ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. No adverse reactions have been reported for Ammonia 13 Injection based on 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 13 Injection based on review of the published literature, publicly available reference sources, and adverse drug reaction reporting system 6). To report SUSPECTED ADVERSE REACTIONS, contact Ionetix Corporation at 415 677-5869 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Long term animal studies have not been performed to evaluate the carcinogenic potential of Ammonia 13 Injection. Genotoxicity assays and impairment of male and female fertility studies with Ammonia 13 Injection have not been performed.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Ammonia 13 Injection is 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 13 and retained in the cells. The presence of ammonia 13 and glutamine 13 in the myocardium allows for PET imaging of the myocardium. 12.2 Pharmacodynamics. Following intravenous injection, ammonia 13 enters the myocardium through the coronary arteries. The PET technique measures myocardial blood flow based on the assumption of three-compartmental disposition of intravenous ammonia 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 13 extracted into the myocardial cells, is 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 13 Injection is cleared from the blood with 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 minutes (effective half-life less than 1.67 minutes).The mass dose of Ammonia 13 Injection is very small as compared to the normal range of ammonia in the blood (0.72-3.30 mg) in healthy adult man [see Description (11.1)]. Plasma protein binding of ammonia 13 or its 13 metabolites has not been studied.Ammonia 13 undergoes five-enzyme step metabolism in the liver to yield urea 13 (the main circulating metabolite). It is also metabolized to glutamine 13 (the main metabolite in tissues) by glutamine synthesis in the skeletal muscles, liver, brain, myocardium, and other organs. Other metabolites of ammonia 13 include small amounts of 13 amino acid anions (acidic amino acids) in the forms of glutamate 13 or aspartate 13.Ammonia 13 is eliminated from the body by urinary excretion mainly as urea 13.The pharmacokinetics of Ammonia 13 Injection have not been studied in renally impaired, hepatically impaired, or pediatric patients.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. In descriptive, prospective, blinded image interpretation study of adult patients with known or suspected coronary artery disease, myocardial perfusion deficits in stress and rest PET images obtained with Ammonia 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 0 to 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 (total occlusion) to (normal).With increasing impairment of flow reserve, the subjective PET defect severity increased. PET defect score of or higher was positively correlated with flow reserve impairment (SFR<3).

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. None. None 4).

DESCRIPTION SECTION.

11 DESCRIPTION. 11.1 Chemical Characteristics. Ammonia 13 Injection is 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 13NH3 with molecular weight of 16.02, and has the following chemical structure:Ammonia 13 Injection is provided as 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 [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 theoretical mass dose of 0.5-1 picomoles (8.47-16.94 picograms) of ammonia.. Chemical Structure. 11.2 Physical Characteristics. Nitrogen N13 decays by emitting positron to Carbon C13 (stable) and has 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 DisintegrationEnergy Positron(+)1001190 keV (Max.) Gamma(+-) Produced by positron annihilation 200511 keVThe specific gamma ray constant (point source air kerma coefficient) for nitrogen N13 is 5.9 R/hr/mCi (1.39 10-6 Gy/hr/kBq) at cm. The half-value layer (HVL) of lead (Pb) for 511 keV photons is mm. Selected coefficients of attenuation are listed in Table as function of lead shield thickness. For example, the use of 39 mm thickness of lead will attenuate the external radiation by factor of about 1000. Table 3: Radiation Attenuation of 511 keV Photons by lead (Pb) shieldingShield Thickness (Pb) mmCoefficient of Attenuation40.580.25130.1260.01390.001520.0001Table 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 13MinutesFraction Remaining0 Calibration time 1.00050.706100.499150.352200.249250.176300.124.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Rest Imaging Study 2.1): Aseptically withdraw Ammonia 13 Injection from its container and administer 10-20 mCi (0.368 0.736 GBq) as bolus through catheter inserted into large peripheral vein.Start imaging minutes after the injection and acquire images for total of 10-20 minutes.Stress Imaging Study 2.2): If rest imaging study is performed, begin the stress imaging study 40 minutes or more after the first Ammonia N13 injection to allow sufficient isotope decay. Administer pharmacologic stress-inducing drug in accordance with its labeling.Aseptically withdraw Ammonia 13 Injection from its container and administer 10-20 mCi (0.368 0.736 GBq) of Ammonia 13 Injection as bolus at minutes after the administration of the pharmacologic stress-inducing drug.Start imaging minutes after the Ammonia 13 Injection and acquire images for 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.. Aseptically withdraw Ammonia 13 Injection from its container and administer 10-20 mCi (0.368 0.736 GBq) as bolus through catheter inserted into large peripheral vein.. Start imaging minutes after the injection and acquire images for total of 10-20 minutes.. If rest imaging study is performed, begin the stress imaging study 40 minutes or more after the first Ammonia N13 injection to allow sufficient isotope decay. Administer pharmacologic stress-inducing drug in accordance with its labeling.. Aseptically withdraw Ammonia 13 Injection from its container and administer 10-20 mCi (0.368 0.736 GBq) of Ammonia 13 Injection as bolus at minutes after the administration of the pharmacologic stress-inducing drug.. Start imaging minutes after the Ammonia 13 Injection and acquire images for total of 10-20 minutes.. 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 13 Injection from its container and administer 10-20 mCi (0.368 0.736 GBq) as bolus through catheter inserted into large peripheral vein.Start imaging minutes after the injection and acquire images for total of 10-20 minutes.. 2.2 Stress Imaging Study. If rest imaging study is performed, begin the stress imaging study 40 minutes or more after the first Ammonia 13 injection to allow sufficient isotope decay. Administer pharmacologic stress-inducing drug in accordance with its labeling.Aseptically withdraw Ammonia 13 Injection from its container and administer 10-20 mCi (0.368 0.736 GBq) of Ammonia 13 Injection as bolus at minutes after the administration of the pharmacologic stress-inducing drug.Start imaging minutes after the Ammonia 13 Injection and acquire images for 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 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 of the International Commission on Radiation Protection.1Table 1: 13 Absorbed Radiation Dose Per Unit Activity (rem/mCi) for Adults and Pediatric Groups.OrganAdult15 year old10 year old5 year old1 year oldAdrenals0.00850.00960.0160.0250.048Bladder 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 intestine0.00670.0081000130.0210.041Upper large intestine,ULI 0.00670.00780.0130.0210.037Lower large intestineLLI 0.00700.00780.0130.0200.037Heart0.00780.00960.0150.0230.041Kidneys0.0170.0210.0310.0480.089Liver0.0150.0180.0290.0440.085Lungs0.00930.0110.0180.0290.056Ovaries0.00630.00850.0140.0210.041Pancreas0.00700.00850.0140.0210.041Red 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 13 Injection visually for particulate matter and discoloration before administration, whenever solution and container permit. Do not administer Ammonia 13 Injection containing particulate matter or discoloration; dispose of these unacceptable or unused preparations in safe manner, in compliance with applicable regulations.Wear waterproof gloves and effective shielding when handling Ammonia 13 Injection.Use aseptic technique to maintain sterility during all operations involved in the manipulation and administration of Ammonia 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 13 Injection, assay the dose in properly calibrated dose calibrator.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Glass vial (10 mL) or Syringe (5mL) containing 0.138-1.387 GBq (3.75-37.5 mCi/mL) of Ammonia 13 Injection in aqueous 0.9 sodium chloride solution (approximately or mL volume).. Glass vial containing between 0.8325 Gbq to 8.325 Gbq (22.5-225mCi) or 5-mL syringe containing between 0.555 GBq to 5.55 GBq (15 mCi-150mCi) of Ammonia 13 Injection in aqueous 0.9% sodium chloride solution (approximately or mL volume)( 3).

DRUG INTERACTIONS SECTION.

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

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. Ammonia 13 Injection is clear and colorless solution packaged in 10 mL single dose glass vial containing between 0.8325 GBq to 8.325 GBq (22.5 mCi to 225 mCi) or in 5 mL single dose syringe containing between 0.555 GBq to 5.55 GBq (15 mCi to 150 mCi) of [13N] ammonia, at the end of synthesis (EOS) reference time, in 0.9% sodium chloride injection solution in approximately or mL volume. The recommended dose of radioactivity (10-20 mCi) is associated with theoretical mass dose of 0.5-1 picomoles (8.47-16.94 picograms) of Ammonia.. StorageStore at 25C (77F); excursions permitted to 15-30C (59-86F). Use the solution within 45 minutes of the End of Synthesis (EOS) calibration.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Ammonia 13 Injection 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 13 Injection is 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).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. 17.1 Pre-study Hydration. Instruct patients to drink plenty of water or other fluids (as tolerated) in the 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 hours after administration of Ammonia 13 Injection.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Ammonia 13 Injection is 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 13 and retained in the cells. The presence of ammonia 13 and glutamine 13 in the myocardium allows for PET imaging of the myocardium.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Long term animal studies have not been performed to evaluate the carcinogenic potential of Ammonia 13 Injection. Genotoxicity assays and impairment of male and female fertility studies with Ammonia 13 Injection have not been performed.

NURSING MOTHERS SECTION.

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 13 Injection, use alternative infant nutrition sources (e.g. stored breast milk or infant formula) for hours (>10 half-lives of radioactive decay for 13 isotope) after administration of the drug or avoid use of the drug, taking into account the importance of the drug to the mother.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 3.75-37.5 mCi/mL Vial Container Label. 10-mL Vial Label. 5-mL Syringe Label. 5-mL Syringe Label.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of Ammonia 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)].

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Following intravenous injection, ammonia 13 enters the myocardium through the coronary arteries. The PET technique measures myocardial blood flow based on the assumption of three-compartmental disposition of intravenous ammonia 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 13 extracted into the myocardial cells, is measure of myocardial blood flow. Optimal PET imaging of the myocardium is generally achieved between 10 to 20 minutes after administration.

PHARMACOKINETICS SECTION.

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

PREGNANCY SECTION.

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

REFERENCES SECTION.

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.

SPL UNCLASSIFIED SECTION.

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

STORAGE AND HANDLING SECTION.

StorageStore at 25C (77F); excursions permitted to 15-30C (59-86F). Use the solution within 45 minutes of the End of Synthesis (EOS) calibration.

USE IN SPECIFIC POPULATIONS SECTION.

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 hours (>10 half-lives of radioactive decay for 13 isotope) after administration of Ammonia 13 Injection 8.3). The safety and effectiveness of Ammonia 13 Injection has been established in pediatric patients 8.4). 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 hours (>10 half-lives of radioactive decay for 13 isotope) after administration of Ammonia 13 Injection 8.3). The safety and effectiveness of Ammonia 13 Injection has been established in pediatric patients 8.4). 8.1 Pregnancy. Pregnancy Category CAnimal reproduction studies have not been conducted with Ammonia 13 Injection. It is also not known whether Ammonia 13 Injection can cause fetal harm when administered to pregnant woman or can affect reproduction capacity. Ammonia 13 Injection should be given to 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 13 Injection, use alternative infant nutrition sources (e.g. stored breast milk or infant formula) for hours (>10 half-lives of radioactive decay for 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 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)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Ammonia 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 5). 5.1 Radiation Risks. Ammonia 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)].