herapy. 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) ]

s 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.

ver 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.

regnancy only if clearly needed. 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.

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 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.

ne 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.

-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.