Ammonia N 13

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. Ammonia N 13 Injection, USP is a radioactive diagnostic agent for Positron Emission Tomography (PET) indicated for diagnostic PET imaging of the myocardium under rest or pharmacologic stress conditions to evaluate myocardial perfusion in patients with suspected or existing coronary artery disease (1) .

2 DOSAGE AND ADMINISTRATION Rest Imaging Study ( 2.1 ): Aseptically withdraw Ammonia N13 Injection from its container and administer 0.368-0.736 GBq (10-20 mCi) 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. Stress Imaging Study ( 2.2 ): If a rest imaging study is performed, begin the stress imaging study 40 minutes or more after the first Ammonia N 13 Injection USP to allow sufficient isotope decay. Administer a pharmacologic stress-inducing drug in accordance with its labeling. Aseptically withdraw Ammonia N 13 Injection USP from its container and administer 0.368-0.736 GBq (10-20 mCi) of Ammonia N 13 Injection USP 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 USP and acquire Images for a total of 10-20 minutes. Patient Preparation ( 2.3 ): To increase renal clearance of radioactivity and to minimize radiation dose to the bladder, hydrate the patient before the procedure and encourage voiding as soon as each image acquisition is completed and as often as possible thereafter for at least one hour. 2.1 Rest Imaging Study Aseptically withdraw Ammonia N 13 Injection USP from its container and administer 0.368-0.736 GBq (10-20 mCi) 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 USP to allow sufficient isotope decay. Administer a pharmacologic stress-inducing drug in accordance with its labeling. Aseptically withdraw Ammonia N 13 Injection USP from its container and administer 0.368-0.736 GBq (10-20 mCi) of Ammonia N 13 Injection USP 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 USP 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. 1 Table 1: N 13 Absorbed Radiation Dose Per Unit Activity (rem/mCi) for Adults and Pediatric Groups. Organ Age (years) Adult 15 10 5 1 Adrenals 0.0085 0.0096 0.016 0.025 0.048 Bladder wall 0.030 0.037 0.056 0.089 0.17 Bone surfaces 0.0059 0.0070 0.011 0.019 0.037 Brain 0.016 0.016 0.017 0.019 0.027 Breast 0.0067 0.0067 0.010 0.017 0.033 Stomach wall 0.0063 0.0078 0.012 0.019 0.037 Small intestine 0.0067 0.0081 0.013 0.021 0.041 *ULI 0.0067 0.0078 0.013 0.021 0.037 **LLI 0.0070 0.0078 0.013 0.020 0.037 Heart 0.0078 0.0096 0.015 0.023 0.041 Kidneys 0.017 0.021 0.031 0.048 0.089 Liver 0.015 0.018 0.029 0.044 0.085 Lungs 0.0093 0.011 0.018 0.029 0.056 Ovaries 0.0063 0.0085 0.014 0.021 0.041 Pancreas 0.0070 0.0085 0.014 0.021 0.041 Red marrow 0.0063 0.0078 0.012 0.020 0.037 Spleen 0.0093 0.011 0.019 0.030 0.056 Testes 0.0067 0.0070 0.011 0.018 0.035 Thyroid 0.0063 0.0081 0.013 0.021 0.041 Uterus 0.0070 0.0089 0.014 0.023 0.041 Other tissues 0.0059 0.0070 0.011 0.018 0.035 *Upper large intestine, ** Lower large intestine 2.5 Drug Handling Inspect Ammonia N 13 Injection USP visually for particulate matter and discoloration before administration, whenever solution and container permit. Do not administer Ammonia N 13 Injection USP containing particulate matter or discoloration; dispose of these unacceptable or unused preparations in a s …

3 DOSAGE FORMS AND STRENGTHS Glass vial (30 mL) containing 0.138 GBq/mL-1.387 GBq/mL (3.75 mCi/mL-37.5 mCi/mL) of Ammonia N 13 Injection in aqueous 0.9 % sodium chloride solution (approximately 8 mL volume) that is suitable for intravenous administration. Glass vial containing 0.138 GBq/mL-1.387 GBq/mL (3.75 mCi/mL-37.5 mCi/mL) of Ammonia N 13 Injection in aqueous 0.9% sodium chloride solution (approximately 8 mL volume) ( 3 ).

4 CONTRAINDICATIONS None None ( 4 )

6 ADVERSE REACTIONS No adverse reactions have been reported for Ammonia N 13 Injection USP 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. No adverse reactions have been reported for Ammonia N 13 Injection USP based on a review of the published literature, publicly available reference sources, and adverse drug reaction reporting system ( 6 ). To report SUSPECTED ADVERSE REACTIONS, contact Division of Nuclear Medicine, Department of Radiology, Mayo Clinic at 507-284-2511 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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

8 USE IN SPECIFIC POPULATIONS It is not known whether this drug is excreted in human milk. Alternatives to breastfeeding (e.g. using stored breast milk or infant formula) should be used for 2 hours (> 10 half-lives of radioactive decay for N 13 isotope) after administration of Ammonia N 13 Injection USP ( 8.3 ). The safety and effectiveness of Ammonia N 13 Injection USP has been established in pediatric patients ( 8.4 ). 8.1 Pregnancy Pregnancy Category C Animal reproduction studies have not been conducted with Ammonia N 13 Injection USP. It is also not known whether Ammonia N 13 Injection USP can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Ammonia N 13 Injection USP 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 USP, 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 USP 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) ].

12.1 Mechanism of Action Ammonia N 13 Injection USP 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.

11 DESCRIPTION 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, [ 13 N] ammonia, has the molecular formula of 13 NH 3 with a molecular weight of 16.02g 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 0.138 GBq to 1.387 GBQ (3.75 mCi to 37.5mCi) of [ 13 N] ammonia, at the end of synthesis (EOS), in 0.9% aqueous sodium chloride. The pH of the solution is between 4.5 to 7.5. The recommended dose of radioactivity (0.368-0.736 GBq, 10-20 mCi) is associated with a theoretical mass dose of 0.5-1.0 picomoles (8.47-16.94 picograms) of ammonia. 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 0.138 GBq to 1.387 GBQ (3.75 mCi to 37.5mCi) of [ 11.2 Physical Characteristics Nitrogen N 13 decays by emitting positron to Carbon C 13 (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 13 Radiation/Emission % Per Disintegration Energy Positron(β+) 100 1190 keV (Max.) Gamma(±)* 200 511 keV *Produced by positron annihilation The specific gamma ray constant (point source air kerma coefficient) for nitrogen N13 is 1.39 x 10 -6 Gy/hr/kBq (5.9 R/hr/mCi) 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) shielding Shield Thickness (Pb) mm Coefficient of Attenuation 4 0.5 8 0.25 13 0.1 26 0.01 39 0.001 52 0.0001 Table 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 13 Minutes Fraction Remaining 0* 1.000 5 0.706 10 0.499 15 0.352 20 0.249 25 0.176 30 0.124 *Calibration time

16 HOW SUPPLIED/STORAGE AND HANDLING Ammonia N 13 Injection, USP is packaged in 30 mL multiple dose glass vial containing between 1.80 GBq to 18.0 GBq (48.75 mCi to 487.5 mCi) of [ 13 N] ammonia, at the end of synthesis (EOS) reference time, in 0.9% sodium chloride injection solution in approximately 13 mL volume. The recommended dose of radioactivity (10 mCi-20 mCi) is associated with a theoretical mass dose of 0.5-1.0 picomoles (8.47-16.94 picograms) of Ammonia. Store at 20°C to 25°C (68°F to 77°F), excursions permitted between 15°C and 30°C (between 59°F and 86°F) [see USP Controlled Room Temperature]. Use the solution within 60 minutes of the End of Synthesis (EOS) calibration.