ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. In the U.S. Registry, 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 by other or unknown routes of administration.Of the individuals that received Zn-DTPA, 23/62 (37%) received one dose and (13%) received two doses. The remaining 31 individuals received three or more doses. The largest number of Zn-DTPA doses to 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, 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 drugsafetyhameln.co.uk or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

BOXED WARNING SECTION.

WARNING: ASTHMA EXACERBATION WITH NEBULIZATION and DEPLETION OF TRACE METALS DURING THERAPY. Nebulized Zn-DTPA may be associated with asthma exacerbation. (5.1)Zn-DTPA is associated with depletion of trace metals. The risk for depletion increases when Zn-DTPA is administered over several months. Monitor serum zinc levels, serum creatinine, BUN, electrolytes, urinalysis and blood cell counts during Ca-DTPA or Zn-DTPA therapy. (2.4, 5.2). Nebulized Zn-DTPA may be associated with asthma exacerbation. (5.1). Zn-DTPA is associated with depletion of trace metals. The risk for depletion increases when Zn-DTPA is administered over several months. Monitor serum zinc levels, serum creatinine, BUN, electrolytes, urinalysis and blood cell counts during Ca-DTPA or Zn-DTPA therapy. (2.4, 5.2). WARNING: ASTHMA EXACERBATION WITH NEBULIZATION and DEPLETION OF TRACE METALS DURING THERAPYSee full prescribing information for complete boxed warning.Nebulized Zn-DTPA may be associated with asthma exacerbation. (5.1)Zn-DTPA is associated with depletion of trace metals. The risk for depletion increases when Zn-DTPA is administered over several months. Monitor serum zinc levels, serum creatinine, BUN, electrolytes, urinalysis and blood cell counts during Ca-DTPA or Zn-DTPA therapy. (2.4, 5.2). Nebulized Zn-DTPA may be associated with asthma exacerbation. (5.1). Zn-DTPA is associated with depletion of trace metals. The risk for depletion increases when Zn-DTPA is administered over several months. Monitor serum zinc levels, serum creatinine, BUN, electrolytes, urinalysis and blood cell counts during Ca-DTPA or Zn-DTPA therapy. (2.4, 5.2).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Zn-DTPA forms stable chelates with metal ions by exchanging zinc for 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 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 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 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 micromol/kg (0.11 MHD) 30 minutes after contamination followed by inhalation of Zn-DTPA micromol/kg at approximately hours, 1, 2, 3, and 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 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 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. Figure 1. AbsorptionZn-DTPA is poorly absorbed in the gastrointestinal tract. In animal studies, after oral administration, absorption was approximately 5%. In U.S. Registry of 18 patients who received single inhaled or intravenous dose of gram, urine data indicate that the inhaled product was absorbed and resulted in comparable elimination of the radiocontaminant. One study of human subjects that received Ca-DTPA with 14C-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)] DistributionFollowing 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.. MetabolismZn-DTPA undergoes minimal amount of metabolic change in the body.. Adverse Metabolic EffectsZn-DTPA results in minimal depletion of magnesium and manganese.. EliminationZn-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 very small amount of radioactivity (<3%) was detected.. Renal Impaired and/or Compromised Liver Function PatientsAdequate 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.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. All clinical data has come from the treatment of individuals who were accidentally contaminated. Observational data were maintained in 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, 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 doses, gram each, by nebulization (1:1 Zn-DTPA and saline) followed by intravenous doses, the urinary excretion of plutonium after the first nebulized dose was increased by factor of 45.After initial treatment with Ca-DTPA, maintenance treatment was continued with daily gram Zn-DTPA doses administered over 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.

DOSAGE & ADMINISTRATION SECTION.

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 single 1.0 gram Zn-DTPA initial dose. (2.1)in children less than 12 years of age, administer intravenously 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). in adults and adolescents, administer intravenously single 1.0 gram Zn-DTPA initial dose. (2.1). in children less than 12 years of age, administer intravenously single 14 mg/kg Zn-DTPA initial dose, not to exceed 1.0 gram. (2.1). 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). 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 single 1.0 gram initial dose of Zn-DTPA.in children less than 12 years of age, administer intravenously 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.. in adults and adolescents, administer intravenously single 1.0 gram initial dose of Zn-DTPA.. in children less than 12 years of age, administer intravenously single 14 mg/kg initial dose of Zn-DTPA, not to exceed 1.0 gram.. 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 PatientsNo 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 mL) either with slow intravenous push over 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 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 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 TreatmentMeasure 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.. 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.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Instruct patients to:drink plenty of fluids and void frequently to promote dilution of the radioactive chelate in the urine and minimize radiation exposure directly to the bladder.use toilet instead of urinal, and flush several times after each use.clean up spilled urine or feces completely and wash hands thoroughly. Wash clothing or linens separately if blood or urine comes in contact.dispose of any expectorant carefully. Avoid swallowing the expectorant if possible.IInstruct parents and child-care givers to take extra precaution in handling the urine, feces, and expectorants of children to avoid any additional exposure to either the care-giver or to the child.Instruct nursing mothers to take extra precaution in disposing of breast milk. [See Use in Specific Populations (8.3)] drink plenty of fluids and void frequently to promote dilution of the radioactive chelate in the urine and minimize radiation exposure directly to the bladder.. use toilet instead of urinal, and flush several times after each use.. clean up spilled urine or feces completely and wash hands thoroughly. Wash clothing or linens separately if blood or urine comes in contact.. dispose of any expectorant carefully. Avoid swallowing the expectorant if possible.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. In 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 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 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 micromol/kg (0.11 MHD) 30 minutes after contamination followed by inhalation of Zn-DTPA micromol/kg at approximately hours, 1, 2, 3, and 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)].

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Plasma retention and urinary excretion data were obtained in 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 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. Figure 1. AbsorptionZn-DTPA is poorly absorbed in the gastrointestinal tract. In animal studies, after oral administration, absorption was approximately 5%. In U.S. Registry of 18 patients who received single inhaled or intravenous dose of gram, urine data indicate that the inhaled product was absorbed and resulted in comparable elimination of the radiocontaminant. One study of human subjects that received Ca-DTPA with 14C-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)] DistributionFollowing 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.. MetabolismZn-DTPA undergoes minimal amount of metabolic change in the body.. Adverse Metabolic EffectsZn-DTPA results in minimal depletion of magnesium and manganese.. EliminationZn-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 very small amount of radioactivity (<3%) was detected.. Renal Impaired and/or Compromised Liver Function PatientsAdequate 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.

SPL UNCLASSIFIED SECTION.

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

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Nursing Mothers: Women with known or suspected internal contamination with radiocontaminants should not breast feed, whether or not they are receiving chelation therapy. (8.3)Pediatric Use: Safety and effectiveness of intravenous Zn-DTPA were extrapolated from adults. Safety and effectiveness of nebulized route of administration have not been established. (8.4). Nursing Mothers: Women with known or suspected internal contamination with radiocontaminants should not breast feed, whether or not they are receiving chelation therapy. (8.3). Pediatric Use: Safety and effectiveness of intravenous Zn-DTPA were extrapolated from adults. Safety and effectiveness of nebulized route of administration have not been established. (8.4). 8.1 Pregnancy. Pregnancy Category B. Risk SummaryThere 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 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.. 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.

WARNINGS AND PRECAUTIONS SECTION.

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). 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)].