Calcium Disodium Versenate

New Zealand - English - Medsafe (Medicines Safety Authority)

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Active ingredient:
Calcium carbonate 42.4 mg/mL; Edetic acid 123.7 mg/mL; Sodium hydroxide 33.9 mg/mL
Available from:
iNova Pharmaceuticals (New Zealand) Limited
INN (International Name):
Calcium carbonate 42.4 mg/mL
Dosage:
1g/5mL
Pharmaceutical form:
Solution for injection
Composition:
Active: Calcium carbonate 42.4 mg/mL Edetic acid 123.7 mg/mL Sodium hydroxide 33.9 mg/mL Excipient: Water for injection
Units in package:
Ampoule, glass, 6 x 5ml ampoule, 6 dose units
Class:
Prescription
Prescription type:
Prescription
Manufactured by:
Hospira Inc
Product summary:
Package - Contents - Shelf Life: Ampoule, glass, 6 x 5ml ampoule - 6 dose units - 60 months from date of manufacture stored at or below 30°C
Authorization number:
TT50-2810
Authorization date:
1969-12-31

DataSheet

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

Description

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-).

Structural Formula:

. xH

O

Molecular weight 374.27 (anhydrous)

Pharmacology

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

therapy.

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.

Indications

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.

Contraindications

Edetate calcium disodium should not be given during periods of anuria, nor to

patients with active renal disease or hepatitis.

Precautions

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

on fertility.

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.

Laboratory tests:

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.

Adverse Reactions

The following adverse effects have beenassociated with the use of edetate

calcium disodium:

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,

lacrimation), rash..

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

Nomogram)

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

paediatric patients.

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

disease.

Intravenous Administration:

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.

Intramuscular Administration:

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.

Diagnostic Test:

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.

Overdosage

Symptoms:

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.

Treatment:

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.

Presentation

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.

Medicine Classification

Prescription Medicine

Name and address of sponsor

INova Pharmaceuticals (New Zealand) Limited

C/o Simpson Grierson

88 Shortland Street

Auckland

Distributed by: Douglas Pharmaceuticals Limited, Auckland

Telephone:(09) 835 0660

Facsimile: (09) 835 0685

Date of Preparation

16 July 2007

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