Ca-DTPA

Ca-DTPA information, interactions and side effects, Pentetate calcium trisodium injection contains the sodium salt of calcium diethylenetriaminepenta-acetate. Pentetate calcium trisodium is also known as trisodium calcium diethylenetriaminepenta-acetate and is commonly referred to as Ca-DTPA (pentetate calcium trisodium inj) . It has a molecular formula of Na3CaC14H18N3O10 and a molecular weight of 497.4 Daltons. It is represented by the following structural formula:

ca-dtpa1

Ca-DTPA (pentetate calcium trisodium inj) 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.

INDICATIONS

Ca-DTPA (pentetate calcium trisodium inj) is indicated for treatment of individuals with known or suspected internal contamination with plutonium, americium, or curium to increase the rates of elimination.

DOSAGE AND ADMINISTRATION

Chelation treatment is most effective if administered within the first 24 hours after internal contamination and should be started as soon as possible after suspected or known internal contamination. However, even when treatment cannot be started right away, individuals should be given chelation treatment as soon as it becomes available. Chelation treatment is still effective even after time has elapsed following internal contamination however, the chelating effects of Ca-DTPA (pentetate calcium trisodium inj) 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.

Individuals should 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.

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).

Initial Dose

Adults and Adolescents: A single 1.0 gram initial dose of Ca-DTPA (pentetate calcium trisodium inj) administered intravenously.

Pediatrics (less than 12 years of age): A single initial dose of 14 mg/kg administered intravenously not exceed 1.0 gram.

Renally impaired patients: No dose adjustment is needed. However, renal impairment may reduce the rate at which chelators remove radiocontami-nants 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. If Ca-DTPA (pentetate calcium trisodium inj) is not available, proceed with treatment with Zn-DTPA as initial therapy.

Maintenance Treatment

AFTER THE INITIAL DOSE, ON THE NEXT DAY, IF ADDITIONAL CHELATION THERAPY IS INDICATED, IT IS PREFERABLE TO SWITCH TO ZN-DTPA, IF AVAILABLE (SEE ZN-DTPA LABELING) DUE TO THE SAFETY CONCERNS ASSOCIATED WITH PROLONGED CA-DTPA (pentetate calcium trisodium inj) USE. IF ZN-DTPA IS NOT AVAILABLE, TREATMENT MAY CONTINUE WITH CA-DTPA (pentetate calcium trisodium inj) , HOWEVER MINERAL SUPPLEMENTS CONTAINING ZINC SHOULD BE GIVEN CONCOMITANTLY, AS APPROPRIATE.

Adults and Adolescents: The recommended maintenance dose of Ca-DTPA (pentetate calcium trisodium inj) is 1.0 gram once a day administered intravenously.

Pediatrics (less than 12 years of age): The recommended maintenance dose of Ca-DTPA (pentetate calcium trisodium inj) is 14 mg/kg once a day administered intravenously. The maximum daily dose should not exceed 1.0 gram per day.

Renally impaired patients: No dose adjustment is needed. The duration of chelation treatment depends on the amount of internal contamination and individual response to treatment. (See Monitoring)

Methods of Administration

Intravenous administration of Ca-DTPA (pentetate calcium trisodium inj) is recommended and should be used if the route of internal contamination is not known or if multiple routes of internal contamination are likely. Ca-DTPA (pentetate calcium trisodium inj) solution (1 gram in 5 mL) should be administered 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 (pentetate calcium trisodium inj) can be administered by nebulized inhalation as an alternative route of administration. Ca-DTPA (pentetate calcium trisodium inj) should be diluted for neb-ulization at a 1:1 ratio with sterile water or saline. After nebulization, individuals should be encouraged to avoid swallowing any expectorant. Some individuals may experience respiratory adverse events after inhalation therapy. (See WARNINGS) The safety and effectiveness of the nebulized route of administration has not been established in the pediatric population.

The safety and effectiveness of the intramuscular route of injection have not been established. (See OVERDOSE)

Handling

OPC ampoule: to open, turn so that the point faces upward and break off the neck with a downward movement.

Parenteral drug products should be inspected 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.

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.

Ca-DTPA (pentetate calcium trisodium inj) must be given with very careful monitoring of serum zinc and complete blood counts. When appropriate, vitamin or mineral supplements that contain zinc should be administered. (See WARNINGS)

To establish an elimination curve, a quantitative baseline estimate of the total internalized transuranium element(s) and measures of elimination of radioactivity should be obtained 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 chemistries and electrolytes, and urinalysis regularly. If the individual is receiving more than one dose of Ca-DTPA (pentetate calcium trisodium inj) , these laboratory tests should be very carefully monitored and consider mineral supplementation as appropriate. (See CLINICAL PHARMACOLOGY, Pharmacodynamics, Adverse Metabolic Effects)
  • Record any adverse events from Ca-DTPA (pentetate calcium trisodium inj) .

HOW SUPPLIED

Ca-DTPA (pentetate calcium trisodium inj) 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 52919-001-03, 5 mL single-use ampoules, package of 10.

Storage

Store between 15 – 30°C (59 – 86°F).

COLLECTION OF PATIENT TREATMENT DATA

To develop long-term response data and information on the risk of developing late malignancy detailed information on patient treatment should be provided to the manufacturer (see attached Pad of Patient Treatment Data Form. In the case you need additional forms, please see the following web-site: www.ca-dtpa (pentetate calcium trisodium inj) .com). These data should include a record of the radioactive body burden and bioassay results at defined time intervals, a description of measurement methods to facilitate analysis of data, and adverse events.

Questions regarding the use of Ca-DTPA (pentetate calcium trisodium inj) for the treatment of internal contamination with transuranium elements may be referred to:

hameln pharmaceuticals gmbh, Langes Feld 13, 31789 Hameln, Germany. Tel.: +49-5151-581-0. Fax.: +49-5151-581-258. e-mail: welcome@hm-ph.com
Contact person: Dr. Mathias Dewald, Tel.: +49-5151-581-214, Fax.: +49-5151-581-581, e-mail: m.dewald@hm-ph.com.

Ca-DTPA (pentetate calcium trisodium inj)

Patient treatment Data

Send to: hameln pharmaceuticals gmbh Langes Feld 13, 31789 Hameln, Germany

Date of report:

Unique patient identifier

Patient ID

Name:

Date of birth:

Sex: Male Female

Address:

Phone:

Hospitalization: No Yes Where?

Criteria for Diagnosis

Date/time of exposure:

Geographic location/details of exposure:

Lab/field confirmed exposure; method:

Symptoms of Acute Radiation Syndrome:

Contamination

Transuranium element(s) confirmed suspected; list element(s):

Route (check all that apply): Skin Inhalation Wound Burn Ingestion

Anatomic area affected:

Initial radioactivity measurement:

How measured:

Decontamination

External: Skin washed with:

Wound excised/washed:

Contraindications to aerosolized treatment

(h/o lung disease, cough, dyspnea, chest tightness, wheezing)?

Internal:

Ca-DTPA (pentetate calcium trisodium inj) Date/time of initial dose:

Amount:

Total doses:

Route:

Adverse Reaction to Treatment

Adverse Reaction(s) to treatment?

No / Yes; provide details:

Vital signs: Baseline Stable Unstable: Subsequent (if abnormal):

Disposition of patient/outcome of treatment:

Treatment Team Data

Report completed by:

Title:
Organization/affiliation:
Phone:
Email:

Comments

ATTACH COPY OF EMERGENCY RECORDS TO THIS FORM

SIDE EFFECTS

In the U.S. Registry, a total of 646 individuals received at least one dose of either Ca-DTPA (pentetate calcium trisodium inj) or Zn-DTPA. Of these, 632 received Ca-DTPA (pentetate calcium trisodium inj) 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 (pentetate calcium trisodium inj) , 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 (pentetate calcium trisodium inj) 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 (pentetate calcium trisodium inj) . 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 nebu-lized Ca-DTPA (pentetate calcium trisodium inj) , one of whom had a history of asthma.

In the literature, prolonged treatment with Ca-DTPA (pentetate calcium trisodium inj) resulted in depletion of zinc, magnesium, manganese and possibly metalloproteinases.(See WARNINGS)

DRUG INTERACTIONS

Drug-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).

WARNINGS

Ca-DTPA (pentetate calcium trisodium inj) 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, Pharmacodynamics, Adverse Metabolic Effects). Only a single initial dose of Ca-DTPA (pentetate calcium trisodium inj) is recommended. After the initial single dose of Ca-DTPA (pentetate calcium trisodium inj) , if additional chelation therapy is indicated, it is recommended that therapy be continued with Zn-DTPA. (See Zn-DTPA labeling) If Zn-DTPA is not available, chelation therapy may continue with Ca-DTPA (pentetate calcium trisodium inj) but mineral supplements containing zinc should be given concomitantly, as appropriate.

Ca-DTPA (pentetate calcium trisodium inj) should be used with caution in individuals with severe hemochromatosis. Deaths have been reported in patients with severe hemochromatosis that received up to 4 times the recommended daily dose, for more than 1 day, by IM injection. Causal association with these events and drug has not been established. (See OVERDOSE).

Nebulized chelation therapy may be associated with exacerbation of asthma. Caution should be exercised when administering Ca-DTPA by the inhalation route. (See ADVERSE REACTIONS)

PRECAUTIONS

Laboratory Tests

Serum electrolytes and essential metals should be closely monitored during Ca-DTPA (pentetate calcium trisodium inj) treatment. Mineral or vitamin plus mineral supplements that contain zinc should be given as appropriate. (See WARNINGS)

Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies with Ca-DTPA (pentetate calcium trisodium inj) to evaluate carcinogenesis, mutagenesis, and impairment of fertility have not been performed. Data for Ca-DTPA (pentetate calcium trisodium inj) effects on spermatogenesis are not available.

Teratogenic Effects: Pregnancy Category C

There are no human pregnancy outcome data from which to assess the risk of Ca-DTPA (pentetate calcium trisodium inj) exposure on fetal development. Ca-DTPA (pentetate calcium trisodium inj) is believed to be teratogenic based on animal data and because chelation therapy results in the depletion of body stores of zinc which is known to affect DNA and RNA synthesis in humans. There are no animal or human data evaluating the teratogenic effect of the administration of a single dose of Ca-DTPA (pentetate calcium trisodium inj) . Based on its mechanism of action, the likelihood that a single dose or multiple doses of Ca-DTPA (pentetate calcium trisodium inj) is teratogenic in humans cannot be ruled out. In mice, Ca-DTPA (pentetate calcium trisodium inj) has been shown to be teratogenic and embryocidal following five daily injections of 720-2880 µmol Ca-DTPA (pentetate calcium trisodium inj) /kg [2- 8 times the recommended daily human dose of 1 gram based on body surface area (BSA) adjusted dose] given during any period of gestation. The frequency of gross malformations (e.g., exencephaly, spina bifida, and cleft palate) increased with dose, with higher susceptibility in early and mid gestation. Five daily doses of 360 µmol Ca-DTPA (pentetate calcium trisodium inj) /kg in mice, approximately equivalent to the recommended daily human dose (based on BSA) produced no harmful effects. Studies of 2 pregnant dogs given daily injections of 30 µmol Ca-DTPA (pentetate calcium trisodium inj) /kg (approximately half the recommended daily human dose based on BSA) from implantation until parturition showed severe teratogenic effects (especially brain damage).

Multiple doses of Ca-DTPA (pentetate calcium trisodium inj) could result in an increased risk for adverse reproductive outcomes and thus are not recommended during pregnancy. Therefore, treatment of pregnant women should begin and continue with Zn-DTPA, if available, except in cases of high internal radioactive contamination. In these cases, the risk of immediate and delayed radiation-induced toxicity to both the mother and the fetus should be considered in comparison to the risk of Ca-DTPA (pentetate calcium trisodium inj) toxicity. Also, because Ca-DTPA (pentetate calcium trisodium inj) 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 (pentetate calcium trisodium inj) with vitamin or mineral supplements that contain zinc as the initial treatment.

Nursing Mothers

Studies to determine if Ca-DTPA (pentetate calcium trisodium inj) is excreted in breast milk have not been conducted. 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 PRECAUTIONS, Information for Patients)

Pediatric Use

The safety and effectiveness of Ca-DTPA (pentetate calcium trisodium inj) was 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. The safety and effectiveness of the nebulized route of administration has not been established in the pediatric population.

OVERDOSE

In previous clinical studies, three deaths were reported in patients with severe hemochromatosis who were treated with daily IM Ca-DTPA (pentetate calcium trisodium inj) dosed up to 4 gram per day to reduce iron stores. One patient became comatose and died after receiving a total of 14 gram Ca-DTPA (pentetate calcium trisodium inj) , 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)

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