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.

4 CONTRAINDICATIONS None. None ( 4 )

5 WARNINGS AND PRECAUTIONS Nebulized chelation therapy may be associated with exacerbation of asthma. Monitor patients for signs and symptoms of asthma exacerbation when administering Zn-DTPA by the inhalation route. ( 5.1 ) Zn-DTPA is associated with depletion of endogenous trace metals (e.g., zinc, magnesium, manganese). ( 5.2 ) Take appropriate safety measures to minimize contamination of care-takers by contaminated body fluids. ( 5.3 ) 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) ]

7 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). Adequate and well-controlled drug-drug interaction studies in humans were not identified in the literature. ( 7 )

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 drugsafety@hameln.co.uk or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

8.1 Pregnancy Pregnancy Category B Risk Summary There are no adequate and well-controlled studies of Zn-DTPA use in pregnant women. Chelation treatment of pregnant women should begin and continue with Zn-DTPA. Reproduction studies have been performed in pregnant mice at doses up to 31 times (11.5 mmol/kg) the recommended daily human dose and have revealed no evidence of impaired fertility or harm to the fetus due to Zn-DTPA. There was a slight reduction in the average birth weight. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.