2.1 Dose

Administer Ca-DTPA as the initial dose during the first 24 hours after internal contamination. Ca-DTPA is more effective than Zn-DTPA during this time period (see Ca-DTPA labeling). If Ca-DTPA is not available, use Zn-DTPA as initial therapy. On the next day, if additional chelation therapy is indicated, begin daily treatment with Zn-DTPA. If Zn-DTPA is not available, chelation therapy may continue with Ca-DTPA and concomitant mineral supplements containing zinc should be given (see Ca-DTPA labeling).

Do not administer more than one dose per 24 hour period.

If Ca-DTPA is not available during the first 24 hours:

• in adults and adolescents, administer intravenously a single 1.0 gram initial dose of Zn-DTPA.
• in children less than 12 years of age, administer intravenously a single 14 mg/kg initial dose of Zn-DTPA, not to exceed 1.0 gram.

After the first 24 hours, continue chelation therapy with Zn-DTPA:

• in adults and adolescents, administer intravenously 1.0 gram Zn-DTPA once daily.
• in children less than 12 years of age, administer intravenously 14 mg/kg Zn-DTPA once daily, not to exceed 1.0 gram daily.

2.2 General

Chelation treatment is most effective if administered within the first 24 hours after internal contamination. Start chelation treatment as soon as possible after suspected or known internal contamination. When treatment cannot be started right away, give chelation treatment as soon as it becomes available. Chelation treatment is still effective even after time has elapsed following internal contamination. The chelating effects of Zn-DTPA are greatest when the radiocontaminants are still circulating or are in interstitial fluids. The effectiveness of chelation decreases with time following internal contamination as the radiocontaminants become sequestered in liver and bone.

If internal contamination with radiocontaminants other than plutonium, americium, or curium, or unknown radiocontaminants is suspected, additional therapies may be needed (e.g., Prussian blue, potassium iodide).

2.3 Methods of Administration

Use intravenous administration of Zn-DTPA if the route of internal contamination is not known or if multiple routes of internal contamination are likely. Administer Zn-DTPA solution (1 gram in 5 mL) either with a slow intravenous push over a period of 3-4 minutes or by intravenous infusion over 30 minutes 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, Zn-DTPA can be administered by nebulized inhalation as an alternative route of administration.

Dilute Zn-DTPA for nebulization at a 1:1 ratio with sterile water or saline. After nebulization, encourage patients to avoid swallowing any expectorant. Some individuals may experience respiratory adverse events after inhalation therapy. [See Warnings and Precautions (5.1)] The safety and effectiveness of the nebulized route of administration have not been established in the pediatric population.

The safety and effectiveness of the intramuscular route of injection have not been established.

2.4 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.

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

5.1 Asthma Exacerbation

Nebulized chelation therapy is associated with asthma exacerbation. Monitor patients for signs and symptoms of asthma exacerbation when administering Zn-DTPA by the inhalation route. [See Adverse Reactions (6)]

5.2 Depletion of Body Trace Mineral Stores

Zn-DTPA treatment may lead to depletion of body stores of endogenous metals (e.g. magnesium, manganese). The risk for depletion increases when Zn-DTPA is administered over several months. Monitor serum zinc levels, electrolytes and blood cell counts during Ca-DTPA or Zn-DTPA therapy. Give mineral or vitamin plus mineral supplements as appropriate. [See Dosage and Administration (2.4)]

5.3 Risks to Care-takers

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, Zn-DTPA treatment increases excretion of radioactivity in the urine. Take appropriate safety measures to minimize contamination of others. [See Patient Counseling Information (17)]

8.1 Pregnancy

8.3 Nursing mothers

It is not known whether Zn-DTPA is excreted in human milk. 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 Warnings and Precautions (5.3)]

8.4 Pediatric use

The safety and effectiveness of Zn-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 dose is based on body size adjustment for an intravenous drug that is renally cleared [See Dosage and Administration (2.1)]. The safety and effectiveness of the nebulized route of administration have not been established in the pediatric population.

12.1 Mechanism of Action

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

12.2 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 micromol/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, 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).

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 micromol/kg (0.11 MHD) 30 minutes after contamination followed by inhalation of Zn-DTPA 2 micromol/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 Zn-DTPA forms chelates with radioactive contaminants found in the circulation, interstitial fluid, and tissues. When Zn-DTPA is administered by inhalation, 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. Give chelation treatment as soon as possible after known or suspected internal contamination with transuranium elements has occurred. [See Dosage and Administration (2.1, 2.2)]

12.3 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.

Figure 1: Percent of 14C-DTPA Distribution

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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

13.2 Animal Toxicology and/or Pharmacology

[See Clinical Pharmacology (12)]

16.2 Storage

Store between 15-30°C (59-86°F).

16.3 Handling

Inspect parenteral drug products 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.

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