Pentetate calcium trisodium

1 INDICATIONS AND USAGE Ca-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 calcium 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. ( 2.1 , 2.2 ) In adults and adolescents, administer intravenously a single 1.0 gram Ca-DTPA dose. ( 2.1 ) In children less than 12 years of age, administer intravenously, a single 14 mg/kg Ca-DTPA dose, not to exceed 1.0 gram. ( 2.1 ) Zn-DTPA is recommended for maintenance chelation therapy after the first 24 hours. If Zn-DTPA is unavailable, chelation therapy may continue with Ca-DTPA. ( 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. If Ca-DTPA is not available, use Zn-DTPA as the initial therapy. On the next day, if additional chelation therapy is indicated, begin daily treatment with Zn-DTPA (see Zn-DTPA labeling). If Zn-DTPA is not available, chelation therapy may continue with Ca-DTPA; concomitant mineral supplements containing zinc should be given. [See Warnings and Precautions (5.2) ] Do not administer more than one dose per 24 hour period. Adults and Adolescents A single 1.0 gram initial dose of Ca-DTPA administered intravenously. Children less than 12 years of age A single 14 mg/kg initial dose of Ca-DTPA administered intravenously, not to exceed 1.0 gram. If Zn-DTPA is not available For adults and adolescents, the recommended maintenance dose is 1.0 gram Ca-DTPA once daily administered intravenously. For children less than 12 years of age, the recommended maintenance dose is 14 mg/kg Ca-DTPA once daily administered intravenously, not to exceed 1.0 gram per day. 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 Ca-DTPA are greatest when 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 Ca-DTPA if the route of internal contamination is not known or if multiple routes of internal contamination are likely. Administer Ca-DTPA solution (1 gram in 5 mL) either with a slow intravenous push over a period of 3-4 minutes or by intravenous infusion 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 within the preceding 24 hours, Ca-DTPA can be administered by nebulized inhalation as an alternative route of administration. Dilute Ca-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. [See Overdosage (10) ] 2.4 Monitoring When possible, obtain baseline blood and urine samples (CBC with differential, serum creatinine, BUN and electrolytes, urinalysis, and blood and urine radioassays) before initiating treatment. Ca-DTPA must be given with very careful monitoring of serum zinc and complete blood counts. When appropriate, administer vitamin or mineral supplements that contain zinc. [See Warnings and Precautions (5.2) ] 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. If the individual is receiving more than one dose of Ca-DTPA, consider mineral supplementation as appropriate based on these laboratory tests. Record any adverse events from Ca-DTPA.

4 CONTRAINDICATIONS None. None ( 4 )

5 WARNINGS AND PRECAUTIONS Nebulized Ca-DTPA may be associated with exacerbation of asthma. Monitor patients for signs and symptoms of asthma exacerbation when administering Ca-DTPA by the inhalation route. ( 5.1 ) Ca-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 ) Use Ca-DTPA with caution in individuals with severe hemochromatosis. ( 5.4 ) 5.1 Asthma Exacerbation Nebulized Ca-DTPA is associated with asthma exacerbation. Monitor patients for signs and symptoms of asthma exacerbation when administering Ca-DTPA by the inhalation route. [See Adverse Reactions (6) ] 5.2 Depletion of Body Trace Mineral Stores Ca-DTPA is associated with depletion of endogenous trace metals (e.g., zinc, magnesium, manganese). The magnitude of depletion increases with split daily dosing, with increasing dose, and with increased treatment duration. [See Clinical Pharmacology (12.3) ] Only a single initial dose of Ca-DTPA is recommended. Use Zn-DTPA if additional chelation therapy is indicated (See Zn-DTPA labeling). If Zn-DTPA is not available, chelation therapy may continue with Ca-DTPA but give mineral supplements containing zinc concomitantly, as appropriate. Monitor serum zinc levels, electrolytes and blood cell counts during Ca-DTPA or Zn-DTPA therapy. Give mineral or vitamin plus mineral supplements that contain zinc 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, Ca-DTPA treatment increases excretion of radioactivity in the urine. Take appropriate safety measures to minimize contamination of others. [See Patient Counseling Information (17) ] 5.4 Risks for Patients with Hemochromatosis Use of only a single Ca-DTPA dose is particularly important for patients with hemochromatosis. Deaths have been reported in patients with severe hemochromatosis who received Ca-DTPA for more than 1 day, by intramuscular injection. [See Overdosage (10) ]

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, 632 received Ca-DTPA by one or more routes of administration. Three hundred and twenty-six individuals were dosed by inhalation, 293 by intravenous injection, and 60 by other or unknown routes of administration. Of the individuals that received Ca-DTPA, 393/632 (62%) received one dose and 65 (10%) received two doses. The remaining 174 individuals received three or more doses. The largest number of Ca-DTPA doses to a single individual was 338 delivered over 6.5 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, 18 adverse events occurred after treatment with Ca-DTPA. Adverse events included headache, lightheadedness, chest pain, allergic reaction, dermatitis, metallic taste, nausea and diarrhea, and injection site reactions. Cough and/or wheezing were experienced by 2 individuals receiving nebulized Ca-DTPA, one of whom had a history of asthma. In literature reports, prolonged treatment with Ca-DTPA resulted in depletion of zinc, magnesium, manganese and possibly metalloproteinases. [See Warnings and Precautions (5.2) ] There is limited experience with Ca-DTPA. Adverse events included headache, lightheadedness, chest pain, allergic reaction, dermatitis, metallic taste, nausea and diarrhea, and injection site reactions. ( 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 C Risk Summary There are no adequate and well-controlled studies of Ca-DTPA use in pregnant women. Ca-DTPA chelation therapy causes depletion of body stores of zinc, a trace metal essential for fetal development [see Warnings and Precautions (5.2) ] . The consequences of zinc depletion and results of animal studies suggest a teratogenic risk in humans. Ca-DTPA was teratogenic and embryotoxic in mice at daily doses 2 to 8 times the recommended daily human dose, based on body surface area (BSA), with a dose-dependent increase in the frequency of gross malformations. Ca-DTPA was teratogenic in dogs at approximately half the recommended daily human dose based on BSA, as described below. There are no animal or human data evaluating the teratogenic effect of a single dose of Ca-DTPA. Ca-DTPA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Clinical Considerations Chelation treatment of pregnant women should begin and continue with Zn-DTPA, if available, except in cases of high internal radioactive contamination. Because Ca-DTPA is more effective than Zn-DTPA in the first 24 hours after internal contamination, it may be appropriate to use a single dose of Ca-DTPA with vitamin or mineral supplements that contain zinc as the initial treatment. Animal Data Ca-DTPA is teratogenic and embryotoxic in mice during any period of gestation following five daily subcutaneous injections of 720 to 2880 micromol Ca-DTPA/kg [2 to 8 times the recommended daily human dose of 1 gram based on BSA]. The frequency of gross malformations (e.g., exencephaly, spina bifida, cleft palate, ablepharia, and polydactyly) and fetal mortality increased with dose, with higher susceptibility in early and mid gestation. Five daily doses of 360 micromol Ca-DTPA/kg in mice, approximately equivalent to the recommended daily human dose (based on BSA) produced no harmful effects. A study of two pregnant dogs given daily intravenous injections of 30 micromol Ca-DTPA/kg (approximately half the recommended daily human dose based on BSA) from implantation until parturition showed severe teratogenic effects (brain damage), and decrease in the number of surviving pups.