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WHITE PAPER

Reproducible Quantification in PET•CT: Clinical Relevance and Technological Approaches

Partha Ghosh, MD

The Influence of Quantification on Clinical Decision Making 1

The Factors Influencing the Accuracy and Reproducibility of Quantitative Results 2

Patient Preparation and Protocol 2

Patient Size 2

Post Injection Delay Times 2

Plasma Glucose Levels 2

Acquisition and Reconstruction Parameters 2

Instrumentation 5

Detector System 5

Calibration Method 6

Registration and Attenuation Correction Methods 7

Quantification Software 11

PET Oncology Follow-up with SUVpeak 11

PET Cardiac Perfusion with Myocardial Blood Flow 13

Conclusion 16

References 16

Table of Contents

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The Influence of Quantification on Clinical Decision Making Metabolic imaging with PET/CT using 18F Fludeoxyglucose (18F FDG)* as well as other imaging biomarkers has achieved wide acceptance in oncology, cardiology and neurology not only because of the unique metabolic information generated by this modality, but also because of its ability to quantify biological processes. Such quantitative parameters generated by PET/CT imaging act as valuable tools for characterization of lesions as well as for monitoring response to therapy.

The fundamental quantitative parameter in PET is the Standard-ized Uptake Value (SUV), which is calculated as follows:

This value can be normalized to body weight as in the above equation or normalized to body surface area or lean body mass. Traditionally the SUVmax (pixel with the highest SUV within a given region of interest (ROI) in a tumor) has been used for tumor characterization and follow up although the reproducibility of this measurement is subject to significant variation.

INDICATIONS AND USAGEFludeoxyglucose F18 Injection is indicated for positron emis-sion tomography (PET) imaging in the following settings:

• Oncology: For assessment of abnormal glucose metabolism to assist in the evaluation of malignancy in patients with known or suspected abnormalities found by other testing modalities, or in patients with an existing diagnosis of cancer.

• Cardiology: For the identification of left ventricular myocardium with residual glucose metabolism and reversible loss of systolic function in patients with coro-nary artery disease and left ventricular dysfunction, when used together with myocardial perfusion imaging.

• Neurology: For the identification of regions of abnormal glucose metabolism associated with foci of epileptic seizures (1).

IMPORTANT SAFETY INFORMATIONRadiation RisksRadiation-emitting products, including 18F FDG, may increase the risk for cancer, especially in pediatric patients. Use the smallest dose necessary for imaging and ensure safe handling to protect the patient and health care worker.

Blood Glucose AbnormalitiesIn the oncology and neurology setting, suboptimal imaging may occur in patients with inadequately regulated blood glucose levels. In these patients, consider medical therapy and laboratory testing to assure at least two days of normo-glycemia prior to 18F FDG administration.

Adverse ReactionsHypersensitivity reactions with pruritus, edema and rash have been reported; have emergency resuscitation equipment and personnel immediately available.

Full prescribing information may be found at the end of this white paper.

SUV = Activity Concentration (kBq/ml)

Inj. dose (MBq) BodyWt (kg)

Accurate and reproducible measurement of SUV is critical to the clinical efficacy of PET/CT imaging since the quantitative parameter is often used to guide clinical decision making. This is especially true for characterization of equivocal lesions like lung nodules where an SUV of 2.5 or higher has been traditionally regarded as the criteria to label a lesion as malignant and subject it to biopsy1. A prospective study1 attempted to differentiate malignant from benign lung nodules in 87 patients. When a mean SUV of greater than or equal to 2.5 was used for detecting malignancy, the sensitivity, specificity and accuracy were 97 percent, 82 percent and 92 percent, respectively. In addition, there was a significant correlation between the doubling time of tumor volume and the SUV.

SUV-based quantification is also critical for proper evaluation of response to therapy of tumors using PET/CT, an approach which is being increasingly adopted in oncology for monitoring chemo-therapy and chemoradiation therapy, as well as to modify therapy regimes in cases of non-response which may be ascertained early using sequential PET/CT imaging during therapy. Initial tumor response to effective chemotherapy is usually a decrease in tumor metabolic activity with subsequent decrease in tumor size based on the degree of cell killing and resulting intratumoral necrosis and fibrosis. Often the time lag between metabolic response and morphological response is significant, measured in weeks. A series of studies involving response evaluation of various tumors using PET/CT has shown the advantage of PET/CT in demonstra-tion of early response or non-response to therapy much before decrease in tumor volume could be detected on CT. Although

* Important safety information on Fludeoxyglucose 18F injection can be found on the previous page. The full prescribing information can be found on pages 18-25.

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The Factors Influencing the Accuracy and Reproducibility of Quantitative Results SUV is subject to several sources of variability arising from the patient and the PET/CT system, including acquisition and recon-struction parameters, as well as statistical variations related to system calibration and evaluation methodology.

Patient Preparation and Protocol

Patient SizeBody habitus is a source of variability in SUV since conventional SUV normalizes for body weight. However, fat has a much lower 18F FDG uptake compared to muscle and organs, such as the liver. Several tissues show progressive increase in SUV with increasing body weight due to the proportionally higher fat content7. SUV normalized to lean body mass (SUL) reduces body fat percentage related variability. However, not all centers may use standardized SUV normalization criteria and thus intersystem variability may persist.

Post Injection Delay TimesThe waiting period between 18F FDG injection and PET/CT acquisi-tion has been shown to have an impact on SUV8. Several studies have demonstrated progressive increase in SUV in malignant lung tumors subjected to dual time point acquisitions9. These observa-tions suggest that SUV can vary widely depending on delay in acquisition post injection, and standardization of the post injec-tion delay is important for reproducible and reliable results, as has been adopted in most current clinical trials. The European Association of Nuclear Medicine (EANM) procedure guidelines for oncologic PET imaging10 recommend the interval between 18F FDG administration and the start of acquisition to be 60 minutes. Recording of the actual interval and time of injection is also recommended. Adherence to same post injection delay for repeat imaging of the same patient with a tolerance of +/- 5 minutes is recommended in the context of therapy response assessment.

Plasma Glucose LevelsThe plasma glucose level also has a major effect on SUV. Hyper-glycemia has been shown to cause a significant reduction in tissue FDG uptake and consequently a reduction in SUV11. Such variations demand strict monitoring and management of plasma glucose level prior to PET/CT studies in order to reduce SUV variability.

Acquisition and Reconstruction ParametersAccurate measurement of injected dose is key to accurate and reproducible SUV calculation. Attention to calibration of the dose calibrator as well as measurement of residual activity in syringe after injection is of utmost importance. SUV calculation depends on the measurement of activity concentration in kBq/ml and is thus affected by factors such as recovery coefficients (RC) and partial volume effects (PVE). The recovery coefficient of a PET/CT system can be defined as the ratio of the measured activity in a lesion divided by the true activity. It decreases when the struc-

the RECIST criteria based on morphological parameters of tumor has been widely used, it is very often inappropriate in assessing therapy response in certain tumors. Several newer cancer thera-pies have a more cytostatic than cytocidal effect and good tumor response may be associated predominantly with a decrease in metabolism, even in the absence of a major shrinkage in tumor size. Quantitative evaluation of tumor metabolism, as indicated by PET SUV, is increasingly being adopted as an adjunct to RECIST for clinical trials involving therapy response evaluation, especially those related to such cytostatic and targeted therapies. Therapy response evaluation using molecular imaging biomarkers corre-lates better with patient outcome than do size measurements, which could significantly reduce the costs of drug development and, thereby, eventually decrease drug costs in clinical practice.

The percentage decline of SUV that fits into the profile of a responding tumor differs among cancer types. In lung, gastric and esophageal cancers, declines in SUVmax of 20 to 35 percent after one to two doses of therapy have been shown to be predictive of favorable outcomes2. However, in lymphomas and ovarian carcinoma, a larger drop in SUVmax following initial therapy is observed in responding lesions3,4. The levels of SUV change required to conform to the clinical profile of a favorable response varies widely and depends primarily on tumor biology. Thus a relatively modest decrease in SUVmax may constitute a good response in some tumors. Cytostatic chemotherapy agents may block tumor growth but the SUVmax may remain constant or decrease slightly. Studies have demonstrated significant vari-ability of SUVmax values in test-retest measurements, ranging between 6 to 10 percent5 with increase in variability with higher SUVmax values. Due to such variability, the level of SUVmax change which is to be considered a positive indicator for therapy response is subject to controversy. The European Organization for Research and Treatment of Cancer (EORTC) PET study group6 suggested a reduction of a minimum of 15 percent to 25 percent in tumor SUVmax or SUVmean to reflect a partial metabolic response (PR) after one cycle of chemotherapy and greater than 25 percent after more than one treatment cycle. Decrease in test-retest variability of SUV secondary to technological innovations and improved standardization of data acquisition and reconstruction should improve criteria for therapy response assessment. On the road to reliable response assessment based on quantitative results, it is therefore desirable to define true thresholds for progressive disease and partial response. As a prerequisite, scan-ners would have to be accurate to within a small margin.

Tumor volume estimation based on PET as well as delinea-tion of gross tumor volume (GTV) for PET/CT-based radiation therapy planning usually involves determining a threshold as a percentage value of the SUVmax of a tumor. Thus the accuracy of the highest SUV of a tumor is a key component for accurate delin-eation of tumor margins if threshold-based Volume of Interest (VOI) generation tools are used.

In view of the clinical relevance of accurate and reproducible SUV in PET imaging, it is important to look at the variables that affect SUV and patient-specific, as well as system- and technology-specific measures, that could reduce such variability.

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ture is smaller than a few times the practical image resolution or when such structure occupies a portion of the voxel due to inad-equate sampling. In both situations, the recovery coefficient is typically less than 100 percent and SUV may be calculated lower than the actual value. Hoffman et al12 evaluated this problem and assessed the recovery coefficient for images of cylinder with uniform radioactivity distribution. He demonstrated a relation-ship between system resolution, cylinder diameter and recon-struction parameters, especially the Full Width at Half Maximum (FWHM) of the reconstruction filter. He concluded that RC of a cylinder with diameter equal to the resolution FWHM of the imaging system was only 50 percent. Such RC equally affects the SUV calculation. Typically, Gaussian filters of 5 to 10 mm FWHM are applied resulting in a clinical image resolution of 7 to 12 mm. PVE increases with decreasing image resolution. PVE becomes mainly important for lesions smaller than three times the FWHM, such as lesions 20 mm or less. Recovery coefficient and partial volume effects also strongly depend on object geometry with maximum effect in irregular shaped tumors.

With iterative reconstruction methods, a sufficient number of iterations need to be applied to ensure sufficient convergence of the algorithm. SUV increases of up to 70 percent have been shown when using higher numbers of iterations.

Data acquisition settings such as time per bed position, the amount of overlap between subsequent bed positions, acquisi-tion mode (2D or 3D) and 18F FDG dose affect scan statistics and/ or the noise equivalent count rate of PET studies. Poorer scan statistics and lower image signal-to-noise ratio (SNR) result in an upward bias of SUV, especially when using the SUVmax as final outcome parameter. CT attenuation correction (CT AC) can influ-ence SUV in cases with patient motion (e.g., breathing), which may cause a mismatch between PET and CT and thus result in incorrect attenuation correction. The latter may be minimized by breathing instructions (breath holding at mid-inspiration volume or shallow breathing) during CT scanning. Truncation of CT due to smaller CT field of view (FOV) may lead to faulty attenuation correction and SUV errors and should therefore be avoided.

Such variability can be significantly improved by technological developments including higher performance PET detector mate-rial (LSO) with higher count rate efficiencies; higher resolution scanners with smaller crystal elements and voxel sizes (HI-REZ crystals) as well as newer reconstruction algorithms that improve lesion contrast and resolution throughout the entire FOV (Point Spread Function (PSF) reconstruction such as HD•PET). More-over, acquisition and reconstruction with time of flight (TOF) (Siemens ultraHD•PET) dramatically reduce background noise and increases lesion contrast, which can impact small lesion detectability. Higher system resolution with smaller voxel size reduces partial volume effects, improving the accuracy of SUV.

Attempts are being made to improve standardization of PET/CT-based clinical trials in order to enhance the reliability of SUV across multiple systems in order to reduce variability. A PET imaging working group was formed by the Netherlands Society of Haemato-Oncology13. The group specifically aimed at stan-dardization of 18F FDG PET studies in order to allow inter-institute interchangeability of SUV. This group recommended well-defined guidelines for patient preparation, data acquisition, image recon-struction and inter-institutional standardization of image quality parameters based on standardized phantom studies. Several of the recommendations are discussed below.

The Netherlands study group recommended a strict adherence to injected dose, post injection delay and iterative reconstruc-tion guidelines among centers in order to improve SUV reliability. Matching of image resolution as closely as possible among centers in multi-centre trials to avoid differences in SUV was recommended. The group also recommended guidelines for ROI selection in lesions to help standardization. Fixed size ROI providing ‘SUVpeak’, maximum pixel values providing ‘SUVmax’ or the average ROI value within a 2D or 3D ROI providing ‘SUVmean’ were all put into standardized guidelines. Recommendations for patient preparation were specified in order to minimize patient-related or other physiological effects on SUV accuracy and reproducibility. Moreover, guidelines aimed at optimizing

Patient- and system-specific factors influence the accuracy and reproducibility of SUV. Improvements in image quality, attenuation correction method-ology, system calibration and quality control, as well as adequacy of quantitative software tools, together influence the ultimate SUV accuracy and diagnostic confidence.

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18F FDG uptake in the tumor, minimizing uptake in surrounding tissues (muscle, brown fat) and minimizing SUV variability were put forward. Recommendations for the administration procedure were given to ensure that the net dose given to the patient is exactly known, primarily by avoiding unknown remaining activities during preparation and administration. 18F FDG dose was specified as a function of patient weight, scanning mode, percentage bed overlap and acquisition time per bed position.

Interchangeability of SUV between acquisitions in different scan-ners and in different institutions is affected by the overall spatial resolution of the PET images after reconstruction, filtering or smoothing and processing. Comparison of data from different scanners requires standardized reconstruction and filtering in order to match image resolution across scanners so as to allow for SUV interchangeability. SUV outcome is also determined by data analysis procedures. Common ROI strategies are the use of fixed sized 2D or 3D ROI, manually defined ROI in one or more axial slices and 3D ROI based on region growing procedures while applying a user-specified threshold.

Boellaard et al14 performed a simulation study to determine the effects of noise, image resolution and ROI definition on the accuracy of SUVs. Experiments and simulations were based on thorax phantoms with tumors of 10, 15, 20 and 30 mm diameter and tumor-to-background ratios (TBRs) of 2, 4 and 8. Fifty sino-grams were generated at three noise levels. All sinograms were reconstructed using ordered subset expectation maximization (OSEM) with two iterations and 16 subsets, with or without a 6 mm Gaussian filter. For each tumor, the maximum pixel value and the SUVmean (from ROI based on isocontour and on adaptive threshold of 50 percent and 70 percent), as well as 3D ROI of one cubic centimeter volume (SUVpeak) placed in the zone of the highest uptake were calculated. The results indicated that the maximum pixel value within an object increases with image noise level and with increasing object size. Based on this experimental

evidence, the Netherlands group advocates phantom-based standardization of PET/CT systems as a prerequisite for partici-pation in clinical trials. The guidelines mandate the maximum voxel value or SUVmax to be always reported. However, use of larger VOI may provide SUV estimates with better precision. Therefore, in response monitoring settings, use of 3D VOI with a threshold of 41 percent, 50 percent or 60 percent of the SUVmax is recommended to be used consistently in all sequential scans of a patient13. When such threshold-based VOIs are not adequate, smaller VOI obtained with higher percentage threshold values can be applied. The guidelines included quality control (QC)measurements using torso abdominal phantom with multiple 18F FDG-filled spheres of various sizes with a lesion-to-background ratio of 8 to be used to calculate reproducibility of SUVmax and SUVmean at different threshold-based VOIs. VOIs based on adap-tive threshold of 41 percent of maximum SUV provide VOI with a volume close to real sphere volumes used.

As reflected by the studies and observations of working groups for standardization of PET-based therapy clinical trials, the vari-ability of SUV between sequential observations on the same system or different systems exert considerable influence on the interpretation of such trials. This highlights the need for adequate PET/CT hardware and software optimization to reduce system-related variability of quantification parameters. Such variability may be related to non-optimized quality control and calibration procedures, photomultiplier drifts due to tempera-ture and other factors, system sensitivity fluctuations, PET and CT misregistrations related to minor patient motion, etc. Special focus on PET/CT hardware design and engineering to reduce or eliminate such variability introducing factors by optimizing and automating quality control and calibration procedures, as well as software-based autoregistration of PET and CT and automated use of appropriate quantitative measures like SUVpeak in order to reduce statistical variability, would possibly increase the reli-ability of SUV for response monitoring.

Figure 1: PET Detector Materials Properties

PET Detector Material Properties

Property Characteristic Desired Value LSO BGO GSO Nal

Density (g/cc) Defines detection efficiency of detector and scanner sensitivity

High 7.4 7.1 6.7 3.7

Effective atomic number High 65 75 59 51

Decay time (nsec) Defines detector dead time and randoms rejection Low 40 300 60 230

Relative light output (%) Impacts spacial and energy resolution High 75 15 35 100

Energy resolution (%) Influences scatter rejection Low 10.0 10.1 9.5 7.8

Nonhygroscopic Simplifies manufacturing, improves reliability and reduces service costs

Yes Yes Yes Yes No

Ruggedness Yes Yes Yes No No

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Instrumentation

As discussed in the preceding chapters, the accuracy of quantita-tive values, like SUV derived from PET/CT imaging, depends not only on patient-specific variables such as injected dose and blood glucose level but, more importantly, on system-specific factors like detector sensitivity and resolution, as well as consistency of system calibration, PET and CT coregistration and appropriate algorithms for image reconstruction.

Detector System

The detector system is at the heart of the PET scanner. Its design determines the key performance characteristics. The elements of the detector system are the crystal, the photomultiplier tube and the processing electronics. Opposing crystals in a PET detector ring receive the coincident photons emitted secondary to a posi-tron annihilation and convert them into a light signal, which is then received and amplified by a photomultiplier tube. In order for the opposing photons to be recognized as a single coincident event, they must strike the detectors located opposite each other in the PET gantry within a small duration of time. This is called the coincidence window. The detector material is key to count rate efficiency. The detector performance characteristics are determined by the material, crystal size, detector geometry and the quantity of crystal elements in a PET/CT system.

Crystal MaterialCount rate efficiency of a PET crystal depends on factors like scin-tillation decay time and light output. Crystal and photomultiplier tubes, along with system electronics, need to optimally perform to obtain very short coincidence windows. A short coincidence window leads to higher true count rates and lower scatter and random events, which constitute noise. Crystal decay time and light output contribute to the ability to achieve shorter coinci-dence windows. Coincidence windows for current generation PET detector materials are in the range of 4.1 nanoseconds. Conventional PET scintillator materials like bismuth germanium oxide (BGO), gadolinium oxyorthosilicate (GSO) or sodium iodide doped with thallium (Nal) are characterized by larger coincidence windows. Adoption of newer crystal material, like lutetium oxyor-thosilicate (LSO), pioneered by Siemens, has increased count rate efficiency and made 3D scanning possible, which has significantly improved acquisition speeds and image quality.

As shown in the comparative chart of various PET detector materials (Figure 1), LSO has high density and a high atomic number for fast scintillation decay time and a high light output for improved energy and position determination. This enables Siemens Biograph™ PET•CT systems to achieve high count rate efficiencies even with low injected dose.

With LSO, seemingly opposing requirements are achieved at the same time: for oncology imaging, superb image quality is demon-strated even at fast acquistion speeds, while for dynamic perfu-sion imaging, high count rates are recorded without detector saturations due to rapid decay times.

Crystal GeometryThe size of individual crystal elements in a detector block in the PET gantry is a key factor that influences the resolution of acquired PET image. High resolution images not only improve lesion detection and diagnostic accuracy, but also improve the accuracy of quantification due to lower partial volume effects, as mentioned previously in this paper. Biograph mCT achieves the industry’s finest volumetric resolution* of 87 cubic mm with a maximum image matrix of 400x400 due to the OptisoHD detec-tion system, with an arrangement of 13x13 crystals per detector block of 4x4x20 mm crystal elements. Such high resolution imaging decreases partial volume effects compared to conven-tional detector designs and achieves the highest NEMA and volumetric resolution for clinical PET.* Due to the high resolution and optimum count rate efficiency of Biograph mCT, visualization of small lesions is enhanced along with the quantitative accuracy of the SUV generated.

Crystal VolumeThe volume of crystal material available in a gantry not only deter-mines the FOV per PET bed position and the coverage, but also the count rate during 3D acquisition. As the amount of crystal increases, the amount of coincident photons also increases along with an increase in the true count rate capability. Siemens has pioneered the concept of increasing the amount of crystal mate-rial within a system by increasing the number of detector rings in order to create a larger solid angle for PET acquisition with consequent increase in true count rate capability in 3D mode. As a result, the number of bed positions and the time per bed decrease at the same time for a compounded effect on scan time reduction. Therefore, a unique four ring detector design (TrueV) on the Biograph system is available to enable scans at half the time or half the dose compared to conventional three ring designs. When combined with TOF technology (ultraHD•PET), imaging can be performed at half the time and half the dose compared to conventional three ring designs. The increase in count rate efficiency also helps achieve optimum counting statis-

OptisoHD detector design with 13x13 LSO crystal matrix and photomultiplier tube assembly.

13x13 LSO array

Crystals

Light guide

2x2 PMT array

Voltage divider

* Based on competitive literature available at time of publication; data on file.

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tics even at very high resolutions in order to achieve superb quan-titative accuracy even with significant reductions in acquisition time. Quantitative accuracy is compromised with low count rate and high noise levels. Thus improved count rate capabilities due to crystal and detector-related innovations help improve quantita-tive accuracy of the system.

Calibration Method

As mentioned earlier, the reproducibility and accuracy of a quan-titative parameter like SUV is influenced by the overall system performance. Factors such as inherent detector drift, shifting PMT gains due to temperature and voltage variations and other factors may affect quantification accuracy. To compensate for these effects and ensure consistent results, appropriate calibra-tion mechanisms need to be employed. Simpler methods use line sources with spread out calibration intervals that measure a subset of performance parameters. However, more compre-hensive methods are required to more closely replicate the char-acteristics of a patient15 and also to allow for more advanced acquisition technologies, like TOF. In order to optimize the procedure for consistent system calibration and to ensure repro-ducibility and accuracy of quantitative measurements, Biograph mCT incorporates a daily phantom-based quality control and calibration protocol termed as Quanti•QC. Quanti•QC measures and calibrates a large array of system parameters on a regular basis in order to fine tune the system for optimum performance and reproducible quantitative measurements and to eliminate system-related variables. In addition, the tightly regulated water-cooled gantry ensures system temperature stability for consistent performance.

Quanti•QCThe process employs daily system calibration using a cylindrical 20 cm diameter, 27 cm long phantom with approximately two mCi of 68Ge and, among other steps, performs 11 automated steps to achieve normalization of the PET scanner:

1. Block Noise2. Block Efficiency3. Measured Randoms4. Scanner Efficiency5. Scatter Ratio6. Scanner Efficiency Correction Factor7. Image Plane Efficiency8. Block Timing Offset9. Block Timing Width10. Time Alignment Residual11. Time Alignment Fit (x/y)

Individual crystal efficiencies, like light output, may change within a detector block and may lead to inaccuracies in counting efficiency. The block noise check analyzes the efficiencies of each crystal within a detector block. The efficiency of each crystal is compared to the average efficiency of all crystals in the same location in all blocks. Any crystals with large deviation are flagged as defects while others are effectively compensated through calibration. This ensures consistent performance among all crystal elements within a detector block.

With multiple detector blocks within a detector ring, inconsisten-cies within individual detector blocks can increase noise and arti-facts. The block efficiency checks the efficiency of entire detector blocks against each other. Deviations >20 percent are flagged as failed; those below the threshold can effectively be calibrated to ensure a uniform image.

3D PET acquisition benefits from short coincidence windows to decrease random coincidences which may severely increase image noise. Thus the objective of every PET detector design and calibration method is to improve true count rates and eliminate randoms. The measured randoms test compares the measured amount of randoms from the phantom against the calculated number given by the singles rate squared. A variation above 3 percent is classified as a failed test. The obvious source of error is an improperly set coincidence window. Thus the measured randoms test helps ensure the proper operation of the coinci-dence detection system. The scanner efficiency, also called sensitivity, is defined as the counts per second per Becquerel per cubic centimeter (cps/Bq/cc). Sensitivity is primarily determined by the amount of LSO in the scanner and should not change over time. However, sensi-tivity may vary due to the phantom activity or volume being entered incorrectly or hardware failures leading to failure to detect true coincidence events. Measurement and calibration for optimized sensitivity can be performed only with a phantom, since a volume reference is required. The phantom activity in Bq/cc is required to calculate the sensitivity in cps/Bq/cc from the corrected cps rate. The test is passed with a deviation < 30 percent from the expected sensitivity. Utilization of a daily QC protocol based on a 68Ge phantom calibrating for system sensitivity, as well as all other parameters mentioned earlier, marks the key difference of Biograph mCT from the conventional line source-based calibration approach and defines the commitment of Siemens to reproducible quantita-tive accuracy.

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Scatter of photons is an essential component of PET acquisition and can degrade image quality and add to image noise. The scatter ratio check, which is a part of the daily calibration, also requires a phantom, since only volumes exhibit scattering. The 20 cm diameter 68Ge polyethylene phantom used for daily calibra-tion in Biograph mCT has a known scatter fraction of 32 percent on a 4-ring PET system. Based on the relationship between scatter fraction and tube drift in the PET photomultiplier tubes (PMT), the scatter test is a highly sensitive indicator of PMT drift. If the scatter test fails, a detector setup is required.

Further checking of the accuracy of calibration is performed by the scanner efficiency correction factor check which determines if the absolute image calibration has been computed correctly. Again, a volumetric phantom is required to compare the fully corrected PET image to the actual current radioactivity in the phantom. The test is passed with a deviation <30 percent from the expected value. The test is similar to the scanner efficiency test, but based on actual reconstructed images rather than the raw sinogram.

The image plane efficiency test is an additional validation to check if normalization is achieved in all image planes. In the world of 3D PET scanning, there are many more counts in the center of each ring than between the rings and at the ends of the FOV. The normalization corrects for these statistical differences by computing a plane efficiency for each axial slice in the image. If these corrections are not accurate, there would be streaks in the coronal view of a patient.

TOF acquisition involves determination of the time interval between two coincident photons and using that information to determine the origin of the coincidence photons. This tech-nique reduces background activity and improves lesion contrast significantly. The block timing offset and width test is related to TOF calibration. Since the test is performed with the 20 cm phantom in the center of the FOV, it is expected that the blocks on opposite sides of the gantry would have the majority of their emission events in the center time bin of the TOF sinogram. This phenomenon can be observed by histogramming all the emission events into the 13 time bins provided in the TOF sinogram. These histograms should also have a characteristic width based on the phantom size. Regular calibration for such TOF specific factors ensures optimal image quality since introduction of TOF adds additional variables to the PET acquisition process.

The time alignment fit and residual analyzes the consistency between the spatial and temporal dimensions of the TOF sino-gram. In order to improve image quality using TOF reconstruction methods, the information in the TOF sinogram must be consis-tent between the time and spatial domains of the sinogram.

Phantom-based daily Quanti•QC based on measurement, calibra-tion and optimization of such a wide range of parameters is key to the consistent and reproducible quantitative accuracy and image quality performance of Biograph mCT. Such a comprehen-sive calibration approach performed as a daily routine is a key differentiator of Biograph mCT from other approaches.

Registration and Attenuation Correction Methods

Correct attenuation correction (AC) of PET is of crucial impor-tance not only for optimum image quality but also for the accu-racy of measured quantitative values. In addition to relevance to oncologic imaging, PET quantification expands to parameters like myocardial blood flow relevant to PET myocardial perfusion imaging. Since CT-based attenuation correction is key for proper image generation for both whole-body PET/CT for oncology as well as PET in cardiology and neurology, any approach to improve attenuation correction also helps quantitative accuracy.

The key to correct CT attenuation correction (CT AC) is accurate coregistration of PET and CT. For whole-body PET/CT acquisition, inaccurate coregistration can be based on several factors: system-related CT and PET misregistrations may be related to patient bed deflection and misregistration due to minor patient motion between PET and CT acquisitions. Specific artifacts related to such misregistrations have been defined in the literature and are recognized by clinicians. However, the impact of such misregis-trations on quantitative accuracy have not yet been clearly delin-eated. Similar misregistrations between CT and PET in cardiac PET myocardial perfusion or reversibility studies have been more widely studied since the artifacts can often be significant and may lead to clinical interpretation errors. In the era of quantita-tive myocardial blood flow imaging with PET, improper attenua-tion correction due to CT and PET misregistration due to different breathing patterns and diaphragmatic positions during CT and PET acquisition may cause inaccurate flow values and create attenuation correction-generated perfusion abnormalities16.

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Cantilever Patient Handling System DesignBiograph mCT eliminates system-introduced misregistration by ensuring absence of any patient bed deflection between the CT and PET by a unique cantilever patient handling system (SMART PHS). Although PET/CT systems are integrated, the PET and CT scanner components are still placed in sequential order. Changes in patient position due to mechanical variations within the patient handling system need to be avoided between the PET and CT scans. Conventional designs, where the imaging pallet alone supports the patient within the CT and PET imaging field, incur various degrees of deflection, which may lead to an offset between the PET and CT acquisitions. A cantilever design where the patient handling system moves as one avoids deflec-tion, resulting in consistency between the two scans, thereby improving registration accuracy.

Auto Cardiac RegistrationMisregistration in PET/CT in cardiac imaging is common since the position of the heart and diaphragm can be vastly different during the short CT acquisition compared to the longer PET acqui-sition. Respiratory cycles can cause the left ventricle (LV) to be translated up to 22 mm17, and heart motion during the CT acqui-sition can also lead to stepping artifacts in the CT AC images18. This may cause parts of the LV in the emission image, typically in the lateral mid-apical region, to invade the lung parenchyma in the CT AC and lead to incorrect µ values. The resulting emission image will then have a decrease of counts in such areas, which may be misread as a real perfusion defect caused by cardiovas-cular disease19.

The most common correction method used in clinical practice is a manual checking and alignment after the data is acquired20, though this can be subject to inter and intra-user variability. It is also time-consuming21. A different approach is to acquire a number of fast, low-dose CT scans during free breathing, and then choose the best-aligned CT in order to perform AC22. However, it is still time-consuming to consider each CT in turn, and leads to additional imaging time and radiation dose to the patient.

An automated process of registration of PET and CT data has the potential to significantly improve quality and accuracy of cardiac PET by eliminating faulty CT AC-related artifacts and consequent quantitative inaccuracies and also by eliminating time consuming and often inaccurate manual coregistration required for correct alignment. SMART Auto Cardiac Registration, a feature on Biograph mCT, is an automatic translation algorithm to align the PET image with a single CT in order to reduce time spent manu-ally aligning datasets, improve reproducibility, and reduce dose, by only requiring one CT.

For the Auto Cardiac Registration on Biograph mCT, a translation-only registration algorithm has been implemented that uses the Mutual Information similarity function23 and a Powell optimizer24

to determine the optimal translation. Mutual Information is a popular image similarity measure for registration of multi-modality images. It is a measure of the statistical dependence between two random variables or the amount of information that one variable contains about the other. It can be qualitatively explained as a measure of how well one image explains the other.

Figure 2: Conventional vs Cantilever Patient Handling System

The conventional patient bed design (left) shows significant deflection between the CT and PET which leads to systematic misregistration between the CT and PET. The cantilever design of the SMART PHS of Biograph mCT (right) shows no deflection between the two gantries and the resulting image also shows perfect coregistration.

Conventional SMART PHS

CT PETCT PET

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Figure 3: Conventional vs Auto Cardiac Registration

Improvement in anterolateral wall uptake (arrow) following correct alignment of cardiac perfusion PET and CT prior to attenuation correction. Inferior wall attenuation correction is evident in spite of slight misalignment of CT and PET in the upper row. However, subtle decrease in anterolateral wall in the corrected image due to misalignment (upper row) is absent when the CT and PET are correctly aligned (bottom row).

Given that both PET and CT images show certain clearly discern-able similarities as in landmarks like clearly defined organs, discernable differences in uptake and Hounsfield Unit (HU) levels between various organs and surrounding tissues like heart and lungs, liver and abdomen, etc., an image intensity histogram is able to measure the amount of information available in the two images combined and the similarities between the two in order to achieve coregistration. The similarity function is modified by means of a weighting function that ensures that the algorithm focuses on the alignment of the LV, not on other structures.

The location of the LV is identified during an automated pre-processing step, where the LV is detected and cropped in the axial, coronal and sagittal dimensions of the PET non-AC dataset,

and the CT dataset is then registered to it. While the registra-tion is calculated mainly using the information inside the LV, the whole CT image volume is translated with respect to the emission image prior to reconstruction.

Auto Cardiac Registration has been validated to perform at least as well as a clinical manual registration for the purpose of AC of PET/CT when separate free breathing CT scans are acquired for both rest and stress, and for healthy and diseased patients25.

Misaligned CT and PET

Uncorrected PET

Uncorrected PET

Attenuation- Corrected PET

Attenuation- Corrected PET

PET and CT Fusion

PET and CT Fusion

Correctly aligned CT and PET

1010

The SMART Neuro AC algorithm on Biograph mCT takes advan-tage of the brain’s fairly simple and consistent geometry and tissue distribution. It approximates the mu-map for a PET only brain scan based on the ability to find the tissue/air boundary around head from a non-attenuation corrected (NAC) PET scan.

To accommodate all possible tracers in brain imaging, an adap-tive thresholding of the edge map is required, using a method of polar boundary processing. Once the perimeter of the head has been determined, bone inside the air/skin boundary is modeled

PET-only Attenuation Correction Recent focus on neurological applications of PET, including epileptic foci determination with 18F FDG as well as potential new applications like brain amyloid imaging have led to innovations in attenuation correction for PET brain acquisition. Attenuation correction approaches for PET brain without a CT is desirable due to avoidance of radiation dose as well as eliminating radiation to sensitive organs like the lens of the eye. However, such attenua-tion correction algorithms need not only maintain image quality but also ensure quantitative accuracy similar to brain PET with CT AC.

Figure 4: Conventional vs Neuro AC Attenuation Correction

Conventional CT AC

SMART Neuro AC

18F FDG brain PET following Neuro AC without CT appears identical to the same data attenuation corrected using CT. Note absence of any discernable difference in uptake patterns and intensity between the two corrected PET images.

CT mu-map

Calculated mu-map

Attenuation-Corrected PET

Attenuation-Corrected PET

1111

Figure 5: Conventional SUVmax vs SUVpeak quantification

Conventional1 Pixel (SUVmax)

Siemens syngo.via1 cm3 (SUVpeak)

Graphical representation of individual voxels with SUV involving a lung tumor after (top) and before (bottom) therapy. Pre-therapy and post-therapy SUVmax evaluation (left) shows a 17.6 percent decrease in metabolic activity, which reflects inadequate tumor response. SUVpeak calculation (right) based on an average of multiple voxels involving the region with highest uptake shows a far more significant tumor response with a 30.3 percent decrease in metabolic activity.

Since SUVmax is subject to significant statistical variation, SUVpeak promises to be more reflective of true response as well as more robust to statistical variations.

using image morphology. At 4 mm from the boundary, a 4 mm segment of bone is introduced. The assigned mu values for the three classes of mu are:

air = 0.000 cm-1 tissue = 0.093 cm-1 bone = 0.140 cm-1

Testing was performed on a total of 129 patient scans using both qualitative and quantitative methods. The patient population covers a variety of tracers3, scanner types2 and sites4. Results indicate that 60 percent of the brain pixels are below 5 percent error and almost 99 percent of brain pixels are below 10 percent error (absolute value) as defined to be the percent difference between the reconstructed PET values using the calculated mu-map vs. the values using the CT-based mu-map. The algo-rithm also demonstrated good timing performance by creating a mu-map from an uncorrected PET in about six seconds.

Quantification Software

PET Oncology Follow-up with SUVpeakCurrent practice incorporates SUVmax (the maximum value of SUV in a single voxel within a tumor ROI) as the major quantitative parameter. However, since SUVmax is essentially a single voxel ROI, it is subject to larger statistical variation compared to other SUV measurement criteria. Average SUV within a tumor ROI has been used in several studies but suffers from a lack of reproduc-ibility, since it depends on the tumor ROI, which may be subject to individual variations based on physician preferences regarding thresholding or manual margin drawings. Thus, for the majority of studies and clinical trials, SUVmax has remained the default choice in spite of its limitations. SUVmax is highly dependent on the statistical quality of the images and the voxel size depending on the acquisition matrix. The SUVmax variability increases as the lesion matrix size is increased from 128x128 to 256x256. Vari-ability increases with fewer counts as the patient size increases

1212

and the count statistics decrease5. The measured activity concentration in a small volume of a PET image depends on the activity in neighboring voxels. Activity levels in the neighboring voxels may cause a spill-in or spill-out of activity in any voxel being evaluated for SUV. This partial volume effect, combined with sensitivity to image noise, is the reason SUVmax in a single voxel within a tumor ROI is subject to inaccuracies. SUVmax will increase with a higher level of image noise, which may be due to shorter acquisition time. Lower injected dose may also contribute to higher noise due to suboptimal count statistics for a standard acquisition time.

SUVs obtained from larger, fixed ROIs are more reproducible than single pixel SUVs as is usual for calculation of SUVmax. Nahmias and Wahl et al26 studied 26 patients with 18F FDG PET in two separate occasions with a mean interval of 3+/-2 (SD) days with

comparable dose and post injection delays. SUVmax and SUVmean were determined for tumor ROI drawn on the first study and transferred onto the second study. SUVmax changes between two studies were significantly higher than SUVmean and in some cases it increased by 1.5 SUV units in which the SUVmax was above 7.5. Thus the variability in hottest tumors was higher than the ones with lower 18F FDG uptake. This calls into question the reliability of depending on SUVmax for therapy response evaluation in varie-gated tumors with fluctuating metabolic levels. SUVmean, on the other hand, was more reproducible and the variation from large ROIs did not differ more than 0.5 units. SUVpeak measurements (a fixed sphere of one cubic cm volume centered on the hottest area of the tumor) are more reproducible since they involve representing the mean value of a few voxels representing the hottest tumor area. This makes it close to SUVmax in terms of its representation of the maximum tumor metabolism, yet it could

Figure 6: Comparison of SUVmax, SUVpeak and tumor volume across three time points

SUVmax 20.73

SUVpeak 16.30

Tumor Vol 20.7 cm3

May 8, 2008

SUVmax 15.19

SUVpeak 8.81

Tumor Vol 6.22 cm3

May 20, 2008

SUVmax 9.12

SUVpeak 5.4

Tumor Vol 2.81 cm3

June 4, 2008

1313

AMMONIA N 13 INJECTION

INDICATIONS AND USAGE

Ammonia N 13 Injection 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.

IMPORTANT SAFETY INFORMATION

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.

ADVERSE REACTIONS

No adverse reactions have been reported for Ammonia N 13 Injection based on a review of the published litera-ture, publicly available reference sources, and adverse drug reaction reporting system.

avoid the statistical fluctuations of SUVmax due to incorporation of a larger number of voxels within the hottest tumor area. Velas-quez et al27 assessed the repeatability of SUVmax, SUVpeak, and SUVmean in 62 patients in a multicenter phase I oncology trial who underwent double baseline 18F FDG PET studies. The varia-tion of SUVmax between two baseline studies was much larger than the other parameters including SUVpeak and SUVmean. This suggests that values obtained from regions with multiple voxels are more statistically reproducible and dependable for clinical trials. Although SUVpeak promises to have less statistical variation, the parameters used to calculate SUVpeak, like sphere diameter, impacts the reproducibility. A recent study28 evaluated the impact of different volumes for SUVpeak estimation on the reproducibility of SUVpeak and tumor response using pre- and post-therapy 18F FLT** PET/CT studies in a series of 17 patients with various solid tumors. In this study, 24 different SUVpeaks were determined for each FLT avid tumor. There was substantial variation in both SUVpeak and percentage tumor response with changes in SUVpeak sphere diameter. SUVpeak of a lesion was calculated to be up to 49 percent higher or 46 percent lower than the mean when values obtained using 24 different sphere volumes were compared. Similar variation (from 49 percent above to 35 percent below the mean) was also seen for percentage tumor response. The study supported the recommendation of adopting a 1.2 cm diameter sphere with a volume of 1 cubic cm as a standard for SUVpeak definition for tumors larger than 2 cm in diameter.

The sequential 18F FDG PET study in Figure 6 illustrates the variation between SUVmax and SUVpeak for evaluation of therapy response. The lung mass shows decrease in 18F FDG uptake and SUVmax as well as SUVpeak. SUVmax and SUVpeak varies between 21 to 40 percent for individual acquisitions. Decline in SUVmax is less pronounced compared to SUVpeak with 56 percent vs. 66 percent, respectively. This is inherent to the SUVmax metric of the highest SUV in a VOI and could be more influenced by statistical variation.

PET Cardiac Perfusion with Myocardial Blood FlowMyocardial perfusion imaging at peak stress and at rest using PET/CT with 13N NH3 or 82Rb has been widely accepted as a reli-able method of detection of myocardial ischemia secondary to coronary artery disease29. Standard methods of evaluation based on relative perfusion where the image is normalized to the region of highest perfusion may occasionally underestimate the degree of ischemia and in some cases of balanced ischemia (secondary to triple vessel disease), miss the ischemia completely. A normal relative perfusion in patients with multivessel balanced disease is not uncommon.

Dynamic PET myocardial perfusion imaging using list mode acquisition can be used to calculate absolute myocardial blood flow (MBF) values in different myocardial segments as well as Coronary Flow Reserve (CFR) which is defined as the ratio of MBF at peak stress to that at rest. In normally perfused healthy myocardium, blood flow at peak stress is 3 to 4 times higher than that at rest. A CFR of 2.5 or higher is usually associated with absence of significant coronary artery or microvascular disease29.Unlike standard 82Rb and 13N NH3 MPI acquisitions that start around 90 seconds and three minutes post-radionuclide admin-istration respectively, dynamic list mode acquisition starts with radionuclide administration to obtain data upon radionuclide arrival in the right and left ventricle. The List Mode (LM) acquisi-tion continues for 6-8 minutes and 6-10 minutes for 82Rb and 13N NH3, respectively. Rest and stress radiopharmaceutical admin-istration consist of approximately 1110 MBq (30 mCi) 82Rb or 370-740 MBq (10-20 mCi) 13NH3. Time activity curves are gener-ated for myocardial segments as well as for a voxel in the LV for generation of the arterial input function. MBF is calculated from the time activity curves using tracer kinetic modeling based on a one tissue compartment (82Rb) or two tissue compartment (13N NH3) models.

**18F FLT is an investigational drug and is not approved for clinical use in the U.S.

1414

ConventionalRelative Perfusion

Siemens syngo.viaAbsolute Flow

Figure 7: Conventional relative perfusion vs. myocardial blood flow31

Graphical representation of perfusion imaging in patient with global ischemia (top) and in a normal patient (bottom). In conventional relative perfusion imaging, the polar plot display results are normalized to the highest activity observed. The relative perfusion pattern on the polar map in the upper left illustration would appear normal since the region with the highest perfusion itself is already ischemic. In cases of overall depressed perfusion, an adequately perfused reference section is missing, which may result in misleading information.

With myocardial blood flow, an absolute measure is available that can be compared to established normal values. In the top right illustration, the peak stress values in all segments range from 0.76 to 0.99 ml/min/g while the lower limit of normal is at around 2.0 ml/min/g. This suggests significant ischemia in all myocardial segments (balanced ischemia) which reflects uniform levels of stenosis in all coronary arteries (triple vessel disease). This helps reduce inconclusive results even in cases of balanced disease.

In comparison, a polar plot of stress myocardial perfusion in normal patients (bottom left) again shows a uniform perfusion pattern and the stress

myocardial blood flow values (bottom right) are also in the normal range with values between 2.39 and 3.11 ml/min/g29,31.

1515

The syngo® MBF software offers a simplified method of calcu-lation of MBF and CFR values for both 13N NH3 and 82Rb with automated delineation of myocardial margins and placement of the LV ROI for the arterial input function generation. MBF and CFR values of individual myocardial voxels and arterial territories as well as multiple distinct myocardial segments are depicted as numerical values as well as parametric polar plots with appro-priate scaling.

The mean +/- standard deviation (SD) of MBF and CFR in normal controls using 13N NH3 and syngo MBF is 0.86 +/-0.29 ml/g/min (rest MBF), 2.05 +/-0.73 ml/g/min (stress MBF), and 2.65 +/- 1.17 (CFR). Rubidium-82 values in normal controls also have similar stress and resting flow values29,31.

Inducible ischemia due to coronary artery disease is commonly associated with reduced MBF response to stress. A stress MBF of 1.8-2.0 ml/g/min is usually regarded as the lower limit of normal29,31. Resting flow rates have a larger normal range although flow rates below 0.40 ml/gm/min are usually associated with resting ischemia.

Figure 8: Relative perfusion compared to myocardial blood flow in case of balanced ischemia.

Reduced stress MBF response is also seen in microvascular disease such as that associated with diabetes. Thus MBF needs to be interpreted with caution in the absence of clearly defined suspicion of coronary artery disease.

Several factors affect the accuracy of MBF. These include injected dose, volume and speed of injection, patient motion and adequacy of CT attenuation correction. Since the cardiac and diaphragm positions during the fast CT may be different compared to that in the PET acquisition acquired for longer time, the potential for misregistration and artifacts related to faulty attenuation correction is significant and this may impact MBF accuracy as well. Biograph mCT incorporates automated coreg-istration for CT and PET for accurate attenuation correction of cardiac PET which improves the accuracy for CT attenuation correction and also the reliability of MBF.

1616

Several studies have established the value of MBF measurements in the evaluation of coronary artery disease as well as the charac-terization of luminal stenosis and myocardial microvasculature. A recent study30 evaluated MBF using 13N NH3 and correlated with stenosis on CT angiography. Myocardium supplied by vessels with significant stenosis showed significantly lower stress MBF (1.63 +/- 0.51 ml/g/min) compared to those with normal coronary arteries (2.13 +/ 0.54 ml/g/min).

The clinical example depicted in Figure 8 illustrates the value of MBF in diagnosis of balanced ischemia related to triple vessel disease in a patient with suspected coronary artery disease where visual interpretation of relative perfusion did not clearly demon-strate any segmental ischemia.

Figure 8 shows a 13N NH3 myocardial perfusion PET•CT of a 65-year-old woman with progressive dyspnea and signs of heart failure. The stress rest PET images do not show well-defined hypo-perfused areas. However, the MBF values show grossly decreased MBF throughout the entire LV at peak stress with normal MBF at rest, suggestive of balanced ischemia probably related to triple vessel disease. Anterior wall MBF at peak stress is 0.92 ml/g/min (lower limit of normal 2 ml/g/min) while resting MBF is 0.75 ml/g/min which is within normal limits.

ConclusionWhen evaluating the factors influencing the accuracy and repro-ducibility of quantitative results on PET, it becomes obvious that all elements in the imaging workflow need to be controlled and optimized in order to avoid variations across devices, patients and time as postulated by the RSNA Quantitative Imaging Biomarkers Alliance (QIBA).

Biograph mCT together with syngo.via quantification software*** helps minimize system-based sources of variation by effectively reducing manual interaction and automating steps, such as quality control and image quantification.

Now, for the first time, Biograph mCT gives you quantifiable results that are accurate and reproducible over time, along with high count rate efficiency and superior resolution. With its unique combination of intelligent software, daily calibration and precise anatomical and functional co-registration, Biograph mCT makes a quantifiable difference in diagnostic confidence, therapy planning and treatment monitoring.

References

1 Duhaylongsod, FG et al. (1995 Jul). Detection of primary and recurrent lung cancer by means of F-18 fluorodeoxyglucose positron emission tomography (FDG PET). J Thorac Cardiovasc Surg, 110 (1), 130-139.

2 Weber, WA et al. (2001 June 15). Prediction of response to preoperative chemotherapy in adenocarcinomas of the esophagogastric junction by metabolic imaging. J Clin Oncol, 19 (12), 3058-3065.

3 Lin, C et al. (2007 Oct). Early 18F-FDG PET for prediction of prognosis in patients with diffuse large B-cell lymphoma: SUV-based assessment versus visual analysis. J Nucl Med, 48 (10), 1626-1632.

4 Avril, N et al. (2005 Oct 20). Prediction of response to neoad-juvant chemotherapy by sequential F-18-fluorodeoxyglucose positron emission tomography in patients with advanced-stage ovarian cancer. J Clin Oncol, 23 (30), 7445-7453.

5 Wahl, RL et al. (2009 May). From RECIST to PERCIST: Evolving Considerations for PET response criteria in solid tumors. J Nucl Med, 50 Suppl 1, 122S-150S.

6 Young, H et al. (1999 Dec). Measurement of clinical and subclinical tumor response using 18F fluorodeoxyglucose and positron emission tomography: review and 1999 EORTC recommendations. Eur J Cancer, 35, 1773-1782.

7 Zasadny, KR et al. (1993 Dec). Standardized uptake values of normal tissues at PET with 2-[flourine-18]-fluoro-2-deoxy- D-glucose: variations with body weight and a method for correction. Radiology, 189 (3), 847-850.

8 Hamberg, LM et al. (1994 Aug). The dose uptake ratio as an index of glucose metabolism: useful parameter or over-simplification? J Nucl Med, 35 (8), 1308-1312.

9 MacDonald, K et al. (2011 Mar). The role of dual time point FDG PET imaging in the evaluation of solitary pulmonary nodules with an initial standard uptake value less than 2.5. Clin Radiol, 66 (3), 244-250.

10 Boellaard, R et al. (2010 Jan). FDG PET and PET/CT: EANM procedure guidelines for tumor PET imaging: version 1.0. Eur J Nucl Med Mol Imaging, 37, 181-200.

11 Lindholm, P et al. (1993 Jan). Influence of the blood glucose concentration on FDG uptake in cancer—a PET study. J Nucl Med, 34 (1), 1-6.

*** syngo.PET MBF is not yet commercially available in the U.S.

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12 Hoffman, EJ et al. (1979 June). Quantitation in positron emission computed tomography: 1. Effect of object size. J Comut Assist Tomogr, 3 (3), 299-308.

13 Boellaard, R et al. (2008 Dec). The Netherlands protocol for standardization and quantification of FDG whole body PET studies in multi-centre trials. Eur J Nucl Med Mol Imaging, 35 (12), 2320-2333.

14 Boellaard, R et al. (2004 Sep). Effects of noise, image reso-lution, and ROI definition on the accuracy of standard uptake values: a simulation study. J Nucl Med, 45 (9), 1519-1527.

15 Lockhart, C. M. et al. (2011 Feb). Quantifying and reducing the effect of calibration error on variability of PET/CT standard-ized uptake value measurements, J Nuc Med, Vol. 52, No. 2.

16 Moller et al. (2007) Artifacts form misaligned CT in cardiac perfusion PET/CT studies: Frequency, effects and potential solutions. J Nucl Med, 48, 188-193.

17 Goetze, S et al. (2007). Attenuation Correction in Myocardial Perfusion SPECT/CT: Effects of Misregistration and Value of Reregistration. J Nucl Med, 48, 1090-1095.

18 Hamill, J et al. (2008). Real-Time MRI for Assessment of PET/CT Attenuation Correction Protocols. IEEE Nuclear Science Symposium Conference Record, 3761-3768.

19 Gould, K et al. (2007). Frequent Diagnostic Errors in Cardiac PET/CT Due to Misregistration of CT Attenuation and Emission PET Images: A Definitive Analysis of Causes, Consequences, and Corrections. J Nucl Med, 48, 1112-1121.

20 Goetze, S et al. (2007). Attenuation Correction in Myocardial Perfusion SPECT/CT: Effects of Misregistration and Value of Reregistration. J Nucl Med, 48, 1090-1095.

21 Martinez-Moller, A et al. (2007). Artifacts from Misaligned CT in Cardiac Perfusion PET/CT Studies: Frequency, Effects and Potential Solutions. J Nucl Med, 48, 188-193.

22 Streeter, J et al. (2007). Attenuation correction of stress PET 82Rb with ultrafast CT images. J Nucl Med, 48, 446P.

23 Viola P, et al. (1997). Alignment by Maximization of Mutual Information. Intl J Computer Vision, 24, 137-154.

24 Press, WH et al. (1992). Numerical recipes in C (2nd ed.). University Press, Cambridge, England.

25 Bond, S et al. (TO COME) Automatic Registration of Emission and Transmission Images in Cardiac PET/CT and Cardiac SPECT/CT.

26 Nahmias, C et al. (2008 Nov). Reproducibility of standard-ized uptake value measurements determined by 18F FDG PET in malignant tumors. J Nucl Med, 49 (11), 1804-1808.

27 Velasquez, LM et al. (2009 Oct). Repeatability of 18F FDG PET in a multi-centre phase I study of patients with advanced gastrointestinal malignancies. J Nucl Med, 50 (10), 1646-1654.

28 Vanderhoek, M et al. (2012 Jan). Impact of the definition of peak standardized uptake value on quantification of treatment response. J Nuc Med, 53, 4-11.

29 Paolo, G et al. (2009). The Clinical Value of Myocardial Blood Flow Measurement. J Nucl Med, 50, 1076-1087.

30 Liga, R et al. (2011 Nov). Structural Abnormalities of the Coronary Arterial Wall—in Addition to Luminal Narrowing— Affect Myocardial Blood Flow Reserve. J Nucl Med, 52 (11), 1704-1712.

31 Hutchins, GD et al. (1990). Noninvasive quantification of regional blood flow in the human heart using 13N ammonia and dynamic positron emission tomographic imaging. J Amer Coll Cardio, 5, 1032-1042.

1818

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use Fludeoxyglucose F 18 Injection safely and effectively. See full prescribing information for Fludeoxyglucose F 18 Injection.

Fludeoxyglucose F 18 Injection, USPFor intravenous use Initial U.S. Approval: 2005

----------------------RECENT MAJOR CHANGES---------------------Warnings and Precautions (5.1, 5.2) 7/2010Adverse Reactions (6) 7/2010

----------------------INDICATIONS AND USAGE---------------------Fludeoxyglucose F18 Injection is indicated for positron emission tomography (PET) imaging in the following settings:• Oncology: For assessment of abnormal glucose metabolism to

assist in the evaluation of malignancy in patients with known or suspected abnormalities found by other testing modalities, or in patients with an existing diagnosis of cancer.

• Cardiology: For the identification of left ventricular myocar-dium with residual glucose metabolism and reversible loss of systolic function in patients with coronary artery disease and left ventricular dysfunction, when used together with myocardial perfusion imaging.

• Neurology: For the identification of regions of abnormal glucose metabolism associated with foci of epileptic seizures (1).

-----------------DOSAGE AND ADMINISTRATION-----------------Fludeoxyglucose F18 Injection emits radiation. Use procedures to minimize radiation exposure. Screen for blood glucose abnormalities.• In the oncology and neurology settings, instruct patients to fast

for 4 to 6 hours prior to the drug’s injection. Consider medical therapy and laboratory testing to assure at least two days of normoglycemia prior to the drug’s administration (5.2).

• In the cardiology setting, administration of glucose-containing food or liquids (e.g., 50 to 75 grams) prior to the drug’s injec-tion facilitates localization of cardiac ischemia (2.3).

Aseptically withdraw Fludeoxyglucose F18 Injection from its container and administer by intravenous injection (2).The recommended dose:• for adults is 5 to 10 mCi (185 to 370 MBq), in all indicated

clinical settings (2.1).• for pediatric patients is 2.6 mCi in the neurology setting (2.2).Initiate imaging within 40 minutes following drug injection; acquire static emission images 30 to 100 minutes from time of injection (2).

----------------DOSAGE FORMS AND STRENGTHS----------------Multi-dose 30mL and 50mL glass vial containing 0.74 to 7.40 GBq/mL (20 to 200 mCi/mL) Fludeoxyglucose F18 Injection and 4.5mg of sodium chloride with 0.1 to 0.5% w/w ethanol as a stabilizer (approximately 15 to 50 mL volume) for intravenous administration (3).

------------------------CONTRAINDICATIONS------------------------None

-------------------WARNINGS AND PRECAUTIONS------------------• Radiation risks: use smallest dose necessary for imaging (5.1).• Blood glucose abnormalities: may cause suboptimal imaging (5.2).

----------------------ADVERSE REACTIONS----------------------Hypersensitivity reactions have occurred; have emergency resus-citation equipment and personnel immediately available (6).To report SUSPECTED ADVERSE REACTIONS, contact PETNET Solutions, Inc. at 877-473-8638 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

------------------USE IN SPECIFIC POPULATIONS------------------• Pregnancy Category C: No human or animal data. Consider

alternative diagnostics; use only if clearly needed (8.1).• Nursing mothers: Use alternatives to breast feeding (e.g., stored

breast milk or infant formula) for at least 10 half-lives of radio-active decay, if Fludeoxyglucose F 18 Injection is administered to a woman who is breast-feeding (8.3).

• Pediatric Use: Safety and effectiveness in pediatric patients have not been established in the oncology and cardiology settings (8.4).

See 17 for PATIENT COUNSELING INFORMATION

Revised: 1/2011

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1 INDICATIONS AND USAGE 1.1 Oncology 1.2 Cardiology 1.3 Neurology

2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dose for Adults 2.2 Recommended Dose for Pediatric Patients 2.3 Patient Preparation 2.4 Radiation Dosimetry 2.5 Radiation Safety – Drug Handling 2.6 Drug Preparation and Administration 2.7 Imaging Guidelines

3 DOSAGE FORMS AND STRENGTHS4 CONTRAINDICATIONS5 WARNINGS AND PRECAUTIONS

5.1 Radiation Risks 5.2 Blood Glucose Abnormalities

6 ADVERSE REACTIONS7 DRUG INTERACTIONS

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use

11 DESCRIPTION 11.1 Chemical Characteristics 11.2 Physical Characteristics

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES 14.1 Oncology 14.2 Cardiology 14.3 Neurology

15 REFERENCES16 HOW SUPPLIED/STORAGE AND DRUG HANDLING17 PATIENT COUNSELING INFORMATION

* Sections or subsections omitted from the full prescribing information are not listed.

FULL PRESCRIBING INFORMATION: CONTENTS*

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGEFludeoxyglucose F18 Injection is indicated for positron emission tomography (PET) imaging in the following settings:

1.1 Oncology

For assessment of abnormal glucose metabolism to assist in the evaluation of malignancy in patients with known or suspected abnormalities found by other testing modalities, or in patients with an existing diagnosis of cancer.

1.2 Cardiology

For the identification of left ventricular myocardium with residual glucose metabolism and reversible loss of systolic function in patients with coronary artery disease and left ventricular dysfunction, when used together with myocar-dial perfusion imaging.

1.3 Neurology

For the identification of regions of abnormal glucose metabolism associated with foci of epileptic seizures.

2 DOSAGE AND ADMINISTRATIONFludeoxyglucose F18 Injection emits radiation. Use proce-dures to minimize radiation exposure. Calculate the final dose from the end of synthesis (EOS) time using proper radioactive decay factors. Assay the final dose in a prop-erly calibrated dose calibrator before administration to the patient [see Description (11.2)].

2.1 Recommended Dose for AdultsWithin the oncology, cardiology and neurology settings, the recommended dose for adults is 5 to 10 mCi (185 to 370 MBq) as an intravenous injection.

2.2 Recommended Dose for Pediatric PatientsWithin the neurology setting, the recommended dose for pediatric patients is 2.6 mCi, as an intravenous injection. The optimal dose adjustment on the basis of body size or weight has not been determined [see Use in Special Popula-tions (8.4)].

2.3 Patient Preparation

• To minimize the radiation absorbed dose to the bladder, encourage adequate hydration. Encourage the patient to drink water or other fluids (as tolerated) in the 4 hours before their PET study.

• Encourage the patient to void as soon as the imaging study is completed and as often as possible thereafter for at least one hour.

• Screen patients for clinically significant blood glucose abnormalities by obtaining a history and/or laboratory tests [see Warnings and Precautions (5.2)]. Prior to Fludeoxyglucose F 18 PET imaging in the oncology and neurology settings, instruct patient to fast for 4 to 6 hours prior to the drug’s injection.

• In the cardiology setting, administration of glucose-containing food or liquids (e.g., 50 to 75 grams) prior to Fludeoxyglucose F 18 Injection facilitates localization of cardiac ischemia

2020

Table 1. Estimated Absorbed Radiation Doses (rem/mCi) After Intravenous Administration of Fludeoxyglucose F 18 Injectiona

OrganNewborn(3.4 kg)

1-year old(9.8 kg)

5-year old(19 kg)

10-year old(32 kg)

15-year old(57 kg)

Adult(70 kg)

Bladder wallb 4.3 1.7 0.93 0.60 0.40 0.32

Heart wall 2.4 1.2 0.70 0.44 0.29 0.22

Pancreas 2.2 0.68 0.33 0.25 0.13 0.096

Spleen 2.2 0.84 0.46 0.29 0.19 0.14

Lungs 0.96 0.38 0.20 0.13 0.092 0.064

Kidneys 0.81 0.34 0.19 0.13 0.089 0.074

Ovaries 0.80 0.8 0.19 0.11 0.058 0.053

Uterus 0.79 0.35 0.19 0.12 0.076 0.062

LLI wall* 0.69 0.28 0.15 0.097 0.060 0.051

Liver 0.69 0.31 0.17 0.11 0.076 0.058

Gallbladder wall 0.69 0.26 0.14 0.093 0.059 0.049

Small intestine 0.68 0.29 0.15 0.096 0.060 0.047

ULI wall** 0.67 0.27 0.15 0.090 0.057 0.046

Stomach wall 0.65 0.27 0.14 0.089 0.057 0.047

Adrenals 0.65 0.28 0.15 0.095 0.061 0.048

Testes 0.64 0.27 0.14 0.085 0.052 0.041

Red marrow 0.62 0.26 0.14 0.089 0.057 0.047

Thymus 0.61 0.26 0.14 0.086 0.056 0.044

Thyroid 0.61 0.26 0.13 0.080 0.049 0.039

Muscle 0.58 0.25 0.13 0.078 0.049 0.039

Bone surface 0.57 0.24 0.12 0.079 0.052 0.041

Breast 0.54 0.22 0.11 0.068 0.043 0.034

Skin 0.49 0.20 0.10 0.060 0.037 0.030

Brain 0.29 0.13 0.09 0.078 0.072 0.070

Other tissues 0.59 0.25 0.13 0.083 0.052 0.042

a MIRDOSE 2 software was used to calculate the radiation absorbed dose. Assumptions on the biodistribution based on data from Gallagher et al.1 and

Jones et al.2

b The dynamic bladder model with a uniform voiding frequency of 1.5 hours was used. *LLI = lower large intestine; **ULI = upper large intestine

2.4 Radiation DosimetryThe estimated human absorbed radiation doses (rem/mCi) to a newborn (3.4 kg), 1-year old (9.8 kg), 5-year old (19 kg), 10-year old (32 kg), 15-year old (57 kg), and adult (70 kg) from intravenous administration of Fludeoxyglucose F 18 Injection are shown in Table 1. These estimates were calculated based on human2 data and using the data published by the International Commission on Radiological Protection4 for Fludeoxyglucose 18F. The dosimetry data

show that there are slight variations in absorbed radiation dose for various organs in each of the age groups. These dissimilarities in absorbed radiation dose are due to devel-opmental age variations (e.g., organ size, location, and overall metabolic rate for each age group). The identified critical organs (in descending order) across all age groups evaluated are the urinary bladder, heart, pancreas, spleen, and lungs.

2121

2.5 Radiation Safety – Drug Handling• Use waterproof gloves, effective radiation shielding,

and appropriate safety measures when handling Flude-oxyglucose F18 Injection 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 radio-nuclides, and whose experience and training have been approved by the appropriate governmental agency autho-rized to license the use of radionuclides.

• Calculate the final dose from the end of synthesis (EOS) time using proper radioactive decay factors. Assay the final dose in a properly calibrated dose calibrator before administration to the patient [see Description (11.2)].

• The dose of Fludeoxyglucose F18 used in a given patient should be minimized consistent with the objectives of the procedure, and the nature of the radiation detection devices employed.

2.6 Drug Preparation and Administration

• Calculate the necessary volume to administer based on calibration time and dose.

• Aseptically withdraw Fludeoxyglucose F18 Injection from its container.

• Inspect Fludeoxyglucose F18 Injection visually for particu-late matter and discoloration before administration, whenever solution and container permit.

• Do not administer the drug if it contains particulate matter or discoloration; dispose of these unacceptable or unused preparations in a safe manner, in compliance with appli-cable regulations.

• Use Fludeoxyglucose F 18 Injection within 12 hours from the EOS.

2.7 Imaging Guidelines

• Initiate imaging within 40 minutes following Fludeoxyglu-cose F 18 Injection administration.

• Acquire static emission images 30 to 100 minutes from the time of injection.

3 DOSAGE FORMS AND STRENGTHSMultiple-dose 30mL and 50mL glass vial containing 0.74 to 7.40 GBq/mL (20 to 200 mCi/mL) of Fludeoxyglucose F 18 Injection and 4.5 mg of sodium chloride with 0.1 to 0.5% w/w ethanol as a stabilizer (approximately 15 to 50 mL volume) for intravenous administration.

4 CONTRAINDICATIONSNone

5 WARNINGS AND PRECAUTIONS

5.1 Radiation RisksRadiation-emitting products, including Fludeoxyglucose F 18 Injection, may increase the risk for cancer, especially in pediatric patients. Use the smallest dose necessary for imaging and ensure safe handling to protect the patient and health care worker [see Dosage and Administration (2.5)].

5.2 Blood Glucose AbnormalitiesIn the oncology and neurology setting, suboptimal imaging may occur in patients with inadequately regulated blood glucose levels. In these patients, consider medical therapy and laboratory testing to assure at least two days of normo-glycemia prior to Fludeoxyglucose F 18 Injection adminis-tration.

6 ADVERSE REACTIONSHypersensitivity reactions with pruritus, edema and rash have been reported in the post-marketing setting. Have emergency resuscitation equipment and personnel imme-diately available.

7 DRUG INTERACTIONSThe possibility of interactions of Fludeoxyglucose F 18 Injection with other drugs taken by patients undergoing PET imaging has not been studied.

8 USE IN SPECIFIC POPULATIONS

8.1 PregnancyPregnancy Category CAnimal reproduction studies have not been conducted with Fludeoxyglucose F 18 Injection. It is also not known whether Fludeoxyglucose F 18 Injection can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Consider alternative diag-nostic tests in a pregnant woman; administer Fludeoxyglu-cose F 18 Injection only if clearly needed.

8.3 Nursing Mothers

It is not known whether Fludeoxyglucose F 18 Injection is excreted in human milk. Consider alternative diagnostic tests in women who are breast-feeding. Use alternatives to breast feeding (e.g., stored breast milk or infant formula) for at least 10 half-lives of radioactive decay, if Fludeoxy-glucose F 18 Injection is administered to a woman who is breast-feeding.

8.4 Pediatric Use

The safety and effectiveness of Fludeoxyglucose F 18 Injec-tion in pediatric patients with epilepsy is established on the basis of studies in adult and pediatric patients. In pediatric patients with epilepsy, the recommended dose is 2.6 mCi. The optimal dose adjustment on the basis of body size or weight has not been determined. In the oncology or cardi-ology settings, the safety and effectiveness of Fludeoxyglu-cose F 18 Injection have not been established in pediatric patients.

2222

11 DESCRIPTION

11.1 Chemical CharacteristicsFludeoxyglucose F 18 Injection is a positron emitting radiopharmaceutical that is used for diagnostic purposes in conjunction with positron emission tomography (PET) imaging. The active ingredient 2-deoxy-2-[18F]fluoro-D-glucose has the molecular formula of C6H1118FO5 with a molecular weight of 181.26, and has the following chemical structure:

Fludeoxyglucose F 18 Injection is provided as a ready to use sterile, pyrogen free, clear, colorless solution. Each mL contains between 0.740 to 7.40GBq (20.0 to 200 mCi) of 2-deoxy-2-[18F]fluoro-D-glucose at the EOS, 4.5 mg of sodium chloride and 0.1 to 0.5% w/w ethanol as a stabilizer. The pH of the solution is between 4.5 and 7.5. The solu-tion is packaged in a multiple-dose glass vial and does not contain any preservative.

11.2 Physical Characteristics

Fluorine F 18 decays by emitting positron to Oxygen O 16 (stable) and has a physical half-life of 109.7 minutes. The principal photons useful for imaging are the dual 511 keV gamma photons, that are produced and emitted simultane-ously in opposite direction when the positron interacts with an electron (Table 2).

Table 2. Principal Radiation Emission Data for Fluorine F 18

Radiation/Emission % Per Disintegration Mean Energy

Positron(ß+) 96.73 249.8 keV

Gamma(±)* 193.46 511.0 keV

* Produced by positron annihilation From: Kocher, D.C. Radioactive Decay Tables DOE/TIC-I 1026, 89 (1981)

The specific gamma ray constant (point source air kerma coefficient) for fluorine F 18 is 5.7 R/hr/mCi (1.35 x 10-6 Gy/hr/kBq) at 1 cm. The half-value layer (HVL) for the 511 keV photons is 4 mm lead (Pb). The range of attenuation coefficients for this radionuclide as a function of lead shield thickness is shown in Table 3. For example, the interposition of an 8 mm thickness of Pb, with a coef-ficient of attenuation of 0.25, will decrease the external radiation by 75 percent.

Table 3. Radiation Attenuation of 511 keV Photons by lead (Pb) shielding

Shield thickness (Pb) mm

Coefficient of attenuation

0 0.00

4 0.50

8 0.25

13 0.10

26 0.01

39 0.001

52 0.0001

For use in correcting for physical decay of this radionuclide, the fractions remaining at selected intervals after calibra-tion are shown in Table 4.

Table 4. Physical Decay Chart for Fluorine F 18

Minutes Fraction Remaining

0* 1.000

15 0.909

30 0.826

60 0.683

110 0.500

220 0.250

*calibration time

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of ActionFludeoxyglucose F 18 is a glucose analog that concentrates in cells that rely upon glucose as an energy source, or in cells whose dependence on glucose increases under patho-physiological conditions. Fludeoxyglucose F 18 is trans-ported through the cell membrane by facilitative glucose transporter proteins and is phosphorylated within the cell to [18F] FDG-6-phosphate by the enzyme hexokinase. Once phosphorylated it cannot exit until it is dephosphorylated by glucose-6-phosphatase. Therefore, within a given tissue or pathophysiological process, the retention and clearance of Fludeoxyglucose F 18 reflect a balance involving glucose transporter, hexokinase and glucose-6-phosphatase activi-ties. When allowance is made for the kinetic differences between glucose and Fludeoxyglucose F 18 transport and phosphorylation (expressed as the “lumped constant” ratio), Fludeoxyglucose F 18 is used to assess glucose metabolism.

In comparison to background activity of the specific organ or tissue type, regions of decreased or absent uptake of Fludeoxyglucose F 18 reflect the decrease or absence of glucose metabolism. Regions of increased uptake of Flude-oxyglucose F 18 reflect greater than normal rates of glucose metabolism.

2323

12.2 PharmacodynamicsFludeoxyglucose F 18 Injection is rapidly distributed to all organs of the body after intravenous administration. After background clearance of Fludeoxyglucose F 18 Injection, optimal PET imaging is generally achieved between 30 to 40 minutes after administration.

In cancer, the cells are generally characterized by enhanced glucose metabolism partially due to (1) an increase in activity of glucose transporters, (2) an increased rate of phosphoryla-tion activity, (3) a reduction of phosphatase activity or, (4) a dynamic alteration in the balance among all these processes. However, glucose metabolism of cancer as reflected by Fludeoxyglucose F 18 accumulation shows considerable variability. Depending on tumor type, stage, and location, Fludeoxyglucose F 18 accumulation may be increased, normal, or decreased. Also, inflammatory cells can have the same variability of uptake of Fludeoxyglucose F 18.

In the heart, under normal aerobic conditions, the myocar-dium meets the bulk of its energy requirements by oxidizing free fatty acids. Most of the exogenous glucose taken up by the myocyte is converted into glycogen. However, under ischemic conditions, the oxidation of free fatty acids decreases, exogenous glucose becomes the preferred myocardial substrate, glycolysis is stimulated, and glucose taken up by the myocyte is metabolized immediately instead of being converted into glycogen. Under these conditions, phosphorylated Fludeoxyglucose F 18 accumulates in the myocyte and can be detected with PET imaging.

In the brain, cells normally rely on aerobic metabolism. In epilepsy, the glucose metabolism varies. Generally, during a seizure, glucose metabolism increases. Interictally, the seizure focus tends to be hypometabolic.

12.3 PharmacokineticsDistribution: In four healthy male volunteers, receiving an intravenous administration of 30 seconds in duration, the arterial blood level profile for Fludeoxyglucose F 18 decayed triexponentially. The effective half-life ranges of the three phases were 0.2 to 0.3 minutes, 10 to 13 minutes with a mean and standard deviation (STD) of 11.6 (±) 1.1 min, and 80 to 95 minutes with a mean and STD of 88 (±) 4 min.

Plasma protein binding of Fludeoxyglucose F 18 has not been studied.

Metabolism: Fludeoxyglucose F 18 is transported into cells and phosphorylated to [18F]FDG-6- phosphate at a rate proportional to the rate of glucose utilization within that tissue. [F 18]-FDG-6-phosphate presumably is metabolized to 2-deoxy-2-[F 18]fluoro-6-phospho-D-mannose([F 18]FDM-6-phosphate).

Fludeoxyglucose F 18 Injection may contain several impuri-ties (e.g., 2-deoxy-2-chloro-D-glucose (ClDG)). Biodistribu-tion and metabolism of ClDG are presumed to be similar

to Fludeoxyglucose F 18 and would be expected to result in intracellular formation of 2-deoxy-2-chloro-6-phospho-D-glucose (ClDG-6-phosphate) and 2-deoxy-2-chloro-6phospho-D-mannose (ClDM-6-phosphate). The phos-phorylated deoxyglucose compounds are dephosphorylated and the resulting compounds (FDG, FDM, ClDG, and ClDM) presumably leave cells by passive diffusion. Fludeoxyglu-cose F 18 and related compounds are cleared from non-cardiac tissues within 3 to 24 hours after administration. Clearance from the cardiac tissue may require more than 96 hours. Fludeoxyglucose F 18 that is not involved in glucose metabolism in any tissue is then excreted in the urine.

Elimination: Fludeoxyglucose F 18 is cleared from most tissues within 24 hours and can be eliminated from the body unchanged in the urine. Three elimination phases have been identified in the reviewed literature. Within 33 minutes, a mean of 3.9% of the administrated radioactive dose was measured in the urine. The amount of radiation exposure of the urinary bladder at two hours post-adminis-tration suggests that 20.6% (mean) of the radioactive dose was present in the bladder.

Special Populations: The pharmacokinetics of Fludeoxy-glucose F 18 Injection have not been studied in renally-impaired, hepatically impaired or pediatric patients. Flude-oxyglucose F 18 is eliminated through the renal system. Avoid excessive radiation exposure to this organ system and adjacent tissues.

The effects of fasting, varying blood sugar levels, condi-tions of glucose intolerance, and diabetes mellitus on Fludeoxyglucose F 18 distribution in humans have not been ascertained [see Warnings and Precautions (5.2)].

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of FertilityAnimal studies have not been performed to evaluate the Fludeoxyglucose F 18 Injection carcinogenic potential, mutagenic potential or effects on fertility.

14 CLINICAL STUDIES

14.1 OncologyThe efficacy of Fludeoxyglucose F 18 Injection in positron emission tomography cancer imaging was demonstrated in 16 independent studies. These studies prospectively evaluated the use of Fludeoxyglucose F 18 in patients with suspected or known malignancies, including non-small cell lung cancer, colo-rectal, pancreatic, breast, thyroid, melanoma, Hodgkin’s and non-Hodgkin’s lymphoma, and various types of metastatic cancers to lung, liver, bone, and axillary nodes. All these studies had at least 50 patients and used pathology as a standard of truth. The Fludeoxyglucose F 18 Injection doses in the studies ranged from 200 MBq to 740 MBq with a median and mean dose of 370 MBq.

2424

In the studies, the diagnostic performance of Fludeoxyglu-cose F 18 Injection varied with the type of cancer, size of cancer, and other clinical conditions. False negative and false positive scans were observed. Negative Fludeoxyglu-cose F 18 Injection PET scans do not exclude the diagnosis of cancer. Positive Fludeoxyglucose F 18 Injection PET scans can not replace pathology to establish a diagnosis of cancer. Non-malignant conditions such as fungal infections, inflammatory processes and benign tumors have patterns of increased glucose metabolism that may give rise to false-positive scans. The efficacy of Fludeoxyglucose F 18 Injection PET imaging in cancer screening was not studied.

14.2 CardiologyThe efficacy of Fludeoxyglucose F 18 Injection for cardiac use was demonstrated in ten independent, prospective studies of patients with coronary artery disease and chronic left ventricular systolic dysfunction who were scheduled to undergo coronary revascularization. Before revasculariza-tion, patients underwent PET imaging with Fludeoxyglucose F 18 Injection (74 to 370 MBq, 2 to 10 mCi) and perfusion imaging with other diagnostic radiopharmaceuticals. Doses of Fludeoxyglucose F 18 Injection ranged from 74 to 370 MBq (2 to 10 mCi). Segmental, left ventricular, wall-motion assessments of asynergic areas made before revasculariza-tion were compared in a blinded manner to assessments made after successful revascularization to identify myocar-dial segments with functional recovery.

Left ventricular myocardial segments were predicted to have reversible loss of systolic function if they showed Fludeoxyglucose F 18 accumulation and reduced perfusion (i.e., flow-metabolism mismatch). Conversely, myocardial segments were predicted to have irreversible loss of systolic function if they showed reductions in both Fludeoxyglucose F 18 accumulation and perfusion (i.e., matched defects).

Findings of flow-metabolism mismatch in a myocardial segment may suggest that successful revascularization will restore myocardial function in that segment. However, false-positive tests occur regularly, and the decision to have a patient undergo revascularization should not be based on PET findings alone. Similarly, findings of a matched defect in a myocardial segment may suggest that myocar-dial function will not recover in that segment, even if it is successfully revascularized. However, false-negative tests occur regularly, and the decision to recommend against coronary revascularization, or to recommend a cardiac transplant, should not be based on PET findings alone. The reversibility of segmental dysfunction as predicted with Fludeoxyglucose F 18 PET imaging depends on successful coronary revascularization. Therefore, in patients with a low likelihood of successful revascularization, the diag-nostic usefulness of PET imaging with Fludeoxyglucose F 18 Injection is more limited.

14.3 NeurologyIn a prospective, open label trial, Fludeoxyglucose F 18 Injection was evaluated in 86 patients with epilepsy. Each patient received a dose of Fludeoxyglucose F 18 Injec-tion in the range of 185 to 370 MBq (5 to 10 mCi). The mean age was 16.4 years (range: 4 months to 58 years; of these, 42 patients were less than 12 years and 16 patients were less than 2 years old). Patients had a known diagnosis of complex partial epilepsy and were under evaluation for surgical treatment of their seizure disorder. Seizure foci had been previously identified on ictal EEGs and sphenoidal EEGs. Fludeoxyglucose F 18 Injection PET imaging confirmed previous diagnostic findings in 16% (14/87) of the patients; in 34% (30/87) of the patients, Fludeoxyglucose F 18 Injection PET images provided new findings. In 32% (27/87), imaging with Fludeoxyglucose F 18 Injection was inconclusive. The impact of these imaging findings on clinical outcomes is not known.

Several other studies comparing imaging with Flude-oxyglucose F 18 Injection results to subsphenoidal EEG, MRI and/or surgical findings supported the concept that the degree of hypometabolism corresponds to areas of confirmed epileptogenic foci. The safety and effectiveness of Fludeoxyglucose F 18 Injection to distinguish idiopathic epileptogenic foci from tumors or other brain lesions that may cause seizures have not been established.

15 REFERENCES

1. Gallagher B.M., Ansari A., Atkins H., Casella V., Christman D.R., Fowler J.S., Ido T., MacGregor R.R., Som P., Wan C.N., Wolf A.P., Kuhl D.E., and Reivich M. “Radiopharmaceuticals XXVII. 18F-labeled 2-deoxy-2-fluoro-d-glucose as a radiopharmaceutical for measuring regional myocardial glucose metabolism in vivo: tissue distribution and imaging studies in animals,” J Nucl Med, 1977; 18, 990-6.

2. Jones S.C., Alavi, A., Christman D., Montanez, I., Wolf, A.P., and Reivich M. “The radiation dosimetry of 2 [F-18] fluoro-2-deoxy-D-glucose in man,” J Nucl Med, 1982; 23, 613-617.

3. Kocher, D.C. “Radioactive Decay Tables: A handbook of decay data for application to radiation dosimetry and radiological assessments,” 1981, DOE/TIC-I 1026, 89.

4. ICRP Publication 53, Volume 18, No. l-4,1987, pages 75-76.

2525

16 HOW SUPPLIED/STORAGE AND DRUG HANDLING

Fludeoxyglucose F 18 Injection is supplied in a multi-dose, capped 30 mL and 50 mL glass vial containing between 0.740 to 7.40GBq/mL (20 to 200 mCi/mL), of no carrier added 2deoxy-2-[F 18] fluoro-D-glucose, at end of synthesis, in approximately 15 to 50 mL. The contents of each vial are sterile, pyrogen-free and preservative-free.

NDC 40028-511-30; 40028-511-50

Receipt, transfer, handling, possession, or use of this product is subject to the radioactive material regulations and licensing requirements of the U.S. Nuclear Regula-tory Commission, Agreement States or Licensing States as appropriate.

Store the Fludeoxyglucose F 18 Injection vial upright in a lead shielded container at 25°C (77°F); excursions permitted to 15-30°C (59-86°F).

Store and dispose of Fludeoxyglucose F 18 Injection in accordance with the regulations and a general license, or its equivalent, of an Agreement State or a Licensing State.

The expiration date and time are provided on the container label. Use Fludeoxyglucose F 18 Injection within 12 hours from the EOS time.

17 PATIENT COUNSELING INFORMATION

Instruct patients in procedures that increase renal clearance of radioactivity. Encourage patients to:• drink water or other fluids (as tolerated) in the 4 hours

before their PET study.• void as soon as the imaging study is completed and as

often as possible thereafter for at least one hour.

Manufactured by: PETNET Solutions Inc. 810 Innovation Drive Knoxville, TN 37932

Distributed by: PETNET Solutions Inc. 810 Innovation Drive Knoxville, TN 37932

PN0002262 Rev. AMarch 1, 2011

AMMONIA N 13 - ammonia n-13 injection

PETNET Solutions, Inc.

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use Ammonia N 13 Injection safely and effectively. See full prescribing information for Ammonia N 13 Injection. Ammonia N 13 Injection for intravenous use Initial U.S. Approval: 2007

INDICATIONS AND USAGE

Ammonia N 13 Injection 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). DOSAGE AND ADMINISTRATION

Rest Imaging Study (2.1):

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.

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 N13 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.

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.

DOSAGE FORMS AND STRENGTHS

Glass vial containing 0.138-1.387 GBq (3.75-37.5 mCi/mL) of Ammonia N 13 Injection in aqueous 0.9 % sodium

chloride solution (The total volume in the vial will vary) (3). CONTRAINDICATIONS

None (4) WARNINGS AND PRECAUTIONS

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 (5). 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 system ( 6).6).

To report SUSPECTED ADVERSE REACTIONS, contact PETNET Solutions, Inc. at 877-473-8638 or FDA at 1-800-

FDA-1088 or www.fda.gov/medwatch.

26

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 (8.3).

The safety and effectiveness of Ammonia N 13 Injection has been established in pediatric patients (8.4).

See 17 for Patient Counseling Information, Patient Counseling Information, Patient Counseling Information, and

Patient Counseling Information

Revised: 01/2011

FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION

2.1 Rest Imaging Study 2.2 Stress Imaging Study 2.3 Patient Preparation 2.4 Radiation Dosimetry 2.5 Drug Handling

3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS

5.1 Radiation Risks 6 ADVERSE REACTIONS 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use

11 DESCRIPTION 11.1 Chemical Characteristics 11.2 Physical Characteristics

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION

17.1 Pre-study Hydration 17.2 Post-study Voiding 17.3 Post-study Breastfeeding Avoidance

Drug Product Label

*

Sections or subsections omitted from the full prescribing information are not listed

27

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

Ammonia N 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.

2 DOSAGE AND ADMINISTRATION

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.1

Table 1: N 13 Absorbed Radiation Dose Per Unit Activity (rem/mCi) for Adults and Pediatric Groups.

Organ Adult 15 - year old 10 - year old 5 - year old 1 - year old

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 00013 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

28

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 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 0.138-1.387 GBq (3.75-37.5 mCi/mL) of Ammonia N 13 Injection in aqueous 0.9 %

sodium chloride solution (the total volume in the vial will vary) that is suitable for intravenous administration.

4 CONTRAINDICATIONS

None

5 WARNINGS AND PRECAUTIONS

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.

29

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 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C

Animal 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 DESCRIPTION

11.1 Chemical Characteristics

Ammonia N 13 Injection 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 13NH3 with a molecular weight of 16.02, and has the following chemical structure:

Ammonia N 13 Injection 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 [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 0.05-0.1

picomoles (8.47-16.94 picograms) of ammonia.

30

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 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 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) 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

12 CLINICAL PHARMACOLOGY

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.

31

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 NONCLINICAL TOXICOLOGY

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).

32

33

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 1. Annals of the ICRP. Publication 53. Radiation dose to patients from radiopharmaceuticals. New York:

Pergamon Press, 1988. 2. 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/STORAGE AND HANDLING

Ammonia N 13 Injection is packaged in 30 mL multiple dose glass vial containing between 1.11 GBq to 11.1 GBq

(30 mCi to 300 mCi) of [13N] ammonia, at the end of synthesis (EOS) reference time, in 0.9% sodium chloride

injection solution. The total volume in the vial will vary. The recommended dose of radioactivity (10-20 mCi) is

associated with a theoretical mass dose of 0.05-0.1 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 30 minutes of the End of

Synthesis (EOS) calibration.

17 PATIENT COUNSELING INFORMATION

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.

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