Kit For The Preparation Of Technetium Tc 99M Albumin Aggregated

1 INDICATIONS AND USAGE PULMOTECH MAA, after radiolabeling with technetium-99m, is indicated for: Lung scintigraphy as an adjunct in the evaluation of pulmonary perfusion in adults and pediatric patients. Peritoneovenous shunt scintigraphy as an aid in the evaluation of its patency in adults. PULMOTECH MAA, after radiolabeling with technetium-99m is a radioactive diagnostic agent indicated for: Lung scintigraphy as an adjunct in the evaluation of pulmonary perfusion in adults and pediatric patients. ( 1 ) Peritoneovenous shunt scintigraphy as an aid in the evaluation of its patency in adults. ( 1 )

2 DOSAGE AND ADMINISTRATION For lung perfusion scintigraphy, the following recommended activity is administered by intravenous injection. • Adults : 37 MBq to 148 MBq (1 mCi to 4 mCi) and 200,000 particles to 700,000 particles. ( 2.3 ) • Pediatric patients aged 4 weeks and older : 0.925 MBq/kg to 1.85 MBq/kg of body weight (0.025 mCi/kg to 0.05 mCi/kg); the minimum activity is 7.4 MBq (0.2 mCi). The number of particles will vary with age and body weight of the pediatric patient. ( 2.3 ) • Pediatric patients aged less than 4 weeks : 7.4 MBq to 18.5 MBq (0.2 mCi to 0.5 mCi); 10,000 particles to 50,000 particles. ( 2.3 ) For peritoneovenous shunts scintigraphy in adults: 37 MBq to 111 MBq (1 mCi to 3 mCi) and 200,000 particles to 700,000 particles by intraperitoneal injection. ( 2.4 ) See Full Prescribing Information for radiation safety, patient preparation, drug preparation, administration, imaging, and radiation dosimetry information. ( 2.1 , 2.2 , 2.5 , 2.6 , 2.7 ) 2.1 Radiation Safety – Drug Handling After radiolabeling of PULMOTECH MAA, the vial contains Technetium Tc 99m Albumin Aggregated Injection. Handle Technetium Tc 99m Albumin Aggregated Injection with appropriate safety measures to minimize radiation exposure [see Warnings and Precautions ( 5.4 )] . Use waterproof gloves, effective radiation shielding, and other appropriate safety measures when preparing and handling Technetium Tc 99m Albumin Aggregated Injection. Radiopharmaceuticals should be used by or under the control of healthcare providers 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 Albumin Aggregated Injection and to continue to drink and void frequently following administration to reduce radiation exposure [see Warnings and Precautions ( 5.4 )] . 2. 3 Recommended Dosage for Lung Perfusion Scintigraphy Adult Patients The recommended activity for lung perfusion scintigraphy in adult patients is 37 MBq to 148 MBq (1 mCi to 4 mCi) by intravenous injection. The range of particle numbers per single injection should be 200,000 to 700,000 with the recommended number of approximately 350,000. Depending on the activity added and volume of the final radiolabeled product, the volume of the dose may vary from 0.2 mL to 1.9 mL. The number of particles available per dose of Technetium Tc 99m Albumin Aggregated Injection will vary depending on the physical decay of technetium-99m that has occurred. The number of particles in any dose and volume to be administrated may be calculated as follows: Where: V a = volume to be administered in mL D = desired activity to be administered in MBq (mCi) C = concentration at calibration time of Sodium Pertechnetate Tc 99m Injection to be added to the reaction vial in MBq/mL (mCi/mL) Fr = fraction of Technetium-99m remaining after the time of calibration from Table 6 [see Description ( 11.3 )] P = number of particles in dose to be administered V a = volume to be administered in mL V Tc = volume of Sodium Pertechnetate Tc 99m Injection added to reaction vial in mL N = number of particles per vial. The number of particles per vial for the lot is located on the vial label. Pediatric Patients Aged 4 Weeks and Older The recommended activity for lung perfusion scintigraphy in pediatric patients aged 4 weeks and older by intravenous injection is based on body weight and ranges from 0.925 MBq/kg to 1.85 MBq/kg (0.025 mCi/kg to 0.05 mCi/kg). The minimum recommended dose for lung perfusion scintigraphy in this age is 7.4 MBq (0.2 mCi). The number of particles will vary with age and body weight of the pediatric patient. Particle numbers administered in four different age and weight categories are shown in Table 1. Table 1 – Particle Numbers Administered in Four Different Age and Weight Categories of Pediatric Patients Receiving Maximum Recommended Activity of Technetium Tc 99m Albumin Aggregated Injection for Lung Perfusion Scintigraphy Age 15 years 10 years 5 years 1 year Weight (kg) 55 33.5 20.3 12.1 Maximal recommended activity MBq 103.6 mCi 2.8 MBq 62.9 mCi 1.7 MBq 37 mCi 1 MBq 22.2 mCi 0.6 Range of particles administered 200,000 to 700,000 200,000 to 300,000 200,000 to 300,000 50,000 to 150,000 Pediatric Patients Aged Less Than 4 Weeks (Neonates) The recommended activity for lung perfusion scintigraphy in neonates by intravenous injection is 7.4 MBq to 18.5 MBq (0.2 mCi to 0.5 mCi). The number of particles in neonates for lung perfusion scintigraphy ranges from 10,000 to 50,000. Use the lowest possible number of particles for neonates. image description 2.4 Recommended Dosage for Peritoneo veno us Shunt Scintigraphy in Adults The recommended activity for peritoneovenous shunt scintigraphy in adult patients is 37 MBq to 111 MBq (1 mCi to 3 mCi) by intraperitoneal injection and the number of particles per single injection should be 200,000 to 700,000 with the recommended number of approximately 350,000. Depending on the activity added and volume of the final radiolabeled product, the volume of the dose may vary from 0.2 mL to 1.9 mL. For calculation of the number of particles to be administered, see Recommended Dosage for Lung Perfusion Scintigraphy in Adult Patients [see Dosage and Administration ( 2.3 )] . Assure uniform mixing with peritoneal fluid. Alternatively, administer the drug by percutaneous transtubal injection. The recommended activity for percutaneous transtubal administration in adult patients is 12 MBq to 37 MBq (0.3 mCi to 1 mCi) in a volume not to exceed 0.5 mL. 2. 5 Directions for Drug Preparation and Handling Procedural Precautions Perform all transfer and vial stopper entries using aseptic techniques. Wear waterproof gloves during the entire preparation procedure and during subsequent patient dose withdrawals from the PULMOTECH MAA vial. Make all transfers of Sodium Pertechnetate Tc 99m Injection during the preparation procedure with an adequately shielded syringe. Keep the prepared Technetium Tc 99m Albumin Aggregated Injection in the dispensing vial shield described below (with cap in place) during the useful life of the radioactive preparation. Make all withdrawals and injections of the Technetium Tc 99m Albumin Aggregated Injection with an adequately shielded syringe. Procedure for the Preparation , Storage, and Handling of Technetium Tc 99m Albumin Aggregated Injection If PULMOTECH MAA reaction vials are stored in the refrigerator, remove a vial and allow the contents to come to room temperature for approximately 5 minutes. Remove the protective cap from the reaction vial and swab the rubber septum with an alcohol swab or a suitable bacteriostatic agent to disinfect the surface. Place the vial in a suitable dispensing vial shield fitted with a shielded cap. Calculate the amount of Sodium Pertechnetate Tc 99m Injection (2 mL to 13 mL) to be added to the reaction vial. In choosing the amount of Sodium Pertechnetate Tc 99m Injection to be used in the preparation of Technetium Tc 99m Albumin Aggregated Injection ensure that the radioactive dose will contain the desired number of macroaggregated albumin (MAA) particles, while taking into account the number of patients, administered activity, and radioactive decay. The recommended maximum activity of Sodium Pertechnetate Tc 99m Injection to be added to the reaction vial is 6.85 GBq (185 mCi). Calculate the amount of radioactivity per vial required to be added to maintain the number of particles per dose within a recommended range, for adults 200,000 to 700,000 and for pediatric patients as per Table 1 [see Dosage and Administration ( 2.3 , 2.4 ) ] . During or prior to addition of Sodium Pertechnetate Tc 99m Injection do not vent the reaction vial. After adding Sodium Pertechnetate Tc 99m Injection to the reaction vial in the dispensing vial shield (with cap in place), mix the contents by inverting the vial at a frequency of one (1) inversion per second for 2 minutes (approximately 120 inversions total) and allow to stand for a minimum of 15 minutes at room temperature. Once prepared the product will have a turbid white appearance. Assay the product in a suitable dose calibrator and record the total activity of Technetium Tc 99m Albumin Aggregated Injection, total volume, number of MAA particles, radioactive concentration, time and date of preparation, onto the radioassay information label and attach it to the dispensing vial shield. 0.9% Sodium Chloride Injection, USP may be used as a diluent for the radiolabeled product to achieve the desired number of particles and radioactivity. Prior to withdrawing a dose, gently agitate the contents of the radiolabeled PULMOTECH MAA vial to resuspend any settled technetium Tc 99m albumin aggregated particles. Failure to mix the reaction vial contents adequately before use may result in a non-homogenous suspension with a resulting non-uniform distribution of radioactivity in the lung. Since the vials contain nitrogen to prevent oxidation of the complex, the vials should not be vented. If repeated withdrawals are made from the vial, the contents should not be replaced with air. Store the radiolabeled PULMOTECH MAA in the dispensing vial shield in a refrigerator at 2°C to 8°C (36°F to 46°F). Use within 18 hours from the time of radiolabeling. Dispose unused radiolabeled PULMOTECH MAA in compliance with appropriate regulations. 2. 6 Administration and Imaging Instructions Position the patient under the imaging apparatus before administration of Technetium Tc 99m Albumin Aggregated Injection because of rapid lung clearance of technetium Tc 99m albumin aggregated. Using proper shielding, visually inspect for foreign particulate matter and discoloration prior to administration. Do not administer if foreign particulates are found in the preparation. Mix the contents of the vial by gentle inversion just prior to withdrawing a patient dose. Withdraw the patient dose aseptically using a sterile needle (18 gauge to 21 gauge) and a shielded syringe. Measure the patient dose by a suitable radioactivity calibration system immediately prior to administration. Mix the contents of the syringe just before injection. Slow injection is recommended. If blood is drawn into the syringe, any unnecessary delay prior to injection may lead to clot formation. Begin lung imaging immediately after intravenous injection of the radiopharmaceutical. Due to high kidney uptake, imaging later than one-half hour after administration is not recommended. For peritoneovenous shunt imaging, obtain serial images of both the shunt and target organ. 2.7 Radiation Dosimetry Intravenous Administration Estimated radiation absorbed doses from intravenous administration are shown in Table 2. Table 2. Estimated Radiation Absorbed Doses From Intravenous Administration of Technetium Tc 99m Albumin Aggregated Injection for Lung Perfusion Scintigraphy Absorbed Dose per Activity Administered (microGy/MBq) Organs Adults 15 years 10 years 5 years 1 year Neonates Total body 4.05 3.96 7.63 8.38 13.5 32.4 Lungs 59.5 74.3 138 157 297 1027 Liver 4.86 11.6 28.6 16.8 27 75.7 Spleen 4.59 --* -- -- -- -- Kidneys 2.97 -- -- -- -- -- Bladder Wall 2 hour void 4.8 hour void No voiding intervals 8.11 14.9 -- -- -- 39.6 -- 62 -- -- 83.8 -- 67.6 -- -- 114 -- -- Testes 2 hour void 4.8 hour void No voiding intervals 1.62 1.76 -- -- -- 3.47 -- -- 3.18 -- -- 5.14 -- -- 5.86 -- -- 16.8 Ovaries 2 hour void 4.8 hour void No voiding intervals 2.03 2.3 -- -- -- 3.96 -- -- 7 -- -- 5.14 -- -- 9.01 -- -- 20.5 *--: Not available Intraperitoneal Administration Estimated radiation absorbed doses from intraperitoneal administration are shown in Table 3. Table 3. Estimated Radiation Absorbed Doses From Intraperitoneal Administration of Technetium Tc 99m Albumin Aggregated Injection for Peritoneovenous Shunt Scintigraphy in Adults Absorbed Dose per Activity Administered (microGy/MBq) Organs Shunt Patency (Open) Shunt Patency (Closed) Lung 62.2 15.1 Ovaries or Testes 1.62 to 2.7 15.1 Organ in the Peritoneal Cavity --* 15.1 Total Body 3.24 5.14 *--: Not available

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in labeling: Patients with Pulmonary Hypertension [ see Warnings and Precautions ( 5.1 ) ] . Hypersensitivity Reactions [ see Warnings and Precautions ( 5.2 ) ] . The following adverse reactions associated with the use of technetium Tc 99m albumin aggregated products including PULMOTECH MAA have been identified in clinical studies or postmarketing reports. Because these reactions are 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. Cardiovascular Disorders : Deaths in patients with severe pulmonary hypertension Immune System Disorders : Hypersensitivity reactions such as anaphylaxis, impairment of cardiac and circulatory functions in the form of changes in respiration, pulse, and blood pressure, chest pain, and syncope, urticaria, reddening of the face, sweating, and nausea Skin and Subcutaneous Tissue Disorders : Injection site reactions The following adverse reactions have been reported: Death in patients with severe pulmonary hypertension, anaphylaxis, impairment of cardiac and circulatory functions in the form of changes in respiration, pulse, and blood pressure, chest pain, and possible syncope, urticaria, reddening of the face, sweating, nausea, and injection site reaction. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact CURIUM US LLC at 1-866-789-2211 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

12.3 Pharmacokinetics Distribution Organ selectivity is a direct result of particle size. At 10 micrometer and below, the albumin aggregates are taken up by the reticuloendothelial system. Above 10 to 15 micrometer, the aggregates become lodged in the lung capillaries by a purely mechanical process. Distribution of aggregated albumin in the lungs is a function of regional pulmonary blood flow. The albumin aggregated is sufficiently fragile for the capillary micro-occlusion to be temporary. Erosion and fragmentation reduce the particle size, allowing passage of the aggregates through the pulmonary alveolar capillary bed. The fragments then accumulate in the reticuloendothelial system. Elimination Elimination of the technetium Tc 99m albumin aggregated particles from the normal and abnormal human lungs occurs with a biological half-life of 10.8 hours (range 6.9 to 19 hours, n=5).