NDC 70651-002 Pentetate Zinc Trisodium

Pentetate Zinc Trisodium

NDC Product Code 70651-002

NDC 70651-002-03

Package Description: 10 AMPULE in 1 PACKAGE > 5 mL in 1 AMPULE

NDC Product Information

Pentetate Zinc Trisodium with NDC 70651-002 is a a human prescription drug product labeled by Hameln Pharma Gmbh. The generic name of Pentetate Zinc Trisodium is pentetate zinc trisodium. The product's dosage form is injection, solution, concentrate and is administered via intravenous; respiratory (inhalation) form.

Labeler Name: Hameln Pharma Gmbh

Dosage Form: Injection, Solution, Concentrate - A sterile preparation for parenteral use which, upon the addition of suitable solvents, yields a solution conforming in all respects to the requirements for Injections.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Pentetate Zinc Trisodium Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • PENTETATE ZINC TRISODIUM 1000 mg/5mL

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • WATER (UNII: 059QF0KO0R)
  • ZINC OXIDE (UNII: SOI2LOH54Z)
  • SODIUM HYDROXIDE (UNII: 55X04QC32I)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Intravenous - Administration within or into a vein or veins.
  • Respiratory (inhalation) - Administration within the respiratory tract by inhaling orally or nasally for local or systemic effect.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Lead Chelating Activity - [MoA] (Mechanism of Action)
  • Lead Chelator - [EPC] (Established Pharmacologic Class)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Hameln Pharma Gmbh
Labeler Code: 70651
FDA Application Number: NDA021751 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: NDA - A product marketed under an approved New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 08-11-2004 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

End Marketing Date: 05-31-2026 What is the End Marketing Date?
This is the date the product will no longer be available on the market. If a product is no longer being manufactured, in most cases, the FDA recommends firms use the expiration date of the last lot produced as the EndMarketingDate, to reflect the potential for drug product to remain available after manufacturing has ceased. Products that are the subject of ongoing manufacturing will not ordinarily have any EndMarketingDate. Products with a value in the EndMarketingDate will be removed from the NDC Directory when the EndMarketingDate is reached.

Exclude Flag: N - NO What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA"s requests for correction to deficient or non-compliant submissions ("Y"), or because the listing certification is expired ("E"), or because the listing data was inactivated by FDA ("I"). Values = "Y", "N", "E", or "I".

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Pentetate Zinc Trisodium Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

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)

1 Indications And Usage

Zn-DTPA is indicated for treatment of individuals with known or suspected internal contamination with plutonium, americium, or curium to increase the rates of elimination.

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 a single 1.0 gram initial dose of Zn-DTPA.in children less than 12 years of age, administer intravenously a 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.

Other

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.

  • 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.

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 a 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.

AbsorptionZn-DTPA is poorly absorbed in the gastrointestinal tract. In animal studies, after oral administration, absorption was approximately 5%. In a U.S. Registry of 18 patients who received a single inhaled or intravenous dose of 1 gram, urine data indicate that the inhaled product was absorbed and resulted in a comparable elimination of the radiocontaminant. One study of 2 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 a 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 a 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.

Zn-DTPAPatient treatment DataSend to: hameln pharmaceuticals ltd, Nexus, Gloucester Business Park, Gloucester, GL3 4AG, United Kingdom

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 5 mL) either with a slow intravenous push over a 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 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.

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 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.

3 Dosage Forms And Strengths

1000 mg / 5 mL single-use ampoules.

4 Contraindications

None.

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)]

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, 62 received Zn-DTPA by one or more routes of administration. Forty-eight individuals were dosed by intravenous administration, 18 by inhalation and 8 by other or unknown routes of administration.Of the individuals that received Zn-DTPA, 23/62 (37%) received one dose and 8 (13%) received two doses. The remaining 31 individuals received three or more doses. The largest number of Zn-DTPA doses to a 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, 1 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.

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).

Teratogenic Effects

Pregnancy Category B

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.

10 Overdosage

Overdose with Zn-DTPA has not been reported.

11 Description

Pentetate zinc trisodium injection contains the sodium salt of zinc diethylenetriaminepentaacetate. Pentetate zinc trisodium is also known as trisodium zinc diethylenetriaminepentaacetate and is commonly referred to as Zn-DTPA. It has a molecular formula of Na3ZnC14H18N3O10 and a molecular weight of 522.7 Daltons. It is represented by the following structural formula:Zn-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 zinc trisodium (obtained from 150.51 mg pentetic acid, 31.14 mg zinc oxide and NaOH) and water for injection, USP. The pH of the solution is adjusted with NaOH and is between 6.5-7.5.

12.1 Mechanism Of Action

Zn-DTPA forms stable chelates with metal ions by exchanging zinc for a 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 a 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 a 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 a 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 2 micromol/kg (0.11 MHD) 30 minutes after contamination followed by inhalation of Zn-DTPA 2 micromol/kg at approximately 6 hours, 1, 2, 3, and 6 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 2 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 7 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

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

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

13.2 Animal Toxicology And/Or Pharmacology

[See Clinical Pharmacology (12)]

14 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 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 3 doses, 1 gram each, by nebulization (1:1 Zn-DTPA and saline) followed by 6 intravenous doses, the urinary excretion of plutonium after the first nebulized dose was increased by a factor of 45.After initial treatment with Ca-DTPA, maintenance treatment was continued with daily 1 gram Zn-DTPA doses administered over a 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.

16 How Supplied

Zn-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 zinc trisodium.NDC 70651-002-03: 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.

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 a toilet instead of a 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)]

18 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 Patient Treatment Data Form). To obtain additional forms, please use the enclosed form as a template or see the following website: www.zn-dtpa.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 Zn-DTPA for the treatment of internal contamination with transuranium elements may be referred to:hameln pharmaceuticals ltdNexusGloucester Business ParkGloucester, GL3 4AGUnited KingdomTel: + 44 / 1452 / 621661Fax: +44 / 1452 / 632732e-mail: drugsafety@hameln.co.ukContact person: Richard WysockiPhone: +44 / 1452 / 621661Fax: +44 / 1452 / 632732Email: r.wysocki@hameln.co.ukRevised: 10/201644640/17/16

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