Pentetate Zinc Trisodium

1 INDICATIONS AND USAGE Zn-DTPA is indicated for treatment of individuals with known or suspected internal contamination with plutonium, americium, or curium to increase the rates of elimination. Pentetate zinc trisodium injection is a radiomitigation chelator indicated for treatment of individuals with known or suspected internal contamination with plutonium, americium, or curium to increase the rates of elimination. ( 1 )

2 DOSAGE AND ADMINISTRATION Chelation treatment is most effective if administered within the first 24 hours. Administer Ca-DTPA, if available, as the initial dose. ( 2.1 , 2.2 ) If Ca-DTPA is not available during the first 24 hours, in adults and adolescents, administer intravenously a single 1.0 gram Zn-DTPA initial dose. ( 2.1 ) in children less than 12 years of age, administer intravenously a single 14 mg/kg Zn-DTPA initial dose, not to exceed 1.0 gram. ( 2.1 ) After the first 24 hours, continue chelation therapy with Zn-DTPA: in adults and adolescents, administer intravenously 1.0 gram Zn-DTPA once daily. ( 2.1 ) in children less than 12 years of age, administer intravenously 14 mg/kg Zn-DTPA once daily, not to exceed 1.0 gram daily. ( 2.1 ) See Full Prescribing Information for dose ( 2.1 ) and nebulized chelation therapy. ( 2.3 ) 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. Renally Impaired Patients No dose 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. Because dialysis fluid will become radioactive, radiation precautions must be taken to protect personnel, other patients, and the general public. 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. During Treatment Measure the radioactivity in blood, urine, and fecal samples weekly to monitor the radioactive contaminant elimination rate. Monitor CBC with differential, BUN, serum creatinine and electrolytes, and urinalysis measurements. Record any adverse events from Zn-DTPA.

6 ADVERSE REACTIONS In the U.S. Registry, a total of 646 individuals received at least one dose of either Ca-DTPA or Zn-DTPA. Of these, 62 received Zn-DTPA by one or more routes of administration. Forty-eight individuals were dosed by intravenous administration, 18 by inhalation and 8 by other or unknown routes of administration. Of the individuals that received Zn-DTPA, 23/62 (37%) received one dose and 8 (13%) received two doses. The remaining 31 individuals received three or more doses. The largest number of Zn-DTPA doses to a single individual was 574 doses delivered over 3.5 years. Overall, the presence or absence of adverse events was recorded in 310/646 individuals. Of these 19 (6.1%) individuals reported at least one adverse event. The total number of recorded adverse events was 20. Of the 20 adverse events, 1 individual treated with Zn-DTPA reported headache, lightheadedness, and pelvic pain. Two individuals experienced cough and/or wheezing with nebulized Ca-DTPA therapy however there was no report of such events with nebulized Zn-DTPA. There is limited experience with Zn-DTPA. Nebulized chelation therapy may be associated with exacerbation of asthma. Headache, light headedness, and pelvic pain have been reported. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact the hameln Pharmacovigilance Department at +44 (0) 7706 210 133 or [email protected] or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

12.3 Pharmacokinetics Plasma retention and urinary excretion data were obtained in 2 subjects that received 750 kBq of 14 C-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 14 C-DTPA Distribution Figure 1 Absorption Zn-DTPA is poorly absorbed in the gastrointestinal tract. In animal studies, after oral administration, absorption was approximately 5%. In a U.S. Registry of 18 patients who received a single inhaled or intravenous dose of 1 gram, urine data indicate that the inhaled product was absorbed and resulted in a comparable elimination of the radiocontaminant. One study of 2 human subjects that received Ca-DTPA with 14 C-DTPA by inhalation revealed approximately 20% absorption from the lungs. Human or animal bioavailability comparisons for Zn-DTPA are not available after administration by inhalation and intravenous injection. [See Clinical Studies (14) ] Distribution Following intravenous administration, Zn-DTPA is rapidly distributed throughout the extracellular fluid space. No significant amount of Zn-DTPA penetrates into erythrocytes or other cells. No accumulation of Zn-DTPA in specific organs has been observed. There is little or no binding of the chelating agent by the renal parenchyma. Metabolism Zn-DTPA undergoes a minimal amount of metabolic change in the body. Adverse Metabolic Effects Zn-DTPA results in minimal depletion of magnesium and manganese. Elimination Zn-DTPA is cleared from the plasma in the first few hours after dosing through urinary excretion by glomerular filtration. Renal tubular excretion has not been documented. In stool samples, only a very small amount of radioactivity (<3%) was detected. Renal Impaired and/or Compromised Liver Function Patients Adequate and well-controlled pharmacokinetic and pharmacodynamic studies in renally impaired and/or hepatically impaired patients 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.