New Zealand - English - Medsafe (Medicines Safety Authority)
CALCIUM DISODIUM VERSENATE
Edetate calcium disodium
WARNINGS:CalciumDisodium Versenate is capable of producing toxic effects
which can be fatal. Lead encephalopathy is relatively rare in adults, but occurs
more often in paediatric patients inwhom it may be incipient and thus
overlooked. The mortality rate in paediatric patients has been high. Patients with
lead encephalopathy and cerebral oedema may experiencea 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.
Name of themedicine
Edetate calcium disodium
Calcium Disodium Versenate (edetate calcium disodiuminjection, USP) is a
sterile, injectable, chelating agentinconcentrated solution for intravenous
infusion or intramuscular injection. Each 5 ml ampoule contains 1000 mg of
edetate calcium disodium (equivalent to200 mg/ml) in water for injection.
Chemically, this product is called [[N,N'-1,2-ethanediyl-bis[N-(carboxymethyl)-
glycinato]](4-)-N,N',O,O',O N ,O N ']-,disodium, hydrate,(OC-6-21)-Calciate(2-).
Molecular weight 374.27 (anhydrous)
The pharmacologic effects of edetate calcium disodiumare due to the formation
of chelates with divalentand 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 mobilised are not significant. Copper is not mobilised 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, butthe excretion of zinc isconsiderablyincreased.
Edetate calcium disodium is poorly absorbedfrom the gastrointestinal tract. In
blood, all the active substance 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 plasmaconcentration found in spinal fluid.
The half life of edetate calcium disodiumis 20 to 60 minutes. It is excreted
primarily by the kidney, with about 50%excreted in one hour and over 95%
within 24 hours. Almost none ofthe compound is metabolised.
The primary source of lead chelated by Calcium Disodium Versenate is from
bone; subsequently, soft-tissue lead is redistributed to bone when chelation is
stopped. There is also some reduction inkidney lead levelsfollowing chelation
It has been shown in animals that following a single dose of Calcium Disodium
Versenate urinary lead output increases,blood lead concentration decreases, but
brain lead is significantly increased due tointernal redistribution of lead. (See
Warnings.) These data are in agreement with the recent results of others in
experimental animals showing that after afive day course oftreatment there is
no net reduction in brain lead.
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 paediatric populations and adults.
Chelation therapy should not replace effective measures toeliminate or reduce
further exposure to lead.
Edetate calcium disodium should not be given during periods of anuria, nor to
patients with active renal disease or hepatitis.
See boxed warning. Edetate calcium disodium may produce the same renal
damage aslead poisoning, such as proteinuria and microscopic haematuria.
Treatment-induced nephrotoxicity is dose-dependent and may be reduced by
assuring adequate diuresis before therapy begins. Urine flow must be monitored
throughout therapy which must be stopped ifanuria or severe oliguria develop.
The proximal tubule hydropic degeneration usually recovers upon cessation of
therapy. Edetate calcium disodiummustbe used in reduced doses in patients
with pre-existing mild renal disease.Patients should be monitored for cardiac
rhythm irregularities and other ECG changes during intravenous therapy.
Information for patients:
Patients should be instructed to immediatelyinform their physician if urine output
stops for a period of 12 hours.
Use in Children:
Since lead poisoning occurs in paediatric populations and adults but is frequently
more severe in paediatric patients, Calcium Disodium Versenate is used in
patients of all ages. The intramuscularroute is preferred by some for young
paediatric patients. In cases where theintravenous route is necessary, avoid
rapid infusion (seeWarnings). Urine flow must be monitored throughout therapy;
Calcium Disodium Versenate therapy mustbe stopped if anuria orsevere oliguria
develops. (SeePrecautions) At no time should the recommended daily dosage
be exceeded. (SeeDosage andAdministration)
Carcinogenesis, Mutagenesis, Impairment of Fertility:
Long term animal studies have notbeen conducted with edetate calcium
disodium to evaluate its carcinogenic potential, mutagenic potential or its effect
Use in Pregnancy:
One reproduction study was performed in rats at doses up to 13 times the human
dose and revealednoevidence ofimpairedfertility or harm to the foetus due to
Calcium Disodium Versenate. Another reproduction study performed in rats at
doses up to about 25 to 40 times the human dose revealed evidence of foetal
malformations due to Calcium Disodium Versenate, which were prevented by
simultaneous supplementation of dietaryzinc. There are however, no adequate
and well controlled studies in pregnantwomen. Because animal reproduction
studies are not always predictive of human response, this medicine should be
used during pregnancy onlyif clearly needed.
Labour and Delivery:
Calcium Disodium Versenate has no recognised use during labour and delivery,
and its effects during these processes are unknown.
Use in lactation:
It is not known whetherthis medicine is secreted in human milk. Because many
medicines are secreted in human milk, caution should be exercised when
Calcium Disodium Versenate is administered to a nursing woman.
Interactions with other substances:
There is no known interference with standard clinical laboratory tests. Steroids
enhance the renal toxicity of edetate calcium disodium in animals. Edetate
calcium disodium interferes with the action of zinc insulin preparations by
chelating the zinc.
Urinalysis and urine sediment, renal andhepatic function and serum electrolyte
levels should be checked before each course of therapyand then be monitored
daily during therapy in severe cases, andin less serious cases after the second
and fifth day of therapy. Therapy must bediscontinued at thefirst sign of renal
toxicity. The presence of large renal epithelial cells or increasing number of red
blood cells in urinary sediment or greater proteinuria call for immediate stopping
of edetate calcium disodium administration. Alkaline phosphatase values are
frequently depressed (possibly due to decreased serum zinclevels), but return to
normal within 48 hoursafter cessationof therapy. Elevated erythrocyte
protoporphyrin levels (>35 mcg/dl of whole blood) indicate the need to perform a
venous blood lead determination. If the whole blood lead concentration is
between 25-55 mcg/dl a mobilisation test can be considered. (SeeDiagnostic
Test) An elevation of urinary coproporphyrin (adults: >250 mcg/day; paediatric
patients under 36 Kg >75 mcg/day) and elevation of urinary delta aminolevulinic
acid (ALA) (adults: >4 mg/day; paediatric patients: >3 mg/m 2 /day) are associated
with blood lead levels >40 mcg/dl.Urinary coproporphyrin may be falsely
negative in terminal patients and in severely iron-depleted paediatric patients
who are not regenerating haeme. In growing paediatric patients long bone x-rays
showing lead lines and abdominal x-raysshowing radio-opaque material in the
abdomen may be of help in estimating the level of exposure to lead.
The following adverse effects have beenassociated with the use of edetate
Bodyas 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 distaltubules 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 SGPTare common, and return to normal
within 48 hours after cessation of therapy.
Immunogenic:histamine-like reactions (sneezing, nasal congestion,
Hematopoietic:transient bone marrow depression, anaemia.
Metabolic:zinc deficiency, hypercalcemia.
Dosage and Administration
When a source for the lead intoxication hasbeen identified, the patient should be
removed from the source, if possible.
The recommended dose of Calcium Disodium Versenate for asymptomatic adults
and paediatric patients whoseblood lead level is <70 mcg/dl but >20 mcg/dl
(World Health Organisation recommended upper allowable level) is 1000
mg/m 2 /day whether given intravenously or intramuscularly. (See Surface Area
Surface Area Nomogram
For adults with lead nephropathy, thefollowing dosing regimen has been
suggested: 500 mg/m 2 every 24 hours for 5 days for patients with serum
creatinine levels of 2-3 mg/dl, every 48 hours for 3 doses for patients with
creatinine levels of 3-4 mg/dl, and onceweekly for patients with creatinine levels
above 4 mg/dl. These regimens maybe repeated at one month intervals.
Calcium Disodium Versenate, 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 Calcium Disodium Versenate be used inconjunction with BAL (dimercaprol).
Please consult published protocols and specialized references for dosage
recommendations of combination therapy.
Therapy of lead poisoning in adultsand paediatric patients with Calcium
Disodium Versenate 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 severity of the lead toxicity and the
patient's tolerance of the medicine.
Calcium Disodium Versenate is equallyeffective 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
Acutely ill individuals maybe dehydrated from vomiting.Since edetate calcium
disodium is excreted almost exclusively inthe 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 isestablished, further intravenous fluid is
restricted to basal water and electrolyte requirements. Administration of Calcium
Disodium Versenate should be stopped wheneverthere is cessation of urine flow
in order to avoid unduly high tissue levels of the substance. Edetate calcium
disodium must be used in reduced dosesin patients with pre-existing mild renal
Add the total daily dose of Calcium Disodium Versenate (1000 mg/m 2 /day) to
250-500 ml of 5% glucose or 0.9% sodiumchloride injection. The total daily dose
should be infused over a period of8-12 hours. Calcium Disodium Versenate
injection is incompatible with 10% glucose, 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.
The total daily dosage (1000 mg/m 2 /day) should be divided into equal doses
spaced 8-12 hours apart. Lignocaine or procaine should be added to the Calcium
Disodium Versenate injection to minimise pain at the injection site. The final
lignocaine or procaine concentrationof 5 mg/ml (0.5%) can be obtained as
follows: 0.25 ml of 10% lignocaine solution per 5 ml (entirecontent of ampoule)
concentrated Calcium Disodium Versenate;1 ml of 1% lignocaine or procaine
solution per ml of concentrated Calcium Disodium Versenate. When used alone,
regardless of method of administration, Calcium Disodium Versenate should not
be given at doses larger than those recommended.
Several methods have been described for lead mobilisation tests using edetate
calcium disodium to assess body stores.
These procedures have advantages and disadvantages that should be reviewed
in current references. Edetate calciumdisodium mobilisation tests should not be
performed insymptomatic patients and inpatients with blood lead levels above
55 mcg/dl for whom appropriatetherapy is indicated.
Parenteral medicines should be inspected visually for particulate matter and
discolouration prior to administration, whenever solution and container permit.
Inadvertent administration of 5times the recommended dose, infused
intravenously over a 24 hour period, toan asymptomatic 16month old patient
with a blood lead content of 56 mcg/dldid not cause any ill effects. Edetate
calcium disodium can aggravate thesymptoms of severe lead poisoning;
therefore, most toxic effects (cerebral oedema, renal tubular necrosis) appear to
be associated with lead poisoning.
Because ofcerebral oedema, a therapeuticdose may be lethal to an adult or a
paediatric patient with lead encephalopathy. Higherdosage of edetate calcium
disodium may produce a moresevere zinc deficiency.
Cerebral oedema should be treated withrepeated doses of mannitol. Steroids
enhance the renal toxicity of edetate calcium disodium in animals and therefore,
are no longer recommended. Zinc levels must be monitored. Good urinary output
must be maintained because diuresis willenhance elimination. It is not known if
edetate calcium disodium is dialysable.
Calcium Disodium Versenate injection,5 ml ampoule containing 200 mg of
edetate calcium disodium per ml (1g per ampoule), in boxes containing 6
ampoules. Store at controlledroom temperature 15°-30°C.
Name and address of sponsor
INova Pharmaceuticals (New Zealand) Limited
C/o Simpson Grierson
88 Shortland Street
Distributed by: Douglas Pharmaceuticals Limited, Auckland
Telephone:(09) 835 0660
Facsimile: (09) 835 0685
Date of Preparation
16 July 2007