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Management FDA-approved

This is a current list of all FDA-approved radiopharmaceuticals. USP <825> requires the use of conventionally manufactured drug products (e.g., NDA, ANDA) for Immediate Use. Nuclear practitioners that receive radiopharmaceuticals that originate from sources other than the manufacturers listed in these tables may be using unapproved copies.

Radiopharmaceutical Manufacturer Trade names Approved indications in adults (Pediatric use as noted) 1 -11 choline Various - Indicated for PET imaging of patients with suspected prostate recurrence based upon elevated blood prostate specific antigen (PSA) levels following initial and non-informative bone , computerized (CT) or magnetic resonance imaging (MRI) to help identify potential sites of recurrence for subsequent histologic confirmation 2 Carbon-14 Halyard Health PYtest Detection of gastric urease as an aid in the diagnosis of H.pylori in the stomach 3 Copper-64 dotatate Curium Detectnet™ Indicated for use with positron emission tomography (PET) for localization of receptor positive neuroendocrine tumors (NETs) in adult patients 4 -18 Life Molecular Neuraceq™ Indicated for Positron Emission Tomography (PET) imaging of the to Imaging estimate β amyloid neuritic plaque in adult patients with cognitive impairment who are being evaluated for Alzheimer’s disease (AD) or other causes of cognitive decline 5 Fluorine-18 Eli Lilly Amyvid™ 6 Fluorine-18 Eli Lilly TAUVID™ Indicated for (PET) imaging of the brain to estimate the density and distribution of aggregated tau neurofibrillary tangles (NFTs) in adult patients with cognitive impairment who are being evaluated for Alzheimer’s disease (AD) 7 Fluorine-18 Blue Earth Axumin™ A radioactive diagnostic agent indicated for positron emission tomography (PET) flucicovine Diagnostics imaging in men with suspected prostate cancer recurrence based on elevated blood prostate specific antigen (PSA) levels following prior treatment

Package inserts may be viewed at nps.cardinal.com/MSDSPI/Main.aspx Radiopharmaceuticals that may potentially have unapproved copies of FDA- approved commercially available radiopharmaceuticals in the marketplace. Rev.22 | 6.1.21 1 of 6 Manufacturer Trade names Approved indications in adults (Pediatric use as noted) 8 Fluorine-18 Various - PET bone imaging agent to delineate areas of altered osteogenesis

9 Fluorine-18 Various - As a PET imaging agent to: fludeoxyglucose • Assess abnormal metabolism in oncology • Assess myocardial hibernation • Identify regions of abnormal glucose metabolism associated with foci of epileptic seizures 10 Fluorine-18 Zionexa CERIANNA™ Indicated for positron emission tomography (PET) imaging for the detection of fluoroestradiol estrogen receptor (ER)-positive lesions as an adjunct to in patients with recurrent or 11 Fluorine-18 GE Healthcare Vizamyl™ Indicated for Positron Emission Tomography (PET) imaging of the brain to estimate β amyloid neuritic plaque density in adult patients with cognitive impairment who are being evaluated for Alzheimer’s disease (AD) or other causes of cognitive decline 12 -67 citrate Curium - Useful to demonstrate the presence/extent of: • Hodgkin’s disease • Lymphoma Lantheus Medical - • Bronchogenic carcinoma Imaging Aid in detecting some acute inflammatory lesions 13 Gallium-68 dotatate Advanced NETSPOT™ A radioactive diagnostic agent indicated for use with positron emission Accelerator tomography (PET) for localization of somatostatin receptor positive Applications neuroendocrine tumors (NETs) in adult and pediatric patients

14 Gallium-68 dotatoc University of Iowa - A radioactive diagnostic agent indicated for use with positron emission tomography (PET) for localization of somatostatin receptor positive neuroendocrine tumors (NETs) in adult and pediatric patients 15 Gallium-68 PSMA-11 University of - Indicated for positron emission tomography (PET) of prostate-specific membrane California antigen (PSMA) positive lesions in men with prostate cancer: • With suspected who are candidates for initial definitive therapy • With suspected recurrence based on elevated serum prostate-specific antigen (PSA) level 16 Indium-111 chloride Curium - Indicated for radiolabeling: • ProstaScint® used for in vivo diagnostic imaging procedures 17 Indium-111 BWXT - Indicated for radiolabeling autologous leukocytes which may be used as an oxyquinoline adjunct in the detection of inflammatory processes to which leukocytes migrate, GE Healthcare - such as those associated with abscesses or other infection 18 Indium-111 pentetate GE Healthcare - For use in cisternography 19 Indium-111 Curium Octreoscan™ An agent for the scintigraphic localization of primary pentetreotide and metastatic neuroendocrine tumors bearing somatostatin receptors

Package inserts may be viewed at nps.cardinal.com/MSDSPI/Main.aspx Radiopharmaceuticals that may potentially have unapproved copies of FDA- approved commercially available radiopharmaceuticals in the marketplace. Rev.22 | 6.1.21 2 of 6 Radiopharmaceutical Manufacturer Trade names Approved indications in adults (Pediatric use as noted) 20 I-123 GE Healthcare AdreView™ Indicated for use in the detection of primary or metastatic or as an adjunct to other diagnostic tests. Indicated for scintigraphic assessment of sympathetic innervation of the myocardium by measurement of the heart to mediastinum (H/M) ratio of radioactivity uptake in patients with New York Heart Association (NYHA) class II or class III heart failure and left ventricular ejection fraction (LVEF) ≤ 35%. Among these patients, it may be used to help identify patients with lower one and two year mortality risks, as indicated by an H/M ratio ≥ 1.6. Limitations of Use: In patients with congestive heart failure, its utility has not been established for: selecting a therapeutic intervention or for monitoring the response to therapy; using the H/M ratio to identify a patient with a high risk for death. 21 Iodine I-123 GE Healthcare DaTscan™ Indicated for striatal transporter visualization using SPECT brain imaging to assist in the evaluation of adult patients with suspected Parkinsonian syndromes (PS) in whom it may help differentiate essential tremor due to PS (idiopathic Parkinson’s disease, multiple system atrophy and progressive supranuclear palsy) 22 Iodine I-123 Cardinal Health - Indicated for use in the evaluation of : capsules • Function Curium - • Morphology

23 Iodine I-125 human IsoTex Diagnostics Jeanatope Indicated for use in the determination of: serum albumin • Total blood • Plasma volume 24 Iodine I-125 IsoTex Diagnostics Glofil-125 Indicated for evaluation of glomerular filtration iothalamate 25 Iodine I-131 human IsoTex Diagnostics Megatope Indicated for use in determinations of: serum albumin • Total blood and plasma volumes • Cardiac output • Cardiac and pulmonary blood volumes and circulation times • Protein turnover studies • Heart and great vessel delineation • Localization of the placenta • Localization of cerebral 26 Iodine-131 iobenguane Progenics® AZEDRA® Indicated for the treatment of adult and pediatric patients 12 years and older Pharmaceuticals with iobenguane scan positive, unresectable, locally advanced or metastatic pheochromocytoma or paraganglioma who require systemic anticancer therapy 27 Iodine I-131 DRAXIMAGE HICON™ Diagnostic: sodium iodide • Performance of the radioactive iodide (RAI) uptake test to evaluate thyroid function • Localizing metastases associated with thyroid malignancies International - Therapeutic: Inc • Treatment of • Treatment of carcinoma of the thyroid 28 Lu-177 Advanced LUTATHERA® Indicated for the treatment of somatostatin receptor-positive dotatate Accelerator gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including Applications foregut, midgut, and hindgut neuroendocrine tumors in adults.

Package inserts may be viewed at nps.cardinal.com/MSDSPI/Main.aspx Radiopharmaceuticals that may potentially have unapproved copies of FDA- approved commercially available radiopharmaceuticals in the marketplace. Rev.22 | 6.1.21 3 of 6 Radiopharmaceutical Manufacturer Trade names Approved indications in adults (Pediatric use as noted) 29 Molybdenum Curium Ultra- Generation of Tc-99m for administration or Mo-99 generator TechneKow™ radiopharmaceutical preparation V4 Used to produce sodium pertechnetate Tc 99m injection, USP a radioactive diagnostic agent and can be used in the preparation of FDA-approved diagnostic Lantheus Medical Technelite® radiopharmaceuticals. Imaging Indicated in: • Salivary Gland Imaging NorthStar Medical RadioGenix™ • Nasolacrimal Drainage System Imaging() Radioisotopes LLC System • Thyroid Imaging (adults & pediatrics) • Vesicoureteral Imaging (direct isotopic ) (adults and pediatrics)

30 -13 Various - 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 31 -223 dichloride Bayer HealthCare Xofigo® Indicated for the treatment of patients with castration-resistant prostate cancer, Pharmaceuticals symptomatic bone metastases and no known visceral metastatic disease Inc. 32 Rubidium-82 chloride Bracco Diagnostics Cardiogen-82® PET myocardial perfusion agent that is useful in distinguishing normal from DRAXIMAGE Ruby-Fill® abnormal myocardium in patients with suspected myocardial infarction 33 Samarium-153 Lantheus Medical Quadramet® Indicated for relief of pain in patients with confirmed osteoblastic metastatic lexidronam Imaging bone lesions that enhance on radionuclide bone scan 34 -89 chloride Q BioMed - Indicated for the relief of bone pain in patients with painful skeletal metastases 35 -99m Lantheus Medical Neurolite® SPECT imaging as an adjunct to conventional CT or MRI imaging in the bicisate Imaging localization of in patients in whom stroke has already been diagnosed 36 Technetium-99m DRAXIMAGE* - • As an adjunct in the detection of altered regional cerebral perfusion in stroke exametazine • Leukocyte labeled scintigraphy as an adjunct in the localization of intra GE Healthcare Ceretec™ abdominal infection and inflammatory bowel disease* 37 Technetium-99m Curium Pulmotech™ • An adjunct in the evaluation of pulmonary perfusion (adult and pediatric) macroaggregated • Evaluation of peritoneo-venous (LaVeen) shunt patency DRAXIMAGE - albumin 38 Technetium-99m Bracco Diagnostics Choletec® As a hepatobiliary imaging agent mebrofenin Sun Pharmaceutical - Industries 39 Technetium-99m DRAXIMAGE MDP-25 As a bone imaging agent to delineate areas of altered osteogenesis medronate Cardinal Health - Sun Pharmaceutical - Industries 40 Technetium-99m Curium Technescan In patients > 30 days of age as a renal imaging agent for use in the diagnosis of: mertiatide MAG3™ • Congenital and acquired abnormalities • Renal failure • Urinary tract obstruction and calculi Diagnostic aid in providing: Sun Pharmaceutical - • Renal function Industries • Split function • Renal angiograms • Renogram curves for whole and renal cortex

Package inserts may be viewed at nps.cardinal.com/MSDSPI/Main.aspx Radiopharmaceuticals that may potentially have unapproved copies of FDA- approved commercially available radiopharmaceuticals in the marketplace. Rev.22 | 6.1.21 4 of 6 Radiopharmaceutical Manufacturer Trade names Approved indications in adults (Pediatric use as noted) 41 Technetium-99m Curium Technescan™ As a bone imaging agent to delineate areas of altered osteogenesis oxidronate HDP (adult and pediatric use) 42 Technetium-99m DRAXIMAGE - • Brain imaging pentetate • Kidney imaging: - To assess renal perfusion - To estimate glomerular filtration rate • ventilation imaging and evaluation of pulmonary embolism when paired with perfusion imaging in adult and pediatric patients 43 Technetium-99m Curium Technescan™ • As a bone imaging agent to delineate areas of altered osteogenesis pyrophosphate PYP™ • As a cardiac imaging agent used as an adjunct in the diagnosis of acute myocardial infarction Sun Pharmaceutical - • As a blood pool imaging agent useful for: Industries - Gated blood pool imaging - Detection of sites of gastrointestinal bleeding 44 Technetium-99m red Curium UltraTag™ Tc99m-labeled red blood cells are used for: blood cells • Blood pool imaging including cardiac first pass and gated equilibrium imaging • Detection of sites of gastrointestinal bleeding 45 Technetium-99m Cardinal Health - Myocardial perfusion agent that is indicated for: sestamibi • Detecting coronary artery disease by localizing myocardial ischemia Curium - (reversible defects) and infarction (non-reversible defects) • Evaluating myocardial function DRAXIMAGE - • Developing information for use in patient Lantheus Medical Cardiolite® management decisions Imaging Planar breast imaging as a second line diagnostic drug after to assist in the evaluation of breast lesions in patients with an abnormal Sun Pharmaceutical - mammogram or a palpable breast mass Industries 46 Technetium-99m Curium - • Brain Imaging (including cerebral radionuclide )* sodium pertechnetate • Thyroid Imaging* • Salivary Gland Imaging Lantheus Medical - • Placenta Localization Imaging • Blood Pool Imaging (including )* • Imaging (direct isotopic cystography) for the detection NorthStar Medical - of vesico-ureteral reflux* Radioisotopes LLC • Nasolacrimal Drainage System Imaging (*adult and pediatric use) 47 Technetium-99m GE Healthcare - An aid in the scintigraphic evaluation of renal parenchymal disorders succimer 48 Technetium-99m Sun Pharmaceutical - • Imaging areas of functioning retriculoendothelial cells in the , colloid Industries spleen and * • It is used orally for: - Esophageal transit studies* - Gastroesophageal reflux scintigraphy* - Detection of pulmonary aspiration of gastric contents* • Aid in the evaluation of peritoneo-venous (LeVeen) shunt patency • To assist in the localization of lymph nodes draining a primary tumor in patients with breast cancer or malignant melanoma when used with a hand-held gamma counter (*adult and pediatric use)

Package inserts may be viewed at nps.cardinal.com/MSDSPI/Main.aspx Radiopharmaceuticals that may potentially have unapproved copies of FDA- approved commercially available radiopharmaceuticals in the marketplace. Rev.22 | 6.1.21 5 of 6 Radiopharmaceutical Manufacturer Trade names Approved indications in adults (Pediatric use as noted) 49 Technetium-99m GE Healthcare Myoview™ Myocardial perfusion agent that is indicated for: tetrofosmin • Detecting coronary artery disease by localizing myocardial ischemia (reversible defects) and infarction (non-reversible defects) • The assessment of left ventricular function (left ventricular ejection fraction and wall motion) 50 Technetium-99m Cardinal Health Lymphoseek® Indicated with or without scintigraphic imaging for: tilmanocept • Lymphatic mapping using a handheld gamma counter to locate lymph nodes draining a primary tumor site in adult and pediatric patients age one month and older with tumors for which this procedure is a component of intraoperative management. • Guiding sentinel lymph node biopsy using a handheld gamma counter in patients with clinically node negative squamous cell carcinoma of the oral cavity, breast cancer or melanoma. 51 Thallium-201 Curium - • Useful in myocardial perfusion imaging for the diagnosis and localization chloride of myocardial infarction GE Healthcare - • As an adjunct in the diagnosis of ischemic heart disease (atherosclerotic coronary artery disease) Lantheus Medical - • Localization of sites of parathyroid hyperactivity in patients with elevated Imaging serum and parathyroid hormone levels 52 Xenon-133 gas Curium - • The evaluation of pulmonary function and for imaging the Lantheus Medical - • Assessment of cerebral flow Imaging 53 Yttrium-90 Eckert & Ziegler - Indicated for radiolabeling: chloride Nuclitec • Zevalin® used for procedures 54 Yttrium-90 Acrotech Zevalin® Indicated for the: Biopharma • Treatment of relapsed or refractory, low-grade or follicular B-cell non-Hodgkin’s lymphoma (NHL) • Treatment of previously untreated follicular NHL in patients who achieve a partial or complete response to first-line chemotherapy

Package inserts may be viewed at nps.cardinal.com/MSDSPI/Main.aspx

Any reader of this document is cautioned that Cardinal Health makes no representation, guarantee, or warranty, express or implied as to the accuracy and appropriateness of the information contained in this document, and will bear no responsibility or liability for the results or consequences of its use. The information provided on this document is non-promotional. It is intended for informational purposes only and is not intended to promote or recommend any individual product. Contact the applicable manufacturer if you have any questions regarding a product listed on this document.

© 2021 Cardinal Health. All Rights Reserved. CARDINAL HEALTH and the Cardinal Health LOGO are trademarks cardinalhealth.com of Cardinal Health and may be registered in the US and/or in other countries. All other marks are the property of their respective owners Lit. No. 1NPS21-1497625-01 (06/2021) Rev.22 | 6.1.21 6 of 6 EXTERNAL The specific constant for I 123 is 1.6R/hr-mCi at 1 cm. The first half value thickness of lead (Pb) for I 123 is 0.005 cm. A range of values for the relative attenuation of the radiation emitted by this radionuclide that results from the interposition of various thicknesses of Pb is shown in Table 2. For example, the use of 1.63 cm. of lead will decrease the external radiation exposure Denver, CO 80011 by a factor of about 1,000. Table 2 Radiation Attenuation by Lead Shielding2 Shield Thickness (Pb), cm. Coefficient of Attenuation 0.036 0.5 0.120 10-1 0.240 10-2 Sodium Iodide I 123 0.358 10-3 0.477 10-4 2Shleien, Bernard, The Health Physics and Radiological Diagnostic-Capsules Health Handbook, Table 6.1.2, 169, (1992) Note that these estimates of attenuation do not take into for Oral Administration consideration the presence of contaminants. To correct for physical decay of I 123, the fractions that remain at selected intervals after the time of calibration are shown in Table 3. DESCRIPTION Table 3 Sodium Iodide I 123 (Na 123 I) for diagnostic use Sodium Iodide I 123 Decay Chart: Half-Life 13.2 Hours is supplied in capsules for oral administration. The capsules are available in strengths of 3.7, 7.4 and 14.8 Hours Fraction Hours Fraction megabecquerels (MBq) (100, 200 and 400 uCi) I 123 at time Remaining Remaining of calibration. 0* 1.000 18 .389 3 .854 21 .332 The radionuclidic composition at calibration is not less 6 .730 24 .284 than 97.0 percent I 123, not more than 2.9 percent I 9 .623 27 .242 125 and not more than 0.1 percent all others (I 121 or 12 .535 30 .207 Te 121.) The radionuclidic composition at expiration 15 .455 time is not less than 87.2 percent I 123, not more than *Time of Calibration 12.4 percent I 125 and not more than 0.4 percent all others. The ratio of the concentration of I 123 and I 125 CLINICAL PHARMACOLOGY changes with time. Graph 1 shows the maximum con- Sodium Iodide I 123 is readily absorbed from the upper centration of each as a function of time. . Following absorption, the iodide is distributed primarily within the extracellular fluid of the body. It is trapped and organically bound by the thyroid and % OF TOTAL ACTIVITY concentrated by the stomach, choroid plexus and salivary glands. It is excreted by the kidneys.

The fraction of the administered dose which is accumu- lated in the thyroid gland may be a measure of thyroid function in the absence of unusually high or low iodine intake or administration of certain drugs which influence iodine accumulation by the thyroid gland. Accordingly, the patient should be questioned carefully regarding previous medication and/or procedures involving radio- graphic media. Normal subjects can accumulate approxi- mately 10-50% of the administered iodine dose in the thyroid gland, however, the normal and abnormal ranges are established by individual physician’s criteria. The mapping (imaging) of Sodium Iodide I 123 distribution Graph 1 in the thyroid gland may provide useful information concerning thyroid anatomy and definition of normal Radionuclidic Concentration of I 123 and I 125 and/or abnormal functioning of tissue within the gland. PHYSICAL CHARACTERISTICS INDICATION AND USE Sodium Iodide I 123 decays by with a Administration of Sodium Iodide I 123 is indicated as a physical half-life of 13.2 hours. The photon that is useful diagnostic procedure to be used in evaluating thyroid for detection and imaging studies is listed in Table 1. function and/or morphology. CONTRAINDICATIONS Table 1 To date there are no known contraindications to the use Principal Radiation Emission Data1 of Sodium Iodide I 123 capsules. Mean Energy WARNINGS Radiation Mean %/Disintegration (keV) Females of childbearing age and children under 18 should Gamma-2 83.4 159 not be studied unless the benefits anticipated from the performance of the test outweigh the possible risk of 1Kocher, David C., Data Tables, exposure to the amount of associated DOE/TIC-11026, 122, (1981) with the test. PRECAUTIONS RADIATION DOSIMETRY General The estimated absorbed radiation doses to several organs The contents of the capsule are radioactive. Adequate of an average patient (70 kg) from oral administration of shielding of the preparation must be maintained at all the maximum dose of 14.8 MBq (400 uCi) of I 123 are times. shown in Table 4 for thyroid uptakes of 5, 15, and 25%. For comparison at these three values of thyroid uptake, Do not use after the expiration time and date (30 hours the estimated radiation doses from doses of 3.7 MBq after calibration time) stated on the label. (100 uCi) I 131, also used as thyroid imaging agent, The prescribed Sodium Iodide I 123 dose should be are also included. administered as soon as practical from the time of receipt Table 4 of product (i.e., as close to calibration time as possible) Radiation Dose Estimates as a Function in order to minimize the fraction of radiation exposure of Maximum Thyroid Uptake due to relative increase of radionuclidic contaminants for I 1231 Sodium Iodide with time. At Time of Calibration and Expiry Compared to I 131 Sodium Iodide I 123, as well as other radioactive drugs, Estimated Radiation Absorbed Dose must be handled with care and appropriate safety measures Maximum should be used to minimize radiation exposure to clinical Target Thyroid Organ Uptake (%) I 123 I 131 personnel. Care should also be taken to minimize radiation mGy/14.8 MBq mGy/3.7 MBq exposure to the patient consistent with proper patient (rads/400 uCi) (rads/100 uCi) management. TOC TOE Thyroid 5 25 (2.5) 75 (7.5) 260 (26) Radiopharmaceuticals should be used only by physicians 15 77 (7.7) 230 (23) 780 (78) who are qualified by training and experience in the safe 25 130 (13) 410 (41) 1300 (130) use and handling of and whose experience Liver 5 0.089 (0.0089) 0.13 (0.013) 0.16 (0.016) 15 0.10 (0.010) 0.18 (0.018) 0.28 (0.028) and training have been approved by the appropriate 25 0.11 (0.011) 0.24 (0.024) 0.41 (0.041) government agency authorized to license the use of Ovaries 5 0.18 (0.018) 0.19 (0.019) 0.18 (0.018) radionuclides. 15 0.17 (0.017) 0.18 (0.018) 0.18 (0.018) 25 0.16 (0.016) 0.18 (0.018) 0.17 (0.017) Carcinogenesis, Mutagenesis, Impairment of Fertility Red 5 0.12 (0.012) 0.16 (0.016) 0.15 (0.015) No long-term animal studies have been performed to Marrow 15 0.12 (0.012) 0.18 (0.018) 0.21 (0.021) 25 0.13 (0.013) 0.19 (0.019) 0.27 (0.027) evaluate carcinogenic potential, mutagenic potential, or Stomach 5 0.96 (0.096) 0.98 (0.098) 1.7 (0.17) whether Sodium Iodide I 123 affects fertility in males Wall 15 0.89 (0.089) 0.91 (0.091) 1.5 (0.15) or females. 25 0.82 (0.082) 0.85 (0.085) 1.4 (0.14) Small 5 0.70 (0.070) 0.71 (0.071) 1.2 (0.12) Pregnancy Category C Intestine 15 0.65 (0.065) 0.67 (0.067) 1.1 (0.11) Animal reproduction studies have not been conducted 25 0.60 (0.060) 0.62 (0.062) 0.99 (0.099) with this drug. It is also not known whether Sodium Testes 5 0.076 (0.0076) 0.089 (0.0089) 0.12 (0.012) 15 0.072 (0.0072) 0.087 (0.0087) 0.12 (0.012) Iodide I 123 can cause fetal harm when administered to 25 0.068 (0.0068) 0.085 (0.0085) 0.12 (0.012) a pregnant woman or can affect reproductive capacity. Bladder 5 1.7 (0.17) 1.7 (0.17) 2.9 (0.29) Sodium Iodide I 123 should be given to a pregnant 15 1.6 (0.16) 1.6 (0.16) 2.7 (0.27) woman only if clearly needed. 25 1.4 (0.14) 1.5 (0.15) 2.4 (0.24) Skeleton 5 0.11 (0.011) 0.16 (0.016) 0.12 (0.012) Ideally examinations using radiopharmaceuticals, espe- 15 0.12 (0.012) 0.18 (0.018) 0.18 (0.018) 25 0.14 (0.014) 0.21 (0.021) 0.24 (0.024) cially those elective in nature, in women of childbearing Total 5 0.11 (0.011) 0.16 (0.016) 0.24 (0.024) capability should be performed during the first few Body 15 0.14 (0.014) 0.25 (0.025) 0.47 (0.047) (approximately ten) days following the onset of menses. 25 0.17 (0.017) 0.35 (0.035) 0.70 (0.070) Nursing Mothers 1 Concentration at Time of Calibration: 97% I 123, 2.9% I 125, 0.1% Te 121 Concentration at Time of Expiry: 87.2% I 123, 12.4% I 125, 0.4% Te 121 Since I 123 is excreted in human milk, formula-feeding All Iodine Kinetics treated as in MIRD Dose Estimate Report 5. Bladder voiding should be substituted for breast-feeding if the agent interval, 4.8 hours. 121 dosimetry taken from ICRP 30. must be administered to the mother during lactation. HOW SUPPLIED Pediatric Use Sodium Iodide I 123 is supplied as capsules for oral Safety and effectiveness in children have not been estab- administration in strengths of 3.7 MBq (100uCi), 7.4 MBq (200 lished. uCi) and 14.8 MBq (400uCi) at time of calibration. Each gelatin capsule contains 0.45 - 0.65 g of sucrose. The ADVERSE REACTIONS capsules are packaged in plastic vials containing either one or Although rare, reactions associated with the administra- five capsules of a single strength per vial. The plastic vial is tion of Sodium Iodide isotopes for diagnostic use include, packaged in a lead shield with a label identical to that affixed in decreasing order of frequency, nausea, vomiting, chest to the plastic vial. A package insert is pain, tachycardia, itching skin, rash and hives. supplied with each lead shield.

DOSAGE AND ADMINISTRATION The -I (Iodine) content for a 100 uCi capsule is 5.2 ng the -I The recommended oral dose for the average patient (70 content for a 200 uCi capsule is 10.4 ng the -I content for a kg) is 3.7 to 14.8 MBq (100-400 uCi). The lower part of 400uCi capsule is 20.8 ng at TOC. the dosage range 3.7 MBq (100 uCi) is recommended for uptake studies alone, and the higher part 14.8 MBq Dispense and preserve capsules in well-closed containers (400 uCi) for thyroid imaging. The determination of that are adequately shielded. Store at room temperature, I 123 concentration in the thyroid gland may be initiated below 86ºF. at six hours after administering the dose and should be The contents of the capsules are radioactive. Adequate measured in accordance with standardized procedures. shielding and handling precautions must be maintained. The patient dose should be measured by a suitable radio- THIS PACKAGE INSERT ISSUED MAY 2003 active calibration system immediately prior to adminstra- tion. The capsules can be utilized up to thirty (30) hours after calibration time and date. Thereafter discard the Denver, CO 80011 capsules in accordance with standard safety procedures. The user should wear waterproof gloves at all times when handling the capsules or container. Sodium Iodide I 123 1-020-14 Printed in U.S.A. HIGHLIGHTS OF PRESCRIBING INFORMATION Initiate imaging within 40 minutes following drug injection; acquire static emission images 30 - 100 minutes from time of injection (2). These 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 ------DOSAGE FORMS AND STRENGTHS ------Injection. Multiple-dose glass vial containing either 0.74 - 11.1 GBq (20 - 300 mCi/mL) or 0.74 - 18.5 GBq (20 - 500 mCi/mL) of Fludeoxyglucose F-18 Injection and 4.5 mg of sodium chloride in citrate buffer (approximately 10-30 mL volume) for intravenous administration (3). Fludeoxyglucose F-18 Injection, USP Initial U.S. Approval: 2005 ------CONTRAINDICATIONS ------INDICATIONS AND USAGE ------None (4) Fludeoxyglucose F-18 Injection is indicated for positron emission tomography (PET) imaging in ------WARNINGS AND PRECAUTIONS ------the following settings: • Radiation risks: use smallest dose necessary for imaging (5.1). • Oncology: For assessment of abnormal glucose metabolism to assist in the evaluation of • Blood glucose abnormalities: may cause suboptimal imaging (5.2). malignancy in patients with known or suspected abnormalities found by other testing ------ADVERSE REACTIONS ------modalities, or in patients with an existing diagnosis of cancer (1). Hypersensitivity reactions have occurred; have emergency resuscitation equipment and • Cardiology: For the identification of left ventricular myocardium with residual glucose personnel immediately available (6). metabolism and reversible loss of systolic function in patients with coronary artery disease and left ventricular dysfunction, when used together with myocardial perfusion imaging (1). To report SUSPECTED ADVERSE REACTIONS, contact Cardinal Health at 1-800-618- • Neurology: For the identification of regions of abnormal glucose metabolism associated with 2768 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. foci of epileptic seizures (1). ------USE IN SPECIFIC POPULATIONS ------DOSAGE AND ADMINISTRATION ------• Pregnancy Category C: No human or animal data. Consider alternative diagnostics; use only Fludeoxyglucose F-18 Injection emits radiation. Use procedures to minimize radiation exposure. if clearly needed (8.1). Screen for blood glucose abnormalities. • Nursing mothers: Use alternatives to breast feeding (e.g., stored breast milk or infant • In the oncology and neurology settings, instruct patients to fast for 4 – 6 hours prior to the formula) for at least 10 half-lives of radioactive decay, if Fludeoxyglucose F-18 Injection is drug’s injection. Consider medical therapy and laboratory testing to assure at least two days administered to a woman who is breast-feeding (8.3). of normoglycemia prior to the drug’s administration (5.2). • Pediatric Use: Safety and effectiveness in pediatric patients have not been established in the • In the cardiology setting, administration of glucose-containing food or liquids (e.g., 50 – 75 oncology and cardiology settings (8.4). grams) prior to the drug’s injection facilitates localization of cardiac ischemia (2.3). See 17 for PATIENT COUNSELING INFORMATION Aseptically withdraw Fludeoxyglucose F-18 Injection from its container and administer by Revised: 09/2018 intravenous injection (2). The recommended dose: • for adults is 5 – 10 mCi (185 – 370 MBq), in all indicated clinical settings (2.1). • for pediatric patients is 2.6 mCi in the neurology setting (2.2).

FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 8.1 Pregnancy 1.1 Oncology 8.3 Nursing Mothers 1.2 Cardiology 8.4 Pediatric Use 1.3 Neurology 11 DESCRIPTION 2 DOSAGE AND ADMINISTRATION 11.1 Chemical Characteristics 2.1 Recommended Dose for Adults 11.2 Physical Characteristics 2.2 Recommended Dose for Pediatric Patients 12 CLINICAL PHARMACOLOGY 2.3 Patient Preparation 12.1 Mechanism of Action 2.4 Radiation Dosimetry 12.2 Pharmacodynamics 2.5 Radiation Safety – Drug Handling 12.3 2.6 Drug Preparation and Administration 13 NONCLINICAL TOXICOLOGY 2.7 Imaging Guidelines 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 3 DOSAGE FORMS AND STRENGTHS 14 CLINICAL STUDIES 4 CONTRAINDICATIONS 14.1 Oncology 5 WARNINGS AND PRECAUTIONS 14.2 Cardiology 5.1 Radiation Risks 14.3 Neurology 5.2 Blood Glucose Abnormalities 15 REFERENCES 6 ADVERSE REACTIONS 16 HOW SUPPLIED/STORAGE AND HANDLING 7 DRUG INTERACTIONS 17 PATIENT COUNSELING INFORMATION 8 USE IN SPECIFIC POPULATIONS *Sections or subsections omitted from the full prescribing information are not listed.

FULL PRESCRIBING INFORMATION 2.3 Patient Preparation 1 INDICATIONS AND USAGE • To minimize the radiation absorbed dose to the bladder, encourage adequate hydration. Fludeoxyglucose F-18 Injection is indicated for positron emission tomography (PET) imaging in Encourage the patient to drink or other fluids (as tolerated) in the 4 hours before their the following settings: PET study. • 1.1 Oncology Encourage the patient to void as soon as the imaging study is completed and as often as possible thereafter for at least one hour. For assessment of abnormal glucose metabolism to assist in the evaluation of malignancy in • Screen patients for clinically significant blood glucose abnormalities by obtaining a history patients with known or suspected abnormalities found by other testing modalities, or in patients and/or laboratory tests [see Warnings and Precautions (5.2)]. Prior to Fludeoxyglucose F-18 with an existing diagnosis of cancer. PET imaging in the oncology and neurology settings, instruct patient to fast for 4 – 6 hours 1.2 Cardiology prior to the drug’s injection. For the identification of left ventricular myocardium with residual glucose metabolism and • In the cardiology setting, administration of glucose-containing food or liquids (e.g., 50 – 75 reversible loss of systolic function in patients with coronary artery disease and left ventricular grams) prior to Fludeoxyglucose F-18 Injection facilitates localization of cardiac ischemia. dysfunction, when used together with myocardial perfusion imaging. 2.4 Radiation Dosimetry 1.3 Neurology The estimated human absorbed radiation doses (rem/mCi) to a newborn (3.4 kg), 1-year old For the identification of regions of abnormal glucose metabolism associated with foci of (9.8 kg), 5-year old (19 kg), 10-year old (32 kg), 15-year old (57 kg), and adult (70 kg) from epileptic seizures. intravenous administration of Fludeoxyglucose F-18 Injection are shown in Table 1. These 2 2 DOSAGE AND ADMINISTRATION estimates were calculated based on human data and using the data published by the International Commission on Radiological Protection4 for Fludeoxyglucose 18F. The dosimetry Fludeoxyglucose F-18 Injection emits radiation. Use procedures to minimize radiation exposure. data show that there are slight variations in absorbed radiation dose for various organs in each of Calculate the final dose from the end of synthesis (EOS) time using proper radioactive decay the age groups. These dissimilarities in absorbed radiation dose are due to developmental age factors. Assay the final dose in a properly calibrated dose calibrator before administration to the variations (e.g., organ size, location, and overall metabolic rate for each age ). The patient [see Description (11.2)]. identified critical organs (in descending order) across all age groups evaluated are the urinary 2.1 Recommended Dose for Adults bladder, heart, pancreas, spleen, and lungs. Within the oncology, cardiology and neurology settings, the recommended dose for adults is 5 - 10 mCi (185 – 370 MBq) as an intravenous injection. 2.2 Recommended Dose for Pediatric Patients Within 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 Populations (8.4)]. Table 1. Estimated Absorbed Radiation Doses (rem/mCi) After Intravenous 8 USE IN SPECIFIC POPULATIONS a Administration of Fludeoxyglucose F-18 Injection 8.1 Pregnancy Newborn 1-year old 5-year old 10-year old 15-year old Adult Pregnancy Category C Organ (3.4 kg) (9.8 kg) (19 kg) (32 kg) (57 kg) (70 kg) Animal reproduction studies have not been conducted with Fludeoxyglucose F-18 Injection. It is b Bladder wall 4.3 1.7 0.93 0.60 0.40 0.32 also not known whether Fludeoxyglucose F-18 Injection can cause fetal harm when Heart wall 2.4 1.2 0.70 0.44 0.29 0.22 administered to a pregnant woman or can affect reproduction capacity. Consider alternative Pancreas 2.2 0.68 0.33 0.25 0.13 0.096 diagnostic tests in a pregnant woman; administer Fludeoxyglucose F-18 Injection only if clearly Spleen 2.2 0.84 0.46 0.29 0.19 0.14 needed. Lungs 0.96 0.38 0.20 0.13 0.092 0.064 8.3 Nursing Mothers Kidneys 0.81 0.34 0.19 0.13 0.089 0.074 It is not known whether Fludeoxyglucose F-18 Injection is excreted in human milk. Consider Ovaries 0.80 0.8 0.19 0.11 0.058 0.053 alternative diagnostic tests in women who are breast-feeding. Use alternatives to breast feeding Uterus 0.79 0.35 0.19 0.12 0.076 0.062 (e.g., stored breast milk or infant formula) for at least 10 half-lives of radioactive decay, if LLI wall* 0.69 0.28 0.15 0.097 0.060 0.051 Fludeoxyglucose F-18 Injection is administered to a woman who is breast-feeding. Liver 0.69 0.31 0.17 0.11 0.076 0.058 8.4 Pediatric Use Gallbladder wall 0.69 0.26 0.14 0.093 0.059 0.049 The safety and effectiveness of Fludeoxyglucose F-18 Injection in pediatric patients with Small intestine 0.68 0.29 0.15 0.096 0.060 0.047 epilepsy is established on the basis of studies in adult and pediatric patients. In pediatric patients ULI wall** 0.67 0.27 0.15 0.090 0.057 0.046 with epilepsy, the recommended dose is 2.6 mCi. The optimal dose adjustment on the basis of Stomach wall 0.65 0.27 0.14 0.089 0.057 0.047 body size or weight has not been determined. Adrenals 0.65 0.28 0.15 0.095 0.061 0.048 In the oncology or cardiology settings, the safety and effectiveness of Fludeoxyglucose F-18 Testes 0.64 0.27 0.14 0.085 0.052 0.041 Injection have not been established in pediatric patients. Red marrow 0.62 0.26 0.14 0.089 0.057 0.047 11 DESCRIPTION Thymus 0.61 0.26 0.14 0.086 0.056 0.044 11.1 Chemical Characteristics Thyroid 0.61 0.26 0.13 0.080 0.049 0.039 Fludeoxyglucose F-18 Injection is a positron emitting radiopharmaceutical that is used for Muscle 0.58 0.25 0.13 0.078 0.049 0.039 diagnostic purposes in conjunction with positron emission tomography (PET) imaging. The 18 18 Bone surface 0.57 0.24 0.12 0.079 0.052 0.041 active ingredient 2-deoxy-2-[ F]fluoro-D-glucose has the molecular formula of C6H11 FO5 with Breast 0.54 0.22 0.11 0.068 0.043 0.034 a molecular weight of 181.26, and has the following chemical structure: 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 2.5 Radiation Safety – Drug Handling • Use waterproof gloves, effective radiation shielding, and appropriate safety measures when Fludeoxyglucose F-18 Injection is provided as a ready to use sterile, pyrogen free, clear, handling Fludeoxyglucose F-18 Injection to avoid unnecessary radiation exposure to the colorless citrate buffered solution. Each mL contains between either 0.74 - 11.1 GBq patient, occupational workers, clinical personnel and other persons. (20 - 300 mCi/mL) or 0.74 - 18.5 GBq (20 - 500 mCi/mL) of 2 deoxy-2-[18F]fluoro-D-glucose at • Radiopharmaceuticals should be used by or under the control of physicians who are qualified the EOS, 4.5 mg of sodium chloride in citrate buffer. The pH of the solution is between 4.5 and by specific training and experience in the safe use and handling of radionuclides, and whose 7.5. The solution is packaged in a multiple-dose glass vial and does not contain any preservative. experience and training have been approved by the appropriate governmental agency 11.2 Physical Characteristics authorized to license the use of radionuclides. Fluorine F-18 has a physical half-life of 109.7 minutes and decays to Oxygen O-18 (stable) by • Calculate the final dose from the end of synthesis (EOS) time using proper radioactive decay positron decay. The principal photons useful for imaging are the dual 511 keV “annihilation” factors. Assay the final dose in a properly calibrated dose calibrator before administration to gamma photons that are produced and emitted simultaneously in opposite directions when the the patient [see Description (11.2)]. positron interacts with an electron (Table 2). • The dose of Fludeoxyglucose F-18 used in a given patient should be minimized consistent Table 2. Principal Radiation Emission Data for Fluorine F-18 with the objectives of the procedure, and the nature of the radiation detection devices employed. Radiation/Emission % Per Disintegration Mean Energy 2.6 Drug Preparation and Administration Positron(β+) 96.73 249.8 keV • Calculate the necessary volume to administer based on calibration time and dose. Gamma(±)* 193.46 511.0 keV • Aseptically withdraw Fludeoxyglucose F-18 Injection from its container. * Produced by positron annihilation • Inspect Fludeoxyglucose F-18 Injection visually for particulate matter and discoloration From: Kocher, D.C. Radioactive Decay Tables DOE/TIC-I 1026, 89 (1981) before administration, whenever solution and container permit. The specific gamma ray constant (point source air kerma coefficient) for fluorine F-18 is • Do not administer the drug if it contains particulate matter or discoloration; dispose of these 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 unacceptable or unused preparations in a safe manner, in compliance with applicable photons is 4 mm lead (Pb) or 2.9 mm (W) alloy. The range of attenuation coefficients regulations. for this radionuclide as a function of shield thickness is shown in Table 3. For example, the • Use Fludeoxyglucose F-18 Injection within 12 hours from the EOS. interposition of an 8 mm thickness of Pb or 5.8 mm thickness of W alloy, with a coefficient of 2.7 Imaging Guidelines attenuation of 0.25, will decrease the external radiation by 75%. • Initiate imaging within 40 minutes following Fludeoxyglucose F-18 Injection administration. Table 3. Radiation Attenuation of 511 keV Photons by Lead (Pb) and Tungsten (W) Alloy • Acquire static emission images 30 – 100 minutes from the time of injection. Shielding 3 DOSAGE FORMS AND STRENGTHS Shield Thickness Shield Thickness Coefficient of (Pb) mm (W) Alloy mm Attenuation Multiple-dose glass vial containing either 0.74 - 11.1 GBq (20 - 300 mCi/mL) or 0.74 - 18.5 GBq (20 - 500 mCi/mL) of Fludeoxyglucose F-18 Injection and 4.5 mg of sodium 0 0 0.00 chloride in citrate buffer (approximately 10 - 30 mL volume) for intravenous administration. 4 2.9 0.50 4 CONTRAINDICATIONS 8 5.8 0.25 None 13 9.4 0.10 5 WARNINGS AND PRECAUTIONS 26 18.7 0.01 5.1 Radiation Risks 39 27.6 0.001 Radiation-emitting products, including Fludeoxyglucose F-18 Injection, may increase the risk 52 37.4 0.0001 for cancer, especially in pediatric patients. Use the smallest dose necessary for imaging and For use in correcting for physical decay of this radionuclide, the fractions remaining at selected ensure safe handling to protect the patient and health care worker [see Dosage and intervals after calibration are shown in Table 4. Administration (2.5)]. Table 4. Physical Decay Chart for Fluorine F-18 5.2 Blood Glucose Abnormalities Minutes Fraction Remaining In the oncology and neurology setting, suboptimal imaging may occur in patients with inadequately regulated blood glucose levels. In these patients, consider medical therapy and 0* 1.000 laboratory testing to assure at least two days of normoglycemia prior to Fludeoxyglucose F-18 15 0.909 Injection administration. 30 0.826 6 ADVERSE REACTIONS 60 0.683 Hypersensitivity reactions with pruritus, edema and rash have been reported in the post- 110 0.500 marketing setting. Have emergency resuscitation equipment and personnel immediately 220 0.250 available. 440 0.060 7 DRUG INTERACTIONS * calibration time The possibility of interactions of Fludeoxyglucose F-18 Injection with other drugs taken by patients undergoing PET imaging has not been studied. 12 CLINICAL PHARMACOLOGY to establish a diagnosis of cancer. Non-malignant conditions such as fungal 12.1 Mechanism of Action , 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 Fludeoxyglucose F-18 is a glucose analog that concentrates in cells that rely upon glucose as an Injection PET imaging in cancer screening was not studied. energy source, or in cells whose dependence on glucose increases under pathophysiological conditions. Fludeoxyglucose F-18 is transported through the cell membrane by facilitative 14.2 Cardiology glucose transporter proteins and is phosphorylated within the cell to [18F] FDG-6-phosphate by The efficacy of Fludeoxyglucose F-18 Injection for cardiac use was demonstrated in ten the enzyme hexokinase. Once phosphorylated it cannot exit until it is dephosphorylated by independent, prospective studies of patients with coronary artery disease and chronic left glucose-6-phosphatase. Therefore, within a given tissue or pathophysiological process, the ventricular systolic dysfunction who were scheduled to undergo coronary revascularization. retention and clearance of Fludeoxyglucose F-18 reflect a balance involving glucose transporter, Before revascularization, patients underwent PET imaging with Fludeoxyglucose F-18 Injection hexokinase and glucose-6-phosphatase activities. When allowance is made for the kinetic (74 – 370 MBq, 2 – 10 mCi) and perfusion imaging with other diagnostic radiopharmaceuticals. differences between glucose and Fludeoxyglucose F-18 transport and phosphorylation Doses of Fludeoxyglucose F-18 Injection ranged from 74-370 MBq (2-10 mCi). Segmental, left (expressed as the ''lumped constant'' ratio), Fludeoxyglucose F-18 is used to assess glucose ventricular, wall-motion assessments of asynergic areas made before revascularization were metabolism. compared in a blinded manner to assessments made after successful revascularization to identify In comparison to background activity of the specific organ or tissue type, regions of decreased myocardial segments with functional recovery. or absent uptake of Fludeoxyglucose F-18 reflect the decrease or absence of glucose Left ventricular myocardial segments were predicted to have reversible loss of systolic function metabolism. Regions of increased uptake of Fludeoxyglucose F-18 reflect greater than normal if they showed Fludeoxyglucose F-18 accumulation and reduced perfusion (i.e., flow- rates of glucose metabolism. metabolism mismatch). Conversely, myocardial segments were predicted to have irreversible loss of systolic function if they showed reductions in both Fludeoxyglucose F-18 accumulation 12.2 Pharmacodynamics and perfusion (i.e., matched defects). Fludeoxyglucose F-18 Injection is rapidly distributed to all organs of the body after intravenous Findings of flow-metabolism mismatch in a myocardial segment may suggest that successful administration. After background clearance of Fludeoxyglucose F-18 Injection, optimal PET revascularization will restore myocardial function in that segment. However, false-positive tests imaging is generally achieved between 30 to 40 minutes after administration. occur regularly, and the decision to have a patient undergo revascularization should not be based In cancer, the cells are generally characterized by enhanced glucose metabolism partially due to on PET findings alone. Similarly, findings of a matched defect in a myocardial segment may (1) an increase in activity of glucose transporters, (2) an increased rate of phosphorylation suggest that myocardial function will not recover in that segment, even if it is successfully activity, (3) a reduction of phosphatase activity, or (4) a dynamic alteration in the balance revascularized. However, false-negative tests occur regularly, and the decision to recommend among all these processes. However, glucose metabolism of cancer as reflected by against coronary revascularization, or to recommend a cardiac transplant, should not be based on Fludeoxyglucose F-18 accumulation shows considerable variability. Depending on tumor type, PET findings alone. The reversibility of segmental dysfunction as predicted with stage, and location, Fludeoxyglucose F-18 accumulation may be increased, normal, or Fludeoxyglucose F-18 PET imaging depends on successful coronary revascularization. decreased. Also, inflammatory cells can have the same variability of uptake of Fludeoxyglucose Therefore, in patients with a low likelihood of successful revascularization, the diagnostic F-18. usefulness of PET imaging with Fludeoxyglucose F-18 Injection is more limited. In the heart, under normal aerobic conditions, the myocardium meets the bulk of its energy 14.3 Neurology requirements by oxidizing free fatty acids. Most of the exogenous glucose taken up by the In a prospective, open label trial, Fludeoxyglucose F-18 Injection was evaluated in 86 patients myocyte is converted into glycogen. However, under ischemic conditions, the oxidation of free with epilepsy. Each patient received a dose of Fludeoxyglucose F-18 Injection in the range of fatty acids decreases, exogenous glucose becomes the preferred myocardial substrate, glycolysis 185-370 MBq (5-10 mCi). The mean age was 16.4 years (range: 4 months - 58 years; of these, is stimulated, and glucose taken up by the myocyte is metabolized immediately instead of being 42 patients were less than 12 years and 16 patients were less than 2 years old). Patients had a converted into glycogen. Under these conditions, phosphorylated Fludeoxyglucose F-18 known diagnosis of complex partial epilepsy and were under evaluation for surgical treatment of accumulates in the myocyte and can be detected with PET imaging. their seizure disorder. Seizure foci had been previously identified on ictal EEGs and sphenoidal In the brain, cells normally rely on aerobic metabolism. In epilepsy, the glucose metabolism EEGs. Fludeoxyglucose F-18 Injection PET imaging confirmed previous diagnostic findings in varies. Generally, during a seizure, glucose metabolism increases. Interictally, the seizure focus 16% (14/87) of the patients; in 34% (30/87) of the patients, Fludeoxyglucose F-18 Injection PET tends to be hypometabolic. images provided new findings. In 32% (27/87), imaging with Fludeoxyglucose F-18 Injection 12.3 Pharmacokinetics was inconclusive. The impact of these imaging findings on clinical outcomes is not known. Distribution: In four healthy male volunteers, receiving an intravenous administration of Several other studies comparing imaging with Fludeoxyglucose F-18 Injection results to 30 seconds in duration, the arterial blood level profile for Fludeoxyglucose F-18 decayed subsphenoidal EEG, MRI and/or surgical findings supported the concept that the degree of triexponentially. The effective half-life ranges of the three phases were 0.2-0.3 minutes, hypometabolism corresponds to areas of confirmed epileptogenic foci. The safety and 10-13 minutes with a mean and standard deviation (STD) of 11.6 (±) 1.1 min, and effectiveness of Fludeoxyglucose F-18 Injection to distinguish idiopathic epileptogenic foci 80-95 minutes with a mean and STD of 88 (±) 4 min. from tumors or other brain lesions that may cause seizures have not been established. Plasma protein binding of Fludeoxyglucose F-18 has not been studied. 15 REFERENCES Metabolism: Fludeoxyglucose F-18 is transported into cells and phosphorylated to [18F]-FDG-6- 1. Gallagher B.M., Ansari A., Atkins H., Casella V., Christman D.R., Fowler J.S., Ido T., phosphate at a rate proportional to the rate of glucose utilization within that tissue. [F-18]-FDG- MacGregor R.R., Som P., Wan C.N., Wolf A.P., Kuhl D.E., and Reivich M. 6-phosphate presumably is metabolized to 2-deoxy-2-[F-18]fluoro-6-phospho-D-mannose([F- “Radiopharmaceuticals XXVII. 18F-labeled 2-deoxy-2-fluoro-d-glucose as a 18]FDM-6-phosphate). radiopharmaceutical for measuring regional myocardial glucose metabolism in vivo: tissue distribution and imaging studies in animals,” J Nucl Med, 1977; 18, 990-6. Fludeoxyglucose F-18 Injection may contain several impurities (e.g., 2-deoxy-2-chloro-D- 2. Jones S.C., Alavi, A., Christman D., Montanez, I., Wolf, A.P., and Reivich M. “The glucose (ClDG)). Biodistribution and metabolism of ClDG are presumed to be similar to radiation dosimetry of 2 [F-18] fluoro-2-deoxy-D-glucose in man,” J Nucl Med, 1982; 23, Fludeoxyglucose F-18 and would be expected to result in intracellular formation of 2-deoxy-2- 613-617. chloro-6-phospho-D-glucose (ClDG-6-phosphate) and 2-deoxy-2-chloro-6-phospho-D-mannose 3. Kocher, D.C. “Radioactive Decay Tables: A handbook of decay data for application to (ClDM-6-phosphate). The phosphorylated deoxyglucose compounds are dephosphorylated and radiation dosimetry and radiological assessments,” 1981, DOE/TIC-I 1026, 89. the resulting compounds (FDG, FDM, ClDG, and ClDM) presumably leave cells by passive 4. ICRP Publication 53, Volume 18, No. l-4,1987, pages 75-76. diffusion. Fludeoxyglucose 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 16 HOW SUPPLIED/STORAGE AND HANDLING than 96 hours. Fludeoxyglucose F-18 that is not involved in glucose metabolism in any tissue is Fludeoxyglucose F-18 Injection is supplied in a multi-dose, capped 10 mL or 30 mL glass vial then excreted in the urine. containing between either 0.74 - 11.1 GBq (20 - 300 mCi/mL) or 0.74 - 18.5 GBq Elimination: Fludeoxyglucose F-18 is cleared from most tissues within 24 hours and can be (20 - 500 mCi/mL), of no carrier added 2-deoxy-2-[F-18] fluoro-D-glucose, at end of synthesis, eliminated from the body unchanged in the urine. Three elimination phases have been identified in approximately 10-30 mL. The contents of each vial are sterile, pyrogen-free and preservative- in the reviewed literature. Within 33 minutes, a mean of 3.9% of the administrated radioactive free. dose was measured in the urine. The amount of radiation exposure of the urinary bladder at two NDC 65857-100-30 (30 mL) hours post-administration suggests that 20.6% (mean) of the radioactive dose was present in the 0.74 - 11.1 GBq (20 - 300 mCi/mL) bladder. NDC 65857-150-30 (30 mL) Special Populations: 0.74 - 18.5 GBq (20 - 500 mCi/mL) The pharmacokinetics of Fludeoxyglucose F-18 Injection have not been studied in renally- Receipt, transfer, handling, possession, or use of this product is subject to the radioactive impaired, hepatically impaired or pediatric patients. Fludeoxyglucose F-18 is eliminated through material regulations and licensing requirements for the U.S. Nuclear Regulatory Commission, the renal system. Avoid excessive radiation exposure to this organ system and adjacent tissues. Agreement States or Licensing States as appropriate. The effects of fasting, varying blood sugar levels, conditions of glucose intolerance, and Store the Fludeoxyglucose F-18 Injection vial upright in a lead or tungsten alloy shielded diabetes mellitus on Fludeoxyglucose F-18 distribution in humans have not been ascertained container at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). [see Warnings and Precautions (5.2)]. The expiration date and time are provided on the container label. Use Fludeoxyglucose F-18 13 NONCLINICAL TOXICOLOGY Injection within 12 hours from the EOS time. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 17 PATIENT COUNSELING INFORMATION Animal studies have not been performed to evaluate the Fludeoxyglucose F-18 Injection Instruct patients in procedures that increase renal clearance of radioactivity. Encourage patients carcinogenic potential, mutagenic potential or effects on fertility. to: 14 CLINICAL STUDIES • drink water or other fluids (as tolerated) in the 4 hours before their PET study. 14.1 Oncology • void as soon as the imaging study is completed and as often as possible thereafter for at least The efficacy of Fludeoxyglucose F-18 Injection in positron emission tomography cancer one hour. imaging was demonstrated in 16 independent studies. These studies prospectively evaluated the Manufactured by: use of Fludeoxyglucose F-18 in patients with suspected or known malignancies, including non- Cardinal Health 414, LLC small cell lung cancer, colo-rectal, pancreatic, breast, thyroid, melanoma, Hodgkin's and non- 7000 Cardinal Place Hodgkin's lymphoma, and various types of metastatic to lung, liver, bone, and axillary Dublin, OH 43017 nodes. All these studies had at least 50 patients and used pathology as a standard of truth. The Distributed by: Fludeoxyglucose F-18 Injection doses in the studies ranged from 200 MBq to 740 MBq with a median and mean dose of 370 MBq. Cardinal Health 414, LLC 7000 Cardinal Place In the studies, the diagnostic performance of Fludeoxyglucose F-18 Injection varied with the Dublin, OH 43017 type of cancer, size of cancer, and other clinical conditions. False negative and false positive scans were observed. Negative Fludeoxyglucose F-18 Injection PET scans do not exclude the diagnosis of cancer. Positive Fludeoxyglucose F-18 Injection PET scans cannot replace NPS-PI-0003 ver 3.0 HIGHLIGHTS OF PRESCRIBING INFORMATION ------CONTRAINDICATIONS ------These highlights do not include all the information needed to use Sodium Fluoride F-18 Injection, None (4). USP, safely and effectively. See full prescribing information for Sodium Fluoride F-18 Injection, ------WARNINGS AND PRECAUTIONS ------USP. • Allergic Reactions: As with any injectable drug product, allergic reactions and anaphylaxis may occur. Emergency resuscitation equipment and personnel should be immediately available (5.1). Sodium Fluoride F-18 Injection, USP • Cancer Risk: Sodium Fluoride F-18 Injection, USP, may increase the risk of cancer. Use the For Intravenous Use smallest dose necessary for imaging and ensure safe handling to protect the patient and health Initial U.S. Approval: 2011 care worker (5.2). ------INDICATIONS AND USAGE ------ADVERSE REACTIONS ------Sodium Fluoride F-18 Injection, USP, is a radioactive diagnostic agent for positron emission No adverse reactions have been reported for Sodium Fluoride F-18 Injection, USP, based on a review of tomography (PET) indicated for imaging of bone to define areas of altered osteogenic activity (1). the published literature, publicly available reference sources, and adverse drug reaction reporting ------DOSAGE AND ADMINISTRATION ------systems (6). • Sodium Fluoride F-18 Injection, USP, emits radiation and must be handled with appropriate safety measures (2.1). • Administer 300-450 MBq (8–12 mCi) as an intravenous injection in adults (2.4). To report SUSPECTED ADVERSE REACTIONS, contact Cardinal Health at 1-800-618-2768 or • Administer approximately 2.1 MBq/kg in children with a minimum of 19 MBq (0.5 mCi) and a FDA at 1-800-FDA-1088 or www.fda.gov/medwatch maximum of 148 MBq (4 mCi) as an intravenous injection (2.5). ------USE IN SPECIFIC POPULATIONS ------• Imaging can begin 1–2 hours after administration; optimally at one hour post administration • Pregnancy: No human or animal data. Any radiopharmaceutical, including Sodium Fluoride F-18 (2.7). Injection, USP, may cause fetal harm. Use only if clearly needed (8.1) • Encourage patients to void immediately prior to imaging the lumbar spine and bony pelvis (2.7). • Nursing: A decision should be made whether to interrupt nursing after Sodium Fluoride F-18 ------DOSAGE FORMS AND STRENGTHS ------Injection, USP, administration or not to administer Sodium Fluoride F-18 Injection, USP, taking Multiple-dose vial containing 370–7,400 MBq/mL (10–200 mCi/mL) of no-carrier-added sodium into consideration the importance of the drug to the mother. (8.3) fluoride F-18 at the end of synthesis (EOS) reference time in aqueous 0.9% sodium chloride solution (3). • Pediatrics: Children are more sensitive to radiation and may be at higher risk of cancer from Sodium Fluoride F-18 Injection, USP, is a clear, colorless, sterile, pyrogen-free and preservative-free Sodium Fluoride F-18 Injection, USP (8.4). solution for intravenous administration. See 17 for PATIENT COUNSELING INFORMATION Revised: 08/2015 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 8.4 Pediatric Use 2 DOSAGE AND ADMINISTRATION 11 DESCRIPTION 2.1 Radiation Safety - Drug Handling 11.1 Chemical Characteristics 2.2 Radiation Safety - Patient Preparation 11.2 Physical Characteristics 2.3 Drug Preparation and Administration 12 CLINICAL PHARMACOLOGY 2.4 Recommended Dose for Adults 12.1 Mechanism of Action 2.5 Recommended Dose for Pediatric Patients 12.2 Pharmacodynamics 2.6 Radiation Dosimetry 12.3 Pharmacokinetics 2.7 Imaging Guidelines 13 NONCLINICAL TOXICOLOGY 3 DOSAGE FORMS AND STRENGTHS 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 4 CONTRAINDICATIONS 14 CLINICAL STUDIES 5 WARNINGS AND PRECAUTIONS 14.1 Metastatic Bone Disease 5.1 Allergic Reactions 14.2 Other Bone Disorders 5.2 Radiation Risks 15 REFERENCES 6 ADVERSE REACTIONS 16 HOW SUPPLIED/STORAGE AND HANDLING 7 DRUG INTERACTIONS 17 PATIENT COUNSELING INFORMATION 8 USE IN SPECIFIC POPULATIONS 17.1 Pre-Study Hydration 8.1 Pregnancy 17.2 Post-Study Voiding 8.3 Nursing Mothers *Sections or subsections omitted from the full prescribing information are not listed. FULL PRESCRIBING INFORMATION International Commission on Radiological Protection for Sodium Fluoride Injection [2]. The bone, bone marrow and urinary bladder are considered target and critical organs. 1 INDICATIONS AND USAGE Sodium Fluoride F-18 Injection, USP, is indicated for diagnostic positron emission tomography (PET) Table 1. Estimated Absorbed Radiation Doses after Intravenous Administration of Sodium imaging of bone to define areas of altered osteogenic activity. Fluoride F-18 Injection, USP 2 DOSAGE AND ADMINISTRATION Estimated Radiation Dose mGy/MBq 2.1 Radiation Safety - Drug Handling Adult 15 year 10 year 5 year 1 year Organ 70 kg* 56.8 kg† 33.2 kg† 19.8 kg† 9.7 kg† • Wear waterproof gloves and effective shielding when handling Sodium Fluoride F-18 Injection, USP. Use appropriate safety measures, including shielding, consistent with proper patient Adrenals 0.0062 0.012 0.018 0.028 0.052 management to avoid unnecessary radiation exposure to the patient, occupational workers, clinical Brain 0.0056 N/A N/A N/A N/A personnel, and other persons. Bone surfaces 0.060 0.050 0.079 0.13 0.30 • 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 Breasts 0.0028 0.0061 0.0097 0.015 0.030 and training have been approved by the appropriate governmental agency authorized to license the GI use of radionuclides. Gallbladder wall 0.0044 N/A N/A N/A N/A • Use aseptic technique to maintain sterility during all operations involved in the manipulation and Stomach wall 0.0038 0.008 0.013 0.019 0.036 administration of Sodium Fluoride F-18 Injection, USP. • The dose of Sodium Fluoride F-18 Injection, USP, should be minimized consistent with the Small intestine 0.0066 0.012 0.018 0.028 0.052 objectives of the procedure, and the nature of the radiation detection devices employed. Upper large intestine wall 0.0058 0.010 0.016 0.026 0.046 • The final dose for the patient should be calculated using proper decay factors from the time of End Lower large intestine wall 0.012 0.016 0.025 0.037 0.063 of Synthesis (EOS), and measured by a suitable radioactivity calibration system before Heart wall 0.0039 N/A N/A N/A N/A administration [see Description (11.2)]. Kidneys 0.019 0.025 0.036 0.053 0.097 2.2 Radiation Safety - Patient Preparation Liver 0.0040 0.0084 0.013 0.021 0.039 • To minimize the radiation-absorbed dose to the bladder, encourage adequate hydration. Encourage the patient to ingest at least 500 mL of fluid immediately prior and subsequent to the administration Lungs 0.0041 0.0084 0.013 0.020 0.039 of Sodium Fluoride F-18 Injection, USP. Muscle 0.0060 N/A N/A N/A N/A • Encourage the patient to void one-half hour after administration of Sodium Fluoride F-18 Injection, Ovaries 0.011 0.016 0.023 0.036 0.063 USP, and as frequently thereafter as possible for the next 12 hours. Pancreas 0.0048 0.0096 0.015 0.023 0.044 2.3 Drug Preparation and Administration Red marrow 0.028 0.053 0.088 0.18 0.38 • Calculate the necessary volume to administer based on calibration time and dose. Skin 0.0040 N/A N/A N/A N/A • Inspect Sodium Fluoride F-18 Injection, USP, visually for particulate matter and discoloration before administration, whenever solution and container permit. Spleen 0.0042 0.0088 0.014 0.021 0.041 • Do not administer Sodium Fluoride F-18 Injection, USP, containing particulate matter or Testes 0.0078 0.013 0.021 0.033 0.062 discoloration; dispose of these unacceptable or unused preparations in a safe manner, in compliance Thymus 0.0035 N/A N/A N/A N/A with applicable regulations. Thyroid 0.0044 0.0084 0.013 0.020 0.036 • Aseptically withdraw Sodium Fluoride F-18 Injection, USP, from its container. Urinary bladder wall 0.25 0.27 0.4 0.61 1.1 2.4 Recommended Dose for Adults Uterus 0.019 0.023 0.037 0.057 0.099 Administer 300–450 MBq (8–12 mCi) as an intravenous injection. Other tissue N/A 0.010 0.015 0.024 0.044 2.5 Recommended Dose for Pediatric Patients Effective 0.027 0.034 0.052 0.086 0.17 In reported clinical experience in approximately 100 children, weight based doses (2.1 MBq/kg) ranging Dose Equivalent mSv/MBq from 19 MBq–148 MBq (0.5 mCi–4 mCi) were used. 2.6 Radiation Dosimetry * Data from Nuclear Regulatory Commission Report, Radiation Dose Estimates for Radiopharmaceuticals, NUREG/CR-6345, page 10, 1996. The age/weight- based estimated absorbed radiation doses (mGy/MBq) from intravenous injection of † Data from ICRP publication 53, Radiation Dose to Patients from Radiopharmaceuticals, Ann ICRP, Sodium Fluoride F-18 Injection, USP, are shown in Table 1. These estimates were calculated based on Volume 18, pages 15 and 74, 1987. human data and using the data published by the Nuclear Regulatory Commission [1] and the 2.7 Imaging Guidelines Table 4 lists the fraction of radioactivity remaining at selected time intervals from the calibration time. • Imaging of Sodium Fluoride F-18 Injection, USP, can begin 1–2 hours after administration; This information may be used to correct for physical decay of the radionuclide. optimally at 1 hour post administration. Table 4. Physical Decay Chart for Fluoride F-18 • Encourage the patient to void immediately prior to imaging the fluoride F-18 radioactivity in the Time Since Calibration Fraction Remaining lumbar spine or bony pelvis. 0* 1.00 3 DOSAGE FORMS AND STRENGTHS 15 minutes 0.909 Multiple-dose vial containing 370–7,400 MBq/mL (10–200 mCi/mL) at EOS reference time of no- carrier-added sodium fluoride F-18 in aqueous 0.9% sodium chloride solution. Sodium Fluoride F-18 30 minutes 0.826 Injection, USP, is a clear, colorless, sterile, pyrogen-free and preservative-free solution for intravenous 60 minutes 0.683 administration. 110 minutes 0.500 4 CONTRAINDICATIONS 220 minutes 0.250 None 440 minutes 0.060 5 WARNINGS AND PRECAUTIONS 12 hours 0.011 5.1 Allergic Reactions 24 hours 0.0001 As with any injectable drug product, allergic reactions and anaphylaxis may occur. Emergency * calibration time resuscitation equipment and personnel should be immediately available. 12 CLINICAL PHARMACOLOGY 5.2 Radiation Risks 12.1 Mechanism of Action Sodium Fluoride F-18 Injection, USP, may increase the risk of cancer. Carcinogenic and mutagenic studies with Sodium Fluoride F-18 Injection, USP, have not been performed. Use the smallest dose Fluoride F-18 normally accumulates in the skeleton in an even fashion, with greater deposition in the necessary for imaging and ensure safe handling to protect the patient and health care worker [see axial skeleton (e.g. vertebrae and pelvis) than in the appendicular skeleton and greater deposition in the Dosage and Administration (2.1)]. bones around joints than in the shafts of long bones. 6 ADVERSE REACTIONS 12.2 Pharmacodynamics No adverse reactions have been reported for Sodium Fluoride F-18 Injection, USP, based on a review of Increased fluoride F-18 ion deposition in bone can occur in areas of increased osteogenic activity during the published literature, publicly available reference sources, and adverse drug reaction reporting growth, infection, malignancy (primary or metastatic) following trauma, or of bone. systems. However, the completeness of these sources is not known. 12.3 Pharmacokinetics 7 DRUG INTERACTIONS After intravenous administration, fluoride F-18 ion is rapidly cleared from the plasma in a biexponential The possibility of interactions of Sodium Fluoride F-18 Injection, USP, with other drugs taken by manner. The first has a half-life of 0.4 h, and the second phase has a half-life of 2.6 h. Essentially patients undergoing PET imaging has not been studied. all the fluoride F-18 that is delivered to bone by the blood is retained in the bone. One hour after administration of fluoride, F-18 only about 10% of the injected dose remains in the blood. Fluoride F-18 8 USE IN SPECIFIC POPULATIONS diffuses through capillaries into bone extracellular fluid space, where it becomes bound by 8.1 Pregnancy chemisorption at the surface of bone crystals, preferentially at sites of newly mineralizing bone. Pregnancy Category C Deposition of fluoride F-18 in bone appears to be primarily a function of blood flow to the bone and the Any radiopharmaceutical including Sodium Fluoride F-18 Injection, USP, has a potential to cause fetal efficiency of the bone in extracting the fluoride F-18. Fluoride F-18 does not appear to be bound to harm. The likelihood of fetal harm depends on the stage of fetal development, and the radionuclide dose. serum proteins. Animal reproductive and developmental toxicity studies have not been conducted with Sodium Fluoride In patients with normal renal function, 20% or more of the fluorine ion is cleared from the body in the F-18 Injection, USP. Prior to the administration of Sodium Fluoride F-18 Injection, USP, to women of urine within the first 2 hours after intravenous administration. childbearing potential, assess for presence of pregnancy. Sodium Fluoride F-18 Injection, USP, should 13 NONCLINICAL TOXICOLOGY be given to a pregnant woman only if clearly needed. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 8.3 Nursing Mothers Studies to assess reproductive toxicity, mutagenesis and carcinogenesis potential of Sodium Fluoride F- It is not known whether Sodium Fluoride F-18 Injection, USP, is excreted into human milk. Because 18 Injection, USP, have not been performed. many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to interrupt nursing after administration of Sodium 14 CLINICAL STUDIES Fluoride F-18 Injection, USP, or not to administer Sodium Fluoride F-18 Injection, USP, taking into 14.1 Metastatic Bone Disease account the importance of the drug to the mother. The body of scientific information related to The doses used in reported studies ranged from 2.7 mCi to 20 mCi (100 MBq to 740 MBq), with an radioactivity decay, drug tissue distribution and drug elimination shows that less than 0.01% of the average median dose of 10 mCi (370 MBq) and an average mean dose of 9.2 mCi (340 MBq). In PET radioactivity administered remains in the body after 24 hours (10 half-lives). To minimize the risks to a imaging of bone metastases with Sodium Fluoride F-18 Injection, USP, focally increased tracer uptake nursing infant, interrupt nursing for at least 24 hours. is seen in both osteolytic and osteoblastic bone lesions. Negative PET imaging results with Sodium 8.4 Pediatric Use Fluoride F-18 Injection, USP, do not preclude the diagnosis of bone metastases. Also, as benign bone In reported clinical experience in approximately 100 children, weight based doses (2.1 MBq/kg) ranging lesions are also detected by Sodium Fluoride F-18 Injection, USP, positive PET imaging results cannot from 19 MBq–148 MBq (0.5 mCi–4 mCi) were used. Sodium Fluoride F-18 was shown to localize to replace biopsy to confirm a diagnosis of cancer. areas of bone turnover including rapidly growing epiphyses in developing long bones. Children are more 14.2 Other Bone Disorders sensitive to radiation and may be at higher risk of cancer from Sodium Fluoride F-18 Injection, USP. The doses used in reported studies ranged from 2.43 mCi to 15 mCi (90 MBq to 555 MBq), with an 11 DESCRIPTION average median dose of 8.0 mCi (300 MBq) and an average mean dose of 7.6 mCi (280 MBq). 11.1 Chemical Characteristics 15 REFERENCES Sodium Fluoride F-18 Injection, USP, is a positron emitting radiopharmaceutical, containing no-carrier- 1. Stabin, M.G., Stubbs, J.B. and Toohey R.E., Radiation Dose Estimates for Radiopharmaceuticals, added, radioactive fluoride F-18 that is used for diagnostic purposes in conjunction with PET imaging. It U.S. Nuclear Regulatory Commission report NUREG/CR-6345, page 10, 1996. is administered by intravenous injection. The active ingredient, sodium fluoride F-18, has the molecular 2. Radiation Dose to Patients from Radiopharmaceuticals, ICRP publication 53, Ann ICRP, 18 pages formula Na[18F] with a molecular weight of 40.99, and has the following chemical structure: 15 and 74, 1987 Na+18F– 3. Kocher, D.C., "Radioactive Decay Data Tables: A Handbook of decay data for application to radiation dosimetry and radiological assessments" DOE/TIC-11026, page 69, 1981. Sodium Fluoride F-18 Injection, USP, is provided as a ready-to-use, isotonic, sterile, pyrogen-free, preservative-free, clear and colorless solution. Each mL of the solution contains between 370 MBq to 16 HOW SUPPLIED/STORAGE AND HANDLING 7,400 MBq (10 mCi to 200 mCi) sodium fluoride F-18, at the EOS reference time, in 0.9% aqueous Sodium Fluoride F-18 Injection, USP, is supplied in a multiple-dose Type I glass vial with elastomeric sodium chloride. The pH of the solution is between 4.5 and 8. The solution is presented in 30 mL stopper and aluminum crimp seal containing between 370 and 7,400 MBq/mL (10–200 mCi/mL) of no multiple-dose glass vials with variable total volume and total radioactivity in each vial. carrier-added sodium fluoride F-18, at the EOS reference time, in aqueous 0.9% sodium chloride 11.2 Physical Characteristics solution. The total volume and total radioactivity per vial are variable. Each vial is enclosed in a shielded container of appropriate thickness. Fluoride F-18 decays by positron (β+) emission and has a half-life of 109.7 minutes. Ninety-seven percent of the decay results in emission of a positron with a maximum energy of 633 keV and 3% of the The product is available in a 30 mL vial configuration with a variable fill volume. The NDC number is: decay results in electron capture with subsequent emission of characteristic X-rays of oxygen. The NDC 65857-300-30 principal photons useful for diagnostic imaging are the 511 keV gamma photons, resulting from the Storage interaction of the emitted positron with an electron (Table 2). Fluorine F-18 atom decays to stable 18O- oxygen. Store at 25°C (77°F) in a shielded container; excursions permitted to 15–30°C (59–86°F). Use the solution within 12 hours of the EOS reference time. Table 2. Principal Emission Data for Fluoride F-18 Handling Radiation/Emission % Per Disintegration Mean Energy Receipt, transfer, handling, possession, or use of this product is subject to the radioactive material Positron(β+) 96.73 249.8 keV regulations and licensing requirements of the U.S. Nuclear Regulatory Commission, Agreement States Gamma(±)* 193.46 511.0 keV or Licensing States as appropriate. * Produced by positron annihilation 17 PATIENT COUNSELING INFORMATION From: Kocher, D.C. Radioactive Decay Data Tables DOE/TIC-11026, 69, 1981 17.1 Pre-Study Hydration The specific gamma ray constant for fluoride F-18 is 5.7 R/hr/mCi (1.35 x 10-6 Gy/hr/kBq) at 1 cm. The Encourage patients to drink at least 500 mL of water prior to drug administration. half-value layer (HVL) for the 511 keV photons is 4.1 mm lead (Pb) or 2.9 mm tungsten (W) alloy. A 17.2 Post-Study Voiding range of values for the attenuation of radiation results from the interposition of various thickness of Pb To help protect themselves and others in their environment, patients should take the following or Tungsten alloy. The range of attenuation coefficients for this radionuclide is shown in Table 3. For precautions for 12 hours after injection: whenever possible, use a toilet and flush several times after each example, the interposition of an 8.3 mm thickness of Pb or 5.8 mm thickness of W alloy with a use; wash hands thoroughly after each voiding or fecal elimination. If blood, urine or feces soil clothing, coefficient of attenuation of 0.25 will decrease the external radiation by 75%. wash the clothing separately. Table 3. Radiation Attenuation of 511 keV Photons by lead (Pb) and Tungsten (W) alloy shielding Manufactured by: Shield Thickness Shield Thickness Coefficient of Cardinal Health 414, LLC (Pb) mm (W) Alloy mm Attenuation 7000 Cardinal Place 0 0 0.00 Dublin, OH 43017 4 3 0.50 Distributed by: 8 6 0.25 Cardinal Health 414, LLC 13 9 0.10 7000 Cardinal Place 26 19 0.01 Dublin, OH 43017 39 28 0.001 53 37 0.0001 HIGHLIGHTS OF PRESCRIBING INFORMATION ------DOSAGE FORMS AND STRENGTHS------These highlights do not include all the information needed to use Ammonia N-13 Injection, USP safely and Glass vial containing 0.138-1.387 GBq (3.75-37.5 mCi/mL) of Ammonia N-13 Injection, USP in aqueous 0.9 % effectively. See full prescribing information for Ammonia N-13 Injection, USP. sodium chloride solution (approximately 8 mL to 10 mL volume) (3).

Ammonia N-13 Injection, USP for intravenous use ------CONTRAINDICATIONS------Initial U.S. Approval: 2007 None (4) ------WARNINGS AND PRECAUTIONS------INDICATIONS AND USAGE------Ammonia N-13 Injection, USP 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). Ammonia N-13 Injection, USP is a radioactive diagnostic agent for Positron Emission Tomography (PET) indicated for diagnostic PET imaging of the myocardium under rest or pharmacologic stress conditions to ------ADVERSE REACTIONS------evaluate myocardial perfusion in patients with suspected or existing coronary artery disease (1). No adverse reactions have been reported for Ammonia N-13 Injection, USP based on a review of the published ------DOSAGE AND ADMINISTRATION------literature, publicly available reference sources, and adverse drug reaction reporting system (6). Rest Imaging Study (2.1): • Aseptically withdraw Ammonia N-13 Injection, USP from its container and administer 10-20 mCi (0.368 To report SUSPECTED ADVERSE REACTIONS, contact Cardinal Health at 1-800-618-2768 or FDA at – 0.736 GBq) as a bolus through a inserted into a large peripheral vein. 1-800-FDA-1088 or www.fda.gov/medwatch • Start imaging 3 minutes after the injection and acquire images for a total of 10-20 minutes. Stress Imaging Study (2.2): ------USE IN SPECIFIC POPULATIONS------• It is not known whether this drug is excreted in human milk. Alternatives to breastfeeding (e.g. using • If a rest imaging study is performed, begin the stress imaging study 40 minutes or more after the first stored breast milk or infant formula) should be used for 2 hours (>10 half-lives of radioactive decay for Ammonia N-13 Injection, USP to allow sufficient decay. N-13 isotope) after administration of Ammonia N-13 Injection, USP (8.3). • Administer a pharmacologic stress-inducing drug in accordance with its labeling. • The safety and effectiveness of Ammonia N-13 Injection, USP has been established in pediatric patients • Aseptically withdraw Ammonia N-13 Injection, USP from its container and administer 10-20 mCi (0.368 (8.4). – 0.736 GBq) of Ammonia N-13 Injection, USP as a bolus at 8 minutes after the administration of the pharmacologic stress-inducing drug. See 17 for PATIENT COUNSELING INFORMATION

• Start imaging 3 minutes after the Ammonia N-13 Injection, USP and acquire images for a total of 10-20 Revised: 12/2015 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.

FULL PRESCRIBING INFORMATION: CONTENTS* 11 DESCRIPTION 1 INDICATIONS AND USAGE 11.1 Chemical Characteristics 2 DOSAGE AND ADMINISTRATION 11.2 Physical Characteristics 2.1 Rest Imaging Study 12 CLINICAL PHARMACOLOGY 2.2 Stress Imaging Study 12.1 Mechanism of Action 2.3 Patient Preparation 12.2 Pharmacodynamics 2.4 Radiation Dosimetry 12.3 Pharmacokinetics 2.5 Drug Handling 13 NONCLINICAL TOXICOLOGY 3 DOSAGE FORMS AND STRENGTHS 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 4 CONTRAINDICATIONS 14 CLINICAL STUDIES 5 WARNINGS AND PRECAUTIONS 15 REFERENCES 5.1 Radiation Risks 16 HOW SUPPLIED/STORAGE AND HANDLING 6 ADVERSE REACTIONS 17 PATIENT COUNSELING INFORMATION 7 DRUG INTERACTIONS 17.1 Pre-study Hydration 8 USE IN SPECIFIC POPULATIONS 17.2 Post-study Voiding 8.1 Pregnancy 17.3 Post-study Breastfeeding Avoidance 8.3 Nursing Mothers 8.4 Pediatric Use *Sections or subsections omitted from the full prescribing information are not listed

FULL PRESCRIBING INFORMATION Table 1: N-13 Absorbed Radiation Dose Per Unit Activity (rem/mCi) for Adults and Pediatric 1 INDICATIONS AND USAGE Groups Organ Adult 15-year old 10-year old 5-year old 1-year old Ammonia N-13 Injection, USP is indicated for diagnostic Positron Emission Tomography (PET) imaging of the *ULI 0.0067 0.0078 0.013 0.021 0.037 myocardium under rest or pharmacologic stress conditions to evaluate myocardial perfusion in patients with **LLI 0.0070 0.0078 0.013 0.020 0.037 suspected or existing coronary artery disease. Heart 0.0078 0.0096 0.015 0.023 0.041 2 DOSAGE AND ADMINISTRATION Kidneys 0.017 0.021 0.031 0.048 0.089 Liver 0.015 0.018 0.029 0.044 0.085 2.1 Rest Imaging Study Lungs 0.0093 0.011 0.018 0.029 0.056 Ovaries 0.0063 0.0085 0.014 0.021 0.041 • Aseptically withdraw Ammonia N-13 Injection, USP from its container and administer 10-20 mCi (0.368 Pancreas 0.0070 0.0085 0.014 0.021 0.041 – 0.736 GBq) as a bolus through a catheter inserted into a large peripheral vein. Red marrow 0.0063 0.0078 0.012 0.020 0.037 • Start imaging 3 minutes after the injection and acquire images for a total of 10-20 minutes. Spleen 0.0093 0.011 0.019 0.030 0.056 Testes 0.0067 0.0070 0.011 0.018 0.035 2.2 Stress Imaging Study Thyroid 0.0063 0.0081 0.013 0.021 0.041 • If a rest imaging study is performed, begin the stress imaging study 40 minutes or more after the first Uterus 0.0070 0.0089 0.014 0.023 0.041 Ammonia N-13 Injection, USP to allow sufficient isotope decay. Other tissues 0.0059 0.0070 0.011 0.018 0.035 * Upper large intestine; ** Lower large intestine • Administer a pharmacologic stress-inducing drug in accordance with its labeling. • Aseptically withdraw Ammonia N-13 Injection, USP from its container and administer 10-20 mCi (0.368 2.5 Drug Handling – 0.736 GBq) of Ammonia N-13 Injection, USP as a bolus at 8 minutes after the administration of the pharmacologic stress-inducing drug. • Inspect Ammonia N-13 Injection, USP visually for particulate matter and discoloration before • Start imaging 3 minutes after the Ammonia N-13 Injection, USP and acquire images for a total of 10-20 administration, whenever solution and container permit. minutes. • Do not administer Ammonia N-13 Injection, USP containing particulate matter or discoloration; dispose 2.3 Patient Preparation 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, USP. 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 • Use aseptic technique to maintain sterility during all operations involved in the manipulation and possible thereafter for at least one hour. administration of Ammonia N-13 Injection, USP. The contents of each vial are sterile and non-pyrogenic. • Use appropriate safety measures, including shielding, consistent with proper patient management to avoid 2.4 Radiation Dosimetry unnecessary radiation exposure to the patient, occupational workers, clinical personnel, and other persons. The converted radiation absorbed doses in rem/mCi are shown in Table 1. These estimates are calculated from the • Radiopharmaceuticals should be used by or under the control of physicians who are qualified by specific Task Group of Committee 2 of the International Commission on Radiation Protection.1 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 Table 1: N-13 Absorbed Radiation Dose Per Unit Activity (rem/mCi) for Adults and Pediatric radionuclides. Groups • Before administration of Ammonia N-13 Injection, USP, assay the dose in a properly calibrated dose Organ Adult 15-year old 10-year old 5-year old 1-year old calibrator. Adrenals 0.0085 0.0096 0.016 0.025 0.048 Bladder wall 0.030 0.037 0.056 0.089 0.17 3 DOSAGE FORMS AND STRENGTHS Bone surfaces 0.0059 0.0070 0.011 0.019 0.037 Brain 0.016 0.016 0.017 0.019 0.027 Glass vial (10 mL) containing 0.138-1.387 GBq (3.75-37.5 mCi/mL) of Ammonia N-13 Injection, USP in Breast 0.0067 0.0067 0.010 0.017 0.033 aqueous 0.9 % sodium chloride solution (approximately 8 mL to 10 mL volume) that is suitable for intravenous Stomach wall 0.0063 0.0078 0.012 0.019 0.037 administration. Small intestine 0.0067 0.0081 00013 0.021 0.041 4 CONTRAINDICATIONS

None 5 WARNINGS AND PRECAUTIONS 12.2 Pharmacodynamics

5.1 Radiation Risks 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 Ammonia N-13 Injection, USP may increase the risk of cancer. Use the smallest dose necessary for imaging and intravenous ammonia N-13 in the myocardium. In this model, the value of the rate constant, which represents the ensure safe handling to protect the patient and health care worker [see Dosage and Administration (2.4)]. 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 6 ADVERSE REACTIONS 20 minutes after administration.

No adverse reactions have been reported for Ammonia N-13 Injection, USP based on a review of the published 12.3 Pharmacokinetics literature, publicly available reference sources, and adverse drug reaction reporting systems. However, the completeness of these sources is not known. Following intravenous injection, Ammonia N-13 Injection, USP 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 7 DRUG INTERACTIONS been estimated to be less than 2 minutes (effective half-life less than 1.67 minutes). The possibility of interactions of Ammonia N-13 Injection, USP with other drugs taken by patients undergoing The mass dose of Ammonia N-13 Injection, USP is very small as compared to the normal range of ammonia in PET imaging has not been studied. the blood (0.72-3.30 mg) in a healthy adult man [see Description (11.1)]. 8 USE IN SPECIFIC POPULATIONS Plasma protein binding of ammonia N-13 or its N-13 metabolites has not been studied.

8.1 Pregnancy 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 Pregnancy Category C 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. Animal reproduction studies have not been conducted with Ammonia N-13 Injection, USP. It is also not known whether Ammonia N-13 Injection, USP can cause fetal harm when administered to a pregnant woman or can Ammonia N-13 is eliminated from the body by urinary excretion mainly as urea N-13. affect reproduction capacity. Ammonia N-13 Injection, USP should be given to a pregnant woman only if clearly The pharmacokinetics of Ammonia N-13 Injection, USP have not been studied in renally impaired, hepatically needed. impaired, or pediatric patients. 8.3 Nursing Mothers 13 NONCLINICAL TOXICOLOGY It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for radiation exposure to nursing infants from Ammonia N-13 Injection, USP, use 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility alternative infant nutrition sources (e.g. stored breast milk or infant formula) for 2 hours (>10 half-lives of Long term animal studies have not been performed to evaluate the carcinogenic potential of Ammonia N-13 radioactive decay for N-13 isotope) after administration of the drug or avoid use of the drug, taking into account Injection, USP. Genotoxicity assays and impairment of male and female fertility studies with Ammonia N-13 the importance of the drug to the mother. Injection, USP have not been performed.

8.4 Pediatric Use 14 CLINICAL STUDIES

The safety and effectiveness of Ammonia N-13 Injection, USP has been established in pediatric patients based on 2 In a descriptive, prospective, blinded image interpretation study of adult patients with known or suspected known metabolism of ammonia, radiation dosimetry in the pediatric population, and clinical studies in adults [see coronary artery disease, myocardial perfusion deficits in stress and rest PET images obtained with Ammonia N-13 Dosage and Administration (2.4)]. (N=111) or Rubidium 82 (N=82) were compared to changes in stenosis flow reserve (SFR) as determined by 11 DESCRIPTION coronary angiography. The principal outcome of the study was the evaluation of PET defect severity relative to SFR. 11.1 Chemical Characteristics 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), Ammonia N-13 Injection, USP is a positron emitting radiopharmaceutical that is used for diagnostic purposes in 13 probable (2), mild (3), moderate (4), and severe (5) defects. Coronary angiograms were used to measure absolute conjunction with positron emission tomography (PET) imaging. The active ingredient, [ N] ammonia, has the 13 and relative stenosis dimensions and to calculate stenosis flow reserve defined as the maximum value of flow at molecular formula of NH with a molecular weight of 16.02, and has the following chemical structure: 3 maximum coronary vasodilatation relative to rest flow under standardized hemodynamic conditions. SFR scores ranged from 0 (total occlusion) to 5 (normal). With increasing impairment of flow reserve, the subjective PET defect severity increased. A PET defect score of 2 or higher was positively correlated with flow reserve impairment (SFR<3).

15 REFERENCES Ammonia N-13 Injection, USP is provided as a ready to use sterile, pyrogen-free, clear and colorless solution. 1. Annals of the ICRP. Publication 53. Radiation dose to patients from radiopharmaceuticals. New York: Each mL of the solution contains between 0.138 GBq to 1.387 GBq (3.75 mCi to 37.5 mCi) of [13N] ammonia, at Pergamon Press, 1988. the end of synthesis (EOS) reference time, in 0.9% aqueous sodium chloride. The pH of the solution is between 2. Demer, L.L.K.L.Gould, R.A.Goldstein, R.L.Kirkeeide, N.A.Mullani, R.W. Smalling, A.Nishikawa, and 4.5 to 7.5. The recommended dose of radioactivity (10-20 mCi) is associated with a theoretical mass dose of 0.5- M.E.Merhige. Assessment of coronary artery disease severity by PET: Comparison with quantitative 1.0 picomoles of ammonia. arteriography in 193 patients. Circulation 1989; 79: 825-35.

11.2 Physical Characteristics 16 HOW SUPPLIED/STORAGE AND HANDLING

Nitrogen N-13 decays by emitting positron to Carbon C-13 (stable) and has a physical half-life of 9.96 minutes. Ammonia N-13 Injection, USP is packaged in 10 mL multiple dose glass vial containing between 1.11–11.1 GBq The principal photons useful for imaging are the dual 511 keV gamma photons that are produced and emitted (30–300 mCi/mL) of [13N] ammonia, at the end of synthesis (EOS) reference time, in 0.9% sodium chloride simultaneously in opposite direction when the positron interacts with an electron (Table 2). injection solution in approximately 8 mL to 10 mL volume. The recommended dose of radioactivity (10-20 mCi) Table 2: Principal Radiation Emission Data for Nitrogen 13 is associated with a theoretical mass dose of 0.5-1.0 picomoles of Ammonia. Radiation/Emission % Per Disintegration Energy NDC 65857-200-10 Positron(β+) 100 1190 keV (Max.) Storage Gamma(±)a 200 511.0 keV a) Produced by positron annihilation. Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). Use the solution within 60 minutes of the End of Synthesis (EOS) calibration. The specific gamma ray constant (point source air kerma coefficient) for nitrogen N-13 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, or 2.9 mm 17 PATIENT COUNSELING INFORMATION tungsten (W) alloy. 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 or 28 mm of tungsten alloy will attenuate the external radiation 17.1 Pre-study Hydration by a factor of about 1000. Instruct patients to drink plenty of water or other fluids (as tolerated) in the 4 hours before their PET study. Table 3: Radiation Attenuation of 511 keV Photons by Lead (Pb) Shielding 17.2 Post-study Voiding Shield Thickness Shield Thickness Coefficient of (Pb) mm (W) Alloy mm Attenuation Instruct patients to void after completion of each image acquisition session and as often as possible for one hour 0 0 0.00 after the PET scan ends. 4 2.9 0.50 8 5.8 0.25 17.3 Post-study Breastfeeding Avoidance 13 9.4 0.10 26 18.7 0.01 Instruct nursing patients to substitute stored breast milk or infant formula for breast milk for 2 hours after administration of Ammonia N-13 Injection, USP. 39 27.6 0.001 Table 4 lists fractions remaining at selected time intervals from the calibration time. This information may be Manufactured by: used to correct for physical decay of the radionuclide. Cardinal Health 414, LLC 7000 Cardinal Place Table 4: Physical Decay Chart for Nitrogen N-13 Dublin, OH 43017 Minutes Fraction Remaining a Distributed by: 0 1.000 Cardinal Health 414, LLC 5 0.706 7000 Cardinal Place 10 0.499 Dublin, OH 43017 15 0.352 20 0.249 Revised: 06/2013 25 0.176 30 0.124 60 0.016 a) calibration time

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Ammonia N-13 Injection, USP is a radiolabeled analog of ammonia that is distributed to all organs of the body after intravenous administration. It is extracted from the blood in the coronary capillaries into the myocardial cells where it is metabolized to glutamine N-13 and retained in the cells. The presence of ammonia N-13 and glutamine N-13 in the myocardium allows for PET imaging of the myocardium. External Radiation Deposition of radioactivity in bone is rapid and appears to be related The technetium Tc 99m labeling reactions involved in preparing the Kit for the Preparation of Technetium The specific gamma ray constant for Tc 99m is 0.78 R/ hour-millicurie at to osteogenic activity as well as the aforementioned skeletal blood agent depend on maintaining the stannous ion in the reduced state. Any Tc99mMedronate 1 cm. The first half-value layer is 0.017 cm lead (Pb). A range of values perfusion. Skeletal uptake is bilaterally uniform, with larger concentrations oxidant present in the sodium pertechnetate Tc 99m supply may, thus, for the relative attenuation of the radiation emitted by this radionuclide in the axial structure and in the long bones. Increased accumulation of adversely affect the quality of the radiopharmaceutical. Hence, sodium that results from interposition of various thicknesses of Pb is shown in radioactivity may be seen, generally, in any bone disease state in which pertechnetate Tc 99m containing oxidants should not be employed. For Diagnostic Use Table 2. To facilitate control of the radiation exposure from millicurie there is increased osteogenesis or a localized increase in osseous blood Radiopharmaceuticals should be used only by physicians who are amounts of this radionuclide, the use of a 0.25 cm thickness of Pb will perfusion; consequently, bone imaging agents generally are not effective qualified by training and experience in the safe use and handling of attenuate the radiation emitted by a factor of about 1,000. in detecting chronic bone diseases. radionuclides. DESCRIPTION TABLE 2 INDICATIONS AND USAGE Carcinogenesis, Mutagenesis, Impairment of Fertility Each reaction vial contains a sterile, nonpyrogenic, nonradioactive Radiation Attenuation by Lead Shielding Technetium Tc 99m medronate may be used as a bone imaging agent to No long-term animal studies have been performed to evaluate carcinogenic lyophilized mixture of 20 mg medronic acid, 1 mg ascorbic acid, 0.13 mg Shield Thickness (Pb) cm Coefficient of Attenuation delineate areas of altered osteogenesis. (minimum) stannous fluoride, SnF and 0.38 mg total tin, maximum potential or whether technetium Tc 99m medronate affects fertility in males 2 0.017 0.5 or females. (as stannous fluoride, SnF2). CONTRAINDICATIONS 0.08 10-1 The pH is adjusted with sodium hydroxide or hydrochloric acid to 6.5 (6.3 None known. 0.16 10-2 Pregnancy to 6.7) prior to lyophilization. The vial does not contain a preservative. Animal reproduction studies have not been conducted with technetium -3 The contents of the vial are lyophilized and sealed under nitrogen at the 0.25 10 WARNINGS Tc 99m medronate. It is also not known whether technetium Tc 99m time of manufacture. 0.33 10-4 This class of compounds is known to complex cations such as calcium. medronate can cause fetal harm when administered to a pregnant woman The pH of the reconstituted product is 5.4 to 6.8. Particular caution should be used with patients who have or who may be To correct for physical decay of technetium Tc 99m, the fractions that or can affect reproductive capacity. Technetium Tc 99m medronate predisposed to hypocalcemia (i.e., alkalosis). The structure of medronic acid is given below: remain at selected intervals after the time of calibration are shown in should be given to a pregnant woman only if clearly needed. Table 3. Preliminary reports indicate interference with brain scans using sodium TABLE 3 pertechnetate Tc 99m injection which have been preceded by a bone Nursing Mothers scan using an agent containing stannous . This interference may Technetium Tc 99m is excreted in human milk during lactation; therefore, Physical Decay Chart: Tc 99m, half-life 6.02 hours result in false-positive or false-negative brain scans. It is recommended, formula-feedings should be substituted for breast-feedings. Fraction Fraction where feasible, that brain scans precede bone imaging procedures. Hours Remaining Hours Remaining Pediatric Use The precise structure of technetium Tc 99m medronate is unknown at 0* 100.0 7 0.447 PRECAUTIONS Safety and effectiveness in children have not been established. this time. 1 0.891 8 0.398 General The contents of the kit before preparation are not radioactive. However, ADVERSE REACTIONS When sterile, pyrogen-free sodium pertechnetate Tc 99m injection is 2 0.794 9 0.355 added to the vial, the diagnostic agent technetium Tc 99m medronate is after the sodium pertechnetate Tc 99m injection is added, adequate Several adverse reactions due to technetium Tc 99m medronate formed for administration by intravenous injection. 3 0.708 10 0.316 shielding of the final preparation must be maintained. have been reported. These were usually hypersensitivity reactions 4 0.631 11 0.282 Contents of the reaction vial are intended only for use in the preparation characterized by itching, various skin rashes, hypotension, chills, nausea PHYSICAL CHARACTERISTICS 5 0.562 12 0.251 of technetium Tc 99m medronate and are NOT to be administered directly and vomiting. There have also been rare cases of dizziness and asthenia Technetium Tc 99m decays by isomeric transition with a physical half- to the patient. associated with the use of technetium Tc 99m medronate. life of 6.02 hours.1 The principal photon that is useful for detection and 6 0.501 Technetium Tc 99m medronate as well as other radioactive drugs, imaging studies is shown in Table 1. *Calibration Time DOSAGE AND ADMINISTRATION must be handled with care. Once sodium pertechnetate Tc 99m is added After preparation with oxidant-free sodium pertechnetate Tc 99m TABLE 1 CLINICAL PHARMACOLOGY to the vial, appropriate safety measures should be used to minimize injection the suggested dose range of technetium Tc 99m medronate Principal Radiation Emission Data During the initial 24 hours following intravenous injection of technetium external radiation to clinical occupational personnel. Care should also be Tc 99m medronate, about 50 percent of the dose is retained in the injection in the average patient (70 kg) is 370 MBq to 740 MBq (10 mCi Mean % per Mean Energy taken to minimize radiation exposure to patients in a manner consistent skeleton, and about 50 percent is excreted in the urine. A minimum to 20 mCi) given intravenously. Imaging post injection is optimal at 1 to Radiation Disintegration (keV) with proper patient management. amount of uptake has been observed in soft-tissue organs, most notably 4 hours. To minimize the radiation dose to the bladder, the patient should be Gamma-2 89.07 140.5 the kidneys. The patient dose should be measured by a suitable radioactivity encouraged to drink fluids and to void immediately before the examination 1 Kocher, David C: Radioactive Decay Data Tables, DOE/TlC-11026, calibration system immediately prior to administration. Clearance of radioactivity from the blood is quite rapid, with about and as often thereafter as possible for the next four to six hours. 108, 1981 10 percent of the injected dose remaining at one hour, and less than Parenteral drug products should be inspected visually for particulate Technetium Tc 99m medronate should be formulated within six (6) 5 and 2 percent at two and four hours, respectively. The rapid blood matter and discoloration prior to administration whenever solution hours prior to clinical use. Optimal imaging results are obtained one to clearance (T ½: 38 to 75 minutes) provides bone to non-osseous tissue and container permit. Shielding should be utilized when preparing the four hours after administration. Technetium Tc 99m medronate injection ratios favoring early imaging. technetium Tc 99m medronate injection. should be discarded six hours after reconstitution. The solution should Following intravenous administration of technetium Tc 99m medronate, not be used if cloudy. skeletal uptake occurs as a function of blood flow to bone and bone The components of the kit are sterile and pyrogen-free. It is essential efficiency in extracting the complex. Bone mineral crystals are generally to follow directions carefully and to adhere to strict aseptic procedures considered to be hydroxyapatite, and the complex appears to have an during preparation. affinity for the hydroxyapatite crystals in bone. Radiation Dosimetry DIRECTIONS FOR PREPARATION OF The effective half-life was assumed to be the physical half-life for all TECHNETIUM Tc 99m MEDRONATE calculated values. The estimated radiation absorbed doses to an average Procedural Precautions patient (70 kg) from an intravenous injection of a maximum dose of The lyophilized powder in the reaction vial is sterile and nonpyrogenic 740 MBq (20 mCi) of technetium Tc 99m medronate are shown in Table 4. and does not contain a preservative. Aseptic procedure and shielded syringes should be used when adding the pertechnetate eluate to TABLE 4 the reaction vial and for withdrawal and administration of the dose of the 124659 Absorbed Radiation Dose finished medronate agent. Waterproof gloves should be worn to prevent Organ mGy/740 MBq rads/20 mCi the possibility of radioactive contamination of the hands. Total Body 1.3 0.13 If sodium pertechnetate Tc 99m must be diluted prior to injection into the Bone Total 7.0 0.70 reaction vial, only preservative-free 0.9% Sodium Chloride Injection USP should be used. Red Marrow 5.6 0.56 Kidneys 8.0 0.80 Preparation KitforthePreparationof Liver 0.6 0.06 Preparation of technetium Tc 99m medronate is done by the following aseptic procedure: Technetium Tc 99m Bladder Wall 2-hr. void 26.0 2.60 1. Waterproof gloves should be worn during the preparation procedure. Medronate 4.8-hr. void 62.0 6.20 2. Place reaction vial in an appropriate lead shield. Ovaries 2-hr. void 2.4 0.24 3. Remove the central disc from the reaction vial and swab the rubber 4.8-hr. void 3.4 0.34 closure of the reaction vial with a germicide. BARCODE 4. With a sterile syringe, aseptically obtain 0.5 mL to 5 mL [up to Testes 2-hr.void 1.6 0.16 18,500 MBq (500 mCi)] of a suitable, oxidant-free, sterile nonpyrogenic FPO 4.8-hr. void 2.2 0.22 sodium pertechnetate. 5. Aseptically add the sodium pertechnetate Tc 99m solution to the Method of Calculation: “S” Absorbed Dose per Unit Cumulated Activity vial. for Selected Radionuclides and Organs, MIRD Pamphlet No. 11, 1975 6. Secure the lead shield cover. Swirl the vial for one minute and let stand for one to two minutes. HOW SUPPLIED 7. Record the date and time of preparation on pressure-sensitive label. Kit for the Preparation of Technetium Tc 99m Medronate is supplied as 8. Affix pressure-sensitive label to shield. kits of 10 reaction vials (NDC 65857-505-10). 9. Examine vial contents. If the solution is not clear and free of Each reaction vial contains a sterile, nonpyrogenic, nonradioactive particulate matter and discoloration on visual inspection, it should lyophilized mixture of 20 mg medronic acid, 1 mg ascorbic acid, 0.13 mg not be used.

(minimum) stannous fluoride, SnF2 and 0.38 mg total tin, maximum (as 10. Measure the radioactivity using a suitable calibration system and stannous fluoride, SnF2). record on the shield label prior to patient administration. The pH is adjusted with sodium hydroxide or hydrochloric acid prior to 11. Aseptically withdraw material for use within six (6) hours of 124659BARCODE lyophilization. The vial does not contain a preservative. The contents preparation. For optimum results, this time should be minimized. of the vial are lyophilized and sealed under nitrogen at the time of The vial contains no bacteriostatic preservative. FPO manufacture. The pH of the reconstituted product is 5.4 to 6.8. The U.S. Nuclear Regulatory Commission has approved this reagent kit Kit Contents for distribution to persons licensed to use byproduct material identified in 10 sterile reaction vials §35.200 of 10 CFR Part 35, to persons who hold an equivalent license 20 pressure-sensitive labels for technetium Tc 99m medronate issued by an Agreement State, and, outside the United States, to persons 1 package insert authorized by the appropriate authority.

Storage Distributed by: Store the product as supplied at 20° to 25°C (68° to 77°F). After Cardinal Health 414, LLC reconstitution store refrigerated at 2° to 8°C (36° to 46°F) (see DOSAGE AND Dublin, OH 43017 ADMINISTRATION). Do not use and discard radiolabeled technetium Tc 99m medronate 6 Revised November 2020 hours after reconstitution.

875014-H01 consistent with seizure occurring shortly after administration of the agent; transient arthritis; Table 1 Radiation Absorbed Doses from Tc 99m Sestamibi 3. Apply 1 drop of ethanol* using a 1 mL syringe with a 22–26 gauge needle, 1.5 cm from the angioedema, arrhythmia, dizziness, syncope, abdominal pain, vomiting, and severe hypersensitiv- bottom of the plate. THE SPOT SHOULD NOT BE ALLOWED TO DRY. ity characterized by dyspnea, hypotension, bradycardia, asthenia, and vomiting within two hours after a second injection of Technetium Tc 99m Sestamibi. A few cases of flushing, edema, Estimated Radiation Absorbed Dose 4. Add 2 drops of Technetium Tc 99m Sestamibi solution, side by side on top of the injection site inflammation, dry mouth, fever, pruritus, rash, urticaria and fatigue have also been ethanol* spot. Return the plate to a desiccator and allow the sample spot to dry attributed to administration of the agent(6). REST (typically 15 minutes). 2.0 hour void 4.8 hour void To report SUSPECTED ADVERSE REACTIONS, contact Cardinal Health at: 5. The TLC tank is prepared by pouring ethanol* to a depth of 3-4 mm. Cover the tank and let Organ rads/ mGy/ rads/ mGy/ 1-800-618-2768 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. it equilibrate for ~10 minutes. ------DRUG INTERACTIONS------30 mCi 1110 MBq 30 mCi 1110 MBq

• Specific drug-drug interactions have not been studied (7). Breasts 0.2 2.0 0.2 1.9 6. Develop the plate in the covered TLC tank in ethanol* for a distance of 5 cm from the point

875028-H03 875028-H03 Gallbladder Wall 2.0 20.0 2.0 20.0 of application. Rev June 2016 2016 June Rev ------USE IN SPECIFIC POPULATIONS------Small Intestine 3.0 30.0 3.0 30.0 In one study of 46 subjects who received Technetium Tc 99m Sestamibi administration, the 7. Cut the TLC plate 4 cm from the bottom and measure the Tc 99m activity in each piece by Upper Large appropriate radiation detector. radioactivity in both children and adolescents exhibited blood PK profiles similar to those Intestine Wall 5.4 55.5 5.4 55.5 previously reported in adults (8.4). Lower Large 8. Calculate the % Tc 99m Sestamibi as: See 17 for PATIENT COUNSELING INFORMATION Intestine Wall 3.9 40.0 4.2 41.1 Revised: [06/ 2016] Stomach Wall 0.6 6.1 0.6 5.8 µCi Top Piece ______

Heart Wall 0.5 5.1 0.5 4.9 % Tc 99m Sestamibi = X 100

Kidneys 2.0 20.0 2.0 20.0 µCi Both Pieces Technetium Tc 99m Sestamibi Injection Injection Sestamibi 99m Tc Technetium FULL PRESCRIBING INFORMATION: CONTENTS* Liver 0.6 5.8 0.6 5.7

Lungs 0.3 2.8 0.3 2.7 TLC Plate Diagram Kit for the Preparation of of Preparation the for Kit Bone Surfaces 0.7 6.8 0.7 6.4 TOP Thyroid 0.7 7.0 0.7 2.4 1 INDICATIONS AND USAGE Ovaries 1.5 15.5 1.6 15.5 2 DOSAGE AND ADMINISTRATION Testes 0.3 3.4 0.4 3.9 SOLVENT 2.1 Image Acquisition Red Marrow 0.5 5.1 0.5 5.0 2.2 Radiation Dosimetry Urinary Bladder Wall 2.0 20.0 4.2 41.1 FRONT 2.3 Instructions for Preparation Total Body 0.5 4.8 0.5 4.8 2.4 Determination of Radiochemical Purity in Technetium Tc 99m Sestamibi 3 DOSAGE FORMS AND STRENGTHS STRESS 4 CONTRAINDICATIONS 2.0 hour void 4.8 hour void 5 WARNINGS AND PRECAUTIONS Organ rads/ mGy/ rads/ mGy/ CUT HERE 5.1 Warnings 30 mCi 1110 MBq 30 mCi 1110 MBq 5.2 General Precautions Breasts 0.2 2.0 0.2 1.8 Kit for the Preparation of 6 ADVERSE REACTIONS Gallbladder Wall 2.8 28.9 2.8 27.8 Technetium Tc 99m Sestamibi Injection 7 DRUG INTERACTIONS Small Intestine 2.4 24.4 2.4 24.4 8 USE IN SPECIFIC POPULATIONS Upper Large 8.1 Pregnancy Intestine Wall 4.5 44.4 4.5 44.4 8.3 Nursing Mothers ORIGIN 8.4 Pediatric Use Lower Large 8.5 Geriatric Use Intestine Wall 3.3 32.2 3.3 32.2 Apply 2 adjacent 9 DRUG ABUSE AND DEPENDENCE Stomach Wall 0.6 5.3 0.5 5.2 drops of sample 9.1 Controlled Substance Heart Wall 0.5 5.6 0.5 5.3 Rev June 2016 9.2 Abuse Kidneys 1.7 16.7 1.7 16.7 BOTTOM 875028-H03 9.3 Dependence Liver 0.4 4.2 0.4 4.1 10 OVERDOSAGE Lungs 0.3 2.6 0.2 2.4 11 DESCRIPTION Bone Surfaces 0.6 6.2 0.6 6.0 *The ethanol used in this procedure should be 95% or greater. Absolute ethanol (99%) should remain 11.1 Physical Characteristics Thyroid 0.3 2.7 0.2 2.4 at ≥95% ethanol content for one week after opening if stored tightly capped, in a cool dry place. 11.2 External Radiation Ovaries 1.2 12.2 1.3 13.3 3 DOSAGE FORMS AND STRENGTHS 12 CLINICAL PHARMACOLOGY Testes 0.3 3.1 0.3 3.4 Kit for the Preparation of Technetium Tc 99m Sestamibi Injection is supplied as a 5-mL vial in kits of 12.3 Pharmacokinetics Red Marrow 0.5 4.6 0.5 4.4 five (5) (NDC # 65857-500-05) and twenty (20) (NDC # 65857-500-20), sterile and non-pyrogenic. 12.4 Metabolism Urinary Bladder Wall 1.5 15.5 3.0 30.0 Prior to lyophilization the pH is between 5.3–5.9. The contents of the vial are lyophilized and stored 12.5 Elimination Total Body 0.4 4.2 0.4 4.2 under nitrogen. Store at 15–25 °C (59–77 °F) before and after reconstitution. Kit for the Preparation of 13 NONCLINICAL TOXICOLOGY Technetium Tc 99m Sestamibi Injection contains no preservatives. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Radiation dosimetry calculations performed by Radiation Internal Dose Information Center, Included in each five (5) vial kit is one (1) package insert, six (6) vial shield labels and six (6) radiation 14 CLINICAL STUDIES Oak Ridge Institute for and Education, PO Box 117, Oak Ridge, TN 37831-0117, warning labels. Included in each twenty (20) vial kit is one (1) package insert, twenty four (24) vial shield labels and twenty four (24) radiation warning labels. HIGHLIGHTS OF PRESCRIBING INFORMATION 15 REFERENCES (865) 576-3448. This reagent kit is approved for distribution to persons licensed by the U.S. Nuclear Regulatory These highlights do not include all the information needed to use Kit for the 16 HOW SUPPLIED/STORAGE AND HANDLING 2.3 Instructions for Preparation Commission to use byproduct material identified in 10 CFR 35.200 or under an equivalent license Preparation of Technetium Tc 99m Sestamibi Injection safely and effectively. 17 PATIENT COUNSELING INFORMATION issued by an Agreement State or Licensing State. See full prescribing information for Kit for the Preparation of Technetium Preparation of the Technetium Tc 99m Sestamibi from the Kit for the Preparation of Technetium Tc 99m 4 CONTRAINDICATIONS Tc 99m Sestamibi Injection. *Sections or subsections omitted from the full prescribing information are not listed. Sestamibi Injection is done by the following aseptic procedure: None known. Kit for the Preparation of Technetium Tc 99m Sestamibi Injection Boiling Water Bath Procedure: a. Prior to adding the Sodium Pertechnetate Tc 99m Injection to the vial, inspect the vial carefully 5 WARNINGS AND PRECAUTIONS Initial U.S. Approval: 1990 for the presence of damage, particularly cracks, and do not use the vial if found. Tear off a 5.1 Warnings ------INDICATIONS AND USAGE------radiation symbol and attach it to the neck of the vial. Technetium Tc 99m Sestamibi is a myocardial perfusion agent indicated for: FULL PRESCRIBING INFORMATION In studying patients in whom cardiac disease is known or suspected, care should be taken to b. Waterproof gloves should be worn during the preparation procedure. Remove the plastic disc assure continuous monitoring and treatment in accordance with safe, accepted clinical procedure. • detecting coronary artery disease by localizing myocardial ischemia (reversible defects) and from the vial and swab the top of the vial closure with alcohol to sanitize the surface. Infrequently, death has occurred 4 to 24 hours after Tc 99m Sestamibi use and is usually associated infarction (non-reversible defects)(1) 1 INDICATIONS AND USAGE c. Place the vial in a suitable radiation shield with a fitted radiation cap. with exercise stress testing [see WARNINGS AND PRECAUTIONS (5.2)]. Myocardial Imaging: Technetium Tc 99m Sestamibi Injection is a myocardial perfusion agent that is in- • evaluating myocardial function and developing information for use in patient management dicated for detecting coronary artery disease by localizing myocardial ischemia (reversible defects) and decisions(1) d. With a sterile shielded syringe, aseptically obtain additive-free, sterile, non-pyrogenic Pharmacologic induction of cardiovascular stress may be associated with serious adverse events such ------DOSAGE AND ADMINISTRATION------infarction (non-reversible defects), in evaluating myocardial function and developing information for use Sodium Pertechnetate Tc 99m Injection [925-5550 MBq, (25–150 mCi)] in approximately 1 to as myocardial infarction, arrhythmia, hypotension, bronchoconstriction and cerebrovascular events. • For Myocardial Imaging: The suggested dose range for I.V. administration of in patient management decisions. Technetium Tc 99m Sestamibi evaluation of myocardial ischemia can 3 mL. Caution should be used when pharmacologic stress is selected as an alternative to exercise; it should Technetium Tc 99m Sestamibi in a single dose to be employed in the average patient be accomplished with rest and cardiovascular stress techniques (e.g., exercise or pharmacologic stress e. Aseptically add the Sodium Pertechnetate Tc 99m Injection to the vial in the lead shield. be used when indicated and in accordance with the pharmacologic stress agent’s labeling. in accordance with the pharmacologic stress agent’s labeling). (70 Kg) is 370–1110 MBq (10–30 mCi) (2). Without withdrawing the needle, remove an equal volume of headspace to maintain Technetium Tc 99m Sestamibi has been rarely associated with acute severe allergic and anaphylactic It is usually not possible to determine the age of a myocardial infarction or to differentiate a recent atmospheric pressure within the vial. myocardial infarction from ischemia. events of angioedema and generalized urticaria. In some patients the allergic symptoms developed • For Breast Imaging: The recommended dose range for I.V. administration of f. Shake vigorously, about 5 to 10 quick upward-downward motions. on the second injection during Tc 99m Sestamibi imaging. Patients who receive Technetium Tc 99m Technetium Tc 99m Sestamibi is a single dose of 740–1110 MBq (20–30 mCi) (2). Breast Imaging: Technetium Tc 99m Sestamibi Injection is indicated for planar imaging as a second g. Remove the vial from the lead shield and place upright in an appropriately shielded and Sestamibi for either myocardial or breast imaging are receiving the same drug. Caution should be ------DOSAGE FORMS AND STRENGTHS------line diagnostic drug after mammography to assist in the evaluation of breast lesions in patients with an contained boiling water bath, such that the vial is suspended above the bottom of the bath, exercised and emergency equipment should be available when administering Technetium Tc 99m Sestamibi. Also, before administering Technetium Tc 99m Sestamibi Injection, patients should be • Kit for the Preparation of Technetium Tc 99m Sestamibi Injection is supplied as a 5-mL abnormal mammogram or a palpable breast mass. and boil for 10 minutes. Timing for 10 minutes is begun as soon as the water begins to boil asked about the possibility of allergic reactions to the drug. vial in kits of five (5) (NDC # 65857-500-05) and twenty (20) (NDC # 65857-500-20) sterile Technetium Tc 99m Sestamibi is not indicated for breast cancer screening, to confirm the presence or again. Do not allow the boiling water to come in contact with the aluminum crimp. and non-pyrogenic (3). absence of malignancy, and it is not an alternative to biopsy. h. Remove the vial from the water bath, place in the lead shield and allow to cool for fifteen 5.2 General Precautions • Prior to lyophilization the pH is between 5.3–5.9. The contents of the vial are minutes. The contents of the vial are intended only for use in the preparation of Technetium Tc 99m Sestamibi 2 DOSAGE AND ADMINISTRATION lyophilized and stored under nitrogen. Store at 15–25 °C (59–77 °F) i. Using proper shielding, the vial contents should be visually inspected. Use only if the solution and are not to be administered directly to the patient without first undergoing the preparative procedure. For Myocardial Imaging: The suggested dose range for I.V. administration of Technetium Tc 99m Ses- before and after reconstitution. is clear and free of particulate matter and discoloration. tamibi in a single dose to be employed in the average patient (70 Kg) is 370–1110 MBq (10–30 mCi). Radioactive drugs must be handled with care and appropriate safety measures should be used to j. Assay the reaction vial using a suitable radioactivity calibration system. Record the minimize radiation exposure to clinical personnel. Also, care should be taken to minimize radiation ------CONTRAINDICTIONS------Technetium Tc 99m concentration, total volume, assay time and date, expiration time and lot exposure to the patients consistent with proper patient management. For Breast Imaging: The recommended dose range for I.V. administration of Technetium Tc 99m • None known. number on the vial shield label and affix the label to the shield. ------WARNINGS AND PRECAUTIONS------Sestamibi is a single dose of 740–1110 MBq (20–30 mCi). Contents of the kit before preparation are not radioactive. However, after the Sodium Pertechnetate k. Store the reaction vial containing the Technetium Tc 99m Sestamibi at 15° to 25 °C until use; Tc 99m Injection is added, adequate shielding of the final preparation must be maintained. The • Pharmacologic induction of cardiovascular stress may be associated with serious 2.1 Image Acquisition at such time the product should be aseptically withdrawn. Technetium Tc 99m Sestamibi components of the kit are sterile and non-pyrogenic. It is essential to follow directions carefully and to adverse events such as myocardial infarction, arrhythmia, hypotension, bronchoconstriction should be used within six hours of preparation. The vial contains no preservative. adhere to strict aseptic procedures during preparation. and cerebrovascular events (5.1). Breast Imaging: It is recommended that images are obtained with a table overlay to separate breast Note: Adherence to the above product reconstitution instructions is recommended. tissue from the myocardium and liver, and to exclude potential activity that may be present in the Technetium Tc 99m labeling reactions depend on maintaining the stannous ion in the reduced state. • Technetium Tc 99m Sestamibi has been rarely associated with acute severe allergic opposite breast. For lateral images, position the patient prone with the isolateral arm comfortably Cardinal Health 414, LLC’s Kit for the Preparation of Technetium Tc 99m Sestamibi Injection is not Hence, Sodium Pertechnetate Tc 99m Injection containing oxidants should not be used. and anaphylactic events of angioedema and generalized urticaria. In some patients the above the head, shoulders flat against the table, head turned to the side and relaxed, with the breast to be used with the Recon-o-Stat™ thermal cycler due to the smaller vial size requirements of this allergic symptoms developed on the second injection during Technetium Tc 99m Sestamibi Technetium Tc 99m Sestamibi should not be used more than six hours after preparation. imaged pendent through an overlay cutout. The breast should not be compressed on the overlay. heating device. imaging (5.1). For anterior images, position the patient supine with both arms behind the head. For either lateral The potential for cracking and significant contamination exists whenever vials containing radioactive Radiopharmaceuticals should be used only by physicians who are qualified by training and experience • Caution should be exercised and emergency equipment should be available when administer- or anterior images, shield the chest and abdominal organs, or remove them from the field of view. material are heated. in the safe use and handling of radionuclides and whose experience and training have been approved ing Technetium Tc 99m Sestamibi (5.1). by the appropriate government agency authorized to license the use of radionuclides. Product should be used within 6 hours after preparation. • Before administering Technetium Tc 99m Sestamibi Injection, patients should be asked about For complete study, sets of images should be obtained five minutes after the injection, and in the Stress testing should be performed only under the supervision of a qualified physician and in a labora- the possibility of allergic reactions to either drug (5.1). following sequence: Final product with radiochemical purity of at least 90% was used in the clinical trials that established tory equipped with appropriate resuscitation and support apparatus. Beginning five minutes after the injection of Technetium Tc 99m Sestamibi: safety and effectiveness. The radiochemical purity was determined by the following method. The most frequent exercise stress test endpoints sufficient to stop the test reported during • The contents of the vial are intended only for use in the preparation of Technetium • ten-minute lateral image of breast with abnormality controlled studies (two-thirds were cardiac patients) were: Tc 99m Sestamibi and are not to be administered directly to the patient without first • ten-minute lateral image of contralateral breast 2.4 Determination of Radiochemical Purity in Technetium Tc 99m Sestamibi undergoing the preparative procedure (5.2). • ten-minute anterior image of both breasts Fatigue 35% 1. Obtain a Baker-Flex Aluminum coated, plastic TLC plate, #1 B-F, pre-cut to Dyspnea 17% ------ADVERSE REACTIONS------2.2 Radiation Dosimetry 2.5 cm x 7.5 cm. Chest Pain 16% The following adverse reactions have been reported in ≤ 0.5% of patients: signs and symptoms The radiation doses to organs and tissues of an average patient (70 Kg) per 1110 MBq (30 mCi) of 2. Dry the plate or plates at 100°C for 1 hour and store in a desiccator. Remove pre-dried plate ST-depression 7% Technetium Tc 99m Sestamibi injected intravenously are shown in Table 1. from the desiccator just prior to use. Arrhythmia 1% 6 ADVERSE REACTIONS 10 OVERDOSAGE Myocardial uptake which is coronary flow dependent is 1.2% of the injected dose at rest and 1.5% of Table 8 Overall Technetium Tc 99m Sestamibi Blinded Results of Target the injected dose at exercise. Table 6 illustrates the biological clearance as well as effective clearance Adverse events were evaluated in 3741 adults who were evaluated in clinical studies. Of these patients, The clinical consequences of overdosing with Technetium Tc 99m Sestamibi are not known. Lesions(a) Identified at Study Entry(b) 3068 (77% men, 22% women, and 0.7% of the patients’ genders were not recorded) were in cardiac (which includes biological clearance and radionuclide decay) of Tc 99m Sestamibi from the heart and liver. Study A clinical trials and 673 (100% women) in breast imaging trials. Cases of angina, chest pain, and death 11 DESCRIPTION Study B have occurred [see WARNINGS AND PRECAUTIONS (5)]. Adverse events reported at a rate of 0.5% or Each 5 mL vial contains a sterile, non-pyrogenic, lyophilized mixture of: STATISTIC Non-Palpable Mass and an [Organ concentrations expressed as percentage of injected dose; data based on an average of 5 Palpable Mass greater after receiving Technetium Tc 99m Sestamibi administration are shown in the following table: • Tetrakis (2-methoxy isobutyl isonitrile) Copper (I) tetrafluoroborate—1 mg Abnormal Mammogram subjects at rest and 5 subjects during exercise.] Table 2 Selected Adverse Events Reported in >0.5% of Patients Who Received Technetium • Sodium Citrate Dihydrate—2.6 mg N=277 Patients with N=206 Patients with Tc 99m Sestamibi in Either Breast or Cardiac Clinical Studies* Number of Patients and Lesions • L-Cysteine Hydrochloride Monohydrate—1 mg Table 6 300 Lesions 240 Lesions • Mannitol—20 mg Body System Breast Studies Cardiac Studies REST STRESS Sensitivity 52(42,62)(c) 76(67,83) Heart Liver Heart Liver Women Women Men Total • Stannous Chloride, Dihydrate, minimum (SnCl2•2H2O)—0.025 mg • Stannous Chloride, Dihydrate (SnCl2•2H2O)—0.075 mg Time Biological Effective Biological Effective Biological Effective Biological Effective Specificity 94(89,96) 85(77,91) n = 673 n = 685 n = 2361 n = 3046 5 min. 1.2 1.2 19.6 19.4 1.5 1.5 5.9 5.8 • Tin Chloride (stannous and stannic) Dihydrate, maximum (as SnCl2•2H2O)—0.086 mg (d) Body as a Whole 21 (3.1%) 6 (0.9%) 17 (0.7%) 23 (0.8%) PPV 79(67,88) 83(74,89) 30 min. 1.1 1.0 12.2 11.5 1.4 1.3 4.5 4.2 1 hour 1.0 0.9 5.6 5.0 1.4 1.2 2.4 2.1 (d) Headache 11 (1.6%) 2 (0.3%) 4 (0.2%) 6 (0.2%) Prior to lyophilization the pH is 5.3 to 5.9. The contents of the vial are lyophilized and stored under NPV 80(74,85) 78(69,84) 2 hours 1.0 0.8 2.2 1.7 1.2 1.0 0.9 0.7 Cardiovascular 9 (1.3%) 24 (3.5%) 75 (3.2%) 99 (3.3%) nitrogen. 4 hours 0.8 0.5 0.7 0.4 1.0 0.6 0.3 0.2 Agreement 80(75,85) 80(75,85) Chest Pain/Angina 0 (0%) 18 (2.6%) 46 (1.9%) 64 (2.1%) Prevalence 32(27,37) 49(43,56) ST segment changes 0 (0%) 11 (1.6%) 29 (1.2%) 40 (1.3%) This drug is administered by intravenous injection for diagnostic use after reconstitution with sterile, A study in a dog myocardial ischemia model reported that Technetium Tc 99m Sestamibi undergoes non-pyrogenic, oxidant-free Sodium Pertechnetate Tc 99m Injection. The pH of the reconstituted Digestive System 8 (1.2%) 4 (0.6%) 9 (0.4%) 13 (0.4%) myocardial distribution (redistribution), although more slowly and less completely than thallous chloride (a) Excludes all discordant lesions not identified at entry and excludes 25 equivocal product is 5.5 (5.0–6.0). No bacteriostatic preservative is present. interpretations from Study A and 32 equivocal interpretations from Study B Nausea 4 (0.6%) 1 (0.1%) 2 (0.1%) 3 (0.1%) T1-201. A study in a dog myocardial infarction model reported that the drug showed no redistribution of any consequence. Definitive human studies to demonstrate possible redistribution have not been (see Tables 9 and 10) Special Senses 132 (19.6%) 62 (9.1%) 160 (6.8%) 222 (7.3%) The precise structure of the technetium complex is Tc 99m[MIBI]6+where MIBI is 2-methoxy isobutyl reported. In patients with documented myocardial infarction, imaging revealed the infarct up to four (b) Some patients had more than one target lesion Taste Perversion 129 (19.2%) 60 (8.8%) 157 (6.6%) 217 (7.1%) isonitrile. hours post dose. (c) Median and approximated 95% Confidence Interval Parosmia 8 (1.2%) 6 (0.9%) 10 (0.4%) 16 (0.5%) (d) PPV=Positive Predict Value; NPV=Negative Predict Value Tetrakis (2-methoxy isobutyl isonitrile) Copper (I) tetrafluoroborate has the following structural formula: 12.4 Metabolism * Excludes the 22 patients whose genders were not recorded. The agent is excreted without any evidence of metabolism. In separate retrospective subset analyses of 259 patients with dense (heterogeneously/extremely dense) and 275 patients with fatty (almost entirely fat/numerous vague ) breast tissue, the In the clinical studies for breast imaging, breast pain was reported in 12 (1.7%) of the patients. 12.5 Elimination Technetium Tc 99m Sestamibi results were similar. Overall, the studies were not designed to compare In 11 of these patients the pain appears to be associated with biopsy/surgical procedures. The major pathway for clearance of Tc 99m Sestamibi is the hepatobiliary system. Activity from the the performance of Technetium Tc 99m Sestamibi with the performance of mammography in patients The following adverse reactions have been reported in < 0.5% of patients: signs and symptoms gall bladder appears in the intestines within one hour of injection. Twenty-seven percent of the injected with breast densities or other coexistent breast tissue disorders. consistent with seizure occurring shortly after administration of the agent; transient arthritis; dose is excreted in the urine, and approximately thirty-three percent of the injected dose is cleared angioedema, arrhythmia, dizziness, syncope, abdominal pain, vomiting, and severe hypersensitivity through the feces in 48 hours. In general the histology seems to correlate with the degree of Technetium Tc 99m Sestamibi uptake. characterized by dyspnea, hypotension, bradycardia, asthenia, and vomiting within two hours after As shown in Tables 9 and 10, the majority of the normal Technetium Tc 99m Sestamibi images are a second injection of Technetium Tc 99m Sestamibi. A few cases of flushing, edema, injection site 13 NONCLINICAL TOXICOLOGY associated with non-malignant tissue (78–81%) and the majority of low, moderate, or high uptake inflammation, dry mouth, fever, pruritus, rash, urticaria, and fatigue have also been attributed to Technetium Tc 99m Sestamibi images are associated with malignant disease (79–83%). In an administration of the agent. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility individual patient, however, the intensity of Technetium Tc 99m Sestamibi uptake can not be used to confirm the presence or absence of malignancy. Equivocal results do not have a correlation with 7 DRUG INTERACTIONS In comparison with most other diagnostic technetium labeled radiopharmaceuticals, the Specific drug-drug interactions have not been studied. radiation dose to the ovaries (1.5 rads/30 mCi at rest, 1.2 rads/30 mCi at exercise) is high. Mini- histology. mal exposure (ALARA) is necessary in women of childbearing capability [see DOSAGE AND 8 USE IN SPECIFIC PATIENTS ADMINISTRATION (2.2)]. Molecular Formula Molecular Weight Table 9 Degree of Technetium Tc 99m Sestamibi Breast Imaging Uptake in Comparison to Histopathology Results in Patients with 8.1 Pregnancy C24H44N4O4BF4Cu 602.98 The active intermediate, Cu(MIBI) BF , was evaluated for genotoxic potential in a battery of five tests. 4 4 Mammographically Detected Non-Palpable Lesions* (Study A) No genotoxic activity was observed in the Ames, CHO/HPRT and sister chromatid exchange tests Pregnancy Category C 11.1 Physical Characteristics (all in vitro). At cytotoxic concentrations (> 20 µg/mL), an increase in cells with chromosome aberrations Normal Uptake Equivocal Uptake Low, Moderate or Technetium Tc 99m decays by isomeric transition with a physical half-life of 6.02 hours.1 was observed in the in vitro human lymphocyte assay. Cu(MIBI)4BF4did not show genotoxic effects High Uptake Animal reproduction and teratogenicity studies have not been conducted with Technetium Tc 99m Photons that are useful for detection and imaging studies are listed below in Table 3. in the in vivo mouse micronucleus test at a dose which caused systemic and bone marrow toxicity N = 249 lesions N = 25 lesions N = 66 lesions Sestamibi. It is also not known whether Technetium Tc 99m Sestamibi can cause fetal harm when (9 mg/kg, > 600 x maximal human dose). administered to a pregnant woman or can affect reproductive capacity. There have been no studies Table 3 Principal Radiation Emission Data Non-malignant** 201 (81%) 14 (56%) 14 (21%) in pregnant women. Technetium Tc 99m Sestamibi should be given to a pregnant woman only if Mean % / Mean 14 CLINICAL STUDIES clearly needed. Radiation Disintegration Energy (KeV) Malignant 48 (19%) 11 (44%) 52 (79%) Gamma -2 89.07 140.5 CLINICAL TRIALS: * Median finding for 3 blinded readers 8.3 Nursing Mothers 1Kocher, David, C., Radioactive Decay Data Tables, DOE/TIC-11026, 108(1981). Technetium Tc 99m Pertechnetate is excreted in human milk during lactation. It is not known whether ** Includes benign tissue, fibroadenoma, benign intramammary nodes, radial scar. Technetium Tc 99m Sestamibi is excreted in human milk. Therefore, formula feedings should be MYOCARDIAL IMAGING: In a trial of rest and stress Technetium Tc 99m Sestamibi imaging, the rela- 11.2 External Radiation substituted for breast feedings. tionship of normal or abnormal perfusion scans and long term cardiac events was evaluated in 521 The specific gamma ray constant for Tc 99m is 5.4 microcoulombs/Kg-MBq-hr (0.78R/mCi-hr) at 1 patients (511 men, 10 women) with stable chest pain. There were 73.9% Caucasians, 25.9% Blacks, Table 10 cm. The first half value layer is 0.017 cm of Pb. A range of values for the relative attenuation of and 0.2% Asians. The mean age was 59.6 years (range: 29 to 84 years). All patients had a baseline 8.4 Pediatric Use Degree of Technetium Tc 99m Sestamibi Breast Imaging Uptake in Comparison to the radiation emitted by this radionuclide that results from interposition of various thicknesses of Pb rest and exercise Technetium Tc 99m Sestamibi scan and were followed for 13.2 ± 4.9 months (range: Safety and effectiveness in the pediatric population have not been established. Histopathology Results in Patients with Palpable Lesions* (Study B) No evidence of diagnostic efficacy or clinical utility of Technetium Tc 99m Sestamibi scan was found in is shown in Table 4. To facilitate control of the radiation exposure from Megabequerel (millicurie) 1 to 24 months). Images were correlated with the occurrence of a cardiac event (cardiac death or non- clinical studies of children and adolescents with Kawasaki disease. amounts of this radionuclide, the use of a 0.25 cm thickness of Pb will attenuate the radiation emitted fatal myocardial infarction). In this trial as summarized in Table 7, 24/521 (4.6%) had a cardiac event. by a factor of 1,000. Normal Uptake Equivocal Uptake Low, Moderate or A prospective study of 445 pediatric patients with Kawasaki disease was designed to determine the High Uptake Table 7 Cardiac Events N = 129 lesions N = 32 lesions N = 115 lesions predictive value of Technetium Tc 99m Sestamibi rest and stress myocardial perfusion imaging to Table 4 Radiation Attenuation by Lead Shielding define a pediatric population with Kawasaki disease that was at risk of developing cardiac events. Shield Thickness (Pb) cm Coefficient of Attenuation Baseline Proportion of patients Proportion of scan Proportion of event- Non-malignant** 100 (78%) 19 (59%) 20 (17%) Cardiac events were defined as cardiac death, MI, hospitalization due to cardiac etiology, heart 0.017 0.5 Scan(a) with events by scan result in patients free patients by failure, CABG or coronary angioplasty. The standard of truth was defined as cardiac events occurring Malignant 29 (22%) 13 (41%) 95 (83%) 0.08 10 -1 results(a) with events; N=24(a) scan results(a) 6 months following the administration of Technetium Tc 99m Sestamibi. Only three cardiac events -2 0.16 10 * Median finding for 3 blinded readers were observed at six months in this study. In all three cases, the scan was negative. No clinically -3 Normal 1/206 (0.5%) 1/24 (4.2%) 205/206 (99.5%) meaningful measurements of sensitivity, specificity or other diagnostic performance parameters could 0.25 10 ** Includes benign tissue, fibroadenoma, benign intramammary nodes, radial scar. -4 (b) (b) (b) be demonstrated in this study. 0.33 10 Abnormal 23/315 (7.3%) 23/24 (95.8%) 292/315 (92.7%) To correct for physical decay of this radionuclide, the fractions that remain at selected intervals after the An estimate of the likelihood of malignancy based on the Technetium Tc 99m Sestamibi uptake score A ten year retrospective case history study of pediatric Kawasaki disease patients who completed time of calibration are shown in Table 5. (a) Note: Similar findings were found in two studies with patients who had pharmacologic stress Technetium Tc 99m Sestamibi myocardial perfusion imaging and who had coronary angiography Technetium Tc 99m Sestamibi imaging. in combination with the mammographic score has not been studied. within three months of the Technetium Tc 99m Sestamibi scan was designed to measure sensitivity Table 5 Physical Decay Chart; Tc 99m Half-Life 6.02 Hours (b) p<0.01 and specificity of Technetium Tc 99m Sestamibi scan. Out of 72 patients who had both evaluable In these two studies approximately 150 additional, non-biopsied lesions were found to be positive Hours Fraction Remaining Hours Fraction Remaining Technetium Tc 99m Sestamibi scans and evaluable angiographic images, only one patient had both an after Technetium Tc 99m Sestamibi imaging. These lesions were identified in sites that did not 0* 1.000 7 0.447 Although patients with normal images had a lower cardiac event rate than those with abnormal abnormal angiogram and an abnormal Technetium Tc 99m Sestamibi scan. No clinically meaningful physically correlate with identified entry criteria mammographic lesions and these lesions were not 1 0.891 8 0.398 images, in all patients with abnormal images it was not possible to predict which patient would be measurements of sensitivity, specificity or other diagnostic performance parameters parameters could likely to have further cardiac events; i.e., such individuals were not distinguishable from other patients palpable. These lesions were not biopsied. Whether these lesions were benign or malignant is not be demonstrated in this study. 2 0.794 9 0.355 known. Technetium Tc 99m Sestamibi uptake can occur in both benign and malignant disease. THE 3 0.708 10 0.316 with abnormal images. In a clinical pharmacology study, 46 pediatric patients with Kawasaki disease received Technetium Tc CLINICAL USEFULNESS OF A POSITIVE TECHNETIUM TC 99M SESTAMIBI IMAGE IN THE ABSENCE OF AN 4 0.631 11 0.282 ABNORMAL MAMMOGRAM OR A PALPABLE LESION IS NOT KNOWN. 99m Sestamibi administration at the following doses: 0.1–0.2 mCi/kg for rest, 0.3 mCi/kg for stress in 5 0.562 12 0.251 The findings were not evaluated for defect location, disease duration, specific vessel involvement, or one day studies; 0.2 mCi/kg for rest and 0.2 mCi/kg for stress in two day studies. intervening management. 6 0.501 15 REFERENCES The radioactivity both in younger children and in adolescents exhibited PK profiles similar to those *Calibration Time previously reported in adults [see CLINICAL PHARMACOLOGY (12)]. In earlier trials, using a template consisting of the anterior wall, inferior-posterior wall and isolated Not applicable. The radiation absorbed doses in adolescents, both at rest and stress, were similar to those observed apex, localization in the anterior or inferior-posterior wall in patients with suspected angina or coronary 12 CLINICAL PHARMACOLOGY 16 HOW SUPPLIED/STORAGE AND HANDLING in adults [see DOSAGE AND ADMINISTRATION (2.2)]. When comparing weight-adjusted radioactivity artery disease was shown. Disease localization isolated to the apex has not been established. Tc 99m The patient dose should be measured by a suitable radioactivity calibration system immediately prior (up to 0.3 mCi/kg) doses administered to adolescents and younger children to the recommended dose Sestamibi has not been studied or evaluated in cardiac disorders other than coronary artery disease. General to patient administration. Radiochemical purity should be checked prior to patient administration. administered to adults (up to 30 mCi), the radiation absorbed doses in both adolescents and younger Technetium Tc 99m Sestamibi is a cationic Tc 99m complex which has been found to accumulate in children were similar to those in adults. BREAST IMAGING: Technetium Tc 99m Sestamibi was evaluated in two multicenter, clinical trials of a viable myocardial tissue in a manner analogous to that of thallous chloride Tl-201. Scintigraphic images Parenteral drug products should be inspected visually for particulate matter and discoloration prior to Adverse events were evaluated in 609 pediatric patients from the three clinical studies described obtained in humans after the intravenous administration of the drug have been comparable to those total of 673 women patients. Overall the mean age was 52 (range 23 to 87 years). The racial and ethnic representation was 70% Caucasian, 15% African-American, 14% Hispanic, and 1% Asian. administration whenever solution and container permit. above. The frequency and the type of the adverse events were similar to the ones observed in the obtained with thallous chloride Tl-201 in normal and abnormal myocardial tissue. Store at 15–25°C (59–77°F) before and after reconstitution. studies of Technetium Tc 99m Sestamibi in adults. Two of the 609 had a serious adverse event: one patient received a Technetium Tc 99m Sestamibi overdose but remained asymptomatic, and one Animal studies have shown that myocardial uptake is not blocked when the sodium pump mechanism Both clinical studies evaluated women who were referred for further evaluation for either: 1) a mammographically detected (with varying degrees of malignant likelihood) but not palpable breast 17 PATIENT COUNSELING INFORMATION patient had an asthma exacerbation following administration. is inhibited. Although studies of subcellular fractionation and electron micrographic analysis of ® ® lesion (study A, n=387, mean age = 54 years), or 2) a palpable breast lesion (study B, n=286, mean age CARDIOLITE and MIRALUMA are different names for the same drug (Kit for the Preparation of heart cell aggregates suggest that Tc 99m Sestamibi cellular retention occurs specifically within the Technetium Tc 99m Sestamibi Injection). Patients should be advised to inform their health care provider 8.5 Geriatric Use = 50 years). In both studies all patients were scheduled for biopsy. mitochondria as a result of electrostatic interactions, the clinical relevance of these findings has not if they had an allergic reaction to the drug or if they had an imaging study with either drug. Of 3068 patients in clinical studies of Technetium Tc 99m Sestamibi for myocardial imaging, been determined. 693 patients were 65 or older and 121 were 75 or older. Technetium Tc 99m Sestamibi (20–30 mCi) was injected intravenously in a vein that was contralateral The mechanism of Tc 99m Sestamibi localization in various types of breast tissue (e.g., benign, CARDIOLITE® and MIRALUMA®, and Recon-o-Stat™ are trademarks of Lantheus Medical Of 673 patients in clinical studies of Technetium Tc 99m Sestamibi for breast imaging, 138 inflammatory, malignant, fibrous) has not been established. to the breast lesion in question. Planar imaging was completed with a high resolution collimator with patients were 65 or older and 30 were 75 or older. a 10% window centered at 140 keV, and 128 x 128 matrix. An initial marker image, that was not used Imaging, Inc. Based on the evaluation of the frequency of adverse events and review of vital signs data, no overall in the data analysis, was obtained using a cobalt Co57 point source as a marker of a palpable mass. 12.3 Pharmacokinetics Distributed by: differences in safety were observed between these subjects and younger subjects. Although reported Pulmonary activity is negligible even immediately after injection. Blood clearance studies indicate that the Images were obtained 5 minutes after injection as follows: lateral image of the affected breast for 10 clinical experience has not identified differences in response between elderly and younger patients, Cardinal Health 414, LLC fast clearing component clears with a t of 4.3 minutes at rest, and clears with a t of 1.6 minutes under minutes, lateral image of the contralateral breast for 10 minutes, and an anterior image of both breasts greater sensitivity of some older individuals cannot be ruled out. 1⁄2 1⁄2 7000 Cardinal Place exercise conditions. At five minutes post injection about 8% of the injected dose remains in circulation. for 10 minutes. For the lateral image the patients were positioned in a prone position. For the anterior Dublin, OH 43017 There is less than 1% protein binding of Technetium Tc 99m Sestamibi in plasma. The myocardial biologi- image, the patients were supine. The Technetium Tc 99m Sestamibi scintigraphic images were read in 9 DRUG ABUSE AND DEPENDENCE cal half-life is approximately six hours after a rest or exercise injection. The biological half-life for the liver a randomized method by two groups of three blinded readers. Technetium Tc 99m Sestamibi uptake was scored as: normal (no uptake), equivocal, low, moderate, or high uptake. The results of Technetium 9.1 Controlled Substance is approximately 30 minutes after a rest or exercise injection. The effective half-life of clearance (which Tc 99m Sestamibi images and mammography were analyzed in comparison to histopathologic findings Not applicable. includes both the biological half-life and radionuclide decay) for the heart is approximately 3 hours, and for the liver is approximately 30 minutes, after a rest or exercise injection. The ideal imaging time reflects the of malignant or non-malignant disease. best compromise between heart count rate and surrounding organ uptake. 9.2 Abuse As shown in Table 8 for the 483 evaluable patients, the sensitivity and specificity of any degree of Not applicable. Technetium Tc 99m Sestamibi uptake appear to vary with the presence or absence of palpable mass. 9.3 Dependence Revised June 2016 Not applicable. HIGHLIGHTS OF PRESCRIBING INFORMATION FULL PRESCRIBING INFORMATION: CONTENTS* These highlights do not include all the information needed to use LYMPHOSEEK 1 INDICATION AND USAGE safely and effectively. See full prescribing information for LYMPHOSEEK. 2 DOSAGE AND ADMINISTRATION 2.1 Radiation Safety – Drug Handling Lymphoseek (technetium Tc 99m tilmanocept) injection, for subcutaneous, 2.2 Recommended Dosing intradermal, subareolar, or peritumoral use 2.3 Drug Preparation Initial U.S. Approval: 2013 2.4 Determination of Radiochemical Purity of Radiolabeled Lymphoseek 2.5 Lymphatic Mapping and Sentinel Lymph Node Biopsy Following Injection RECENT MAJOR CHANGES of Lymphoseek Indications and Usage (1) 5/2021 2.6 Radiation Dosimetry Dosage and Administration, Radiation Dosimetry (2.6) 5/2021 3 DOSAGE FORMS AND STRENGTHS INDICATIONS AND USAGE 4 CONTRAINDICATIONS Lymphoseek is a radioactive diagnostic agent indicated with or without scintigraphic 5 WARNINGS AND PRECAUTIONS imaging for: 5.1 Hypersensitivity Reactions • Lymphatic mapping using a handheld gamma counter to locate lymph nodes 5.2 Radiation Risks draining a primary tumor site in adult and pediatric patients age one month and 6 ADVERSE REACTIONS older with solid tumors for which this procedure is a component of intraoperative 6.1 Clinical Trials Experience management. (1) 8 USE IN SPECIFIC POPULATIONS • Guiding sentinel lymph node biopsy using a handheld gamma counter in patients 8.1 Pregnancy with clinically node negative squamous cell carcinoma of the oral cavity, breast 8.2 Lactation cancer or melanoma. (1) 8.4 Pediatric Use DOSAGE AND ADMINISTRATION 8.5 Geriatric Use • Lymphoseek is supplied as a Kit and must be prepared by radiolabeling with 11 DESCRIPTION technetium Tc 99m and diluting with the supplied diluent or pharmacy-available 12 CLINICAL PHARMACOLOGY sterile 0.9% sodium chloride injection prior to use. (2.3) 12.1 Mechanism of Action • Use aseptic technique and radiation safety precautions during Lymphoseek 12.2 Pharmacodynamics preparation and handling. Determine the total injection volume and number of 12.3 Pharmacokinetics sites to be injected for each patient before preparing Lymphoseek. (2.1, 2.3) 13 NONCLINICAL TOXICOLOGY • Recommended dose of Lymphoseek is 18.5 MBq (0.5 mCi) administered at least 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 15 minutes before initiating intraoperative lymphatic mapping or sentinel node 14 CLINICAL STUDIES biopsy procedures: complete these procedures within 15 hours of Lymphoseek injection. (2.2, 2.3) 14.1 Overview of Clinical Studies • Recommended routes of administration are intradermal, subcutaneous, 14.2 Lymphoscintigraphy subareolar, or peritumoral. (2.3) 14.3 Lymphatic Mapping • Use radiolabeled Lymphoseek within 6 hours of its preparation. (2.3) 14.4 Guiding Sentinel Lymph Node Biopsy • See Full Prescribing Information for important preparation and administration 16 HOW SUPPLIED/STORAGE AND HANDLING instructions. (2) 16.1 How Supplied 16.2 Storage and Handling DOSAGE FORMS AND STRENGTHS 17 PATIENT COUNSELING INFORMATION For Injection: The Kit for preparation of Lymphoseek contains five Tilmanocept Powder vials each containing 250 mcg tilmanocept, and is packaged either with or without *Sections or subsections omitted from the full prescribing information are not listed. five DILUENT for Lymphoseek vials each containing 4.5 mL of sterile buffered saline with phenol. After radiolabeling with technetium Tc 99m and dilution, Lymphoseek FULL PRESCRIBING INFORMATION contains approximately 92.5 MBq (2.5 mCi) and 250 mcg of technetium Tc 99m tilmanocept in 0.5 mL to 5 mL total volume for injection. (3) 1 INDICATIONS AND USAGE Lymphoseek is a radioactive diagnostic agent indicated with or without scintigraphic CONTRAINDICATIONS imaging for: None. (4) • Lymphatic mapping using a handheld gamma counter to locate lymph WARNINGS AND PRECAUTIONS nodes draining a primary tumor site in adult and pediatric patients age one Hypersensitivity: Ask patients about prior reactions to drugs, especially dextran month and older with solid tumors for which this procedure is a component or modified forms of dextran. Observe for hypersensitivity signs and symptoms of intraoperative management. following Lymphoseek injection. Have resuscitation equipment and trained personnel immediately available. (5.1) • Guiding sentinel lymph node biopsy using a handheld gamma counter in patients with clinically node negative squamous cell carcinoma of the oral ADVERSE REACTIONS cavity, breast cancer or melanoma. The most common adverse reactions (incidence < 1%) are injection site irritation and/ or pain. (6.1) 2 DOSAGE AND ADMINISTRATION To report SUSPECTED ADVERSE REACTIONS, contact Cardinal Health at 1-800-618-2768 or www.lymphoseek.com or FDA at 1 800-FDA-1088 or 2.1 Radiation Safety – Drug Handling www.fda.gov/medwatch Lymphoseek is a radioactive drug and should be handled with appropriate safety measures to decrease radiation exposure [see Warnings and Precautions (5.2)]. USE IN SPECIFIC POPULATIONS Use waterproof gloves, effective radiation shielding, and appropriate safety measures Lactation. To decrease radiation exposure to the breastfed child, advise a when preparing and handling Lymphoseek. lactating woman to pump and discard breast milk after the administration of Lymphoseek for 24 hours. (8.2) 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 See 17 for PATIENT COUNSELING INFORMATION radionuclides, and whose experience and training have been approved by the Revised: 5/2021 appropriate governmental agency authorized to license the use of radionuclides. 2.2 Recommended Dosing Once the Reconstituted Vial Volume is established, use the following steps to prepare The recommended dose of Lymphoseek is 18.5 MBq (0.5 mCi) as a radioactivity dose radiolabeled Lymphoseek: and 50 mcg as a mass dose. Administer Lymphoseek at least 15 minutes prior to Radiolabeling initiating intraoperative lymphatic mapping and sentinel node biopsy; complete these procedures within 15 hours after Lymphoseek injection. a. Inspect the Tilmanocept Powder vial for any damage. Do not use if vial integrity appears compromised. Do not vent the Tilmanocept Powder vial Route of Administration and Injection Method prior to or during radiolabeling. The route of administration depends on the tumor location and the planned injection b. Use Technetium Tc 99m pertechnetate, sodium injection solution from a technique and includes: subcutaneous, intradermal, subareolar, or peritumoral technetium Tc 99m generator within 8 hours of its elution. injection. c. Using a sterile syringe, aseptically draw approximately 92.5 MBq (2.5 mCi) Lymphoseek may be administered to a patient as a single injection or as multiple of Technetium Tc 99m pertechnetate sodium injection solution in either injections. The recommended total injection volume for each patient (Table 1) is about 0.35 mL volume (for 0.5 mL Reconstituted Vial Volume) or about 0.1 mL administered in a single syringe; 0.5 mL administered in a single syringe 0.7 mL volume (for 2.5 mL or 5 mL Reconstituted Vial Volume). Assay the or in multiple syringes (0.1 mL to 0.25 mL each); or 1 mL administered in multiple syringe for technetium Tc 99m activity in a dose calibrator. syringes (0.2 mL to 0.5 mL each). d. Write the radioactivity amount, the Reconstituted Vial Volume, date and The lymphatic system architecture and function may be changed by prior , time, expiration time and lot number in the space provided on the radioactive radiation, edema, inflammation or metastatic disease, and may result in changes to product vial label and affix it to the Tilmanocept Powder vial. Place the vial in lymph node localization by a radiopharmaceutical or other tracers, including a radiation shield and sanitize the septum with alcohol wipe. colorimetric agents. Avoid injections into biopsy wound areas that show evidence of edema or inflammation. e. Aseptically add Technetium Tc 99m pertechnetate, sodium injection solution to the Tilmanocept Powder vial. Without withdrawing the needle, In animal studies, locally injected anesthetics have been reported to reduce lymphatic remove an equal volume of headspace gas. Do not vent. flow. Concomitant administration of local anesthetics with Lymphoseek is not recommended and may impair the lymph nodal mapping. f. Remove the needle, gently shake the vial to mix the contents, and then let it stand at room temperature for at least 15 minutes. 2.3 Drug Preparation Reconstitution General Considerations g. Aseptically add the supplied DILUENT for Lymphoseek or pharmacy- • Kit for the preparation of Lymphoseek contains five Tilmanocept Powder available sterile 0.9% sodium chloride injection to the radiolabeled product vials, each containing 250 mcg of tilmanocept from which 50 mcg is in the Tilmanocept Powder vial to bring the volume to the Reconstituted intended for administration to a patient. Vial Volume of 0.5 mL, 2.5 mL, or 5 mL prior to filling the patient dose in syringe(s). To normalize pressure, withdraw an equal volume of headspace The Kit for the preparation of Lymphoseek is packaged either with or º gas. without five DILUENT for Lymphoseek vials each containing 4.5 mL of sterile buffered saline with phenol. h. Each Lymphoseek vial, once radiolabeled and reconstituted, would contain sufficient amount to provide doses for up to four patients when prepared The Kit for the preparation of Lymphoseek may also be diluted with º according to the instructions. pharmacy-available sterile 0.9% sodium chloride injection. º A diluent is used to dilute Lymphoseek after the radiolabeling Quality Control of Radiolabeled Solution procedure. The amount of diluent used varies, depending on the total i. Assay the reconstituted vial for total radioactivity using a dose calibrator. injection volume and the number of syringes used for each patient. Write the technetium Tc 99m activity concentration, total volume, assay • The vial components of the Kit for the preparation of Lymphoseek time and date, expiration time, and lot number on the shield label supplied are intended solely for use in the preparation of Lymphoseek. Do not with the Kit. Affix the label to the shield. administer the unprepared vial components of the Kit directly to a patient. j. Determine the radiochemical purity of the radiolabeled product [see • Follow aseptic procedures during preparation and administration. Dosage and Administration (2.4)]. Do not use if the radiochemical purity is less than 90%. Drug Preparation Instructions k. Withdraw the required volume of the radiolabeled product into the required Prior to preparation of Lymphoseek, determine the planned injection technique and number of syringes. Assay the syringe(s) in a dose calibrator. Write the the number of injections that will be used for a given patient. For each injection radioactivity amount, date and time of assay, volume, and expiration prepare a separate syringe. Based on the planned number of injection syringes and time (this is not to exceed 6 hours from preparation time) on the supplied the planned total injection volume per patient, determine (from Table 1 below) the syringe label and affix it to the syringe(s). Reconstituted Vial Volume of radiolabeled Lymphoseek. Table 1. Preparation of Lymphoseek for Administration Duration of Use and Storage of Radiolabeled Solution Planned Number of Total Injection Reconstituted Vial Volume of l. Store the radiolabeled Lymphoseek in radiation shielding at room Injections for a Patient Volume Per Patient Radiolabeled Lymphoseek temperature. 1 syringe x 0.1 mL 0.1 mL 0.5 mL m. Use the radiolabeled Lymphoseek within 6 hours of preparation. Discard the unused radiolabeled Lymphoseek. 5 syringes x 0.1 mL or 2 syringes x 0.25 mL or 0.5 mL 2.5 mL 1 syringe x 0.5 mL 2.4 Determination of Radiochemical Purity of Radiolabeled Lymphoseek 5 syringes x 0.2 mL or Determine radiochemical purity of the reconstituted radiolabeled Lymphoseek by 4 syringes x 0.25 mL or 1 mL 5 mL Instant Thin Layer (ITLC) using either Whatman Grade 1, 3MM, 2 syringes x 0.5 mL 31ET Chr or Biodex 150-001 Red Strips (cellulose chromatography paper) using the following method: a. Mark the chromatographic strip for origin, mid and solvent front lines with • Lymphoseek is intended to supplement palpation, visual inspection, and a pencil as shown below: other procedures important to lymph node mapping and sentinel node biopsy. Intraoperative lymphatic mapping and sentinel node biopsy using gamma detection of Lymphoseek within lymph nodes should be initiated Solvent no sooner than 15 minutes following injection. In clinical studies of breast Front Line cancer and melanoma, patients also received a concomitant blue dye tracer for comparative detection of lymph nodes. While most lymph nodes 5 cm Mid Line were detected with Lymphoseek, some were detected only with the blue 3.5 cm dye tracer or only with palpation [see Clinical Studies (14)]. 2.5 cm Origin Line 1.75 cm 2.6 Radiation Dosimetry 1 cm from • The radiation doses to organs and tissues of an adult patient weighing Bottom 70 kg given 18.5 MBq (0.5 mCi) of Lymphoseek are shown in Table 3. For Whatman Grade 1, 3MM, Biodex 150-001 31ET Chromatography strip Red Strips pediatric patients, effective dose equivalent ranged from 355 microSv to 1,232 microSv. b. Apply a small drop (3 - 10 microliters) of the reconstituted product at the Table 3. Estimated Absorbed Radiation Dose from 18.5 MBq (0.5 mCi) center of the origin line chromatography strip. Let the product spot dry. Lymphoseek in Adult Patients with Breast Cancer and Melanoma c. Place the strip into a chromatography chamber containing 1 mL of acetone Breast Cancera Melanomab as the developing solvent. Allow the solvent to migrate to the solvent Target Organ mGy (rad) mGy (rad) front line (5 cm from the bottom of the Whatman strips and 3.5 cm for the Biodex strip). Remove the strip from the chamber, let it dry and cut it brain 0.003 (0.0003) 0.0927 (0.0093) in half. Count each half of the strip with a suitable radioactivity counting breast (injection site) 1.659 (0.1659) 0.7903 (0.079) apparatus (dose calibrator or multichannel analyzer). gall bladder wall 0.0349 (0.0035) 0.0712 (0.0071) d. Calculate the percent radiochemical purity (% RCP) as follows: lower large intestine wall 0.0123 (0.0012) 0.057 (0.0057)

Counts (activity) in bottom half small intestine 0.0101 (0.001) 0.0594 (0.0059) % RCP = x 100 Counts (activity) in bottom half + stomach 0.0184 (0.0018) 0.0562 (0.0056) Counts (activity) in top half upper large intestine wall 0.0125 (0.0012) 0.0582 (0.0058) e. Do not use the reconstituted Lymphoseek if the radiochemical purity is less kidney 0.1863 (0.0186) 0.278 (0.0278) than 90%. liver 0.0324 (0.0032) 0.0929 (0.0093) lungs 0.0374 (0.0037) 0.0599 (0.006) 2.5 Lymphatic Mapping and Sentinel Lymph Node Biopsy Following Injection of Lymphoseek muscle 0.0092 (0.0009) 0.0451 (0.0045) • Lymphoscintigraphy may be used to assist in planning the lymph node ovaries 0.187 (0.0187) 0.2991 (0.0299) mapping procedures. In clinical studies, preoperative scintigraphic red marrow 0.0127 (0.0013) 0.0507 (0.0051) imaging was performed using planar imaging techniques and/or SPECT/ bone 0.0177 (0.0018) 0.0878 (0.0088) CT to establish a map of nodal basins and to facilitate intraoperative identification of lymph nodes. Imaging was performed as early as spleen 0.0285 (0.0029) 0.0598 (0.006) immediately after injection and up to 21 hours [see Clinical testes 0.0501 (0.005) 0.1043 (0.0104) Studies (14)]. thymus 0.1168 (0.0117) 0.0577 (0.0058) • Use a handheld gamma counter to identify nodes that concentrated the thyroid 0.088 (0.0088) 0.0464 (0.0046) injected radioactivity. urinary bladder 0.0586 (0.0059) 0.1401 (0.014) • For intraoperative lymphatic mapping, first measure the background radioactivity counts from tissue at least 20 centimeters distal to the total body 0.0195 (0.0019) 0.0547 (0.0055) injection site. The three sigma threshold (background radioactivity counts Effective Dose Equivalent microSv microSv plus three times the square root of the mean background count) may be males 296 202.4 used as an estimate of the threshold for positive localization of females 330.2 251.1 Lymphoseek, as exemplified in Table 2. a Calculated from data of 18 patients with breast cancer who received four Table 2. Examples of Three Sigma Threshold Values peritumoral injections of 4 mcg, 20 mcg, and 100 mcg doses of Lymphoseek. b Calculated from data of 18 patients with melanoma who received four intradermal Background Counta (cpm) Threshold Value (cpm) injections of 20 mcg, 100 mcg, and 200 mcg doses of Lymphoseek. Due to the 5 12 differences in injection sites among patients with melanoma, the injection site was assumed to be the breast for the purposes of this calculation, as it represents the 10 20 nearest anatomical construct for the skin from the anatomical sites appropriately 15 27 included in the estimates. 20 34 25 40 3 DOSAGE FORMS AND STRENGTHS For Injection: The Kit for preparation of Lymphoseek (technetium Tc 99m tilmanocept) 30 47 is supplied as five Tilmanocept Powder vials each containing 250 mcg tilmanocept, 35 53 and is packaged either with or without five DILUENT for Lymphoseek vials each containing 4.5 mL of sterile buffered saline with phenol. After radiolabeling with 40 59 technetium Tc 99m, Lymphoseek contains approximately 92.5 MBq (2.5 mCi) and a Average of three 2-second counts or one 10-second count 250 mcg technetium Tc 99m tilmanocept in 0.5 mL to 5 mL total volume. 4 CONTRAINDICATIONS 8.4 Pediatric Use None. The safety and effectiveness of Lymphoseek have been established in pediatric patients 1 month of age and older. Use of Lymphoseek for this population is 5 WARNINGS AND PRECAUTIONS supported by evidence from adequate and well-controlled studies in adults with additional safety and diagnostic data from an open-label, single-arm trial in 23 5.1 Hypersensitivity Reactions pediatric patients with either melanoma (5), rhabdomyosarcoma (4), or other solid Lymphoseek may pose a risk of hypersensitivity reactions due to its chemical tumors (14) who received Lymphoseek (18.5 MBq and 50 mcg) and underwent similarity to dextran [see Description (11)]. Serious hypersensitivity reactions have intraoperative lymphatic mapping, with or without additional use of preoperative been associated with dextran and modified forms of dextran (such as iron dextran scintigraphic imaging and/or blue dye [see Clinical Studies (14.1)]. Review of drugs). the clinical data, including evaluation of the frequency of adverse reactions and localization of lymph nodes, has not identified differences in safety or efficacy Before administering Lymphoseek, ask patients about prior hypersensitivity reactions between pediatric patients and older patients. to drugs, especially to dextran and modified forms of dextran. Have resuscitation equipment and trained personnel immediately available at the time of Lymphoseek administration. 8.5 Geriatric Use Of the 553 adult patients enrolled in clinical studies of breast cancer, melanoma, and 5.2 Radiation Risks squamous cell carcinoma (SCC) of oral cavity, skin, and lip, 179 (32%) were aged 65 or older. Review of the clinical data, including evaluation of the frequency of adverse Any radiation-emitting product may increase the risk for cancer, especially in reactions, has not identified differences in safety or efficacy between elderly patients pediatric patients. Adhere to the dose recommendations and ensure safe handling (65 to 90 years of age) and younger adult patients (18 to 65 years of age). to decrease the risk for excessive radiation exposure to either patients or health care workers. 11 DESCRIPTION 6 ADVERSE REACTIONS Chemical Characteristics 6.1 Clinical Trials Experience The active ingredient in Lymphoseek, a radioactive diagnostic agent, is technetium Because clinical trials are conducted under widely varying conditions, adverse Tc 99m tilmanocept. Technetium Tc 99m binds to the diethylenetriaminepentaacetic reaction rates observed in the clinical trials of a drug cannot be directly compared to acid (DTPA) moieties of the tilmanocept molecule. rates in the clinical trials of another drug and may not reflect the rates observed in • Chemically, technetium Tc 99m tilmanocept consists of technetium practice. Tc 99m, dextran 3-[(2-aminoethyl)thio]propyl 17-carboxy-10,13,16- In open label, single arm clinical trials, 553 adult patients with either breast cancer, tris(carboxymethyl)-8-oxo-4-thia-7,10,13,16-tetraazaheptadec-1-yl melanoma, or squamous cell carcinoma of the oral cavity, skin, and lip received 3-[[2-[[1-imino-2-(D-mannopyranosylthio)ethyl]amino]ethyl]thio]propyl Lymphoseek. No patients experienced serious adverse reactions. Injection site ether complexes. irritation (4 patients; 0.7%) and pain (1 patient; 0.2%) were reported. • The molecular formula of technetium Tc 99m tilmanocept is 99m [C6H10O5]n.(C19H28N4O9S Tc)b.(C13H24N2O5S2)c.(C5H11NS)a. It contains 3-8 8 USE IN SPECIFIC POPULATIONS conjugated DTPA (diethylenetriaminepentaacetic acid) molecules (b); 12-20 conjugated mannose molecules (c) with 0-17 amine side chains (a) 8.1 Pregnancy remaining free. Risk Summary • The calculated average molecular weight of tilmanocept ranges from There are no available data on Lymphoseek use in pregnant women. Additionally, 15,281 to 23,454 g/mol. animal reproduction studies have not been conducted with technetium Tc 99m tilmanocept. However, all radiopharmaceuticals, including Lymphoseek, have a • Technetium Tc 99m tilmanocept has the following structural formula: potential to cause fetal harm depending on the fetal stage of development and the magnitude of the radiation dose. If considering Lymphoseek administration to a pregnant woman, inform the patient about the potential for adverse pregnancy outcomes based on the radiation dose from the drug and the gestational timing of exposure. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2 to 4% and 15 to 20%, respectively, regardless of drug exposure.

8.2 Lactation Risk Summary No data are available regarding the presence of technetium Tc 99m tilmanocept in human milk, the effects of the drug on the breastfed child, or the effects of the drug on milk production. Exposure of Lymphoseek to a breastfed child can be decreased by temporary discontinuation of breastfeeding [see Clinical Considerations]. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Lymphoseek and any potential adverse effects on the breastfed child from Lymphoseek or from the underlying maternal condition. Clinical Considerations To decrease radiation exposure to the breastfed child, advise a lactating woman to pump and discard breast milk after the administration of Lymphoseek for 24 hours. Lymphoseek (technetium Tc 99m tilmanocept) injection is supplied as a Kit which 12.2 Pharmacodynamics contains five Tilmanocept Powder vials. Each Tilmanocept Powder vial contains the In in vitro studies, technetium Tc 99m tilmanocept exhibited binding to non-radioactive ingredients needed to produce technetium Tc 99m tilmanocept. human mannose binding receptors with a primary binding site affinity of The vial contains a sterile, non-pyrogenic, white to off-white lyophilized powder K = 2.76 x 10-11 M. (under nitrogen) that consists of a mixture of 250 mcg tilmanocept, 20 mg trehalose d dihydrate, 0.5 mg glycine, 0.5 mg sodium ascorbate, and 0.075 mg stannous In clinical studies, technetium Tc 99m tilmanocept has been detectable in lymph chloride dihydrate. nodes within 10 minutes and up to 30 hours after injection. The DILUENT for Lymphoseek contains 4.5 mL sterile buffered saline consisting of 12.3 Pharmacokinetics 0.04% (w/v) potassium phosphate, 0.11% (w/v) sodium phosphate (heptahydrate), In dose-ranging clinical studies, injection site clearance rates were similar across 0.5% (w/v) sodium chloride, and 0.4% (w/v) phenol. all Lymphoseek doses (4 to 200 mcg) with a mean elimination rate constant in the Physical Characteristics range of 0.222 to 0.396/hr, resulting in a drug half-life at the injection site of 1.8 to 3.1 hours. Technetium Tc 99m decays by isomeric transition with a physical half-life of approximately 6 hours. The principal photon that is useful for detection and imaging The amount of the accumulated radioactive dose in the liver, kidney, and bladder studies is listed in Table 4. reached a maximum 1 hour post administration of Lymphoseek and was approximately 1% to 2% of the injected dose in each tissue. Table 4. Principal Radiation Emission Data

Radiation Mean % Disintegration Mean Energy (keV) 13 NONCLINICAL TOXICOLOGY Gamma-2 89.1 140.5 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility From: Kocher, D.C. Radioactive decay data tables. DOE/TIC-11026, 108 (1981). Studies to assess the carcinogenicity potential of tilmanocept have not been conducted. Tilmanocept was not mutagenic in vitro in the Ames bacterial mutation External Radiation assay and in the in vitro mouse lymphoma test, and was negative in the in vivo micronucleus test in mice. The linear mass energy absorption attenuation coefficient for Tc 99m is 18.9 cm-1. The first half-value layer is 0.037 cm of lead (Pb). The use of a 0.25 cm thick Studies on reproductive fertility have not been conducted. standard radiation lead shield will attenuate the radiation emitted by millicurie amounts of technetium Tc 99m by a factor of about 100. A range of values for 14 CLINICAL STUDIES the relative attenuation of the radiation of technetium Tc 99m that results with various thicknesses of lead shielding are displayed in Table 5. 14.1 Overview of Clinical Studies The efficacy and safety of Lymphoseek were assessed in three open-label, Table 5. Radiation Attenuation by Lead Shielding multicenter, single arm trials of adult patients with melanoma, breast cancer, or Shield Thickness, cm of lead (Pb) Coefficient of Attenuation squamous cell carcinoma (SCC) of the oral cavity, skin, and lip (Studies 1, 2, and 3) and one open-label, multicenter, single arm trial of pediatric patients with melanoma, 0.037 0.5 rhabdomyosarcoma, or other solid tumor (Study 4). Prior to the lymph node mapping 0.12 10-1 and sentinel lymph node biopsy procedures, patients had no known regional nodal or 0.24 10-2 metastatic disease by standard clinical staging criteria. 0.36 10-3 • In Studies 1 and 2, Lymphoseek was evaluated in adult patients with breast cancer and melanoma. Diagnostic efficacy for lymphatic mapping was 0.49 10-4 determined by the number of histology-confirmed lymph nodes detected by Lymphoseek and/or the blue dye comparator. Lymphoseek was injected To correct for physical decay of the radionuclide, the fractions that remain at into patients at least 15 minutes prior to initiating lymphatic mapping selected intervals after the time of calibration are shown in Table 6. procedures, and preoperative scintigraphic imaging was performed in 91% of patients. Separately, blue dye was injected shortly prior to initiation of Table 6. Physical Decay Chart; Tc 99m, Half-Life of approximately 6 Hours the surgery. Lymphatic mapping was performed intraoperatively using a Hours Fraction Remaining handheld gamma detection probe followed by excision of lymph nodes identified by Lymphoseek, blue dye, or the surgeon’s visual and palpation 0 1 examination. The resected lymph nodes were evaluated by histopathology. 1 0.891 Lymphoseek localization rate in pathology-positive lymph nodes was also determined. 3 0.708 6 0.501 o In Study 1, of 179 patients who received Lymphoseek, 94 (53%) had known or suspected breast cancer and 85 (47%) had known or 12 0.251 suspected melanoma. The median age was 59 years (range 20 to 90 15 0.178 years) and most (72%) were female. o In Study 2, of 153 patients who received Lymphoseek, 77 (50%) 12 CLINICAL PHARMACOLOGY had known or suspected breast cancer and 76 (50%) had known or suspected melanoma. The median age was 61 years (range 26 to 88 12.1 Mechanism of Action years) and most (68%) were female. Lymphoseek (technetium Tc 99m tilmanocept) is a radioactive diagnostic agent. It accumulates in lymphatic tissue and selectively binds to mannose binding • In Study 3, Lymphoseek was evaluated in adult patients primarily receptors (CD206) located on the surface of macrophages and dendritic cells. with SCC of the oral cavity (T1-T4a, N0, M0). Diagnostic efficacy was Technetium Tc 99m tilmanocept is a macromolecule consisting of multiple units of determined by the patient level false negative rate of sentinel lymph node diethylenetriaminepentaacetic acid (DTPA) and mannose, each covalently attached detection by Lymphoseek as confirmed by pathologic assessment of all to a 10 kDa dextran backbone. The mannose acts as a ligand for the receptor, and lymph nodes removed during planned elective neck dissection (END). the DTPA serves as a chelating agent for labeling with technetium Tc 99m. Lymphoseek was administered at least 15 minutes prior to the scheduled surgery, and preoperative scintigraphic imaging was performed in all patients. Lymphatic mapping was performed intraoperatively using a handheld gamma counter followed by excision of sentinel lymph nodes Table 8. Resected Lymph Nodes and Content of Lymphoseek (LS) and/or Blue identified by Lymphoseek. Additional lymph nodes were removed during Dye (BD) from Studies in Adult Breast Cancer and Melanoma the END based upon tumor location and surgical practice. All resected lymph nodes (sentinel and non-sentinel) were evaluated for histopathology Study Tumor Nodes BD Present LS Present Only BD Only LS Neither at the local site. Lymphoseek-identified nodes determined negative for Present Present BD nor LS n cancer were further evaluated by a central pathology laboratory using Present additional step sectioning and cytokeratin staining. % % % % % (95% CI) (95% CI) (95% CI) (95% CI) (95% CI) o Of the 85 patients who received Lymphoseek, 79 (93%) had intraoral SCC and 6 (7%) had cutaneous SCC. The median age was 59 years 93% 2% 29% 6% (range 23 to 87 years) and most (75%) were male. Melanoma 187 65% (88% , 96%) (0 , 5%) (23% , 37%) (3% , 10%) • In Study 4, Lymphoseek was evaluated in pediatric patients with One melanoma, rhabdomyosarcoma, or other solid tumor. Safety and Breast 70% 89% 7% 26% 4% diagnostic efficacy for lymphatic mapping were determined. Lymphoseek 192 Cancer was injected into patients at least 15 minutes prior to initiating lymphatic (63% , 77%) (83% , 93%) (4% , 12%) (20% , 32%) (2% , 8%) mapping procedures, and preoperative scintigraphic imaging was performed in 91% of patients. Blue dye was injected prior to initiation 59% 99% 0 41% 1% Melanoma 198 of the surgery in 21 patients. Lymphatic mapping was performed (51% , 66%) (97% , 100%) (0 , 2%) (34% , 48%) (0 , 3%) intraoperatively using a handheld gamma detection probe followed by Two excision of lymph nodes identified by Lymphoseek, blue dye (when used 100% adjunctively), or the surgeon’s visual and palpation examination. The Breast 62% 0 38% 0 181 (98% , resected lymph nodes were evaluated by histopathology. Lymphoseek Cancer (55% , 70%) (0 , 2%) (30% , 45%) (0 , 2%) localization rate in pathology-positive lymph nodes was also determined. 100%) o Of the 23 patients who received Lymphoseek, 5 (22%) had melanoma, 4 (17%) had rhabdomyosarcoma, 12 (52%) had non- The percentages may not add to 100% due to rounding. rhabdomyosarcoma soft tissue sarcomas, and 2 (9%) had atypical 95% Confidence Intervals (CI) are based on Exact Binomial and represent the spread in Spitz nevi. The mean age was 11.6 years (range 1.7 to 17 years) the individual estimates. and most (65%) were female. 14.2 Lymphoscintigraphy In Studies 1 and 2 lymphatic mapping was performed in 328 adult patients with melanoma or breast cancer. The overall rate of lymph node detection by An analysis of the four studies was performed to evaluate the agreement in location Lymphoseek at the patient level was 97% (319/328). The average number of lymph of lymph nodes identified by scintigraphic imaging and the handheld gamma nodes detected by Lymphoseek was approximately 2 per patient. counter. At least one scintigraphic “hot spot” was identified in 95% of patients imaged; the percentages were similar across tumor types and age groups. Overall In Study 3 lymphatic mapping was performed in 83 adult patients with SCC of the in the adult patients, there was 84% agreement on a nodal level (when considering oral cavity. The rate of lymph node detection by Lymphoseek at the patient level was all missing observations as disagreement, as worst case scenario) between the 98% (81/83) with a 95% confidence interval of 92% to 100%. The average number location of preoperative scintigraphic imaging hot spots and the intraoperative of lymph nodes identified was 4 per patient. lymph node findings (Table 7). Missing observations took the following form: 43 hot In Study 4 lymphatic mapping was performed in 23 pediatric patients with spots without corresponding hot nodes and 31 hot nodes without corresponding hot melanoma, rhabdomyosarcoma, and other solid tumors. The overall rate of lymph spots. node detection by Lymphoseek at the patient level was 96% (22/23) when the Table 7. Location Agreement between Scintigraphic Imaging and detection rate is defined as at least one lymph node in a patient can be detected. Gamma Counter Findings in Adult Patients The average number of lymph nodes detected by Lymphoseek was approximately 3 per patient. Of the 79 nodes in 21 patients who also received blue dye, all of 47 Melanoma Breast Head and Overall nodes identified by blue dye were also identified by Lymphoseek; a total of 74 nodes Cancer Neck Cancer Results were identified by Lymphoseek. Agreement of 182/206; 116/147; 95/115; 393/468; Hot Spot and Hot 88% 79% 83% 84% 14.4 Guiding Sentinel Lymph Node Biopsy Node Location * (83%, 93%)** (70%, 88%)** (76%, 90%)** (81%, 87%)** In Study 3 in patients with SCC of the oral cavity (n=79), skin (n=5), and lip (n=1), * Denominator equals total number of hot spots and/or hot nodes. Numerator equals pathology findings for Lymphoseek-identified nodes (sentinel lymph nodes) were the numbers where hot spots and hot nodes agreed in location. compared to the pathology findings of all other lymph nodes removed during the scheduled elective node dissection to determine the false negative rate of ** 95% Confidence Intervals. Lymphoseek. Thirty-nine patients were determined to have pathology-positive regional lymph nodes. In these patients, the Lymphoseek false negative rate for 14.3 Lymphatic Mapping detecting patients with cancer-positive nodes was 2.6% (95% CI: 0.06% to 13.5%). In Studies 1 and 2 in adult melanoma and breast cancer, efficacy analyses were In this study the pathology-positive nodes were all found in patients with SCC of the based upon comparisons of the number and proportion of resected lymph nodes oral cavity. that contained a lymph node tracer (Lymphoseek and/or blue dye) or neither Supportive analyses were conducted in Studies 1 and 2 in patients with breast tracer. Evaluable lymph nodes were resected from 176 Study 1 patients and cancer or melanoma, and Study 4 in pediatric patients. The presence or absence of 152 Study 2 patients who received Lymphoseek at the dose of 0.5 to 2 mCi in Lymphoseek in nodes resected from patients determined by pathology staging to 50 mcg administered 15 minutes to 30 hours prior to surgery. Table 8 shows have lymphatic spread of cancer (n=66) was evaluated. The overall patient level rate the distribution of resected lymph nodes by the presence or absence of a tracer. for identifying at least one cancer-positive node in these pathology-positive patients Most of the resected lymph nodes were identified by either Lymphoseek (LS) or (both cancers combined) was 97%. Lymphoseek identified 27 out of 29 node blue dye (BD) or both. Significantly more resected lymph nodes were identified by positive adult patients with breast cancer, all of the 35 node positive adult patients Lymphoseek in comparison to blue dye. with melanoma, and both of the 2 node positive pediatric patients (1 melanoma and 1 rhabdomyosarcoma).

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied The Kit for the preparation of Lymphoseek (technetium Tc 99m tilmanocept) injection (NDC 65857-425-05) includes: • Five multiple dose vials of Tilmanocept Powder, 250 mcg (NDC 65857-400-01) • Prescribing information • Five labels for shields • Twenty-five labels for product vials and individual syringes The Kit for the preparation of Lymphoseek (technetium Tc 99m tilmanocept) injection (NDC 65857-450-05) includes: • Five multiple dose vials of Tilmanocept Powder, 250 mcg (NDC 65857-400-01) • Five vials of DILUENT for Lymphoseek (NDC 65857-401-45) • Prescribing information • Five labels for shields • Twenty-five labels for product vials and individual syringes

16.2 Storage and Handling Storage Store Kit for the preparation of Lymphoseek (technetium Tc 99m tilmanocept) injection in the original packaging at USP controlled room temperature, 20°C to 25°C (68°F to 77°F). Excursions permitted to 15°C to 30°C (59°F to 86°F). Store radiolabeled Lymphoseek in radiation shielding at room temperature. Use radiolabeled Lymphoseek within 6 hours of preparation. Handling This Kit for the preparation of Lymphoseek (technetium Tc 99m tilmanocept) injection is approved for distribution to persons licensed by the U.S. Nuclear Regulatory Commission to use by product material identified in 10 CFR 35.200 or under an equivalent license issued by an Agreement State.

17 PATIENT COUNSELING INFORMATION • Advise patients to seek medical attention for reactions following injection of Lymphoseek such as difficulty breathing, skin rash, or other allergy manifestations. • Inform nursing women to pump and discard breast milk for at least 24 hours following administration of Lymphoseek injection [see Use in Specific Populations (8.2)].

Distributed by: Cardinal Health 414, LLC Dublin, OH 43017 Lymphoseek is a registered trademark of Cardinal Health 414, LLC. Patent: www.lymphoseek.com/patent-information

Lit. No. 1NPS21-1481508 (6/2021)