1. What is the Food and Drug Administration (FDA) announcing today?
The FDA is announcing its decision to approve Hameln's new drug applications (NDAs) for pentetate calcium trisodium injection (Ca-DTPA) and pentetate zinc trisodium injection (Zn-DTPA) for the treatment of internal contamination with plutonium, americium, or curium to increase the rates of elimination of these materials from the body.
This is part of FDA’s continuing efforts to foster the development and availability of drug products for treatment of people who are accidentally contaminated internally with radioactive materials (i.e., radioactive material that gets inside the body), and as countermeasures to terrorist attacks. Contamination with radioactive materials could occur from laboratory or industrial accidents, or through terrorist attacks. Radioactive materials could be spread through an explosion of a radiation dispersal device (RDD), commonly known as a "dirty bomb." A dirty bomb is a conventional explosive device that contains radioactive material. Radioactive materials could also be spread through use of an improvised nuclear device from which only a small portion of the plutonium is consumed in the nuclear reaction and the rest of the plutonium is spread through the air by the explosion.
2. What are Ca-DTPA and Zn-DTPA?
Calcium-DTPA (Ca-DTPA) and Zinc-DTPA (Zn-DTPA) are drug products that have been used investigationally for over 40 years to speed up excretion of the transuranium elements plutonium, americium, and curium from the body. Ca-DTPA and Zn-DTPA bind to these elements and are then excreted in the urine. The FDA has found that when produced under conditions specified in approved new drug applications (NDAs), both of these products can be safe and effective for the treatment of internal contamination with plutonium, americium, or curium. Ca-DTPA and Zn-DTPA do not treat contamination with radioactive iodine, uranium and neptunium, or the complications of radiation exposure (e.g., bone marrow suppression). Other treatments should be initiated if these conditions are suspected.
3. What are plutonium, americium, and curium?
Plutonium, americium, and curium are transuranium elements (elements with atomic numbers higher than uranium). All transuranium elements are radioactive. In addition to their use in laboratory and industrial environments, these elements may be found in nuclear weapons and nuclear power plant waste.
People can become internally contaminated with these radioactive materials by inhalation, ingestion, or direct contact through wounds. Internal contamination with plutonium, americium, or curium can occur through a variety of routes including ingestion, inhalation, or direct contact through wounds. The goal of treatment with Ca-DTPA and Zn-DTPA is to enhance the removal of these radioactive contaminants and hence the risk of possible future biological effects, including the development of certain cancers which may occur years after contamination.
4. How are Ca-DTPA and Zn-DTPA administered?
Ca-DTPA and Zn-DTPA should not be administered simultaneously. FDA recommends that, if both products are available, Ca-DTPA be given as the first dose. If additional treatment is needed, treatment should be switched to Zn-DTPA. This treatment sequence is recommended because Ca-DTPA is more effective than Zn-DTPA during the first 24 hours after internal contamination. After the initial 24 hours, Zn-DTPA and Ca-DTPA are similarly effective, but Ca-DTPA causes more loss of essential metals, such as zinc, from the body. Therefore, Zn-DTPA is preferred for maintenance therapy.
If Ca-DTPA is not available or treatment cannot be started within the first 24 hours after contamination, treatment should begin with Zn-DTPA.
If Zn-DTPA is not available, Ca-DTPA can be given for continued treatment, along with vitamin or mineral supplements that contain zinc.
Ca-DTPA and Zn-DTPA can be administered by nebulizer or directly into the blood stream (i.e. intravenously). If the route of internal contamination is through inhalation alone, then nebulized chelation therapy will suffice. If the routes of contamination are multiple (e.g., inhalation and through wounds), then intravenous chelation therapy is preferred.
The duration of treatment is dictated by the level of internal contamination and the individual’s response to therapy. Levels of internal contamination should be ascertained weekly during chelation therapy to determine when to terminate treatment.
Zn-DTPA is the preferred treatment for the pregnant woman with internal contamination.
5. How soon after internal contamination should someone receive Ca-DTPA or Zn-DTPA to avoid illness?
In most cases of contamination with transuranium elements, it is unlikely that immediate illness would occur. In order to reduce the risks of future biological effects, Ca-DTPA or Zn-DTPA should be taken as soon as possible after internal contamination, following or concurrent with distancing the individual from the radioactive source and appropriate external decontamination. However, even when treatment cannot be started right away, individuals should be given Ca-DTPA or Zn-DTPA as soon as the products are available. Treatment with Ca-DTPA or Zn-DTPA is still effective even after time has elapsed since contamination, but effectiveness decreases once these elements are trapped in the bones.
6. Are there any side effects associated with taking Ca-DTPA or Zn-DTPA?
The main side effect of Ca-DTPA is loss of certain essential nutritional metals, such as zinc, from the body. Zinc can be replaced by taking oral zinc supplements. Although Zn-DTPA may also decrease the levels of certain nutritional metals, the effect (which can be countered by taking mineral supplements) is less than with Ca-DTPA. Chelation therapy administered by nebulized inhalation may cause breathing difficulties in some individuals. In addition, Ca-DTPA should be used with caution in patients suffering from a severe form of a disease called hemochromatosis.
7. What is the basis for FDA’s finding that Ca-DTPA and Zn-DTPA can be found safe and effective?
The FDA has determined that Ca-DTPA and Zn-DTPA, when manufactured under the conditions of approved NDAs, can be found safe and effective for the treatment of individuals with known or suspected internal contamination with plutonium, americium, or curium. This finding is based on data maintained in a U.S. Registry of individuals with internal radioactive contamination with these materials from acute occupational exposure, as well as from a careful review of published literature articles containing reports and data. Both Ca-DTPA and Zn-DTPA were found to increase the excretion of these radioactive materials from the body.
8. Why is FDA revising the Ca-DTPA and Zn-DTPA labeling?
FDA is announcing revisions to the draft Ca-DTPA and Zn-DTPA labeling that were placed on the FDA website in September 2003, based on additional literature articles and clinical data. FDA is also revising the guidance on submitting NDAs for Ca-DTPA and Zn-DTPA to highlight the revised labeling. The revised labeling represent the FDA’s current thinking on the Ca-DTPA and Zn-DTPA products in several areas:
FDA recommends nebulized Zn-DTPA for adults whose internal contamination is only by inhalation;
The safety and efficacy of the nebulized route of administration have not been established in the pediatric population for Ca-DTPA or Zn-DTPA;
The safety and effectiveness of the intramuscular route have not been established for Ca-DTPA or Zn-DTPA;
The duration of Ca-DTPA and Zn-DTPA therapy depends on the amount of internal radioactive contamination and the individual’s response to therapy; and
Ca-DTPA should be used with caution in patients suffering from a severe form of a disease called hemochromatosis.
Manufacturers who wish to submit NDAs for these products and who rely on FDA’s finding that Ca-DTPA and Zn-DTPA are safe and effective should submit the revised labeling with their applications.
9. Are there currently any other FDA-approved products to treat internal contamination with transuranium elements?
No, there are currently no other FDA-approved products for treating internal contamination with transuranium elements.
10. How does this relate to FDA’s previous findings that Prussian blue may be safe and efficacious for people internally contaminated with radioactive materials?
Both Prussian blue and the DTPA products are drugs intended to enhance the elimination of radioactive materials from the body. The drugs differ in chemical composition, routes of administration, side effects, and types of radioactive materials that they eliminate from the body. Prussian blue is administered by mouth while the DTPA products are injected in the blood stream or inhaled. The main side effects of Prussian blue are constipation and upset stomach. The main side effect of the DTPA products, especially Ca-DTPA, is a decrease in levels of certain essential nutritional metals. Prussian blue remains in the intestine and binds radioactive cesium and thallium. DTPA products circulate through the blood stream and bind radioactive transuranium elements (i.e., plutonium, americium, curium).
11. How can I get treatment with Ca- DTPA and Zn-DTPA?
Ca-DTPA and Zn-DTPA are available only by prescription and should be given only under the supervision of a physician after assessing your medical condition. These drugs are only effective to treat internal contamination with radioactive plutonium, americium and curium. The duration of treatment depends on the amount of internal contamination a person is exposed to and their response to treatment. Therefore, these drugs should be given only when the physician has determined your need for them.
12. Will Ca-DTPA and Zn-DTPA be added to the National Stockpile?
The U.S. government makes sure that needed medications, especially medicines that may be needed to treat a terrorist threat, are stored in sufficient quantity to provide treatment if there is an emergency.