pentetate zinc trisodium - Hameln Pharmaceuticals

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.

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, 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 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 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. Chelation treatment should be given as soon as possible after known or suspected internal contamination with transuranium elements has occurred. (See DOSAGE ADMINISTRATION)

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.

Pharmacokinetics

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 radiation 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, only 18 had matched pre- and post-chelator urine radioactivity bioassay results available. The majority of these individuals received Ca-DTPA as the initial component to their chelation therapy. When multiple chelator doses were administered over days, the standard of practice was to switch therapy to Zn-DTPA following an initial dose of Ca-DTPA. Although both chelators were considered equipotent 24 hours following internal contamination, Zn-DTPA was considered less toxic. In one individual who received 3 doses, 1 gram each, by nebulization (1:1 Zn-DTPA and saline) followed by 6 intravenous doses, the urinary excretion of plutonium after the first nebulized dose was increased by a factor of 45.

After initial treatment with Ca-DTPA, maintenance treatment was continued with daily 1 gram Zn-DTPA doses administered over a period of days, months or years, depending on the extent of internal contamination and individual response to therapy. Treatment was generally continued until the excretion enhancement factor (EEF) approached 1. The longest treatment duration was 3.5 years. Similar increases in urinary radioactivity elimination were supported by data from the remaining 268 individuals in the U.S. Registry and from the literature.

Treatment over several months with Zn-DTPA could lead to depletion of body stores of endogenous metals (e.g., magnesium, manganese). These elements should be monitored routinely and, if appropriate, mineral or vitamin plus mineral supplements should be provided.

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. 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 caregiver or to the child. Nursing mothers should take extra precaution in disposing of breast milk. (See PRECAUTIONS, Nursing Mothers)

Serum electrolytes and essential metals should be closely monitored during Zn-DTPA treatment. Mineral or vitamin plus mineral supplements may be given as appropriate. (See PRECAUTIONS)

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).

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.

Studies to determine if Zn-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)

The safety and effectiveness of Zn-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.

IT IS PREFERABLE TO ADMINISTER CA-DTPA, IF AVAILABLE, AS THE INITIAL DOSE DURING THE FIRST 24 HOURS AFTER INTERNAL CONTAMINATION BECAUSE CA-DTPA IS MORE EFFECTIVE THAN ZN-DTPA DURING THIS TIME PERIOD. AFTER 24 HOURS, ZN-DTPA AND CA-DTPA ARE EQUALLY EFFECTIVE.

The duration of chelation treatment depends on the amount of internal contamination and individual response to treatment. (See Monitoring)

The intravenous route is recommended and should be used if the route of internal contamination is not known or if multiple routes of internal contamination are likely. Zn-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 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. Zn-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.

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

Handling

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.

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, 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.

Store between 15 - 30°C (59 - 86°F).