Pentetate Calcium Trisodium

Name: Pentetate Calcium Trisodium

Pentetate Calcium Trisodium Dosage and Administration

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.

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).

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)]

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.

Warnings and Precautions

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)]

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)]

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)]

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)]

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

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

Animal Toxicology and/or Pharmacology

[See Clinical Pharmacology (12)]

Clinical Studies

All clinical data has come from the treatment of individuals who were accidentally contaminated. Observational data were maintained in a U.S. Registry of individuals with internal radioactive 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. Seventeen of these individuals received 1 gram of Ca-DTPA as the first dose. Of these, 9 individuals received the first dose by nebulization (1:1 Ca-DTPA and saline) and 8 received Ca-DTPA intravenously. The elimination of radiocontaminants was measured using the ratio of the urine radioactivity before treatment to the maximum urine radioactivity after treatment (the excretion enhancement factor, EEF). As shown in Table 1, after one dose, the mean EEF was 25.7. The descriptive results and variability for the intravenous, inhaled, and combined routes are considered to be similar.

Table 1: Urine Excretion Enhancement Factor (EEF) of Transuranium Elements after an Initial Dose of 1g (Ca-DTPA, N=17)
Results Intravenous Inhaled Combined Routes
Mean 25.9 25.4 25.7
Median 12.5 19.3 12.8
SD 33.8 28.2 30.1
Range 1.1-396.1 0.5-80.0 0.5-396.1

After initial treatment with Ca-DTPA, maintenance treatment was continued with 1 gram Zn-DTPA doses over a period of days, months or years, depending upon the extent of internal contamination and individual response to therapy. Most patients received a single dose of Ca-DTPA. The longest treatment duration was approximately 6.5 years. Similar increases in urinary radioactivity elimination following chelator administration were supported by data from the remaining 268 individuals in the U.S. Registry and from the literature.

Collection of patient treatment data

To develop long-term response data and information on the risk of developing late malignancy, provide detailed information on patient treatment to the manufacturer (see Patient Treatment Data Form). In case you need additional forms, please use the enclosed form as a template or see the following website: www.ca-dtpa.com. 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 for the treatment of internal contamination with transuranium elements may be referred to:

hameln pharmaceuticals ltd
Nexus
Gloucester Business Park
Gloucester, GL3 4AG
United Kingdom
Tel: + 44 / 1452 / 621661
Fax: +44 / 1452 / 632732
e-mail: drugsafety@hameln.co.uk

Contact person: Richard Wysocki
Phone: +44 / 1452 / 621661
Fax: +44 / 1452 / 632732
Email: r.wysocki@hameln.co.uk

Revised: 10/2016

44641/17/16

PRINCIPAL DISPLAY PANEL - 5 mL Ampoule Package

Pentetate calcium
trisodium injection

5 mL

1000 mg

10 x 5 mL Single-Dose Ampoules
For intravenous or inhalation use only.

hameln

Pentetate Calcium Trisodium 
Pentetate Calcium Trisodium injection, solution, concentrate
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:70651-001
Route of Administration INTRAVENOUS, RESPIRATORY (INHALATION) DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
Pentetate Calcium Trisodium (pentetic acid) Pentetate Calcium Trisodium 1000 mg  in 5 mL
Inactive Ingredients
Ingredient Name Strength
Water  
Sodium hydroxide  
Calcium carbonate  
Packaging
# Item Code Package Description
1 NDC:70651-001-03 10 AMPULE in 1 PACKAGE
1 5 mL in 1 AMPULE
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA021749 08/11/2004
Labeler - hameln pharma plus gmbh (319361341)
Establishment
Name Address ID/FEI Operations
hameln pharmaceuticals gmbh 315869123 MANUFACTURE(70651-001), LABEL(70651-001), ANALYSIS(70651-001), PACK(70651-001)
Revised: 06/2016   hameln pharma plus gmbh

Usual Adult Dose for Radiation Emergency

Initial dose: 1 gram, intravenously
Maintenance dose (if pentetate zinc disodium is unavailable): 1 gram, intravenously
Maximum dose: 1 dose per 24 hour period

Comments:
-Administer during the first 24 hours after internal contamination; it is more effective than pentetate zinc disodium during this period.
-If additional chelation is indicated, pentetate zinc disodium is the preferred agent.
-May use for additional chelation if pentetate zinc disodium is not available; administer concomitant mineral supplements containing zinc.

Use: Treatment of known or suspected internal contamination with plutonium, americium, or curium to increase the rates of elimination.

Precautions

US BOXED WARNINGS:
ASTHMA EXACERBATION WITH NEBULIZATION and DEPLETION OF TRACE METALS DURING THERAPY
-Nebulized pentetate calcium trisodium may be associated with asthma exacerbation.
-This drug is associated with depletion of trace metals such as zinc.
-The magnitude of trace metal depletion increases with split daily dosing, increasing dose, and increased treatment duration.
-Only one dose of pentetate calcium trisodium is recommended.
-Use pentetate zinc if additional chelation therapy is indicated.
-Monitor serum zinc, serum creatinine, BUN, electrolytes, urinalysis, and blood cell counts during therapy.

COLLECTION OF PATIENT DATA
-Provide detailed treatment information (to gather long-term response and malignancy data).
-A form is attached to the prescribing information.
-Forms can be found at: www.ca-dtpa.com
-Include radioactive body burden, bioassay results, measurement methods, and adverse events.


Questions on use of this product, and on treatment of internal radiation may be referred to the manufacturer at welcome@hm-ph.com

Consult WARNINGS section for additional precautions.

Other Comments

Administration advice:
-Administer IV if route of internal contamination is unknown or multiple routes are likely.
-May give slow push over 3 to 4 minutes, or infusion.
-Patients with ONLY inhalation contamination within 24 hours: may nebulize at a 1:1 ratio with sterile water or saline. After nebulization, patients should avoid swallowing any expectorant.
-Pediatrics: safety and efficacy of nebulized treatment has not been established.

Reconstitution/preparation techniques:
-Dilute with 5% dextrose in water (D5W), lactated Ringers solution, or normal saline.
--Slow push: 1 gram in 5 mL
--Infusion: 1 gram in 100 to 250 mL

General:
-If contamination is with something other than plutonium, americium, or curium, or contaminants are unknown, additional therapies may be needed (e.g. Prussian blue, potassium iodide).

Monitoring:
-The manufacturer product information should be consulted.

Patient advice:
-Drink plenty of fluids and void frequently (to dilute and minimize bladder exposure).
-Use a toilet rather than a urinal; flush several times after each use.
-Wash hands thoroughly after cleaning up spilled urine or feces.
-Wash clothing or linens separately if they get blood or urine on them.
-Dispose of expectorant carefully; avoid swallowing it.

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