edetate calcium disodium to assess body stores. 7, 9,12,13,18 These procedures have advantages and disadvantages that should be reviewed in current references. Edetate calcium disodium mobilization tests should not be performed in symptomatic patients and in patients with blood lead levels above 55 mcg/dL for whom appropriate therapy is indicated. Parenteral drugs should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. edta-nomogram.jpg

WARNINGS See Boxed Warning.

CONTRAINDICATIONS Edetate calcium disodium should not be given during periods of anuria, nor to patients with active renal disease or hepatitis.

Drug Interactions There is no known drug interference with standard clinical laboratory tests. Steroids enhance the renal toxicity of edetate calcium disodium in animals. 7 Edetate calcium disodium interferes with the action of zinc insulin preparations by chelating the zinc. 7

ADVERSE REACTIONS The following adverse effects have been associated with the use of edetate calcium disodium: Body as a Whole: pain at intramuscular injection site, fever, chills, malaise, fatigue, myalgia, arthralgia. Cardiovascular: hypotension, cardiac rhythm irregularities. Renal: acute necrosis of proximal tubules (which may result in fatal nephrosis), infrequent changes in distal tubules and glomeruli. Urinary: glycosuria, proteinuria, microscopic hematuria and large epithelial cells in urinary sediment. Nervous System: tremors, headache, numbness, tingling. Gastrointestinal: cheilosis, nausea, vomiting, anorexia, excessive thirst. Hepatic: mild increases in SGOT and SGPT are common, and return to normal within 48 hours after cessation of therapy. Immunogenic: histamine-like reactions (sneezing, nasal congestion, lacrimation), rash. Hematopoietic: transient bone marrow depression, anemia. Metabolic: zinc deficiency, hypercalcemia. To report SUSPECTED ADVERSE REACTIONS, contact Rising Pharma Holdings, Inc. at 1-844-874-7464 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

CLINICAL PHARMACOLOGY The pharmacologic effects of edetate calcium disodium are due to the formation of chelates with divalent and trivalent metals. A stable chelate will form with any metal that has the ability to displace calcium from the molecule, a feature shared by lead, zinc, cadmium, manganese, iron and mercury. The amounts of manganese and iron mobilized are not significant. Copper 1 is not mobilized and mercury is unavailable for chelation because it is too tightly bound to body ligands or it is stored in inaccessible body compartments. The excretion of calcium by the body is not increased following intravenous administration of edetate calcium disodium, but the excretion of zinc is considerably increased. 1 Edetate calcium disodium is poorly absorbed from the gastrointestinal tract. In blood, all the drug is found in the plasma. Edetate calcium disodium does not appear to penetrate cells; it is distributed primarily in the extracellular fluid with only about 5% of the plasma concentration found in spinal fluid. The half-life of edetate calcium disodium is 20 to 60 minutes. It is excreted primarily by the kidney, with about 50% excreted in one hour and over 95% within 24 hours. 2 Almost none of the compound is metabolized. The primary source of lead chelated by edetate calcium disodium is from bone; subsequently, soft-tissue lead is redistributed to bone when chelation is stopped. 3,4 There is also some reduction in kidney lead levels following chelation therapy. It has been shown in animals that following a single dose of edetate calcium disodium urinary lead output increases, blood lead concentration decreases, but brain lead is significantly increased due to internal redistribution of lead (see WARNINGS ). 5 These data are in agreement with the recent results of others in experimental animals showing that after a five day course of treatment there is no net reduction in brain lead. 6