NDC 44338-002 Ammonia N 13

Ammonia N-13

NDC Product Code 44338-002

NDC 44338-002-30

Package Description: 30 mL in 1 VIAL, GLASS

NDC Product Information

Ammonia N 13 with NDC 44338-002 is a a human prescription drug product labeled by Wisconsin Medical Cyclotron, Llc. The generic name of Ammonia N 13 is ammonia n-13. The product's dosage form is injection, solution and is administered via intravenous form.

Labeler Name: Wisconsin Medical Cyclotron, Llc

Dosage Form: Injection, Solution - A liquid preparation containing one or more drug substances dissolved in a suitable solvent or mixture of mutually miscible solvents that is suitable for injection.

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.

Ammonia N 13 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.

  • AMMONIA N-13 260 mCi/mL

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.

  • SODIUM CHLORIDE (UNII: 451W47IQ8X)

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.
  • Intravenous - Administration within or into a vein or veins.

Pharmacological Class(es)

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

  • Radioactive Diagnostic Agent - [EPC] (Established Pharmacologic Class)
  • Radiopharmaceutical Activity - [MoA] (Mechanism of Action)

Product Labeler Information

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

Labeler Name: Wisconsin Medical Cyclotron, Llc
Labeler Code: 44338
FDA Application Number: ANDA204356 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: ANDA - A product marketed under an approved Abbreviated 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: 12-23-2014 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2020 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N 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. Values = ‘Y’ or ‘N’.

* Please review the disclaimer below.

Ammonia N 13 Product Label Images

Ammonia N 13 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

1 Indications And Usage

Ammonia N 13 Injection, USP is indicated for diagnostic Positron Emission Tomography (PET) imaging of the myocardium under rest or pharmacologic stress conditions to evaluate myocardial perfusion in patients with suspected or existing coronary artery disease.

2.1 Rest Imaging Study

  • Aseptically withdraw Ammonia N 13 Injection from its container and administer 10-20 mCi (0.368 – 0.736 GBq) as a bolus through a catheter inserted into a large peripheral vein. Start imaging 3 minutes after the injection and acquire images for a total of 10-20 minutes.

2.2 Stress Imaging Study

  • If a rest imaging study is performed, begin the stress imaging study 40 minutes or more after the first Ammonia N 13 Injection to allow sufficient isotope decay.Administer a pharmacologic stress-inducing drug in accordance with its labeling. Aseptically withdraw Ammonia N 13 Injection from its container and administer 10-20 mCi (0.368 – 0.736 GBq) of Ammonia N 13 Injection as a bolus at 8 minutes after the administration of the pharmacologic stress-inducing drug.Start imaging 3 minutes after the Ammonia N 13 Injection and acquire images for a total of 10-20 minutes.

2.3 Patient Preparation

To increase renal clearance of radioactivity and to minimize radiation dose to the bladder, ensure that the patient is well hydrated before the procedure  and encourage voiding as soon as a study is completed and as often as possible thereafter for at least one hour.

2.4 Radiation Dosimetry

The converted radiation absorbed doses in rem/mCi are shown in Table 1. These estimates are calculated from the Task Group of Committee 2 of the International Commission on Radiation Protection.1Table 1: N 13 Absorbed Radiation Dose Per Unit Activity (rem/mCi) for Adults and Pediatric Groups.OrganAge (years)Adult151051Adrenals0.00850.00960.0160.0250.048Bladder wall0.0300.0370.0560.0890.17Bone surfaces0.00590.00700.0110.0190.037Brain0.0160.0160.0170.0190.027Breast0.00670.00670.0100.0170.033Stomach wall0.00630.00780.0120.0190.037Small intestine0.00670.00810.0130.0210.041Upper large intestine,ULI0.00670.00780.0130.0210.037Lower large intestineLLI0.00700.00780.0130.0200.037Heart0.00780.00960.0150.0230.041Kidneys0.0170.0210.0310.0480.089Liver0.0150.0180.0290.0440.085Lungs0.00930.0110.0180.0290.056Ovaries0.00630.00850.0140.0210.041Pancreas0.00700.00850.0140.0210.041Red marrow0.00630.00780.0120.0200.037Spleen0.00930.0110.0190.0300.056Testes0.00670.00700.0110.0180.035Thyroid0.00630.00810.0130.0210.041Uterus0.00700.00890.0140.0230.041Other tissues0.00590.00700.0110.0180.035

2.5 Drug Handling

  • Inspect Ammonia N 13 Injection visually for particulate matter and discoloration before administration, whenever solution and container permit.  Do not administer Ammonia N 13 Injection containing particulate matter or discoloration; dispose of these unacceptable or unused preparations in a safe manner, in compliance with applicable regulations.Wear waterproof gloves and effective shielding when handling Ammonia N 13 Injection.  Use aseptic technique to maintain sterility during all operations involved in the manipulation and administration of Ammonia N 13 Injection. The contents of each vial are sterile and non-pyrogenic.Use appropriate safety measures, including shielding, consistent with proper patient management to avoid unnecessary radiation exposure to the patient, occupational workers, clinical personnel, and other persons.  Radiopharmaceuticals should be used by or under the control of physicians who are qualified by specific training and experience in the safe use and handling of radionuclides, and whose experience and training have been approved by the appropriate governmental agency authorized to license the use of radionuclides.Before administration of Ammonia N 13 Injection, assay the dose in a properly calibrated dose calibrator.

3 Dosage Forms And Strengths

Glass vial (30 mL) containing 0.14-9.62 GBq (3.75-260 mCi/mL) of Ammonia N 13 Injection in aqueous 0.9 % sodium chloride solution  (approximately 6 mL volume) that is suitable for intravenous administration.

4 Contraindications

None

5.1 Radiation Risks

Ammonia N 13 Injection may increase the risk of cancer. Use the smallest dose necessary for imaging and ensure safe handling to protect the patient and health care worker [see Dosage and Administration (2.4)] .

6 Adverse Reactions

No adverse reactions have been reported for Ammonia N 13 Injection based on a review of the published literature, publicly available reference sources, and adverse drug reaction reporting systems. However, the completeness of these sources is not known.

7 Drug Interactions

The possibility of interactions of Ammonia N 13 Injection with other drugs taken by patients undergoing PET imaging has not been studied.

8.1 Pregnancy

Pregnancy Category CAnimal reproduction studies have not been conducted with Ammonia N 13 Injection.  It is also not known whether Ammonia N 13 Injection can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity.  Ammonia N 13 Injection should be given to a pregnant woman only if clearly needed.

8.3 Nursing Mothers

It is not known whether this drug is excreted in human milk.  Because many drugs are excreted in human milk and because of the potential for radiation exposure to nursing infants from Ammonia N 13 Injection, use alternative infant nutrition sources (e.g. stored breast milk or infant formula) for 2 hours (>10 half-lives of radioactive decay for N 13 isotope) after administration of the drug or avoid use of the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use

The safety and effectiveness of Ammonia N 13 Injection has been established in pediatric patients based on known metabolism of ammonia, radiation dosimetry in the pediatric population, and clinical studies in adults [see Dosage and Administration (2.4)].

11.1 Chemical Characteristics

Ammonia N 13 Injection, USP is a positron emitting radiopharmaceutical that is used for diagnostic purposes in conjunction with positron emission tomography (PET) imaging. The active ingredient, [13N] ammonia, has the molecular formula of 13NH3with a molecular weight of 16.02, and has the following chemical structure:Ammonia N 13 Injection, USP is provided as a ready to use sterile, pyrogen-free, clear and colorless solution.  Each mL of the solution contains between 0.14 GBq to 9.62 GBq (3.75 mCi to 260 mCi) of [13N] ammonia, at the end of synthesis (EOS) reference time, in 0.9% aqueous sodium chloride.  The pH of the solution is between 4.5 to 7.5. The recommended dose of radioactivity (10-20 mCi) is associated with a theoretical mass dose of 0.5-1.0 picomoles (8.47-16.94 picograms) of ammonia.

11.2 Physical Characteristics

Nitrogen N13 decays by emitting positron to Carbon C13 (stable) and has a physical half-life of 9.96 minutes.  The principal photons useful for imaging are the dual 511 keV gamma photons that are produced and emitted simultaneously in opposite direction when the positron interacts with an electron (Table 2).Table 2: Principal Radiation Emission Data for Nitrogen 13Radiation/Emission% Per DisintegrationEnergyPositron (β+)1001190 keV (Max.)Gamma (±)Produced by positron annihilation200511 keVThe specific gamma ray constant (point source air kerma coefficient) for nitrogen N13 is 5.9 R/hr/mCi (1.39 x 10-6 Gy/hr/kBq) at 1 cm.  The half-value layer (HVL) of lead (Pb) for 511 keV photons is 4 mm. Selected coefficients of attenuation are listed in Table 3 as a function of lead shield thickness. For example, the use of 39 mm thickness of lead will attenuate the external radiation by a factor of about 1000.Table 3: Radiation Attenuation of 511 keV Photons by lead (Pb) shieldingShield Thickness (Pb) mmCoefficient of Attenuation 40.580.25130.1260.01390.001520.0001Table 4 lists fractions remaining at selected time intervals from the calibration time.  This information may be used to correct for physical decay of the radionuclide.Table 4: Physical Decay Chart for Nitrogen N 13MinutesFraction Remaining 0Calibration time1.00050.706100.499150.352200.249250.176300.124

12.1 Mechanism Of Action

Ammonia N 13 Injection is a radiolabeled analog of ammonia that is distributed to all organs of the body after intravenous administration.  It is extracted from the blood in the coronary capillaries into the myocardial cells where it is metabolized to glutamine N 13 and retained in the cells.  The presence of ammonia N 13 and glutamine N 13 in the myocardium allows for PET imaging of the myocardium.

12.2 Pharmacodynamics

Following intravenous injection, ammonia N 13 enters the myocardium through the coronary arteries.  The PET technique measures myocardial blood flow based on the assumption of a three-compartmental disposition of intravenous ammonia N 13 in the myocardium.  In this model, the value of the rate constant, which represents the delivery of blood to myocardium, and the fraction of ammonia N 13 extracted into the myocardial cells, is a measure of myocardial blood flow. Optimal PET imaging of the myocardium is generally achieved between 10 to 20 minutes after administration.

12.3 Pharmacokinetics

Following intravenous injection, Ammonia N 13 Injection is cleared from the blood with a biologic half-life of about 2.84 minutes (effective half-life of about 2.21 minutes).  In the myocardium, its biologic half-life has been estimated to be less than 2 minutes (effective half-life less than 1.67 minutes).The mass dose of Ammonia N 13 Injection is very small as compared to the normal range of ammonia in the blood (0.72-3.30 mg) in a healthy adult man [see Description (11.1)].Plasma protein binding of ammonia N 13 or its N 13 metabolites has not been studied.Ammonia N 13 undergoes a five-enzyme step metabolism in the liver to yield urea N 13 (the main circulating metabolite).  It is also metabolized to glutamine N 13 (the main metabolite in tissues) by glutamine synthesis in the skeletal muscles, liver, brain, myocardium, and other organs.  Other metabolites of ammonia N 13 include small amounts of N 13 amino acid anions (acidic amino acids) in the forms of glutamate N 13 or aspartate N 13.Ammonia N 13 is eliminated from the body by urinary excretion mainly as urea N 13.The pharmacokinetics of Ammonia N 13 Injection have not been studied in renally impaired, hepatically impaired, or pediatric patients.

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

Long term animal studies have not been performed to evaluate the carcinogenic potential of Ammonia N 13 Injection.  Genotoxicity assays and impairment of male and female fertility studies with Ammonia N 13 Injection have not been performed.

14 Clinical Studies

In a descriptive, prospective, blinded image interpretation study2 of adult patients with known or suspected coronary artery disease, myocardial perfusion deficits in stress and rest PET images obtained with Ammonia N 13 (N=111) or Rubidium 82 (N=82) were compared to changes in stenosis flow reserve (SFR) as determined by coronary angiography. The principal outcome of the study was the evaluation of PET defect severity relative to SFR.PET perfusion defects at rest and stress for seven cardiac regions(anterior, apical, anteroseptal, posteroseptal, anterolateral, posterolateral, and inferior walls) were graded on a 0 to 5 scale defined as normal (0), possible (1), probable (2), mild (3), moderate (4), and severe (5) defects. Coronary angiograms were used to measure absolute and relative stenosis dimensions and to calculate stenosis flow reserve defined as the maximum value of flow at maximum coronary vasodilatation relative to rest flow under standardized hemodynamic conditions. SFR scores ranged from 0 (total occlusion) to 5 (normal).With increasing impairment of flow reserve, the subjective PET defect severity increased. A PET defect score of 2 or higher was positively correlated with flow reserve impairment (SFR<3).

15 References

  • Annals of the ICRP. Publication 53. Radiation dose to patients from radiopharmaceuticals. New York: Pergamon Press, 1988.Demer, L.L.K.L.Gould, R.A.Goldstein, R.L.Kirkeeide, N.A.Mullani, R.W. Smalling, A.Nishikawa, and M.E.Merhige. Assessment of coronary artery disease severity by PET: Comparison with quantitative arteriography in 193 patients. Circulation 1989; 79: 825-35.

16 How Supplied

Ammonia N 13 Injection, USP is packaged in 30 mL multiple dose glass vial containing between 0.83 GBq to 57.72 GBq (22.5 mCi to 1560 mCi) of [13N] ammonia, at the end of synthesis (EOS) reference time, in 0.9% sodium chloride injection solution in approximately 6 mL volume. The recommended dose of radioactivity (10-20 mCi) is associated with a theoretical mass dose of 0.5-1.0 picomoles (8.47-16.94 picograms) of Ammonia.

Storage

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). Use the solution within 50 minutes of the End of Synthesis (EOS) calibration.

17.1 Pre-Study Hydration

Instruct patients to drink plenty of water or other fluids (as tolerated) in the 4 hours before their PET study.

17.2 Post-Study Voiding

Instruct patients to void after completion of each image acquisition session and as often as possible for one hour after the PET scan ends.

17.3 Post-Study Breastfeeding Avoidance

Instruct nursing patients to substitute stored breast milk or infant formula for breast milk for 2 hours after administration of Ammonia N 13 Injection.

Other

Manufactured and Distributed by:Wisconsin Medical Cyclotron, LLC11236 W. Lapham StreetWest Allis, WI 53214Revised: December 2014

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