NEPHROSCAN

11.1 Chemical Characteristics NEPHROSCAN is a sterile, single-dose kit for the preparation of Technetium Tc 99m Succimer Injection a radioactive diagnostic agent, for intravenous use. The active ingredient, succimer is meso-2,3-dimercaptosuccinic acid with a molecular weight of 182.22 g/mol. The chemical structure of succimer is shown below. Subsequent to radiolabeling with sodium pertechnetate Tc 99m, the active moiety technetium Tc 99m succimer is obtained in situ. Each vial contains 1 mg succimer, 0.1 mg ascorbic acid, 0.42 mg stannous (tin) chloride dihydrate, 0.02 mg hydrochloric acid and 0.2 mg sodium hydroxide as a white-yellowish to off-white lyophilized powder. In addition, after radiolabeling with sodium pertechnetate Tc 99m injection, each vial contains up to 1,480 MBq (40 mCi) of technetium Tc 99m succimer in 0.9% sodium chloride injection as a sterile, clear, and colorless solution. pH of the final solution is between 3 and 3.5. FDA approved pH specifications differ from USP. Chemical Structure 11.2 Physical Characteristics Technetium Tc 99m decays by isomeric transition with a physical half-life of 6.02 hours. The principal photon that is useful for detection and imaging studies is listed in Table 3. Table 3 Principal Radiation Emission Data for Technetium Tc 99m Radiation/ Emission Mean % / Disintegration Mean Energy (keV) Gamma 2 89.07 140.5 To correct for physical decay of this radionuclide, the fractions that remain at selected intervals after the time of calibration are shown in Table 4. Table 4 Physical Decay Chart for Tc 99m, half-life 6.02 hours Hours Fraction Remaining Hours Fraction Remaining 0 Calibration time 1.000 7 0.447 1 0.891 8 0.398 2 0.794 9 0.355 3 0.708 10 0.316 4 0.631 11 0.282 5 0.562 12 0.251 6 0.501 11.3 External Radiation The specific gamma ray constant for technetium Tc 99m is 0.78 R/hr-mCi at 1 cm. The first half value layer is 0.017 cm of Pb. To facilitate control of the radiation exposure from millicurie amounts of this radionuclide, the use of a 0.25 cm thickness of Pb will attenuate the radiation emitted by a factor of about 1,000. Table 5 displays the radiation attenuation by lead shielding. Table 5 Radiation Attenuation by Lead (Pb) Shielding Shield Thickness (Pb) mm Coefficient of Attenuation 0.02 0.5 0.08 0.1 0.16 0.01 0.25 0.001 0.33 0.0001

NEPHROSCAN, after radiolabeling with technetium Tc 99m, is indicated for use as an aid in the scintigraphic evaluation of renal parenchymal disorders in adult and pediatric patients including term neonates. NEPHROSCAN, after radiolabeling with technetium Tc 99m, is a radioactive diagnostic agent indicated for use as an aid in the scintigraphic evaluation of renal parenchymal disorders in adults and pediatric patients including term neonates. ( 1 )

Instruct patients to drink a sufficient amount of water before administration and to continue to drink and to void frequently following administration ( 2.2 ) The recommended amount of radioactivity by intravenous injection (bolus) is: For adults: 74 MBq to 222 MBq (2 mCi to 6 mCi) ( 2.3 ) For pediatric patients: 1.85 MBq/kg (0.05 mCi/kg) of body weight with a range of 19 MBq to 74 MBq (0.5 mCi to 2 mCi). ( 2.3 ) Begin image acquisition 1 hour to 4 hours after administration ( 2.7 ) Delay imaging up to 6 hours to 24 hours in patients with severely reduced eGFR ( 2.7 ) See Full Prescribing Information for radiation safety, drug preparation, administration, and radiation dosimetry information ( 2.1 , 2.4 , 2.5 , 2.6 , 2.8 ) 2.1 Radiation Safety – Drug Handling After radiolabeling, handle Technetium Tc 99m Succimer Injection with appropriate safety measures to minimize radiation exposure [see Warnings and Precautions (5.2) ] . Use waterproof gloves, effective radiation shielding, and other appropriate safety measures when preparing and handling Technetium Tc 99m Succimer Injection. Radiopharmaceuticals should be used by or under the control of physicians who are qualified by specific training and experience in the safe use and handling of radionuclides, and whose experience and training have been approved by the appropriate governmental agency authorized to license the use of radionuclides. 2.2 Patient Preparation Instruct patients to drink a sufficient amount of water to ensure adequate hydration prior to administration of Technetium Tc 99m Succimer Injection and to continue to drink and void frequently following administration to reduce radiation exposure [see Warnings and Precautions (5.2) ]. 2.3 Recommended Dosage Adults The recommended amount of radioactivity of Technetium Tc 99m Succimer Injection for renal parenchymal imaging in adults is 74 MBq to 222 MBq (2 mCi to 6 mCi) by intravenous injection (bolus). Pediatric Patients The recommended amount of radioactivity of Technetium Tc 99m Succimer Injection for renal parenchymal imaging in pediatric patients is 1.85 MBq/kg (0.05 mCi/kg) of body weight with a range of 19 MBq to 74 MBq (0.5 mCi to 2 mCi) by intravenous injection (bolus). Weight based pediatric dosing is shown in Table 1. Table 1 Recommended Radioactivity of Technetium Tc 99m Succimer Injection for Pediatric Patients by Body Weight Body Weight (kg) Recommended Radioactivity MBq (mCi) Body Weight (kg) Recommended Radioactivity MBq (mCi) less than 11 kg 19 MBq (0.5 mCi) 25 to 26 49 MBq (1.3 mCi) 11 to 12 21 MBq (0.6 mCi) 27 to 28 52 MBq (1.4 mCi) 13 to 14 26 MBq (0.7 mCi) 29 to 30 56 MBq (1.5 mCi) 15 to 16 30 MBq (0.8 mCi) 31 to 32 59 MBq (1.6 mCi) 17 to 18 33 MBq (0.9 mCi) 33 to 34 63 MBq (1.7 mCi) 19 to 20 37 MBq (1 mCi) 35 to 36 67 MBq (1.8 mCi) 21 to 22 41 MBq (1.1 mCi) 37 to 38 70 MBq (1.9 mCi) 23 to 24 44 MBq (1.2 mCi) 39 or greater 74 MBq (2 mCi) 2.4 Drug Preparation Prepare Technetium Tc 99m Succimer Injection according to the following procedure using asceptic technique: Wear waterproof gloves. Place the kit vial in lead shielding and disinfect the stopper (allow disinfectant to dry). Use a sterile syringe to transfer 5 mL sodium pertechnetate Tc 99m injection obtained from a technetium Tc 99m generator with a maximum activity of 1,480 MBq (40 mCi) to the vial. The volume of sodium pertechnetate Tc 99m injection may be adjusted to 5 mL prior to adding to the kit vial using 0.9% sodium chloride injection, USP. Use the same syringe to withdraw the appropriate gas volume from the vial for pressure compensation. Lightly shake the vial to completely dissolve the powder. Ensure the stopper is well moistened. Incubate the vial for 10 minutes at controlled room temperature 20°C to 25°C (68°F to 77°F). Measure the product activity in a dose calibrator; complete the radiolabeled product vial label and affix to the vial shield. Check radiochemical purity according to the method in 2.5 Radiochemical Purity Determination [see Dosage and Administration (2.5) ]. Use Technetium Tc 99m Succimer Injection within 4 hours and store at 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). 2.5 Radiochemical Purity Determination Determine the radiochemical purity of Technetium Tc 99m Succimer Injection as follows: Activate a 65 × 95-mm silicic acid thin-layer chromatographic (TLC) plate by heating at 100°C to 110°C (212°F to 230°F) for 30 minutes. Cool the TLC plate over silica gel and immediately apply 1 microL of Technetium Tc 99m Succimer Injection about 17 mm from one end of the TLC plate and allow to dry. If necessary, the Technetium Tc 99m Succimer Injection may be diluted with 0.9% sodium chloride injection USP, to a radioactive concentration of 18.5 MBq to 370 MBq (0.5 mCi to 10 mCi) per mL. Develop the TLC plate over a period of about 30 minutes to 45 minutes by ascending chromatography, using a solution of n-butanol saturated with 0.3 N hydrochloric acid ( see Note 1 ). Air-dry the developed TLC Plate. Determine the radioactive distribution on the TLC plate by scanning the chromatogram with a radiochromatographic scanner having a suitably collimated radiation detector. The radioactivity associated with technetium Tc 99m succimer is at Rf between 0.45 and 0.7, hydrolyzed Tc 99m is located at the origin (Rf 0 to 0.15) and the unbound Tc 99m is located at the solvent front (Rf 1) Calculate radiochemical purity using the following formula: Technetium Tc 99m Succimer Injection preparation with not less than 85% radiochemical purity is suitable for administration. Discard preparation with less than 85% radiochemical purity. Note 1: To prepare the n-butanol saturated with 0.3 N hydrochloric acid solution, place 50 mL of 0.3 N HCl and 50 mL of n-butanol in an Erlenmeyer flask. Place the mixture in an ultrasonic bath for 2 hours, during which time the solution heats up to about 50°C. Cool the solution to room temperature. After about 30 minutes to 45 minutes the phase separation of the mixture will complete. Collect the upper phase of the mixture and discard the lower phase. The solution is stable for up to 7 days when stored at controlled room temperature 20°C to 25°C (68°F to 77°F). Image Image 2.6 Administration Prior to use, visually inspect the prepared Technetium Tc 99m Succimer Injection behind a lead glass shield. Only use solutions that are clear without visible particles. In making dosage calculations, correction is to be made for radioactive decay. The radioactive half-life of Tc 99m is 6.0 hours. Using a sterile shielded syringe, aseptically withdraw the prepared Technetium Tc 99m Succimer Injection, and measure the radioactivity in the syringe using a dose calibrator, prior to administration. Ensure that the injected radioactivity is within ±10% of the recommended dose. Discard unused portion. Handle and dispose radioactive material in accordance with applicable regulations. 2.7 Image Acquisition The patient should be placed in the prone or supine position, as required by scanning equipment characteristics. Begin image acquisition 1 hour to 4 hours after the intravenous administration of Technetium Tc 99m Succimer Injection. Delay image acquisition up to 6 hours to 24 hours in patients with severely reduced glomerular filtration rate (eGFR). A specific eGFR threshold at which to delay imaging has not been established [see Warnings and Precautions (5.3) ]. 2.8 Radiation Dosimetry The estimated absorbed radiation doses to an average adult and pediatric patients are shown in Table 2. Table 2 Estimated Radiation Absorbed Dose per Unit of Administered Radioactivity in Selected Organs and Tissues after a Technetium Tc 99m Succimer Injection Dose Absorbed Dose per Unit of Activity Administered (mGy/MBq) Organ Adults 15 years 10 years 5 years 1 year Adrenals 0.012 0.016 0.024 0.035 0.06 Bladder wall 0.018 0.023 0.029 0.031 0.057 Bone surface 0.005 0.0062 0.0092 0.014 0.026 Brain 0.0012 0.0015 0.0025 0.004 0.0072 Breasts 0.0013 0.0018 0.0028 0.0045 0.0084 Gall bladder 0.0083 0.01 0.014 0.022 0.031 Stomach wall 0.0052 0.0063 0.01 0.014 0.02 Colon 0.005 0.0063 0.01 0.014 0.024 Intestine 0.0043 0.0055 0.0082 0.012 0.02 Upper large intestine 0.005 0.0064 0.095 0.014 0.023 Lower large intestine 0.0035 0.0043 0.0065 0.0096 0.016 Heart 0.003 0.0038 0.0058 0.0086 0.014 Kidneys 0.18 0.22 0.3 0.43 0.76 Liver 0.0095 0.012 0.018 0.025 0.041 Lungs 0.0025 0.0035 0.0052 0.008 0.015 Muscles 0.0029 0.0036 0.0052 0.0077 0.014 Oesophagus 0.0017 0.0023 0.0034 0.0054 0.0094 Ovaries 0.0035 0.0047 0.007 0.011 0.019 Pancreas 0.009 0.011 0.016 0.023 0.037 Red marrow 0.0039 0.0047 0.0068 0.009 0.014 Skin 0.0015 0.0018 0.0029 0.0045 0.0085 Spleen 0.013 0.017 0.026 0.038 0.061 Testes 0.0018 0.0024 0.0037 0.0053 0.01 Thymus 0.0017 0.0023 0.0034 0.0054 0.0094 Thyroid 0.0015 0.0019 0.0031 0.0052 0.0094 Uterus 0.0045 0.0056 0.0083 0.011 0.019 Remaining organ 0.0029 0.0037 0.0052 0.0077 0.014 Effective Dose per unit of activity administered (mSv/MBq) 0.0088 0.011 0.015 0.021 0.037

None None ( 4 )

The following clinically significant adverse reactions are discussed elsewhere in the labeling: Hypersensitivity Reactions [see Warnings and Precautions (5.1) ] The following adverse reactions associated with the use of NEPHROSCAN were identified in clinical studies or postmarketing reports. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune System Disorders : Hypersensitivity including urticaria, rash, pruritus, and erythema General Disorders : syncope, fever, and nausea. The following adverse reactions have been reported: urticaria, rash, pruritus, erythema, syncope, fever, and nausea. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Theragnostics, Inc., at 1-888-286-3848 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Storage and Handling Before radiolabeling, store NEPHROSCAN in a refrigerator at 2°C to 8°C (36°F to 46°F) in original carton. Do not freeze. After radiolabeling, store Technetium Tc 99m Succimer Injection upright, shielded, for up to 4 hours, at 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) [see Dosage and Administration (2.4) ]. This preparation is approved for use by persons under license by the Nuclear Regulatory Commission or the relevant regulatory authority of an Agreement State.