ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. Noadverse reactions have been reported for Ammonia 13 Injection based on areview of the published literature, publicly available reference sources, andadverse 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 SOFIE Co. at 1-800-753-5368 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Ammonia 13 Injection is radiolabeled analogof ammonia that is distributed to all organs of the body afterintravenous administration. It isextracted from the blood in the coronary capillaries into the myocardial cellswhere it is metabolized to glutamine 13 and retained in the cells. The presence of ammonia 13 and glutamine N13 in the myocardium allows for PET imaging of the myocardium.. 12.2 Pharmacodynamics. Following intravenous injection, ammonia 13enters the myocardium through the coronary arteries. The PET technique measures myocardial bloodflow based on the assumption of three-compartmental disposition ofintravenous ammonia 13 in the myocardium. In this model, the value of the rate constant, which represents thedelivery of blood to myocardium, and the fraction of ammonia 13 extractedinto the myocardial cells, is measure of myocardial blood flow. Optimal PETimaging of the myocardium is generally achieved between 10 to 20 minutes afteradministration.. 12.3 Pharmacokinetics. Following intravenous injection, Ammonia 13Injection is cleared from the blood with biologic half-life ofabout 2.84 minutes (effective half-life of about 2.21 minutes). In the myocardium, its biologic half-life hasbeen estimated to be less than minutes (effective half-life less than 1.67minutes). The mass dose of Ammonia 13 Injection is verysmall 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 N13 metabolites has not beenstudied. Ammonia 13 undergoes five-enzyme stepmetabolism in the liver to yieldurea 13 (the main circulating metabolite). It is also metabolized to glutamine 13 (the main metabolite intissues) by glutamine synthesis in the skeletal muscles, liver, brain,myocardium, and other organs. Othermetabolites 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 byurinary excretion mainly as ureaN 13. Thepharmacokinetics of Ammonia 13 Injection have not been studied inrenally 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 13NH 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 0.14-9.62 GBq (3.75-260 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 theoretical mass dose of 0.5-1.0 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 DisintegrationMean EnergyProduced by positron annihilation Positron (+)1001190 keV (Max.)Gamma (+-) 200511.0 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 Attenuation00.0040.5080.25130.10260.01390.001520.0001Table 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 Remainingcalibration time 1.00050.706100.499150.352200.249250.176300.124.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION . RestImaging Study 2.1): Aseptically withdraw Ammonia 13 Injection fromits container and administer 10-20 mCi (0.368 0.736 GBq) as bolus through acatheter inserted into large peripheral vein. Start imaging minutes after the injection andacquire images for total of 10-20 minutes. Stress Imaging Study 2.2): If rest imaging study is performed, begin thestress imaging study 40 minutes or more after the first Ammonia N13 injectionto allow sufficient isotope decay. Administer pharmacologic stress-inducing drugin accordance with its labeling. Aseptically withdraw Ammonia 13 Injection fromits container and administer 10-20 mCi (0.368 0.736 GBq) of Ammonia 13Injection as bolus at minutes after the administration of the pharmacologicstress-inducing drug. Start imaging minutes after the Ammonia 13Injection and acquire images for total of 10-20 minutes. Patient Preparation 2.3): To increase renal clearance of radioactivity andto minimize radiation dose to the bladder, hydrate the patient before theprocedure and encourage voiding as soon as each image acquisition is completedand as often as possible thereafter for at least one hour.. Aseptically withdraw Ammonia 13 Injection fromits container and administer 10-20 mCi (0.368 0.736 GBq) as bolus through acatheter inserted into large peripheral vein. Start imaging minutes after the injection andacquire images for total of 10-20 minutes. If rest imaging study is performed, begin thestress imaging study 40 minutes or more after the first Ammonia N13 injectionto allow sufficient isotope decay. Administer pharmacologic stress-inducing drugin accordance with its labeling. Aseptically withdraw Ammonia 13 Injection fromits container and administer 10-20 mCi (0.368 0.736 GBq) of Ammonia 13Injection as bolus at minutes after the administration of the pharmacologicstress-inducing drug. Start imaging minutes after the Ammonia 13Injection and acquire images for total of 10-20 minutes. To increase renal clearance of radioactivity andto minimize radiation dose to the bladder, hydrate the patient before theprocedure and encourage voiding as soon as each image acquisition is completedand as often as possible thereafter for at least one hour.. 2.1 Rest Imaging Study. Aseptically withdraw Ammonia 13 Injection fromits container and administer 10-20 mCi (0.368 0.736 GBq) as abolus through catheter inserted into large peripheral vein. Start imaging minutes after the injection andacquire images for total of 10-20 minutes.. Aseptically withdraw Ammonia 13 Injection fromits container and administer 10-20 mCi (0.368 0.736 GBq) as abolus through catheter inserted into large peripheral vein. Start imaging minutes after the injection andacquire images for total of 10-20 minutes.. 2.2 Stress Imaging Study. If rest imaging study is performed, begin thestress imaging study 40 minutes or more after the first Ammonia 13 injectionto allow sufficient isotope decay.Administer pharmacologic stress-inducing drugin accordance with its labeling. Aseptically withdraw Ammonia 13 Injection fromits container and administer 10-20 mCi (0.368 0.736 GBq) of Ammonia 13Injection as bolus at minutes after the administration of the pharmacologicstress-inducing drug. Start imaging minutes after the Ammonia 13Injection and acquire images for total of 10-20 minutes.. If rest imaging study is performed, begin thestress imaging study 40 minutes or more after the first Ammonia 13 injectionto allow sufficient isotope decay.. Administer pharmacologic stress-inducing drugin accordance with its labeling. Aseptically withdraw Ammonia 13 Injection fromits container and administer 10-20 mCi (0.368 0.736 GBq) of Ammonia 13Injection as bolus at minutes after the administration of the pharmacologicstress-inducing drug. Start imaging minutes after the Ammonia 13Injection and acquire images for total of 10-20 minutes.. 2.3 Patient Preparation. To increase renal clearance of radioactivity andto minimize radiation dose to the bladder, ensure that the patient is wellhydrated before the procedure andencourage voiding as soon as study is completed and as often as possiblethereafter 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. Table 1: 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 intestine0.00670.0081000130.0210.041ULI 0.00670.00780.0130.0210.037LLI 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 tissues0.00590.00700.0110.0180.035Upper large intestine, Lower large intestine. 2.5 Drug Handling. Inspect Ammonia 13 Injection visually forparticulate matter and discoloration before administration, whenever solutionand container permit.Do not administer Ammonia 13 Injectioncontaining particulate matter or discoloration; dispose of these unacceptableor unused preparations in safe manner, in compliance with applicableregulations. Wear waterproof gloves and effective shieldingwhen handling Ammonia 13 Injection. Use aseptic technique to maintain sterilityduring all operations involved in the manipulation and administration ofAmmonia 13 Injection. The contents of each vial are sterile and non-pyrogenic. Use appropriate safety measures, includingshielding, consistent with proper patient management to avoid unnecessaryradiation exposure to the patient, occupational workers, clinical personnel,and other persons. Radiopharmaceuticals should be used by or underthe control of physicians who are qualified by specific training and experiencein the safe use and handling of radionuclides, and whose experience andtraining have been approved by the appropriate governmental agency authorizedto license the use of radionuclides. Before administration of Ammonia 13 Injection,assay the dose in properly calibrated dose calibrator.. Inspect Ammonia 13 Injection visually forparticulate matter and discoloration before administration, whenever solutionand container permit.. Do not administer Ammonia 13 Injectioncontaining particulate matter or discoloration; dispose of these unacceptableor unused preparations in safe manner, in compliance with applicableregulations. Wear waterproof gloves and effective shieldingwhen handling Ammonia 13 Injection. Use aseptic technique to maintain sterilityduring all operations involved in the manipulation and administration ofAmmonia 13 Injection. The contents of each vial are sterile and non-pyrogenic. Use appropriate safety measures, includingshielding, consistent with proper patient management to avoid unnecessaryradiation exposure to the patient, occupational workers, clinical personnel,and other persons. Radiopharmaceuticals should be used by or underthe control of physicians who are qualified by specific training and experiencein the safe use and handling of radionuclides, and whose experience andtraining have been approved by the appropriate governmental agency authorizedto 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 (30 mL) containing 0.14-9.62 GBq (3.75-260 mCi/mL) of Ammonia 13 Injection in aqueous 0.9 sodium chloride solution (approximately mL volume) that is suitable for intravenous administration.. Glass vial (30 mL) containing 0.14-9.62 GBq (3.75-260 mCi/mL) of Ammonia 13 Injection in aqueous 0.9 sodium chloride solution (approximately mL volume) that is suitable for intravenous administration.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Thepossibility of interactions of Ammonia 13 Injection with otherdrugs taken by patients undergoing PET imaging has not been studied.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED. Ammonia 13 Injection is packaged in 30 mL multiple dose glass vial containing between 0.14-9.62 GBq/mL (3.75-260 mCi/mL) of 13N] ammonia, at the end of synthesis (EOS) reference time, in 0.9% sodium chloride injection solution in approximately mL volume. The recommended dose of radioactivity (10-20 mCi) is associated with theoretical mass dose of 0.5-1.0 picomoles (8.47-16.94 picograms) of Ammonia. Store at 25C (77F); excursions permitted to 15-30C (59-86F). Use the solution within 60 minutes of the End of Synthesis (EOS) calibration.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE Ammonia 13 Injection is indicated for diagnosticPositron Emission Tomography (PET) imaging of the myocardium under rest orpharmacologic stress conditions to evaluate myocardial perfusion in patientswith suspected or existing coronary artery disease.. Ammonia 13 Injection is radioactivediagnostic agent for Positron Emission Tomography (PET) indicated fordiagnostic PET imaging of the myocardium under rest or pharmacologic stressconditions to evaluate myocardial perfusion in patients with suspected orexisting coronary artery disease 1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. 17.1 Pre-study Hydration. Instruct patients to drink plenty of water orother fluids (as tolerated) in the hours before their PET study.. 17.2 Post-study Voiding. Instructpatients to void after completion of each image acquisition session and asoften as possible for one hour after the PET scan ends.. 17.3 Post-study Breastfeeding Avoidance. Instruct nursing patients to substitute storedbreast milk or infant formula for breast milk for hours after administrationof Ammonia 13 Injection.

NONCLINICAL TOXICOLOGY SECTION.

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

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

LABEL ON CLOSURE VIAL AND LEAD PIG CONTAINERS. LABEL ON CONTAINER CLOSURE VIAL AND LEAD PIG CONTAINER.

REFERENCES SECTION.

15 REFERENCES. Annals of the ICRP. Publication 53. Radiation dose to patientsfrom radiopharmaceuticals. New York: PergamonPress, 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 withquantitative arteriography in 193 patients. Circulation 1989; 79: 825-35.. Annals of the ICRP. Publication 53. Radiation dose to patientsfrom radiopharmaceuticals. New York: PergamonPress, 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 withquantitative arteriography in 193 patients. Circulation 1989; 79: 825-35.

SPL UNCLASSIFIED SECTION.

Manufactured and distributed by:SOFIE Co. dba SOFIE21000 Atlantic Blvd. Suite 730Dulles, VA 20166USA.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Itis not known whether this drug is excreted in human milk. Alternatives to breastfeeding (e.g. using storedbreast milk or infant formula) should be used for hours (>10 half-lives ofradioactive decay for 13 isotope) after administration of Ammonia 13Injection 8.3). The safety and effectiveness of Ammonia 13Injection has been established in pediatric patients 8.4). Itis not known whether this drug is excreted in human milk. Alternatives to breastfeeding (e.g. using storedbreast milk or infant formula) should be used for hours (>10 half-lives ofradioactive decay for 13 isotope) after administration of Ammonia 13Injection 8.3). The safety and effectiveness of Ammonia 13Injection has been established in pediatric patients 8.4). 8.1 Pregnancy. Pregnancy Category Animalreproduction 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 reproductioncapacity. Ammonia 13 Injection should be givento pregnant woman only if clearly needed.. 8.3 Nursing Mothers. It is not known whether this drug is excreted in humanmilk. Because many drugs are excreted in human milkand because of the potential for radiation exposure to nursing infants fromAmmonia 13 Injection, use alternative infant nutrition sources (e.g. storedbreast milk or infant formula) for hours (>10 half-lives of radioactivedecay for 13 isotope) after administration of the drug or avoid use of thedrug, taking into account the importance of the drug to the mother.. 8.4 Pediatric Use. The safety and effectiveness of Ammonia 13Injection has been established in pediatric patients based on knownmetabolism of ammonia, radiation dosimetry in the pediatric population, andclinical studies in adults [see Dosage and Administration (2.4)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Ammonia 13 Injection may increase the risk ofcancer. Use the smallest dose necessary for imaging and ensure safe handling toprotect the patient and health care worker 5). 5.1 Radiation Risks. Ammonia 13 Injection may increase the risk ofcancer. Use the smallest dose necessary for imaging and ensure safehandling to protect the patient and health care worker [see Dosage and Administration (2.4)].