General

Ca-DTPA forms stable chelates with metal ions by exchanging calcium for a metal of greater binding capacity. The radioactive chelates are then excreted by glomerular filtration into the urine. In animal studies, Ca-DTPA forms less stable chelates with uranium and neptunium in vivo resulting in the deposition of these elements in tissues including the bone. Ca-DTPA treatments are not expected to be effective for uranium and neptunium. Radioactive iodine is not bound by DTPA.

Pharmacodynamics

In a study of rodents internally contaminated with plutonium, the rate of plutonium elimination was measured after treatment with Ca-DTPA and Zn-DTPA given intravenously as a single dose of 10 to 1,000 µmol/kg (0.54 – 54 × maximum human dose, MHD). When treated within one hour of internal contamination, Ca-DTPA resulted in about a 10-fold higher rate of elimination of plutonium in the urine as compared to Zn-DTPA. The chelating capacity of Ca-DTPA is greatest immediately and up to approximately 24 hours after internal contamination when the radiocontaminant is still circulating and readily available for chelation. After the first dose of Ca-DTPA, maintenance treatment with either Ca-DTPA or Zn-DTPA resulted in similar rates of elimination of radioactivity. However, at comparable doses, Ca-DTPA had more toxicity (e.g., more depletion of trace metals, higher rate of mortality, the presence of kidney and liver vacuolization, and small bowel hemorrhagic lesions).

In another study, rodents contaminated with aerosolized plutonium and americium were treated with Ca-DTPA and Zn-DTPA. The treatment schedule involved inhalation of Ca-DTPA 2 µmol/kg (0.11 MHD) 30 minutes after contamination followed by inhalation of Zn-DTPA 2 µmol/kg at approximately 6 hours, 1, 2, 3, and 6 days, then twice weekly to day 26 or day 27. The treatment regime reduced the lung deposit of plutonium and americium to 1-2% of that in untreated animals. Systemic deposit in liver and skeleton were reduced by half.

Literature and U.S. Registry data in humans indicate that intravenous administration of Ca-DTPA forms chelates with radioactive contaminants found in the circulation, interstitial fluid, and tissues. When Ca-DTPA is administered by inhalation within 24 hours of internal radioactive contamination, it can chelate transuranium elements. Expectoration is expected to decrease the amount of radioactive contaminant available for systemic absorption.

The effectiveness of chelation 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. (See DOSAGE AND ADMINISTRATION)

Pharmacokinetics

Plasma retention and urinary excretion data were obtained in 2 subjects that received 750 kBq of 14C-DTPA. As shown in Figure 1, the radiolabeled DTPA was rapidly distributed throughout the extracellular fluid space and was cleared by glomerular filtration. The plasma retention up to 7 hours post dosing was expressed by the sum of three exponential components with average half-lives of 1.4 min, 14.5 min, and 94.4 min. The level of activity in the plasma was below the limit of detection 24 hours after injection. During the study, no detectable activity was exhaled or excreted in the feces. By 24 hours, cumulative urinary excretion was more than 99% of the injected dose.

Clinical Trials

All clinical data has come from the treatment of individuals who were accidentally contaminated. Observational data were maintained in a U.S. Registry of individuals with internal radioactive contamination primarily from acute occupational contamination with plutonium, americium, and curium.

In 286 individuals, bioassays were available to measure urinary radioactivity elimination after chelation therapy. Of these 286 individuals, 18 had matched pre- and post-chelator urine radioactivity bioassay results available. Seventeen of these individuals received 1 gram of Ca-DTPA as the first dose. Of these, 9 individuals received the first dose by nebulization (1:1 Ca-DTPA and saline) and 8 received Ca-DTPA intravenously. The elimination of radiocontaminants was measured using the ratio of the urine radioactivity before treatment to the maximum urine radioactivity after treatment (the excretion enhancement factor, EEF). As shown in Table 1, after one dose, the mean EEF was 25.7. The descriptive results and variability for the intravenous, inhaled, and combined routes are considered to be similar.

After initial treatment with Ca-DTPA, maintenance treatment was continued with 1 gram Zn-DTPA doses over a period of days, months or years, depending upon the extent of internal contamination and individual response to therapy. Most patients received a single dose of Ca-DTPA. The longest treatment duration was approximately 6.5 years. Similar increases in urinary radioactivity elimination following chelator administration were supported by data from the remaining 268 individuals in the U.S. Registry and from the literature.

Information for Patients

Radioactive metals are known to be excreted in the urine, feces, and breast milk. In individuals with recent internal contamination with plutonium, americium, or curium, Ca-DTPA treatment increases excretion of radioactivity in the urine. Appropriate safety measures should be taken to minimize contamination of others. When possible, a toilet should be used instead of a urinal, and it should be flushed several times after each use. Spilled urine or feces should be cleaned up completely and patients should wash their hands thoroughly. If blood or urine comes in contact with clothing or linens, they should be washed separately. Patients should drink plenty of fluids and void frequently. If patients are coughing, any expectorant should be disposed of carefully. Swallowing the expectorant should be avoided if possible. Parents and child-care givers should take extra precaution in handling the urine, feces, and expectorants of children to avoid any additional exposure to either the care-giver or to the child. Nursing mothers should take extra precaution in disposing of breast milk. (See PRECAUTIONS, Nursing Mothers)

Laboratory Tests

Serum electrolytes and essential metals should be closely monitored during Ca-DTPA treatment. Mineral or vitamin plus mineral supplements that contain zinc should be given as appropriate. (See WARNINGS)

Drug-Drug Interactions

Adequate and well-controlled drug-drug interaction studies in humans were not identified in the literature. When an individual is contaminated with multiple radiocontaminants, or when the radiocontaminants are unknown, additional therapies may be needed (e.g., Prussian blue, potassium iodide).

Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies with Ca-DTPA to evaluate carcinogenesis, mutagenesis, and impairment of fertility have not been performed. Data for Ca-DTPA effects on spermatogenesis are not available.

Teratogenic Effects

Nursing Mothers

Studies to determine if Ca-DTPA is excreted in breast milk have not been conducted. Radiocontaminants are known to be excreted in breast milk. Women with known or suspected internal contamination with radiocontaminants should not breast feed, whether or not they are receiving chelation therapy. Precautions should be taken when discarding breast milk. (See PRECAUTIONS, Information for Patients)

Pediatric Use

The safety and effectiveness 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. The dose is based on body size adjustment for an intravenous drug that is renally cleared. The safety and effectiveness of the nebulized route of administration has not been established in the pediatric population.

Initial Dose

Maintenance Treatment

AFTER THE INITIAL DOSE, ON THE NEXT DAY, IF ADDITIONAL CHELATION THERAPY IS INDICATED, IT IS PREFERABLE TO SWITCH TO ZN-DTPA, IF AVAILABLE (SEE ZN-DTPA LABELING) DUE TO 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.

Methods of Administration

Intravenous administration of Ca-DTPA is recommended and should be used if the route of internal contamination is not known or if multiple routes of internal contamination are likely. Ca-DTPA solution (1 gram in 5 mL) should be administered either with a slow intravenous push over a period of 3-4 minutes or by intravenous infusion diluted in 100-250 mL of 5% dextrose in water (D5W), Ringers Lactate, or Normal Saline.

In individuals whose internal contamination is only by inhalation within the preceding 24 hours, Ca-DTPA can be administered by nebulized inhalation as an alternative route of administration. Ca-DTPA should be diluted for nebulization at a 1:1 ratio with sterile water or saline. After nebulization, individuals should be encouraged to avoid swallowing any expectorant. Some individuals may experience respiratory adverse events after inhalation therapy. (See WARNINGS) The safety and effectiveness of the nebulized route of administration has not been established in the pediatric population.

The safety and effectiveness of the intramuscular route of injection have not been established. (See OVERDOSE)

Handling

OPC ampoule: to open, turn so that the point faces upward and break off the neck with a downward movement.

Parenteral drug products should be inspected visually 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 seen subsequent to opening of the ampoule.

Monitoring

When possible, obtain baseline blood and urine samples (CBC with differential, BUN, serum chemistries and electrolytes, urinalysis, and blood and urine radioassays) before initiating treatment.

Ca-DTPA must be given with very careful monitoring of serum zinc and complete blood counts. When appropriate, vitamin or mineral supplements that contain zinc should be administered. (See WARNINGS)

To establish an elimination curve, a quantitative baseline estimate of the total internalized transuranium element(s) and measures of elimination of radioactivity should be obtained by appropriate whole-body counting, by bioassay (e.g., biodosimetry), or fecal/urine sample whenever possible.

Storage

Store between 15 - 30°C (59 - 86°F).