Kit For The Preparation Of Technetium Tc 99M-Labeled Carbon Inhalation Aerosol

1 INDICATIONS AND USAGE TECHNEGAS, when used with sodium pertechnetate Tc 99m in the Technegas Plus System, provides technetium Tc 99m-labeled carbon inhalation aerosol (Technegas Aerosol), for use in adults and pediatric patients aged 6 years and older for: • visualization of pulmonary ventilation • evaluation of pulmonary embolism when paired with perfusion imaging TECHNEGAS, when used with sodium pertechnetate Tc 99m in the Technegas Plus System, provides technetium Tc 99m-labeled carbon inhalation aerosol (Technegas Aerosol), a radioactive diagnostic agent for use in adults and pediatric patients aged 6 years and older for: • visualizationofpulmonaryventilation • evaluationofpulmonaryembolismwhenpairedwithperfusion imaging (1)

2 DOSAGE AND ADMINISTRATION For adult patients, the recommended activity of sodium pertechnetate Tc 99m injection to be loaded in the Technegas Crucible is 400 MBq to 1,000 MBq (10.8 mCi to 27 mCi) to achieve a lung count rate between 1,500 counts per second (cps) and 2,500 cps at the end of the last respiration. (2.2) For pediatric patients aged 6 years and older, a sufficient amount of Technegas Aerosol should be inhaled to achieve between 500 cps and 1,000 cps at the end of last respiration. The radioactivity to be loaded in the Technegas Crucible is a fraction of the recommended activity for adults adjusted by body weight. (2.2) Administer as soon as possible following preparation and complete inhalation within 10 minutes of preparation. (2.2) For drug handling, breathing techniques, preparation, and dosimetry information, see the full prescribing information. (2.1, 2.3, 2.4, 2.5) 2.1 Radiation Safety-Drug Handling Handle Technegas Aerosol with appropriate safety measures to minimize radiation exposure to the patient and healthcare providers. During preparation and handling, use waterproof gloves and effective shielding [see Warnings and Precautions (5.2)]. 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 Recommended Dose The activity present in the lungs after each inhalation varies. Follow the pulmonary count rate during oral inhalation of Technegas Aerosol, using a gamma camera equipped with a standard collimator (low energy, low/medium resolution). For adult patients, the recommended activity of sodium pertechnetate Tc 99m injection to be loaded in the Technegas Crucible is 400 MBq to 1,000 MBq (10.8 mCi to 27 mCi) to achieve a lung count rate between 1,500 counts per second (cps) and 2,500 cps at the end of the last respiration. Discontinue Technegas Aerosol administration at that point. For pediatric patients aged 6 years and older, a sufficient amount of Technegas Aerosol should be inhaled until a lung count rate is obtained between 500 cps and 1,000 cps at the end of last respiration. Discontinue administration at that point. The radioactivity to be loaded in the Technegas Crucible for pediatric patients aged 6 years and older is a fraction of the recommended activity for adults, and is adjusted by body weight as listed in Table 1. Table 1. Crucible Loading Activity of Sodium Pertechnetate Tc 99m Injection for Pediatric Patients Aged 6 Years and Older Weight (kg) Crucible Loading Activity MBq (mCi) 10 133 (3.6) 12 154 (4.2) 14 175 (4.7) 16 196 (5.3) 18 217 (5.9) 20 238 (6.4) 22 259 (7) 24 270 (7.6) 26 301 (8.1) 28 315 (8.5) 30 336 (9.1) 32 357 (9.7) 34 378 (10) 36 392 (11) 38 413 (11) 40 434 (12) 42 448 (12) 44 469 (13) 46 490 (13) 48 504 (14) 50 525 (14) 52-54 553 (15) 56-58 588 (16) 60-62 623 (17) 64-66 658 (18) 68 686 (19) 2.3 Administration Instructions Administer Technegas Aerosol by oral inhalation using an FDA-cleared radionuclide rebreathing system for Technegas Aerosol (e.g., Patient Administration Set from Cyclomedica) that connects directly to the Technegas Plus System (TP) as soon as possible following preparation and complete inhalation within 10 minutes of preparation. Monitor oxygen saturation level in patients with an oximeter [see Warnings and Precautions (5.1)]. Be prepared to allow patients to breathe room air during administration. Do not detach the patient administration set (PAS) from the patient to prevent residual aerosol from being released. Prepare the patient in the imaging room or a preparation room before preparing Technegas Aerosol. For complete instructions on patient preparation, breathing techniques, and operation of the TP during administration, see the User Manual for the TP. To facilitate uniform delivery of the aerosol from the apex-to-base of the lungs, perform the administration with the patient in the supine position. Recommended Breathing Method For adult patients, the recommended breathing method to inhale the aerosol is through the mouthpiece by slow deep breathing from the residual functional capacity (end of calm expiration), followed by a 5-second breath-hold. For patients unable to hold their breath, normal breathing with deep inhalations without breath- holding can be used. For pediatric patients aged 6 years and older, instruct the patient to inhale the aerosol through the mouthpiece or inhalation line by normal breathing with deep inhalations without breath- holding. When the adequate pulmonary counts are achieved for imaging, the patient must continue exhaling air through the filter equipped exhalation circuit of the PAS for five breaths to six breaths to trap residual aerosol being exhaled. The PAS is single use only and should be disposed of as radioactive waste. 2.4 Preparation of Technegas Aerosol Important Preparation Information Prepare Technegas Aerosol in the Technegas Plus System ( TP) using the supplied Technegas Crucible. See the User Manual for a comprehensive description of the setup, operation, and maintenance of the TP. Use Sodium Pertechnetate Tc 99m Injection, USP obtained from a commercially available technetium Tc 99m generator. Only use ultra high purity (> 99.997% purity with less than 3 ppm oxygen) argon gas . The presence of oxygen in argon gas during the process of formation of Technegas Aerosol may lead to formation of Pertechnegas Aerosol (instead of Technegas Aerosol), which may affect the image quality. Wear protective gloves, aprons, and masks for radiation protection and infection control. Handle Technegas Crucibles with forceps. Any oil from the skin will reduce connection efficiency and Technegas yield. Prepare Technegas Aerosol using the TP at 15° to 30oC (59° to 86oF) in a ventilated area that is suitable for using radioactive materials (e.g., Nuclear Medicine Department) near the patient, to enable timely (within 10 minutes) administration [see Dosage and Administration (2.3)]. The maximum use period for the TP is one year or 500 burn cycles, whichever occurs first. After this period, ask Cyclomedica to perform maintenance and recertify the TP for use. Preparation: Using forceps, remove a Technegas Crucible from its blister pack, inspect the crucible to ensure that it is free of chips or cracks, and place it on a clean flat surface. Store unused crucibles in the original packaging. ( Note : When a blister pack of 10 crucibles is used for the first time, remove the tamper-proof seal to facilitate access to the crucibles. Then carefully remove one crucible (for preparation of each patient’s dose) from the blister pack and reinsert the cardboard backing material to cover all remaining crucibles in their respective individual blister pockets. This prevents ingress of any contaminating material from the immediate environment and allows the crucibles to be securely stored). Prepare the Alcohol, USP (i.e.,95%ethanol) wetted crucible. Using a 1mL syringe, fill the crucible reservoir (approximately 0.1 mL) with Alcohol and then draw it back in the syringe. Open the Technegas Plus System drawer and install the Alcohol wetted crucible between the support electrodes using forceps (see the Technegas Plus System User Manual for details on installation of the Technegas Crucible). Rotate the crucible to ensure that good electrical contact is made with the support electrodes (Technegas Contacts); ensure the crucible reservoir is upright. For adult patients, using a 1mL syringe with needle, load 400MBq to 1,000MBq (10.8mCito 27 mCi) of Sodium Pertechnetate Tc99m Injection, USP, in a volume of 0.1 mL while ensuring that the liquid meniscus does not exceed the height of the Crucible (the maximum crucible volume is 0.12 mL, and adding excess volume can lead to radioactive spill in the TP and may lead to formation of aerosol of free pertechnetate Tc 99m that may deteriorate image quality). For the recommended loading activity of Sodium Pertechnetate Tc 99m Injection in pediatric patients aged 6 years and older, refer to Table 1 [see Dosage and Administration (2.2) ]. Close the drawer and run the SIMMER heating cycle to evaporate the liquid fromthecrucible reservoir. The process continues for 6 minutes, leaving a dry white residue of sodium pertechnetate Tc 99m and sodium chloride in the crucible. During this time the TP chamber is also completely filled with the argon gas (note: 100% argon atmosphere is necessary to prepare pure Technegas Aerosol). When the simmer is complete, the display will read: PRESS [START] TO INITIATE BURN. Run the BURN heating cycle, during which the crucible containing the dry residue of sodium chloride and pertechnetate Tc 99m is heated to 2,750°C (4,982°F) for 15 seconds in TP, to produce Technegas Aerosol. At the end of BURN cycle, the display will change to “DISCONNECT THE MAINS PLEASE”. ( Note : At this time the argon gas supply is turned OFF and the argon gas line can be disconnected. The main power on the TP can be switched OFF. The TP will remain powered ON from an internal battery for Technegas Aerosol administration to the patient. The TP may be moved to the patient as required.) Administer Technegas Aerosol as soon as possible following preparation and completethe inhalation within 10 minutes of its preparation. Do not use after 10 minutes of preparation. [See the TP User Manual for connecting the PAS to the patient and to the TP.] The crucible is single use only. The TP breaks the crucible at the end of Technegas Aerosol production to prevent re-use. Crucible fragments are radioactive and should be disposed appropriately. Refer to the Technegas Plus System User Manual for detailed information. 2.5 Radiation Dosimetry The estimated radiation absorbed doses to various organs are shown in Table 2. The dose limiting organ is the lungs at 0.11 mGy/MBq. The effective dose resulting from an estimated inhaled activity of 40 MBq (1.08 mCi) in adults is 0.6 mSv. The effective dose in a 10-year old pediatric patient from estimated inhaled activity of 15 MBq (0.41 mCi) is 0.47 mSv. Table 2. Estimated Radiation Absorbed Dose from Inhalation of Technegas Aerosol Organ Absorbed Dose per Unit Activity Administered (mGy/MBq) Adult 15 Years 10 Years 5 Years** Adrenals 0.0068 0.00911 0.013 0.02 Bone surfaces 0.0049 0.0063 0.0088 0.014 Brain 0.00025 0.00033 0.00058 0.00094 Breast 0.0067 0.0073 0.013 0.019 Gallbladder wall 0.0023 0.0032 0.0055 0.0084 Gastrointestinal tract Stomach wall 0.0044 0.0062 0.0088 0.013 Small intestines wall 0.00087 0.0013 0.0022 0.0039 Colon wall 0.0014 0.0019 0.0034 0.0059 Upper large intestines wall 0.0019 0.0025 0.0046 0.0077 Lower large intestines wall 0.00074 0.001 0.0018 0.0018 Heart wall 0.013 0.017 0.023 0.032 Kidneys 0.002 0.003 0.0046 0.0072 Liver 0.0057 0.0078 0.01 0.015 Lungs 0.11 0.16 0.22 0.33 Muscles 0.0028 0.0036 0.0049 0.0073 Esophagus 0.0082 0.01 0.015 0.019 Ovaries 0.00041 0.00055 0.0011 0.002 Pancreas 0.0052 0.0073 0.01 0.016 Red marrow 0.0033 0.0038 0.005 0.0066 Salivary glands 0.0028 0.0036 0.0063 0.0098 Skin 0.0012 0.0013 0.0022 0.0033 Spleen 0.0048 0.0063 0.0093 0.015 Testes 0.000061 0.000091 0.0002 0.00033 Thymus 0.0082 0.01 0.015 0.019 Thyroid 0.0029 0.0039 0.0069 0.011 Urinary bladder wall 0.00032 0.00045 0.00074 0.0012 Uterus 0.0003 0.00046 0.00083 0.0016 Remaining organs 0.0027 0.0035 0.0047 0.0068 Effective dose (mSv/MBq) 0.015 0.022 0.031 0.047 **Technegas Aerosol is not approved for pediatric patients younger than 6 years old [see Indications and Usage (1)].

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Decreased Oxygen Saturation [see Warnings and Precautions (5.1)] The most common adverse reaction (≥ 1%) was hypoxia. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Cyclomedica Australia Pty Ltd at toll free phone number 1-888-8-586-4396 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety of Technegas Aerosol was evaluated in 291 patients undergoing ventilation studies with prospective data collection. Patients received an amount of Technegas Aerosol to achieve 1,500 cps to 2,500 cps by oral inhalation. The mean age of patients was 60 years (range:18 to 95 years); distribution by race was 92 % White, 7% Black or African American, 0.3 % Asian, and 0.3 % unreported; and distribution by ethnicity was 4% Hispanic/Latino and 96 % non-Hispanic/Latino. Adverse reactions were reported in 10 patients (3.4%). The adverse reaction occurring at ≥ 1% in patients receiving Technegas Aerosol was hypoxia (1%). Adverse reactions reported at < 1% were dizziness, dysgeusia, cough, dyspnea [not otherwise specified], throat irritation, and upper respiratory tract congestion. In one published study, oxygen saturation was monitored in a series of patients undergoing Technegas Aerosol ventilation scintigraphy for suspected pulmonary embolism (n=28) or pulmonary disease (n=10). Of these 38 patients without pre-oxygenation, oxygen saturation fell to < 90% in 26 (68%) patients and < 85% in 15 (39%) patients. The recorded lowest value for each patient was usually observed after the first or second inhalation.

12.3 Pharmacokinetics Distribution After inhalation, Technegas Aerosol is adsorbed on the walls of pulmonary bronchioles and alveoli. The distribution within the lungs is determined by the size and aerodynamic properties of the individual particles. Following inhalation, the particles are retained in the lung. The redistribution of Technegas Aerosol following inhalation to human subjects has been monitored for as long as 70 hours without evidence of particulate translocation. Elimination There is no intravascular clearance, and the elimination of radioactivity occurs by the physical decay of the Technetium-99m. The Technegas Aerosol particles that are deposited in the mouth and along the mucociliary elevator are cleared by swallowing or expectoration. The particles that deposit in the alveolar region are cleared by alveolar macrophages.