Pentetate Calcium Trisodium

Description

11 DESCRIPTION Pentetate calcium trisodium injection contains the sodium salt of calcium diethylenetriaminepentaacetate. Pentetate calcium trisodium is also known as trisodium calcium diethylenetriaminepentaacetate and is commonly referred to as Ca-DTPA. It has a molecular formula of Na 3 CaC 14 H 18 N 3 O 10 and a molecular weight of 497.4 Daltons. It is represented by the following structural formula: Ca-DTPA is supplied as a clear, colorless, hyperosmolar (1260 mOsmol/kg) solution in a colorless ampoule containing 5 mL. The ampoule contents are sterile, non-pyrogenic and suitable for intravenous administration. Each mL of solution contains the equivalent of 200 mg pentetate calcium trisodium (obtained from 158.17 mg pentetic acid, 40.24 mg calcium carbonate and NaOH) in water for injection, USP. The pH of the solution is adjusted with NaOH and is between 7.3-8.3. Chemical Structure

What Is Pentetate Calcium Trisodium Used For?

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 )

Dosage and Administration

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...

Side Effects (Adverse Reactions)

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 [email protected] or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Drug Interactions

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 )

Contraindications

4 CONTRAINDICATIONS None. None ( 4 )

Pregnancy and Breastfeeding

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...

8.3 Nursing mothers It is not known whether Ca-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) ]

Overdosage

10 OVERDOSAGE In previous clinical studies, three deaths were reported in patients with severe hemochromatosis who were treated with daily intramuscular Ca-DTPA dosed up to 4 gram per day to reduce iron stores. One patient became comatose and died after receiving a total of 14 grams Ca-DTPA, and the other two died after two weeks of daily treatment. Causal association with these events and the drug has not been established. [See Warnings and Precautions (5.4) ]

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING Ca-DTPA is supplied as a sterile solution in 5 mL single-use clear glass ampoules at a concentration of 200 mg/mL for intravenous use. Each ampoule contains the equivalent of 1000 mg of pentetate calcium trisodium. NDC 70651-001-03: 5 mL single-dose ampoules, package of 10. 16.2 Storage Store between 15-30°C (59-86°F). 16.3 Handling Inspect parenteral drug products visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The product may be filtered using a sterile filter if particles are seen subsequent to opening of the ampoule. OPC ampoule: to open, turn so that the point faces upward and break off the neck with a downward movement. Figure