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.

tle with time or with exposure to polyvalent cations. these larger particles are likely to be trapped by the pulmonary capillary bed following intravenous injection and result in non-uniform distribution of radioactivity. agitate the vial adequately before administration of sulfur colloid to avoid particle aggregation and non-uniform distribution of radioactivity. discard unused drug after 6 hours from the time of formulation. [see dosage and administration (2.2)]

een 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 0.30 mci); • pulmonary aspiration studies: 11.1 to 18.5 mbq (0.30 to 0.50 mci). in pediatric patients: • 3.7 to 11.1 mbq (0.10 to 0.30 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: 1. liver/spleen imaging: 37 to 296 mbq (1 to 8 mci) by intravenous injection; 2. bone marrow imaging: 111 to 444 mbq (3 to 12 mci) by intravenous injection. in pediatric patients: 3. 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; 4. liver/spleen imaging in newborns: 7.4 to 18.5 mbq (0.20 to 0.50 mci) by intravenous injection; 5. 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: 6. gastroesophageal studies: 5.55 to 11.1 mbq (0.15 to 0.30 mci) by oral administration; 7. pulmonary aspiration studies: 11.1 to 18.5 mbq (0.30 to 0.50 mci) by oral administration. in pediatric patients: 8. gastroesophageal and pulmonary aspiration studies: 3.7 to 11.1 mbq (0.10 to 0.30 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. follow the directions carefully and adhere strictly to aseptic procedures during preparation. prepare technetium tc 99m sulfur colloid injection by the following aseptic procedure: 1. 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. 2. 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). 3. aseptically add the sodium pertechnetate tc 99m to the vial. 4. place a lead cover on the vial shield and dissolve the reagent by gentle swirling. 5. 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 1.5ml solution a into the multi-dose reaction vial and swirl again. 6. 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. 7. 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. 8. 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. 9. record time and date of preparation. 10. allow the preparation to cool to body temperature before use. maintain adequate shielding of the radioactive colloid preparation at all times. 11. where appropriate, dilute the preparation with sterile sodium chloride injection to bring the dosage to within the recommended range. 12. 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. store the reconstituted vial at 20 to 25°c (68 to77°f). discard vial 6 hours after reconstitution. 13. 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 1mci of technetium tc99m 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 (µsv/mbq and mrem/mci) technician preparation of drug* administered drug target µsv/mbq mrem/mci µsv/mbq mrem/mci extremity dose 0.016 0.0575 0.07 0.25 whole body dose 0.0007 0.0025 0.003 0.0125 *using shielded vial and syringe 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.

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. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively. data human data among 14 infants born to pregnant patients exposed to technetium tc 99m sulfur colloid injection for lymph node localization, no birth defects were reported following drug exposure. 8.2 lactation risk summary technetium tc 99m is excreted in human milk during lactation. exposure of technetium tc 99m sulfur colloid injection to a breastfed infant can be minimized 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 technetium tc 99m sulfur colloid injection and any potential adverse effects on the breastfed child from technetium tc 99m sulfur colloid injection or from the underlying maternal condition. clinical considerations to decrease radiation exposure to the breastfed infant, advise a lactating woman to pump and discard breast milk for 24 hours after administration of technetium tc 99m sulfur colloid injection. following higher dose procedures [greater than 370 mbq (10 mci)], patients should minimize close contact with infants for 6 hours after receiving a technetium tc 99m sulfur colloid injection. 8.4 pediatric use the safety and efficacy of technetium tc 99m sulfur colloid kit in pediatric patients has been shown for the following indications: liver, spleen, and bone marrow imaging, and gastroesophageal and pulmonary aspiration studies. 8.5 geriatric use clinical studies of kit for the preparation of technetium tc 99m sulfur colloid injection did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

ated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively. data human data among 14 infants born to pregnant patients exposed to technetium tc 99m sulfur colloid injection for lymph node localization, no birth defects were reported following drug exposure.

stem (res), allowing res rich structures to be imaged. with oral administration, technetium tc 99m sulfur colloid is not absorbed accounting for its function in esophageal transit studies, gastroesophageal reflux scintigraphy, and for the detection of pulmonary aspiration of gastric contents. 12.3 pharmacokinetics following intravenous administration, technetium tc 99m sulfur colloid injection is rapidly cleared from the blood by the reticuloendothelial system with a nominal half-life of approximately 2 1/2 minutes. uptake of the radioactive colloid by organs of the res is dependent upon both their relative blood flow rates and the functional capacity of the phagocytic cells. in the average patient 80 to 90% of the injected collodial particles are phagocytized by the kupffer cells of the liver, 5 to 10% by the spleen and the balance by the bone marrow. following oral ingestion, technetium tc 99m sulfur colloid is distributed primarily through the gastrointestinal tract with elimination primarily through the feces.

60 years, and almost all were female. lymph nodes that contained radioactivity were generally localized based upon increased counts, in comparison to a background threshold (e.g., nodes containing a minimum of radioactive counts 3 times higher than background or containing at least 10 fold higher counts than contiguous nodes). radioactivity was measured using a handheld gamma counter. table 10 shows the tracer localization rates where the tracer localization rate (%) is defined as the percentage of procedures which had at least one lymph node containing the specific tracer. random effect meta-analytic measures were used for estimating various rates of tracer localization by procedure along with the respective confidence intervals. the random effect meta-analytical methods take into account the sample size of each study as well as within and between study variability. in general, most procedures involved the resection of lymph nodes in which a tracer had localized to at least one node. however, in some procedures (estimated at approximately 3.4%) neither tracer was localized to a resected lymph node. the reports were insufficient to establish the basis for failed tracer localization. [ see dosage and administration (2.4) ] table 10 . tracer localization by procedure – breast cancer* number of clinical studies number of procedures bd present (%) sci present (%) only bd present (%) only sci present (%) neither sci nor bd present (%) 15 9,213 85.1 94.1 3.8 12.1 3.4 95% confidence intervals** 81.4, 88.2 91.4, 96.0 2.8, 5.2 9.9, 15.0 2.1, 5.4 bd = blue dye, sci = technetium tc 99m sulfur colloid injection * percentage of procedures in which at least one lymph node contained the specific tracer; the percents do not add to 100% due to rounding. ** 95% confidence intervals are based on meta-analysis and represent the spread in the individual estimates. in some of the publications, different methods of technetium tc 99m sulfur colloid injection administration were compared: intradermal (id), subareolar (sa) and intraparenchymal (ip) methods. generally, more favorable results were seen using the id and sa routes, with less favorable results reported when surgeons used the ip method. 14.2 tracer localization to lymph nodes in malignant melanoma a systematic review of eight publications examined the use of technetium tc 99m sulfur colloid and a blue dye (tracers) to assist surgeons in the localization of lymph nodes among patients with malignant melanoma. a meta-analysis was performed using data from the studies that reported the resected lymph node content of technetium tc 99m sulfur colloid injection and blue dye. four of the eight publications met this criterion and were included in the meta-analysis. within these four studies, the number of reported patients ranged from 12 to 94. the patients received subcutaneous technetium tc 99m sulfur colloid injection doses ranging between 0.25 to 2 mci. the patients were aged 15 to 89 years and most (53 to 70%) were male. lymph nodes that contained radioactivity were generally localized based upon increased counts, in comparison to a background threshold (e.g., nodes containing a minimum of radioactive counts 3 times higher than background). radioactivity was measured using a handheld gamma counter. table 11 shows the tracer localization rates where the tracer localization rate (%) is defined as the percentage of patients who had at least one lymph node containing the specific tracer. random effect meta-analytic measures were used for estimating the various rates of tracer localization by patient along with the respective confidence intervals. the random effect meta-analytical methods take into account the sample size of each study as well as within and between study variability. in general, most patients had resected lymph nodes that contained at least one of the tracers. however, in some patients (estimated at approximately 1.6%) neither tracer was localized to a resected lymph node. the reports were insufficient to establish the basis for failed tracer localization . [ see dosage and administration (2.4)]. table 11 . tracer localization by patient – malignant melanoma* number of clinical studies number of patients bd present (%) sci present (%) only bd present (%) only sci present (%) neither sci nor bd present (%) 4 249 83.6 96.4 3.2 15.5 1.6 95% confidence intervals** 73.4, 90.4 92.0, 98.5 1.4, 6.9 9.6, 24.1 0.4, 6.5 bd = blue dye, sci = technetium tc 99m sulfur colloid injection * percentage of patients in which at least one lymph node contained the specific tracer; the percents do not add to 100% due to rounding. ** 95% confidence intervals are based on meta-analysis and represent the spread in the individual estimates.