KIT FOR THE PREPARATION OF TECHNETIUM TC 99M SULFUR COLLOID

Kit for the Preparation of Technetium Tc 99m Sulfur Colloid Injection contains a Multi-Dose Reaction Vial, a Solution A vial and a Solution B vial which contain the sterile non-pyrogenic, non-radioactive ingredients necessary to produce Technetium Tc 99m Sulfur Colloid Injection for diagnostic use by subcutaneous, intraperitoneal, or intravenous injection or by oral administration. Each 10 mL Multi-Dose Reaction Vial contains, in lyophilized form 2 mg sodium thiosulfate anhydrous, 2.3 mg edetate disodium and 18.1 mg bovine gelatin; a Solution A vial contains 1.8 mL of 0.148 N hydrochloric acid solution and a Solution B vial contains 1.8 mL aqueous solution of 24.6 mg/mL sodium biphosphate anhydrous and 7.9 mg/mL sodium hydroxide. When a solution of sterile and non-pyrogenic Sodium Pertechnetate Tc 99m Injection in isotonic saline is mixed with these components, following the instructions provided with the kit, Technetium Tc 99m Sulfur Colloid Injection is formed. The product is intended for subcutaneous, intraperitoneal, or intravenous injection or for oral administration. The precise structure of Technetium Tc 99m Sulfur Colloid Injection is not known at this time. 11.1 Physical Characteristics Technetium Tc 99m decays by isomeric transition with a physical half-life of 6.02 hours 4 . The principal photon that is useful for detection and imaging studies is listed in Table 7. Table 7. Principal Radiation Emission Data 4 Radiation Mean Percent Per Disintegration Mean Energy (keV) Gamma-2 89.07 140.5 4 Kocher DC: Radioactive decay data tables. DOE/TIC-11026: 108, 1981. 11.2 External Radiation The specific gamma ray constant for Tc 99m is 0.78 R/millicurie-hr at 1cm. The first half-value layer is 0.017 cm of lead (Pb). A range of values for the relative attenuation of the radiation emitted by this radionuclide that results from interposition of various thicknesses of Pb is shown in Table 8. For example, the use of a 0.25 cm thickness of Pb will attenuate the radiation emitted by a factor of about 1,000. Table 8. Radiation Attenuation by Lead Shielding Shield Thickness (Pb) cm Coefficient of Attenuation 0.017 0.5 0.08 10 -1 0.16 10 -2 0.25 10 -3 0.33 10 -4 To correct for physical decay of this radionuclide, the fractions that remain at selected intervals after the time of calibration are shown in Table 9. Table 9. Physical Decay Chart: Tc 99m, half-life 6.02 hours Hours Fraction Remaining Hours Fraction Remaining 0 Calibration time 1.000 6 0.501 1 0.891 7 0.447 2 0.794 8 0.398 3 0.708 9 0.355 4 0.631 10 0.316 5 0.562 11 0.282 - - 12 0.251

Technetium Tc 99m Sulfur Colloid Injection is indicated: In adults, 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. Evaluation of peritoneo-venous (LeVeen) shunt patency. In adults and pediatric patients, for imaging: Areas of functioning reticuloendothelial cells in the liver, spleen and bone marrow. Studies of esophageal transit and gastroesophageal reflux, and detection of pulmonary aspiration of gastric contents. Technetium Tc 99m Sulfur Colloid Injection is a radioactive diagnostic agent indicated: (1) In adults, 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. Evaluation of peritoneo-venous (LeVeen) shunt patency in adults. In adults and pediatric patients for: Imaging areas of functioning reticuloendothelial cells in the liver, spleen and bone marrow. Studies of esophageal transit and gastroesophageal reflux, and detection of pulmonary aspiration of gastric contents.

Technetium Tc 99m Sulfur Colloid Injection emits radiation. Use procedures to minimize radiation exposure. Measure patient dose by a suitable radioactivity calibration system immediately before administration. Minimize Tc 99m Sulfur Colloid radiation exposure and measure patient doses immediately before administration. Breast cancer or malignant melanoma setting: by subcutaneous injection, 3.7 to 37 MBq (0.1 to 1 mCi in volumes ranging from 0.1 to 1 mL) ( 2.1 ) Peritoneo-venous (LeVeen) shunt setting in adults: (2.1) By intraperitoneal injection: 37 to 111 MBq (1 to 3 mCi); By percutaneous transtubal injection: 12 to 37 MBq (0.3 to 1 mCi) in a volume not to exceed 0.5 mL. Imaging areas of functioning reticuloendothelial cells by intravenous injection: (2.1) In adults: Liver/spleen imaging: 37 to 296 MBq (1 to 8 mCi); Bone marrow imaging: 111 to 444 MBq (3 to 12 mCi); In pediatric patients: Liver/spleen imaging in newborns: 7.4 to 18.5 MBq (0.2 to 0.5 mCi); Liver/spleen imaging in children: 0.56 to 2.78 MBq (0.015 to 0.075 mCi) per kg of body weight (BW); Bone marrow imaging: 1.11 to 5.55 MBq (0.03 to 0.15 mCi) per kg of BW. Gastroesophageal and pulmonary aspiration studies by oral route: (2.1) In adults: Gastroesophageal studies: 5.55 to 11.1 MBq (0.15 to 0.3 mCi); Pulmonary aspiration studies: 11.1 to 18.5 MBq (0.3 to 0.5 mCi). In pediatric patients: 3.7 to 11.1 MBq (0.1 to 0.3 mCi). 2.1 Recommended Doses Breast cancer or malignant melanoma setting in adults: 3.7 to 37 MBq (0.1 to 1 mCi) in volumes ranging from 0.1 to 1 mL by subcutaneous injection. Peritoneo-venous (LeVeen) shunt setting in adults: 37 to 111 MBq (1 to 3 mCi) by intraperitoneal injection, or 12 to 37 MBq (0.3 to 1 mCi) in a volume not to exceed 0.5 mL by percutaneous transtubal (efferent limb) injection. Patient repositioning or other measures may be used to help assure uniform mixing of the radiopharmaceutical with peritoneal fluid. Imaging areas of functioning reticuloendothelial cells: In adults: Liver/spleen imaging: 37 to 296 MBq (1 to 8 mCi) by intravenous injection; Bone marrow imaging: 111 to 444 MBq (3 to 12 mCi) by intravenous injection. In pediatric patients: Liver/spleen imaging in children: 0.56 to 2.78 MBq (0.015 to 0.075 mCi) per kg of body weight (BW) by intravenous injection; Liver/spleen imaging in newborns: 7.4 to 18.5 MBq (0.2 to 0.5 mCi) by intravenous injection; Bone marrow imaging: 1.11 to 5.55 MBq (0.03 to 0.15 mCi) per kg of BW by intravenous injection Gastroesophageal and pulmonary aspiration imaging studies: In adults: Gastroesophageal studies: 5.55 to 11.1 MBq (0.15 to 0.3 mCi) by oral administration; Pulmonary aspiration studies: 11.1 to 18.5 MBq (0.3 to 0.5 mCi) by oral administration. In pediatric patients: Gastroesophageal and pulmonary aspiration studies: 3.7 to 11.1 MBq (0.1 to 0.3 mCi) by oral or nasogastric tube administration. For oral administration, combine the radiopharmaceutical with a milk feeding. For nasogastric tube administration, administer the radiopharmaceutical into the stomach then instill a normal volume of dextrose or milk feeding. 2.2 Drug Preparation and Administration The contents of the two Solution vials, the Solution A vial containing the appropriate acidic solution and the Solution B vial containing the appropriate buffer solution, are intended only for use in the preparation of the Technetium Tc 99m Sulfur Colloid Injection and are not to be directly administered to the patient. Do not use Sodium Pertechnetate Tc 99m containing oxidants to reconstitute this kit. The contents of the kit are not radioactive. However, after the Sodium Pertechnetate Tc 99m is added, maintain adequate shielding of the final preparation. Wear waterproof gloves during the preparation procedure. Do not use Sodium Pertechnetate Tc 99m containing more than 10 micrograms per mL of aluminum ion because a flocculent precipitate may occur and such a precipitate may localize in the lung. The contents of the kit are sterile and non-pyrogenic. This preparation contains no bacteriostatic preservative (preservative-free). Follow the directions carefully and adhere strictly to aseptic procedures during preparation. Prepare Technetium Tc 99m Sulfur Colloid Injection by the following aseptic procedure: Remove the dark brown plastic cap from the Sulfur Colloid Multi-Dose Reaction Vial and swab the top of the vial closure with alcohol to sterilize the surface. Complete the radiation label and affix to the vial. Place the vial in an appropriate lead-capped radiation shield labeled and identified. With a sterile shielded syringe, aseptically obtain 1 to 3 mL of a suitable, oxidant-free sterile and non-pyrogenic Sodium Pertechnetate Tc 99m, each milliliter containing a maximum activity of 18,500 MBq (500 mCi). Aseptically add the Sodium Pertechnetate Tc 99m to the vial. Place a lead cover on the vial shield and dissolve the reagent by gentle swirling. Just before use, remove the red cap from the Solution A vial and swab the top of the vial closure with alcohol to sterilize the surface. Using a sterile needle and syringe, aseptically withdraw 1.5 mL Solution A from the vial. Aseptically inject 1.5 mL Solution A into the Multi-Dose Reaction Vial and swirl again. Transfer the Multi-Dose Reaction Vial from vial shield and place in a vigorously boiling water bath (water bath should be shielded with 1/8” to 1/4” lead) deep enough to cover the entire liquid contents of the vial. Keep the vial in the water bath for five minutes. Remove the Multi-Dose Reaction Vial from the water bath and place in the lead shield and allow to cool for three minutes. Swab the vial closure again with an antiseptic. Just before use, remove the blue cap from the Solution B vial and swab the top of the vial closure with alcohol to sterilize the surface. Using a sterile needle and syringe, aseptically withdraw 1.5 mL Solution B from the vial. Aseptically inject 1.5 mL Solution B into the Multi-Dose Reaction Vial and swirl again. Record time and date of preparation. Allow the preparation to cool to body temperature before use. Maintain adequate shielding of the radioactive colloid preparation at all times. Where appropriate, dilute the preparation with sterile Sodium Chloride Injection to bring the dosage to within the recommended range. Mix the Multi-Dose Reaction Vial and aseptically withdraw material with a sterile shielded syringe for use within 6 hours of preparation. For optimum results this time should be minimized. The vial contains no bacteriostatic preservative (preservative-free). Store the reconstituted vial at 20°C to 25°C (68°F to 77°F). Discard vial 6 hours after reconstitution. Carefully agitate the shielded syringe immediately prior to administration of sulfur colloid to avoid particles aggregation and non-uniform distribution of radioactivity. Measure the patient dose by a suitable radioactivity calibration system immediately before administration. Check radiochemical purity before patient administration. Inspect Technetium Tc 99m Sulfur Colloid Injection visually for particulate matter and discoloration before administration, whenever solution and container permit. Do not administer the drug if it contains particulate matter or discoloration; dispose of these unacceptable or unused preparations in a safe manner, in compliance with applicable regulations. 2.3 Radiation Dosimetry Subcutaneous injection to assist in lymph node localization Table 1. Estimated Adult Absorbed Radiation Doses from Subcutaneous Administration of Technetium Tc 99m Sulfur Colloid Injection (mSv/MBq and rem/mCi) 1 Target Organ mSv/MBq rem/mCi Injection Site 9.51 35.2 Lymph Nodes 0.951 3.52 Liver 0.0028 0.0104 Spleen 0.0017 0.00629 Bone Marrow 0.0019 0.00703 Testes 0.0009 0.0033 Ovaries 0.00018 0.00066 Total Body 0.004 0.0148 1 Bergqvist L, Strand S-E, Persson B, et al. Dosimetry in Lymphoscintigraphy of Tc 99m Antimony Sulfide Colloid, J Nucl Med, 23: 698-705, 1982. Intravenous Injection Adult Radiation Doses Table 2. Estimated Adult Absorbed Radiation Doses from Technetium Tc 99m Sulfur Colloid Injection Administration (mSv/MBq and rem/mCi) 2 Diffuse Parenchymal Disease Target Organ Normal Liver Early to Intermediate Intermediate to Advanced mSv/MBq rem/mCi mSv/MBq rem/mCi mSv/MBq rem/mCi Liver 0.091 0.338 0.058 0.213 0.044 0.163 Spleen 0.058 0.213 0.074 0.275 0.115 0.425 Bone Marrow 0.008 0.028 0.012 0.045 0.021 0.079 Testes 0.0003 0.001 0.0005 0.002 0.0008 0.003 Ovaries 0.0016 0.006 0.0022 0.008 0.0032 0.012 Total Body 0.005 0.019 0.005 0.019 0.005 0.018 2 Modified from Summary of Current Radiation Dose Estimates to Humans with Various Liver Conditions from 99m Tc- Sulfur Colloid, MIRD Dose Estimate Report No 3, J Nucl Med 16: 108A-108B, 197. Pediatric Radiation Doses Table 3A. Estimated Pediatric Absorbed Radiation Doses from Technetium Tc 99m Sulfur Colloid Injection Administration of 1 MBq and 1 mCi for Liver/Spleen and Bone Marrow Imaging (in mSv/MBq and rem/mCi) 3 Age Body Weight Newborn 3.5 kg 1 year 12.1 kg 5 years 20.3 kg 10 years 33.5 kg 15 years 55 kg Absorbed Dose Target Organ Liver mSv/MBq 0.86 0.38 0.22 0.18 0.13 rem/mCi 3.2 1.4 0.82 0.67 0.49 Spleen mSv/MBq 0.76 0.32 0.18 0.13 0.09 rem/mCi 2.8 1.2 0.65 0.49 0.33 Red Marrow mSv/MBq 0.16 0.05 0.03 0.022 0.01 rem/mCi 0.58 0.18 0.11 0.081 0.036 Ovaries mSv/MBq 0.04 0.02 0.0103 0.0043 0.0022 rem/mCi 0.14 0.064 0.038 0.016 0.008 Testes mSv/MBq 0.011 0.006 0.004 0.004 0.001 rem/mCi 0.04 0.021 0.013 0.014 0.002 Total Body mSv/MBq 0.032 0.026 0.018 0.012 0.006 rem/mCi 0.12 0.096 0.066 0.043 0.022 3 From Age-dependent "S" values of Henrichs et al, Berlin 1982, except for the 1-year old. The 1-year old "S" values were taken from phantom work of the Metabolism and Dosimetry Group at ORNL. Table 3B. Estimated Pediatric Maximum Absorbed Radiation Doses from Administration of the Maximum Recommended Dose for Technetium Tc 99m Sulfur Colloid Injection (mSv and rem) 3 Age Body Weight Newborn 3.5 kg 1 year 12.1 kg 5 years 20.3 kg 10 years 33.5 kg 15 years 55 kg Maximum Recommended Dose: a* b* a* b* a* b* a* b* a* b* MBq 18.5 22.2 33.3 67.3 55.5 114.7 92.5 186.1 151.7 307.1 mCi 0.5 0.6 0.9 1.82 1.5 3.1 2.5 5.03 4.1 8.3 Maximum Absorbed Dose from Maximum Recommended Dose Administered (mSv and rem) Target Organ Liver mSv 16 19.2 12.6 25.46 12.3 25.42 16.7 33.6 20.1 40.69 rem 1.6 1.92 1.26 2.55 1.23 2.54 1.67 3.36 2.01 4.07 Spleen mSv 14 16.8 10.8 21.83 9.75 20.15 12.2 24.55 13.5 27.33 rem 1.4 1.68 1.08 2.18 0.98 2.02 1.22 2.45 1.35 2.73 Red Marrow mSv 2.9 3.48 1.62 3.27 1.65 3.41 2.03 4.08 1.48 3 rem 0.29 0.35 0.16 0.33 0.17 0.34 0.2 0.41 0.15 0.3 Ovaries mSv 0.7 0.84 0.58 1.17 0.57 1.18 0.4 0.8 0.34 0.69 rem 0.07 0.084 0.058 0.117 0.057 0.118 0.04 0.08 0.034 0.069 Testes mSv 0.2 0.24 0.19 0.38 0.2 0.41 0.35 0.7 0.09 0.18 rem 0.02 0.024 0.019 0.038 0.02 0.041 0.035 0.07 0.009 0.018 Total Body mSv 0.6 0.72 0.86 1.74 0.99 2.05 1.07 2.15 0.9 1.82 rem 0.06 0.072 0.086 0.174 0.099 0.205 0.107 0.215 0.09 0.182 *a liver/spleen imaging *b bone marrow imaging 3 From Age-dependent “S” values of Henrichs et al., Berlin 1982, except for the 1-year old. The 1-year old “S” values were taken from phantom work of the Metabolism and Dosimetry Group at ORNL Oral Administration Table 4. Adult Radiation Absorbed Dose from Oral Administration of 1 mCi of Technetium Tc 99m Sulfur Colloid Injection (mSv/MBq and rem/mCi) Target Organ Assumed Residence Time (hr.) mSv/MBq rem/mCi Stomach Wall 1.5 0.038 0.14 Small Intestine 4 0.07 0.26 Upper Large Intestine Wall 13 0.13 0.48 Upper Large Intestine Wall 24 0.089 0.33 Ovaries - 0.026 0.096 Testes - 0.001 0.005 Total Body - 0.005 0.018 Intraperitoneal Injection Table 5. Adult Absorbed Radiation Dose from Intraperitoneal Injection of 3 mCi of Technetium Tc 99m Sulfur Colloid (mSv/MBq and rem/mCi) Target Organ Shunt Open Shunt Closed mSv/MBq rem/mCi mSv/MBq rem/mCi Liver 0.092 0.34 0.015 0.056 Ovaries and Testes 0.0003 to 0.0016 0.0012 to 0.006 0.015 0.056 Organs in the Peritoneal Cavity - - 0.015 0.056 Total Body 0.0049 0.0180 0.005 0.019 Assumptions: Calculations for the absorbed radiation dose are based upon an effective half-time of 3 hours for the open shunt and 6.02 hours for the closed shunt and an even distribution of the radiopharmaceutical in the peritoneal cavity with no biological clearance. Other Exposure Estimates Table 6. Radiation Doses to Hospital Personnel (mcSv/MBq and mrem/mCi) Technician Preparation of Drug Using shielded vial and syringe Administered Drug Target mcSv/MBq mrem/mCi mcSv/MBq mrem/mCi Extremity Dose 0.016 0.0575 0.07 0.25 Whole Body Dose 0.0007 0.0025 0.003 0.0125 2.4 Imaging Considerations Breast cancer or malignant melanoma setting in adults: In clinical studies, patients received injection of Technetium Tc 99m Sulfur Colloid Injection and a concomitant blue dye tracer in order to enhance the ability to detect lymph nodes. Visual inspection was performed to identify the blue-labeled nodes and a hand held gamma counter was used to identify nodes concentrating the radiopharmaceutical. Multiple methods were used to detect the concentrated radioactivity within lymph nodes. For example, investigators used thresholds of background radioactivity to localize nodes containing a minimum of radioactive counts 3 times higher than the background or containing at least 10 fold higher counts than contiguous nodes. In clinical studies of patients with malignant melanoma, preoperative lymphoscintigraphy was usually performed using planar imaging techniques to establish a road map of nodal basins and to facilitate intraoperative identification of lymph nodes. [see Clinical Studies (14)] Technetium Tc 99m Sulfur Colloid Injection and other tracers may not localize all lymph nodes and the tracers may differ in their extent of lymph node localization. The lymph node localization of Technetium Tc 99m Sulfur Colloid Injection is dependent upon the underlying patency and structure of the lymphatic system, the extent of functional reticuloendothelial cells within lymph nodes and the radiopharmaceutical injection technique. Distortion of the underlying lymphatic system architecture and function by prior surgery, radiation or extensive metastatic disease may result in failure of the radiopharmaceutical and other tracers to localize lymph nodes. The use of Technetium Tc 99m Sulfur Colloid Injection is intended to supplement palpation, visual inspection and other procedures important to lymph node localization. [see Clinical Studies (14)] Peritoneo-venous (LeVeen) shunt setting in adults: Following administration of Technetium Tc 99m Sulfur Colloid Injection into the peritoneal cavity, the radiopharmaceutical mixes with the peritoneal fluid. Clearance from the peritoneal cavity varies from insignificant, which may occur with complete shunt blockage, to very rapid clearance with subsequent transfer into the systemic circulation when the shunt is patent. Following transfer into the systemic circulation, the radiopharmaceutical concentrates within the liver (a target organ). Obtain serial images of both the shunt and liver. An adequate evaluation of the difference between total blockage of the shunt and partial blockage may not be feasible in all cases. Transperitoneal absorption of sulfur colloid into the systemic circulation may occur, but it occurs slowly. Therefore, the most definitive scintigraphic evaluation of shunt patency will generally be obtained if there is visualization of both the shunt itself and the liver and/or spleen within the first three hours post intraperitoneal injection of the radiopharmaceutical. Imaging areas of functioning reticuloendothelial cells in liver, spleen or bone marrow: Altered biodistribution with lung and soft tissue uptake instead of reticuloendothelial system has been reported after intravenous injection. The size and physical-chemical properties of the sulfur colloid particles formed from the components of the kit may determine the biodistribution of the colloid and its uptake by the reticuloendothelial system. Diseases affecting the reticuloendothelial system may also alter the expected uptake pattern. Gastroesophageal and pulmonary aspiration imaging studies: To facilitate the imaging of gastroesophageal reflux consider administering Sulfur Colloid by nasogastric tube.

None None ( 4 )

The most frequently reported adverse reactions, across all categories of use and routes of administration, include rash, allergic reaction, urticaria, anaphylaxis/anaphylactic shock, and hypotension. Less frequently reported adverse reactions are fatal cardiopulmonary arrest, seizures, dyspnea, bronchospasm, abdominal pain, flushing, nausea, vomiting, itching, fever, chills, perspiration, numbness, and dizziness. Local injection site reactions, including burning, blanching, erythema, sclerosis, swelling, eschar, and scarring, have also been reported. The most frequently reported adverse reactions include rash, urticaria, anaphylactic shock, and hypotension. (6) To report SUSPECTED ADVERSE REACTIONS, contact Jubilant DraxImage Inc., dba Jubilant Radiopharma TM at 1-888-633-5343 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Specific drug-drug interactions have not been studied.