Zinc-DTPA Informational Material Package Insert
Nov. 14, 2002
Zn-DTPA (Trisodium zinc diethylenetriaminepentaacetate)
Structural Formula:
Description
IND 14,603, Trisodium zinc diethylenetriaminepentaacetate (Zn-DTPA), is a zinc 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 commonly used in lesser concentrations as a chelating vehicle in FDA-approved nuclear medicine studies.
Zn-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 Zn-DTPA and the analogous Ca-DTPA for DOE. The current supply of Ca-DTPA has been purchased from Heyl GmbH, Berlin, Germany and has been 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 (USA 23) and the European pharmacopeia (Ph.Eur).
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. Zn-DTPA removes toxic metals by exchanging its cations for metals that form more stable complexes with the DTPA ligand. The complex is then excreted in the urine.
The plasma half-life of DTPA is 20-60 minutes. Almost the entire administered dose is excreted in 12 hours, with only a small amount bound to plasma proteins, having a half-life of >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, Zn-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 radioactively marked chelating agents, only a very small amount of radioactivity (<3%) was detected.
One patient with chronic Ca/Zn-DTPA administration for over 3 years was assayed for 24 elements including almost all of the trace metals recognized as essential for good health. Zinc was found to be the only metal excreted more rapidly than normal.[i],5 The 132 mg of zinc contained in 1 g of Zn-DTPA compensates for the loss of 18 mg of zinc that was found to be associated with the injection of 1 g of DTPA salt.
Reviewed and approved for continuation for 12 months by the Oak Ridge Site Wide Institutional Review Board, Nov. 20, 2003.
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.[i]
The efficacy of Ca-DTPA and/or Zn-DTPA treatment for internal contamination with the actinides is good for soluble salts, such as the nitrate or chloride, but is essentially nil for highly insoluble compounds, such as the high-fired oxide. The same effects are 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.
Zn-DTPA is initially 10 times less effective than Ca-DTPA for initial chelation of transuranics; therefore, Ca-DTPA should be used whenever larger body burdens of transuranics are involved. Ca-DTPA is the drug of choice for initial patient management unless contraindicated. After approximately 24 hours, however, Zn-DTPA is for all practical purposes as effective as Ca-DTPA, since the efficiency of both agents is about the same. The comparable efficacy, coupled with its lesser toxicity, makes Zn-DTPA the preferred agent for protracted therapy.
Contraindications
Zn-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.6
Warnings and Precautions
- Fractionation of the recommended 1 g dose (several smaller doses per day) is not recommended although Zn-DTPA does not appear to have the increased toxicity of Ca-DTPA (associated with fractionated treatment).
- Blood pressure should be monitored closely during infusion.
- Discontinue the drug if diarrhea occurs.
Usage in Pregnancy - Pregnancy Category C -
The chelates do not significantly cross-placental barriers. There have been several studies indicating the lack of teratogenic effects by Zn-DTPA at doses up to several times the human intravenous dose of 0.0287 mmol/kg. In these experiments, Zn-DTPA did not show toxicity during pregnancy as did Ca-DTPA. In pregnant mice given a daily dose of 11.5 mmol/kg (400 times the human dose), the only fetal effect observed was a slight reduction in the average birth weight.7 Zn-DTPA is therefore preferred over Ca-DTPA in pregnancy and should be used, if available, to treat a pregnant female with internal transuranic contamination. However, there are no adequate and well-controlled studies of Zn-DTPA in pregnant women. The potential benefits of transuranic decorporation must therefore be weighed against the risk to the fetus.
Adverse Reactions
No serious toxicity in humans has been reported as a result of over 1000 Zn-DTPA administrations in recommended doses. When given repeatedly, with short intervals for recovery, Zn-DTPA treatment may cause nausea, vomiting, diarrhea, chills, fever, pruritus, and muscle cramps in the first 24 hours.
In one patient, long-term, low-dose combination Ca/Zn-DTPA administration was performed using six different schedules: 1 g Ca-DTPA/24h, 1 g Ca-DTPA/12h, 1 g Zn-DTPA/12h, 1 g Zn-DTPA/8h, 1 g Zn-DTPA/12h, 0.5 g Zn-DTPA/12h, 1 g Zn-DTPA/24h and 1 g Zn-DTPA three times a week. After 939 days of such administration, there were no adverse effects observed.2
Overdosage
Zn-DTPA is some 30 times less toxic than Ca-DTPA to mice when given daily at high doses. Acutely lethal doses of Zn-DTPA are estimated at >20 mmol/kg or 10g/kg in the adult male mouse.7 In animal and in human studies, in contrast to experience with Ca-DTPA, there has been no observed decrease in Zn or Mn in the liver, small intestine, or in the kidneys.
Dosage and Administration
Each dose should be 1 gram of Zn-DTPA. The route of administration may be either intravenous infusion of the undiluted solution over a period of 3-4 minutes, intravenous infusion (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.
Clinical experience has shown that aerosol inhalation of Zn-DTPA is more effective than intramuscular injection, apparently because distribution to the body from the lung is slower than from muscle, and results in a longer lasting plasma level. This same relationship exists when comparing the effectiveness of aerosol inhalation of Zn-DTPA to intravenous injection.
Zn-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 Zn-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 the tissue fluids and plasma. However, a post-exposure interval >1 hour does not preclude the administration and effective action of Zn-DTPA.
Combined Ca-DTPA/Zn-DTPA Therapy Guidelines
It must be noted that this is a general guide for DTPA therapy and that treatment must be specifically tailored for individual patients. Ca-DTPA and Zn-DTPA generally can 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 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).
- Administer 1 g Ca-DTPA by the most appropriate route for the particular patient.
- Begin collection of 24-hour urine and fecal samples for bioassay. Whole body and/or chest counting should also be performed. Blood assays may be done if the initial urinalysis was 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 systemically)
- Repeat doses of 1 g Ca-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. Keep in mind 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 on the day following the initial treatment and as indicated medically thereafter. The patient's pulse and blood pressure also should be monitored to determine any effect of the drug. 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. Significant side effects should be reported promptly.
- 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 so, 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 base-line urinary excretion-rate value and give a 1 g Zn-DTPA dose by an appropriate route. Obtain bioassay or urinary excretion 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. If bioassay data indicates that contamination was not excessive, then further chelation therapy may be discontinued at the discretion of the attending physician.
D. When the patient is released from further therapy, he/she should be followed at the routine intervals established by the occupational practice of the facility. A urinalysis is recommended at these examinations.
It is recommended that, at the time of an employment termination, the physician should forward a copy of the medical history to a physician of the patient's choice. In addition, the physician should offer the patient the opportunity to be followed medically by the DOE follow-up system. This should be done to ensure continuity of patient care if he/she should again become contaminated and require therapy at another plant site.
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 of Zn-DTPA during any 24-hour period. Doses should be administered by the route considered most appropriate for the particular patient.
How Supplied
Each ampule provided contains 1 g Zn-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 Zn-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 occurs 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. These physicians must, therefore, set up an accounting system on the supplies of Zn-DTPA and be prepared to report their clinical experience annually, including observations on the safety and efficacy of the Zn-DTPA. The Manager(s) of the Zn-DTPA IND will contact all co-investigators in June of each year to obtain this report. These observations will be incorporated into ORAU's summary report to the FDA for the preceding 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, hematopoietic, 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 an initial 24-hour urine for radioassay and 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 Ringers Lactate, D5W, 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 Zn-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 Wiley, M.D., Ph.D., REAC/TS Director
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.
- 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.
- Morin M., Nenot J.C., and Lafuma J., “The behavior of 237-Np in the rat,” Health Physics. 24:311-315, 1973.
- Mays C.W., et al., “Zn-DTPA Safety in the Mouse Fetus, Health Physics,” 36:526-529, 1979.