Calcium DTPA Informational Material Package Insert
Nov. 14, 2002
Ca-DTPA (Trisodium calcium diethylenetriaminepentaacetate)
Description
IND 4041, Trisodium calcium diethylenetriaminepentaacetate (Ca-DTPA), is a calcium salt of DTPA. It has been used in the U.S. as a chelating agent for plutonium and other transuranic elements such as americium, californium, and curium. DTPA is also used in lesser concentrations as a chelating vehicle in FDA-approved nuclear medicine studies.
Ca-DTPA is distributed by Oak Ridge Associated Universities (ORAU) under contract with the U.S. Department of Energy (DOE), Contract No. DE-AC05-06OR23100. ORAU manages the FDA Investigational New Drug (IND) authorizations for Ca-DTPA and the analogous Zn-DTPA for DOE. The current supply of Ca-DTPA has been purchased from Heyl GmbH, Berlin, Germany and tested extensively by them for chemical stability and chemical purity and by an independent testing company for pyrogenicity. The drug is supplied as one gram in 5 ml of diluent. This formulation has been approved by the US FDA and meets the standards of both the United States Pharmacopeia (USP-23) and the European Pharmacopeia (Ph. Eur).
A series of review papers on the use of DTPA chelators (Ca-DTPA and Zn-DTPA) in decorporation therapy in major United States radiation accidents from 1958 through 1987 has recently been published.
Clinical Pharmacology
DTPA belongs to the group of synthetic polyamino polycarboxylic acids which form stable complexes (metal chelates) with a large number of metal ions. The drug effectively exchanges calcium for another metal of greater binding power and carries it to the kidneys where it is then excreted into the urine.4 The plasma half-life of DTPA is 20-60 minutes. Almost the entire administered dose is excreted in 12 hours. There is a small fraction bound to plasma proteins with a half-life >20 hours. DTPA undergoes only a minimal amount of metabolic change in the body. Only a very minor release of acetate groups has been demonstrated and splitting of ethylene groups has not been detected. Following intravenous administration, Ca-DTPA is rapidly distributed throughout the extracellular fluid space. No significant amount of DTPA penetrates into erythrocytes or other tissue. No accumulation of DTPA in specific organs has been observed. There is little or no binding of the chelate by the renal parenchyma, and it is promptly cleared from the body by glomerular filtration. Tubular excretion has not been observed. Although clearance of the chelate gives useful information on the glomerular filtration rate, the variable percent which is protein bound leads to a measured clearance rate which is lower than that determined by inulin clearance. In stool samples tested with radioactivity marked chelating agents, only a very small amount of radioactivity (<3%) was detected.
*Reviewed and approved for continuation for 12 months by the Oak Ridge Site Wide Institutional Review Board Nov. 20, 2003.
Ca-DTPA can deplete the body of zinc and, to a lesser extent, manganese with repeated dosing. The amount of zinc lost is determined by the amount of DTPA and the frequency of dosage. By depletion of these essential trace metals, Ca-DTPA can then interfere with necessary mitotic cellular processes. Over longer time periods, depletion of zinc due to Ca-DTPA therapy has resulted in transient inhibition of a metalloenzyme, δ-aminolevulinic acid dehydrase (ALAD), in the blood, although without observable clinical effect. Clinical zinc depletion appears to be avoidable by giving zinc replacement concomitantly with therapy.
Ca-DTPA is approximately 10 times more effective than Zn-DTPA for initial chelation of transuranics; therefore, Ca-DTPA should be used whenever larger body burdens of transuranics are involved. Ca-DTPA is the form of choice for initial patient management unless contraindicated. Approximately 24 hours after exposure, Zn-DTPA is, for all practical purposes, as effective as Ca-DTPA. This comparable efficacy, coupled with its lesser toxicity, makes Zn-DTPA the preferred agent for protracted therapy.
Indications and Usage
Ca-DTPA and Zn-DTPA effectively chelate several transuranium ions (plutonium, americium, berkelium, curium, and californium). Their clinical use has been primarily for treatment of internal contamination with plutonium and americium. One patient contaminated with more than 1 mCi of americium had 99% of the total body burden removed with prolonged therapy over 4 years with a combination of Ca-DTPA/Zn-DTPA therapy.2-3
The efficacy of Ca-DTPA and/or Zn-DTPA treatment is good for internal contamination with the soluble plutonium salts, such as the nitrate or chloride, but is essentially nil for highly insoluble compounds, such as the high-fired oxide. The same efficacy is noted experimentally when a soluble (monomeric) form of plutonium is administered that gradually converts to less soluble (polymeric) forms as it is distributed and deposited in various tissues in the body. Thus, chelation is highly dependent not only on the actual metal, but also on the chemical and physical characteristics of the compound at the time of DTPA administration. Because the efficiency of chelation decreases with time, DTPA should be given within 6 hours of exposure, if possible.
Contraindications
Ca-DTPA is contraindicated for minors, pregnant women, patients with the nephrotic syndrome, and in patients with bone marrow depression. (Such patients may be treated with Zn-DTPA.) Ca-DTPA should not to be used as a chelator for uranium or neptunium. Internal contamination with uranium is currently treated by alkalizing the urine with bicarbonate in order to promote excretion. DTPA has also been postulated to form an unstable complex with neptunium, which may increase bone deposition of this actinide.5
Warnings and Precautions
- Ca-DTPA treatment is contraindicated where there is known pre-existing serious kidney disease or depressed myelopoietic function (e.g., leukopenia or thrombocytopenia).
- Kidney function should be normal. Urinalysis should be normal prior to each use. If proteinuria, hematuria or casts develop during use, discontinue drug administrations.
- Fractionation of the recommend 1 g dose (several smaller doses per day) is not recommended.
- Blood pressure should be monitored closely during drug infusion.
- Discontinue the drug if diarrhea occurs.
Pregnancy Category D
Teratogenicity and fetal death have occurred in mice following five daily injections of 720-2880 Fmol Ca-DTPA/kg given throughout the gestation. However, daily doses of 360 Fmol Ca-DTPA/kg in mice, about 10 times the daily human dose, produced no harmful effects. Studies of 2 pregnant beagles given daily injections of Ca-DTPA at 30 Fmol/kg, a daily dose comparable to 1 g in a 70 kg man, starting at 15 days of gestation until the end of pregnancy, have shown severe effects (especially brain damage in the fetuses).6-7
On the basis of these results and the lesser daily intake of zinc by humans compared to rats and mice, it has been postulated that some toxic effects on the human fetus might occur at the recommended daily dose levels of about 30 Fmol Ca-DTPA/kg. In the same experiments, Zn-DTPA did not show similar toxicity. Zn-DTPA is preferred and should be used if available to treat a pregnant female with internal transuranic contamination, although it is doubtful that a single or even several well-spaced doses of Ca-DTPA would be harmful to the pregnant female or fetus, especially if prophylactic zinc is given.
Adverse Reactions
No serious toxicity in human subjects has been reported as a result of over 4500 Ca-DTPA administrations in recommended doses. When given repeatedly, with short intervals for recovery, Ca-DTPA treatment may cause nausea, vomiting, diarrhea, chills, fever, pruritus, and muscle cramps in the first 24 hours. Anosmia (loss of the sense of smell) was observed in one individual after 123 g of Ca-DTPA over twenty-seven months of therapy and possibly could have been related to zinc depletion. After 100 days of no further DTPA administration, the patient's sense of smell improved.
In one patient, low-dose Ca-DTPA administration of 1 g per week showed no adverse effects after one month of such administration.8 Urinary zinc excretion studies suggest that the zinc supply is quickly replenished during this treatment regimen and that any partial depletion of zinc stores, if it occurs at all, would be transient.
Overdosage
Studies in animals indicate that the toxicity of Ca-DTPA depends on the total dose and the dose schedule. When administered to animals in high doses ($ 2000 Fmol/kg - clinical dose range is 10-30 Fmol/kg), the drug can produce severe lesions of the kidneys, intestinal mucosa, and liver, and can be lethal. Increased toxicity from fractionated dose schedules has been demonstrated in dog experiments in which injections at human dose levels, 5.8 Fmol/kg of Ca-DTPA given every 5 hours, were fatal as early as four days after the onset of treatment. The most significant injury occurs in the intestinal epithelium. In rats, continuous infusion of similar total doses per day caused death in 8-14 days, but the same dose given as a single daily injection failed to elicit this response. Toxicity in these cases apparently resulted from depletion of the Zn and Mn ions needed in the enzymatic steps leading to DNA syntheses that renews the epithelial cells in the intestinal epithelium. No untoward effects in rats were noted with doses of 100 Fmol Ca-DTPA given twice weekly and apparently there was no influence on Zn or Mn concentrations over a 44-week period on this dose schedule.
Dosage and Administration
Each dose of Ca-DTPA should be 1 gram and doses should not be fractionated. The route of administration may be either slow intravenous push of the drug over a period of 3-4 minutes, intravenous infusion (1 g in 100-250 ml D5W, Ringers Lactate, or normal saline), or inhalation in a nebulizer (1:1 dilution with water or saline). Intravenous administration should not be protracted over more than 2 hours.
Ca-DTPA may be administered undiluted by intramuscular injection when intravenous administration is not practical, although significant pain at the injection site has resulted when this route is used. The addition of 1-2% procaine to the undiluted Ca-DTPA prior to intramuscular injection has proven to be helpful.
The chelating efficacy is greatest immediately or within one hour of exposure when the radionuclide is circulating in or available to tissue fluids and plasma. However, a post-exposure interval >1 hour does not preclude the administration and effective action of Ca-DTPA.
Combined Ca-DTPA/Zn-DTPA Therapy Guidelines
It should be noted that the statements above are general guidelines for DTPA therapy and that treatment must be specifically tailored for each individual patient. Ca-DTPA and Zn-DTPA may be thought of as two components of transuranic decorporation therapy. If there is any contraindication to the use of Ca-DTPA, the same dose of Zn-DTPA may be substituted.
A. On assurance that a credible incident has occurred and that the exposed person(s) at risk has, in all likelihood, received internal transuranic contamination:
- Obtain the patient’s signature on an informed consent form for DTPA therapy (which should cover both Ca and Zn forms).
- Obtain base-line blood and urine samples (CBC with differential, BUN, serum creatinine, urinalysis and urine radioassay) and as indicated medically thereafter.
- Administer 1 g Ca-DTPA by the most appropriate route.
- Begin collection of 24-hour urine and fecal samples for bioassay. Whole body and chest counting should also be performed. Blood assays may prove helpful if the initial urinalysis is positive for transuranic contamination.
- If long-term use of Ca-DTPA is contemplated, one should consider the use of supplemental zinc therapy (one 220-mg zinc sulfate tablet daily delivers 50 mg zinc systematically).
- Repeat doses of 1 g Calcium DTPA or 1 g Zn-DTPA may be administered daily for up to 5 days per week if the radioassay data or history indicate the need for additional chelation. Note that the majority of patients in the past have received only one dose of DTPA.
- Although no significant side effects of DTPA at the recommended dosage level are known and there are no known contraindications to its use, urinalysis and complete blood counts should be done at the time of the initial treatment and as medically indicated thereafter. The patient's pulse and blood pressure also should be monitored during each drug infusion. Bioassay results and any side effects should be noted and recorded on the standard treatment form and reported to ORAU for the annual DTPA usage survey.
- Additional tests may be ordered at the discretion of the investigator and with the consent of the patient.
B. Before, during and after chelation therapy, pertinent measurements for radioactivity should be made to determine the efficacy of treatment. By the fifth day, evaluate bioassay data for body-burden estimation and decide whether further chelation is necessary. If continued chelation therapy is needed, a Zn-DTPA treatment regimen should be implemented.
- Begin the therapy regimen by administration of Zn-DTPA on a two-dose per week basis, 1 g Zn-DTPA per dose, until such time as excretion rate of the transuranic is not increased by Zn-DTPA administration.
- Wait four to six months, re-establish a base-line urinary excretion-rate value and give a 1 g Zn-DTPA dose by an appropriate route. Obtain bioassay measurements to determine whether the Zn-DTPA increased excretion of the contaminant.
- If medically indicated, begin a second course of Zn-DTPA treatment on a two dose per week basis as in (1) above.
C. Total length of chelation treatment after an accident is dictated by the magnitude of the accident and by the medical judgment of the attending physician.
D. When the patient is released from treatment, he/she should be followed at the routine intervals established by the occupational practice of the facility. A urinalysis is recommended at these examinations.
E. It is recommended that at the time of an employment termination, the treating physician should forward a copy of the medical history to a physician of the patient's choice. This should be done to ensure continuity of patient care and to assist if he/she should again become contaminated and require therapy at another plant site.
F. Patients who have received extensive chronic incorporation of transuranics require unusual therapy and will be treated largely according to the discretion of the investigator. In the past, treatment has not exceeded three 1 g doses during any 24-hour period. Doses should be administered by the route considered most appropriate for the particular patient.
How Supplied
Each ampule contains 1 g Ca-DTPA. The solution should be clear, colorless, and free of crystalline or other material. The ampules should be stored in cool place and away from sunlight.
As a part of the management of the IND for Ca-DTPA, annual quality control tests are performed on randomly selected ampules of the drug. There is no indication that deterioration, pyrogenicity, or loss of sterility occur when the ampules are stored at room temperature. However, if any problem of this nature should be observed, all co-investigators will be notified immediately. Any signs of deterioration (discoloration or cloudiness) of the solution or reaction on the part of the patient should be reported at once to one of the persons listed below.
The Food and Drug Administration (FDA) requires that the Sponsor and Manager(s) of the IND be in a position to account for all ampules sent to investigator-physicians. It is necessary, therefore, to set up an accounting system for the supplies of Ca-DTPA and to be prepared to report each facility’s experience annually. This report should include observations on the safety and efficacy of the Ca-DTPA used according to the protocols submitted with the original request for Ca-DTPA. The Manager(s) of the Ca-DTPA IND will contact each physician/investigator in June annually to obtain a report. This report will be incorporated into ORAU's summary report to the FDA for the prior 12-month period.
Summary of Administration
To maximize efficacy, if the patient has been injured, assure that medical treatment be initiated as soon as possible. However, delay does not preclude the use of DTPA. The patient’s respiratory/hemodynamic status should also be stable prior to administration of the drug. The following guidelines are provided to facilitate rapid initiation of treatment.
- Is it at all likely that the person has received internal contamination with plutonium, americium, berkelium, curium or californium?
- DTPA is not currently approved for use with uranium or neptunium.
- Obtain a history of renal, blood, bone marrow, cardiac or respiratory disorders and, if appropriate, the likelihood of pregnancy.
- Obtain written informed consent for both Ca-DTPA and Zn-DTPA.
- Obtain a 24-hour urine for radioassay and for urinalysis.
- If Ca-DTPA is contraindicated, use Zn-DTPA. Contraindications to the use of Ca-DTPA are current or past history of serious renal disease, bone marrow depression, pregnancy, or age less than 18 years.
- Administer 1 g of Ca-DTPA or Zn-DTPA by IV push over 3-4 minutes, IV infusion in 100-250 ml D5W, Ringers Lactate or normal saline, or by inhalation in a nebulizer (1:1 dilution with water or saline). Administration is approved for use by IM injection, but this is not recommended because of pain considerations.
- Blood pressure before and after DTPA administration should be routinely monitored.
- Follow the remainder of the procedures in the Therapy Guidelines section.
Questions regarding the use of Ca-DTPA may be referred to one of the following personnel at the Oak Ridge Associated Universities, P. O. Box 117, Oak Ridge, TN 37831-0117:
Albert L. Wiley, M.D., Ph.D.
and
Patrick C. Lowry, M.D.
Co-principal Investigators, DTPA IND
(865) 576-3131
Ronald D. Townsend, Ph.D.
Sponsor, DTPA IND
(865) 576-3300
REFERENCES:
- Breitenstein, B.D., Jr., Fry, S.A. and Lushbaugh, C.C. "DTPA therapy: The U.S. Experience 1958-1987," in: The Medical Basis of Radiation Accident Preparedness, 2nd ed., Ricks, R. and Fry, S.A. eds., Elsevier Science Publishing Co., Inc., pp. 397-406, 1990.
- Breitenstein, B.D., "1976 Hanford Americium Exposure Incident: Medical Management and Chelation Therapy," Health Physics, 45:4;855-866, 1983.
- Breitenstein, B.D., and Palmer, H.E. Lifetime Followup of the 1976 Americium Accident Victim. Radiation Protection Dosimetry. 26:317-322, 1989.
- Bruenger, F.W., Taylor, D.M., Taylor, G.N., and Lloyd, R.D. Effectiveness of DTPA treatments following the injection of particulate plutonium. Int J Radiat Biol. 60(5): 803-818, 1991.
- Morin M., Nenot J.C., and Lafuma J., "The behavior of 237-Np in the rat," Health Physics. 24:311-315, 1973.
- Taylor G.N., Mays C.W., "Fetal injury induced by Ca-DTPA in dogs" Health Physics, 35:858-860, 1978.
- Mays C.W., et al., "Zn-DTPA Safety in the Mouse Fetus," Health Physics, 36:526-529, 1979.
- D. R. Kalkwarf, V. W. Thomas, K. K. Nielson, M. L. Mauch, "1976 Hanford Americium Exposure Incident: Urinary Excretion of Trace Metals during DTPA Treatments," Health Physics, 45:4;937-947, 1983.