Pentetate zinc trisodium (Zn-DTPA) is a radiomitigation chelating agent indicated for the treatment of individuals with known or suspected internal contamination with plutonium, americium, or curium. Treatment with Zn-DTPA increases the rate of elimination of these radioactive contaminants. Begin chelation treatment immediately. If treatment cannot be started right away, patients should begin therapy as soon as it becomes available, as treatment is still effective even after time has elapsed since exposure. Do not administer Zn-DTPA simultaneously with pentetate calcium trisodium (Ca-DTPA) due to the duplicative nature of the treatments. If both products are available, give Ca-DTPA as the first dose. If additional chelation treatment is needed, switched to Zn-DTPA, if available. 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 mineral loss. Therefore, Zn-DTPA is preferred for maintenance therapy. When the sources of radiation contamination are multiple or unknown, other therapies (such as potassium iodide, insoluble Prussian blue) can be used in combination with Zinc or calcium DTPA. The Zn-DTPA product labeling contains Black Box Warnings (BBW) regarding the potential for depletion of trace minerals and the potential for asthma exacerbation with inhaled administration.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
NOTE: Advise the patient of the following safety instructions:
-Drink plenty of fluids and void frequently to promote dilution of the radioactive chelates in the urine and minimize radiation exposure directly to the bladder.
-Use a toilet instead of a urinal, and flush several times after each use.
-Clean spilled urine or feces completely, and wash hands thoroughly. Wash clothing or linens separately if blood or urine comes into contact.
-Properly dispose of breast milk.
Route-Specific Administration
Injectable Administration
Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. The product may be filtered using a sterile filter if particles are observed after opening of the ampule.
Intravenous Administration
-Intravenous administration is recommended and should be used if the route of internal contamination is not known or if multiple routes of internal contamination are likely.
-Administer as a slow intravenous push over a period of 3 to 4 minutes or by intravenous infusion over 30 minutes diluted in 100 to 250 mL of 5% Dextrose in Water, Ringer's Lactate, or 0.9% Sodium Chloride for Injection.
Inhalation Administration
-May be administered by nebulized inhalation if the contamination is known to be via inhalation ONLY.
-Dilute Zn-DTPA for nebulization at a 1:1 ratio with Sterile Water or 0.9% Sodium Chloride.
-After treatment, encourage patients to avoid swallowing any expectorant. The expectorant must be disposed of carefully.
In the U.S. Registry, a total of 646 individuals received chelation therapy with at least 1 dose of either pentetate calcium trisodium (Ca-DTPA) or pentetate zinc trisodium (Zn-DTPA). Of these 646 drug recipients, 62 received Zn-DTPA by 1 or more routes of administration. Overall, the presence or absence of adverse events were recorded in 310 individuals. In these reports, 19 individuals (6.1%) experienced at least 1 adverse event, and the total number of recorded adverse events was 20. Of the 20 adverse events, 1 individual treated with Zn-DTPA experienced a headache, lightheadedness or dizziness, and pelvic pain. Two patients who received nebulized Ca-DTPA experienced cough and wheezing. Nebulized chelation therapy, including nebulized Zn-DTPA, may be associated with exacerbation of asthma, coughing, and wheezing.
Chelation therapies can result in an electrolyte imbalance and mineral depletion with prolonged used; however, such complications are less common with the use of pentetate zinc trisodium (Zn-DTPA) when compared to pentetate calcium trisodium (Ca-DTPA). At comparable doses, rodent studies have revealed that Zn-DTPA had less toxicity (e.g., less depletion of trace metals, lower rate of mortality, the absence of kidney and liver vacuolization, and absence of small bowel hemorrhagic lesions) compared to Ca-DTPA administration. However, prolonged Zn-DTPA treatment over several months could lead to depletion of endogenous metals of the body such as magnesium and manganese. Monitor patients for electrolyte imbalances, including hypomagnesemia, during long-term treatment and give mineral or vitamin plus mineral supplements when appropriate.
Before starting treatment with pentetate zinc trisodium (Zn-DTPA), ensure steps are taken to limit radiation exposure. Follow radioactive decontamination safety procedures including the use of appropriate radiation protective attire and close monitoring of personnel and treatment area for radiation levels. Additionally, spread of the radiation contamination must be controlled by establishing a patient decontamination area and a contaminated material disposal site (proper labeling, handling, disposal of contaminated material). Instruct patients on safety measure to be taken to minimize radiation exposure to others or reexposure to self, including use of toilets instead of urinals with multiple flushes with each use, cleaning of spilled urine or feces with thorough handwashing, separate washing of clothing or linens that have come in contact with blood or urine, and proper disposal of breast milk or any expectorant (do not swallow expectorant). Additionally, advise patients to drink plenty of fluids and void frequently to promote dilution of the radioactive chelate in the urine and minimize radiation exposure directly to the bladder.
Pentetate zinc trisodium (Zn-DTPA) decreases exposure to radioactive plutonium, americium, and curium by increasing their rates of elimination; however, the drug does not treat complications due to radiation exposure, such as bone marrow suppression with severe neutropenia and thrombocytopenia. Additional supportive treatment for radiation toxicity symptoms may be needed. Also, in radiological emergencies, the type of elemental exposure may not be known. Zn-DTPA may not bind to or eliminate all radioactive elements involved. Patients contaminated with unknown or multiple radioactive elements may require treatment with other therapies in addition to Zn-DTPA. Whenever possible, obtain a quantitative baseline estimate of the total internalized transuranium element(s) and measures of elimination of radioactivity by appropriate whole-body counting, bioassay (e.g., biodosimetry), or fecal and urine samples.
Treatment with pentetate zinc trisodium (Zn-DTPA) may lead to depletion of endogenous metals, such as magnesium and manganese. The risk for depletion increases with prolonged use over several months. Monitored for electrolyte imbalance, including hypomagnesemia, during long-term treatment. Give mineral or vitamin plus mineral supplements when appropriate.
Nebulized chelation therapy with pentetate zinc trisodium (Zn-DTPA) may be associated with asthma exacerbation. Use caution when administering Zn-DTPA by the inhalation route, particularly to patients with known pulmonary disease.
Renal impairment may reduce the rate at which pentetate zinc trisodium (Zn-DTPA) remove radiocontaminants from the body. In heavily contaminated patients with renal impairment, dialysis may be used to increase the rate of elimination. High-efficiency, high flux dialysis is recommended. Dialysis fluid will become radioactive. Radiation precautions must be taken to protect personnel, other patients, and the public.
No adequate and well-controlled studies have been conducted to evaluate the use of pentetate zinc trisodium (Zn-DTPA) during human pregnancy. In pregnant mice, doses up to 31-times the recommended daily human dose showed no evidence of impaired fertility or harm to the fetus; however, there was a slight reduction in the average birth weight. It is recommended to begin and continue chelation therapy in pregnant with pentetate zinc trisodium (Zn-DTPA), if available, except in cases of high internal radioactive contamination. In these cases, the risk of immediate and delayed radiation-induced toxicity to both the mother and fetus must be considered in comparison to the toxicity risk of pentetate calcium trisodium (Ca-DTPA). For patients with high contamination, it may be appropriate to use a single dose of Ca-DTPA with vitamin or mineral supplements that contain zinc as the initial dose, as Ca-DTPA is more effective than Zn-DTPA in the first 24 hours after internal contamination.
Studies to determine if pentetate zinc trisodium (Zn-DTPA) is excreted in breast milk have not been conducted. Radioactive contaminants are known to be excreted in breast milk. Avoid breast-feeding in patients with known or suspected internal contamination with radiocontaminants, despite receipt of chelation therapy. Take precautions when discarding breast milk.
For treatment of individuals with known or suspected internal contamination with radiation exposure to plutonium, americium, or curium to increase the rates of elimination:
NOTE: When possible, obtain a quantitative baseline estimate of the total internalized transuranium element(s) and measures of elimination of radioactivity by appropriate whole-body counting, bioassay (e.g., biodosimetry), or fecal and urine samples.
NOTE: Start chelation therapy as soon as possible after contamination is suspected, as treatment is most effective if administered within the first 24 hours after internal contamination. If treatment cannot be started right away, chelation therapy should be given as soon as it becomes available. Chelation therapy is still effective even after time has elapsed since exposure; however, effectiveness decreased with time as the radiocontaminants become sequestered in the liver and bone.
NOTE: To develop long-term response data and information on risk of late malignancy, provide detailed information on patient treatment to the manufacturer. Include a record of the radioactive body burden and bioassay results at defined time intervals, a description of measurement methods to facilitate analysis of data, and adverse events. Record these data on the Patient Treatment Data Form that is available from the manufacturer at www.zn-dtpa.com.
-Initial Dose Protocol:
NOTE: Pentetate calcium trisodium (Ca-DTPA) is preferred as the initial dose during the first 24 hours of internal contamination, as Ca-DTPA is more effective than pentetate zinc trisodium (Zn-DTPA) during this time period. If Ca-DTPA is not available, Zn-DTPA may be used as the initial therapy.
Intravenous dosage:
Adults: 1 gram IV single dose.
Children and Adolescents 12 years and older: 1 gram IV single dose.
Children younger than 12 years: 14 mg/kg IV single dose, not to exceed 1 gram. NOTE: Safety and efficacy were established in the adult population and efficacy was extrapolated to the pediatric population for the IV route based on the comparability of pathophysiologic mechanisms. The dose is based on body size adjustment for an IV drug that is renally cleared.
Oral inhalation dosage (nebulized solution):
NOTE: An alternative route of administration for individuals whose internal contamination occurred via inhalation ONLY. Use IV administration if the route of internal contamination is unknown or if multiple routes of internal contamination are likely.
Adults: 1 gram as a single dose via inhaled nebulization in a 1:1 ratio with saline or sterile water.
-Maintenance Treatment Protocol:
NOTE: The duration of chelation treatment depends on the amount of internal contamination and individual response to treatment.
NOTE: After the initial dose of Ca-DTPA, on the next day, if additional chelation therapy is necessary, it is preferable to switch to Zn-DTPA because of the safety concerns associated with prolonged Ca-DTPA use. If Zn-DTPA is not available, treatment may continue with Ca-DTPA; however, mineral supplements containing zinc should be given concomitantly as appropriate.
Intravenous dosage:
Adults: 1 gram IV once daily. Do not administer more than 1 dose per 24-hour period.
Children and Adolescents 12 years and older: 1 gram IV once daily. Do not administer more than 1 dose per 24-hour period.
Children younger than 12 years: 14 mg/kg IV once daily, not to exceed 1 gram per day. Do not administer more than 1 dose per 24-hour period. NOTE: Safety and efficacy were established in the adult population and efficacy was extrapolated to the pediatric population for the IV route based on the comparability of pathophysiologic mechanisms. The dose is based on body size adjustment for an IV drug that is renally cleared.
Oral inhalation dosage (nebulized solution):
NOTE: An alternative route of administration for individuals whose internal contamination occurred via inhalation ONLY. Use IV administration if the route of internal contamination is unknown or if multiple routes of internal contamination are likely.
Adults: 1 gram once daily via inhaled nebulization in a 1:1 ratio with saline or sterile water. Do not administer more than 1 dose per 24-hour period.
Maximum Dosage Limits:
-Adults
1 gram per day IV or via nebulized inhalation.
-Geriatric
1 gram per day IV or via nebulized inhalation.
-Adolescents
1 gram per day IV; safety and efficacy not established for nebulized inhalation.
-Children
12 years: 1 gram per day IV; safety and efficacy not established for nebulized inhalation.
1 to 11 years: 14 mg/kg/dose IV, not to exceed 1 gram per day; safety and efficacy not established for nebulized inhalation.
-Infants
Safety and efficacy not established.
-Neonates
Safety and efficacy not established.
Patients with Hepatic Impairment Dosing
No dosage adjustment is needed.
Patients with Renal Impairment Dosing
No dosage adjustment is needed. However, renal impairment may reduce the rate at which chelators remove radiocontaminants from the body. In heavily contaminated patients with renal impairment, dialysis may be used to increase the rate of elimination. High efficiency, high flux dialysis is recommended. Dialysis fluid will become radioactive; radiation precautions must be taken to protect personnel, other patients, and the public.
*non-FDA-approved indication
There are no drug interactions associated with Pentetate Zinc Trisodium, Zn-DTPA products.
Pentetate zinc trisodium (Zn-DTPA) forms stable chelates with metal ions by exchanging zinc for a metal of greater binding capacity. Zn-DTPA is effective for possible internal contamination with plutonium, americium, or curium. The radioactive chelates are then excreted by glomerular filtration into the urine. Zn-DTPA treatments are not expected to be effective for uranium and neptunium; radioactive iodine is not bound by DTPA. Based on the mechanism of action, Zn-DTPA may bind other elements or minerals (e.g., magnesium), and cause electrolyte or other nutritional imbalances.
Data in animals and humans indicate that intravenous administration of Zn-DTPA forms chelates with radioactive contaminants found in the circulation, interstitial fluid, and tissues. When administered by inhalation, Zn-DTPA can also chelate transuranium elements. Expectoration is expected to decrease the amount of radioactive contaminants available for systemic absorption. The effectiveness of chelation treatment decreases with time after internal contamination because the transuranium elements become incorporated into the tissues. Chelation treatment should be given as soon as possible after known or suspected internal contamination with transuranium elements has occurred.
When the sources of radiation contamination are multiple or unknown, other therapies (such as potassium iodide, insoluble Prussian blue) can be used together with Zn-DTPA.
Pentetate zinc trisodium (Zn-DTPA) is administered intravenously or via nebulized inhalation. Once in the systemic circulation, the drug is rapidly distributed throughout the extracellular space. A significant amount does not penetrate into erythrocytes or other cells, and no accumulation in specific organs has been observed. Further, there is little to no binding of the Zn-DTPA by the renal parenchyma. Zn-DTPA undergoes a minimal amount of metabolic change in the body. Zn-DTPA is cleared through urinary excretion by glomerular filtration from the plasma in the first few hours. Renal tubular excretion has not been documented. In stool samples tested, only a very small amount of radioactivity (less than 3%) was detected.
Affected cytochrome P450 isoenzymes: none
-Route-Specific Pharmacokinetics
Oral Route
Zn-DTPA is poorly absorbed in the gastrointestinal tract. In animal studies, the oral absorption of Zn-DTPA was approximately 5%.
Intravenous Route
In a study of rodents, pentetate calcium trisodium (Ca-DTPA) or Zn-DTPA was given in a single intravenous dose of 10 to 1,000 micromol/kg (0.54- to 54-times the maximum human recommended dose). When rodents were treated within 1 hour of plutonium contamination, Ca-DTPA resulted in a 10-fold higher rate of elimination of plutonium in the urine as compared to Zn-DTPA.
Inhalation Route
Eighteen patients in a U.S. registry received a single 1-gram inhaled or intravenous dose of Ca-DTPA; urine data indicated that the inhaled product was absorbed (approximately 20%) and resulted in an elimination of radioactive contaminants that was comparable to the intravenous dose.
-Special Populations
Renal Impairment
Adequate and well-controlled pharmacokinetic and pharmacodynamic studies in patients with renal impairment were not identified in the literature. Both Zn-DTPA and its radioactive chelates are excreted by glomerular filtration. Impaired renal function may decrease their rates of elimination and increase the serum half-life of Zn-DTPA.
Pediatrics
Specific pharmacokinetic data in children are not available. The safety and efficacy of Zn-DTPA were established in the adult population and efficacy was extrapolated to the pediatric population for the intravenous (IV) route based on the comparability of pathophysiologic mechanisms. The recommended dosage is based on body size adjustment for an IV drug that is renally cleared. No extrapolation data are available for the inhalation route of administration.