Pentetate calcium trisodium contains the sodium salt of calcium diethylenetriaminepentaacetate, a chelating agent. The drug is also known as trisodium calcium diethylenetriaminepentaacetate and is commonly referred to as Ca-DTPA. Ca-DTPA, like its counterpart pentetate zinc trisodium (Zn-DTPA), is given intravenously or by nebulized inhalation and is used to treat known or possible internal contamination with plutonium, americium, or curium. 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 Ca-DTPA and Zn-DTPA simultaneously due to the duplicative nature of the treatments. If both products are available, give Ca-DTPA as the first dose. If additional chelation therapy is needed, switch 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 together with zinc or calcium DTPA. The Ca-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.
Hazardous Drugs Classification
-NIOSH 2016 List: Group 3
-NIOSH (Draft) 2020 List: Table 2
-Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
-Use double chemotherapy gloves and a protective gown. Prepare in a biological safety cabinet or compounding aseptic containment isolator with a closed system drug transfer device. Eye/face and respiratory protection may be needed during preparation and administration.
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 unknown 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 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 Ca-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, 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, 18 occurred after treatment with Ca-DTPA. The adverse events included headache, dizziness, chest pain (unspecified), allergic reaction, dermatitis or rash, dysgeusia (metallic taste), nausea, diarrhea, and injection site reaction. Cough and wheezing were experienced by 2 individuals receiving nebulized Ca-DTPA, 1 of whom had a history of asthma.
The literature reports that prolonged treatment with pentetate calcium trisodium (Ca-DTPA) can result in electrolyte imbalance and mineral depletion, with the depletion of zinc, magnesium (hypomagnesemia), manganese and possibly metalloproteinases. Endogenous metal depletion is increased with higher doses, split daily dosing, and a longer duration of treatment. Depletion of these endogenous metals can interfere with necessary mitotic cellular processes. Over longer periods of time, zinc deficiency due to Ca-DTPA therapy may result in transient inhibition of a metalloenzyme-d-aminolevulinic acid dehydrase (ALAD) in the blood and suppressed hematopoiesis.
Before starting treatment with pentetate calcium trisodium (Ca-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 calcium trisodium (Ca-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. Ca-DTPA may not bind to or eliminate all radioactive elements involved. Patients contaminated with unknown or multiple radioactive elements may require treatment with other agents in addition to Ca-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.
Pentetate calcium trisodium (Ca-DTPA) is associated with depletion of endogenous trace metals, such as zinc, magnesium, and manganese. Administration of high doses results in losses of zinc and manganese mainly from the small intestine, skeleton, pancreas, and testes. Dosing over several days results in mobilization or binding of endogenous metals in exchange for calcium and a consequent impairment of metal-controlled or activated systems. Endogenous metal depletion is increased with higher doses, split daily dosing, and a longer duration of treatment. Depletion of these endogenous metals can interfere with necessary mitotic cellular processes. Over longer periods of time, zinc deficiency due to Ca-DTPA therapy may result in transient inhibition of a metalloenzyme-d-aminolevulinic acid dehydrase (ALAD) in the blood and suppressed hematopoiesis. To minimize the risk, limit use of Ca-DTPA to only the initial chelation therapy dose; switch to pentetate zinc trisodium (Zn-DTPA) after this initial dose. If Zn-DTPA is not available, chelation therapy may continue with Ca-DTPA; however, concomitant use of mineral supplements containing zinc is recommended as appropriate. Monitor for electrolyte imbalance, including hypomagnesemia, during therapy.
Nebulized pentetate calcium trisodium (Ca-DTPA) is associated with asthma exacerbation. In the U.S. Registry of 646 recipients of chelation therapy, 2 individuals experienced cough and wheezing; one patient had a history of asthma. Use caution when administering Ca-DTPA by the inhalation route, particularly to patients with known pulmonary disease.
Administer pentetate calcium trisodium (Ca-DTPA) with extreme caution to individuals with hemochromatosis; use of only a single dose is particularly important for these patients. Three deaths have been reported in patients with severe hemochromatosis who were treated with daily intramuscular Ca-DTPA dosed up to 4 grams per day (4-times the recommended daily dose) to reduce iron stores. Causal association with these events and the drug has not been established.
Renal impairment may reduce the rate at which pentetate calcium trisodium (Ca-DTPA) removes 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.
During pregnancy, begin and continue chelation therapy 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. There are no human pregnancy outcome data with which to assess the risk of Ca-DTPA exposure on fetal development. However, based on animal data, Ca-DTPA is believed to be teratogenic due to depletion of body stores of zinc which is essential for fetal development. In mice, daily doses 2- to 8-times the recommended human dose, based on body surface area (BSA), were teratogenic and embryotoxic with a dose-dependent increase in the frequency of gross malformations. The drug was also teratogenic in dogs at approximately half the recommended daily human dose, based on BSA. There are no animal or human data evaluating the fetal risk with a single dose of Ca-DTPA.
Studies to determine if pentetate calcium trisodium (Ca-DTPA) is excreted in breast milk have not been conducted. Radio 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 the 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.ca-dtpa.com.
-Initial Dose Protocol:
NOTE: Administer pentetate calcium trisodium (Ca-DTPA) as the initial chelation therapy dose during the first 24 hours after internal contamination, as Ca-DTPA is more effective than pentetate zinc trisodium (Zn-DTPA) during this time period. If Ca-DTPA is not available, use Zn-DTPA 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:
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: Prolonged use of Ca-DTPA is not recommended due to safety concerns; therefore, if additional chelation therapy is necessary, it is preferable to switch to Zn-DTPA on the day after the initial Ca-DTPA dose. If Zn-DTPA is not available, treatment may continue with Ca-DTPA; however, mineral supplements containing zinc should be given concomitantly as appropriate.
NOTE: The duration of chelation treatment depends on the amount of internal contamination and individual response to treatment.
Intravenous dosage:
Adults: 1 gram IV once daily. Do not administer more than 1 dose per 24-hour period.
Children and 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:
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 oral inhalation.
-Geriatric
1 gram per day IV or via oral inhalation.
-Adolescents
1 gram per day IV; safety and efficacy not established for oral inhalation.
-Children
12 years: 1 gram per day IV; safety and efficacy not established for oral inhalation.
1 to 11 years: 14 mg/kg/dose IV, not exceed 1 gram per day; safety and efficacy not established for oral 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 Calcium Trisodium, Ca-DTPA products.
Pentetate calcium trisodium (Ca-DTPA) forms stable chelates with metal ions by exchanging calcium for a metal of greater binding capacity. Ca-DTPA is effective for possible internal contamination with plutonium, americium, or curium. The radioactive chelates are excreted by glomerular filtration into the urine. Ca-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, Ca-DTPA may bind other elements or minerals (e.g., magnesium or zinc), and cause electrolyte or other nutritional imbalances. Data from rodent studies indicate that the risk for mineral depletion and other complications is greater with Ca-DTPA compared to pentetate zinc trisodium (Zn-DTPA). Thus, Zn-DTPA is preferred for prolonged use when it is available.
Data in animals and humans indicate that intravenous administration of Ca-DTPA forms chelates with radioactive contaminants found in the circulation, interstitial fluid, and tissues. When administered by inhalation, Ca-DTPA can also chelate transuranium elements. Expectoration is expected to decrease the amount of radioactive contaminant 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) may be needed with Ca-DTPA.
Pentetate calcium trisodium (Ca-DTPA) is poorly absorbed in the gastrointestinal (GI) tract and thus is administered either intravenously or via oral inhalation. There is little or no binding of the chelating agent by the renal parenchyma. Ca-DTPA undergoes a minimal amount of metabolic change in the body. Ca-DTPA is cleared from the plasma in the first few hours by glomerular filtration and urinary excretion. 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 P-450 isoenzymes: None
-Route-Specific Pharmacokinetics
Oral Route
In animal studies, after oral administration, the absorption of Ca-DTPA was approximately 5%.
Intravenous Route
In a study of rodents, Ca-DTPA or pentetate zinc trisodium (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. Eighteen patients in a U.S. Registry received a 1-gram single inhaled or intravenous dose of Ca-DTPA; urine data indicated that the inhaled product was absorbed and the inhaled and intravenous dose resulted in a comparable elimination of the radiocontaminant.
Following intravenous administration, Ca-DTPA is rapidly distributed throughout the extracellular fluid space with no accumulation of Ca-DTPA in specific organs observed.
The safety and efficacy of Ca-DTPA were established in the adult population and efficacy was extrapolated to the pediatric population for the intravenous route based on the comparability of pathophysiologic mechanisms. The recommended dosage is based on body size adjustment for an intravenous drug that is renally cleared.
Inhalation Route
Eighteen patients in a U.S. registry received a 1-gram single inhaled or intravenous dose of Ca-DTPA; urine data indicated that the inhaled product was absorbed and the inhaled and intravenous dose resulted in a comparable elimination of the radiocontaminant. The safety and efficacy of Ca-DTPA was established in the adult population and efficacy was extrapolated to the pediatric population for the intravenous route based on the comparability of pathophysiologic mechanisms. No extrapolation data are available for the inhalation route of administration.
-Special Populations
Hepatic Impairment
Adequate and well-controlled pharmacokinetic and pharmacodynamic studies of Ca-DTPA in hepatically impaired patients were not identified in the literature.
Renal Impairment
Adequate and well-controlled pharmacokinetic and pharmacodynamic studies of Ca-DTPA in renally impaired patients were not identified in the literature. Both Ca-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 Ca-DTPA.
Pediatrics
Specific pharmacokinetic data in children are not available. The safety and efficacy of Ca-DTPA were established in the adult population and efficacy was extrapolated to the pediatric population for the intravenous route based on the comparability of pathophysiologic mechanisms. The recommended dosage is based on body size adjustment for an intravenous drug that is renally cleared. No extrapolation data are available for the inhalation route of administration.