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:

Va = 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

Va = volume to be administered in mL

VTc = 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.

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.

2.4       Recommended Dosage for Peritoneovenous 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

1. 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.
   
2. 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.
   
3. Place the vial in a suitable dispensing vial shield fitted with a shielded cap.
   
4. 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)].
   
5. After adding Sodium Pertechnetate Tc 99m Injection to the reaction vial in the dispensing vial shield (with cap in place), mix the contents by agitation and allow to stand for a minimum of 15 minutes at room temperature. During or prior to addition of Sodium Pertechnetate Tc 99m Injection do not vent the reaction vial. Once prepared the product will have a turbid white appearance.
   
6. 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.
   
7. 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.
   
8. 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.

*--: Not available

Intraperitoneal Administration

Estimated radiation absorbed doses from intraperitoneal administration are shown in Table 3.

*--: Not available

5.1       Patients with Pulmonary Hypertension

Deaths have been reported in patients with severe pulmonary hypertension after the administration of technetium Tc 99m albumin aggregated products [see Adverse Reactions (6)]. Assess patients for history or signs of pulmonary hypertension. PULMOTECH MAA is contraindicated in patients with severe pulmonary hypertension [see Contraindications (4)]. Administer the lowest number of particles possible, have emergency resuscitation equipment available, and monitor patients for adverse reactions.

5.2       Hypersensitivity Reactions

Serious hypersensitivity reactions including anaphylaxis have been reported in patients treated with products containing albumin human, including PULMOTECH MAA [see Adverse Reactions (6)]. Obtain a history of allergy or hypersensitivity reactions. PULMOTECH MAA is contraindicated in patients with a history of hypersensitivity to albumin human [see Contraindications (4)]. Have emergency resuscitation equipment and trained personnel available prior to administration of Technetium Tc 99m Albumin Aggregated Injection. Monitor all patients for hypersensitivity reactions.

5.3       Risk of Temporary Impediment to Blood Flow in Patients with Right-to-Left Heart Shunts

In patients with right-to-left heart shunts, risk for temporary mechanical impediment to blood flow may exist due to the rapid entry of aggregated albumin into the systemic circulation. Administer the lowest possible number of particles of Technetium Tc 99m Albumin Aggregated Injection in these patients.

5.4       Radiation Risks

Technetium Tc 99m albumin aggregated contributes to a patient’s overall long-term cumulative radiation exposure. Long-term cumulative radiation exposure is associated with an increased risk for cancer. Ensure safe handling to minimize radiation exposure to the patient and health care providers. Advise patients to hydrate before and after administration and to void frequently after administration [see Dosage and Administration (2.2)].  

8.1       Pregnancy

Risk Summary

Available data from case reports on Technetium Tc 99m Albumin Aggregated Injection use are insufficient to evaluate drug-associated risks of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Animal reproduction studies with technetium Tc 99m albumin aggregated have not been conducted. Although all radiopharmaceuticals have the potential to cause fetal harm depending on the fetal stage of development and the magnitude of the radiation dose, the radiation exposure to the fetus from technetium Tc 99m albumin aggregated is expected to be low (less than 0.50 mGy) (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Human Data

No adverse fetal effects of radiation risks have been identified for diagnostic procedures involving less than 50 mGy, which represents less than 10 mGy fetal doses.

8.2       Lactation

Risk Summary

Technetium-99m is present in breast milk. There are no data on the effects of technetium Tc 99m albumin aggregated on the breastfed infant or the effects on milk production. PULMOTECH MAA is used for imaging in infants with lung disease; exposure to technetium-99m via breastmilk is expected to be lower. Based on clinical guidelines, exposure of technetium Tc 99m albumin aggregated to a breastfed infant may be minimized by advising a lactating woman to temporarily discontinue breastfeeding and to pump and discard breast milk for a minimum of at least 24 hours after administration of Technetium Tc 99m Albumin Aggregated Injection.

The developmental and health benefits of breastfeeding should be considered along with a mother’s clinical need for PULMOTECH MAA, any potential adverse effects on the breastfed child from technetium Tc 99m albumin aggregated or from the underlying maternal condition.

8.4       Pediatric Use

PULMOTECH MAA, after radiolabeling with technetium Tc-99m, is indicated for lung scintigraphy as an adjunct in the evaluation of pulmonary perfusion in pediatric patients (birth to less than 17 years of age). The safety profile of Technetium Tc99m Albumin Aggregated Injection is similar to the one in adults.

The safety and efficacy of PULMOTECH MAA have not been established for peritoneovenous shunt scintigraphy in pediatric patients.

8.5       Geriatric Use

No formal studies of PULMOTECH MAA in subjects aged 65 and over were performed to determine whether they respond differently from younger adult subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger adult patients. In general, dose selection for an elderly patient should be cautious; administering the low end of the particle dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

11.1       Product Characteristics

PULMOTECH MAA contains albumin aggregated obtained by fractionating material (source blood, plasma, serum, or placentas) from healthy human donors. The macroaggregated albumin (MAA) particles are formed by heat denaturation of stannous chloride treated albumin human under controlled conditions. Each vial contains 2,000,000 to 4,000,000 particles. The particle size distribution of the aggregated albumin is such that not less than 90% are 10 to 90 micrometers in size. There are no aggregated albumin particles greater than 150 micrometers in size as determined by circular equivalents.

PULMOTECH MAA (kit for the preparation of technetium Tc 99m albumin aggregated) injection provides a sterile, non-pyrogenic, non-radioactive, white lyophilized powder in a multiple-dose reaction vial, sealed under an atmosphere of nitrogen, for radiolabeling with Sodium Pertechnetate Tc 99m Injection to prepare Technetium Tc 99m Albumin Aggregated Injection, a radioactive diagnostic agent, for intravenous or intraperitoneal use.

Each reaction vial contains 2 mg of albumin aggregated, albumin human (7.1 mg), stannous chloride (0.1 mg minimum; 0.22 mg maximum stannous and stannic), sodium chloride (9 mg). Hydrochloric acid may have been added for pH adjustment. The pH is between 5 and 7. It contains no preservatives.

11.2       Physical Characteristics

Technetium-99m decays by isomeric transition with a physical half-life of 6.02 hours. The principal photon that is useful for detection and imaging is listed in Table 4.

11.3       External Radiation

The specific gamma ray constant for technetium-99m is 0.78 R/mCi-hr at 1 cm. The first half-value thickness of lead (Pb) for technetium-99m is 0.017 cm. 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 5. For example, the use of 0.25 cm of Pb will decrease the external radiation exposure by a factor of about 1,000.

To correct for physical decay of this radionuclide, the fractions that remain at selected time intervals after the time of calibration are shown in Table 6.

*Calibration Time

12.1       Mechanism of Action

Within 1 to 5 minutes of intravenous injection, over 90 percent of the technetium Tc 99m albumin aggregated particles are trapped in the arterioles and capillaries of the lung.

Following intraperitoneal administration, technetium Tc 99m albumin aggregated 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.

12.2       Pharmacodynamics

The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of technetium Tc 99m albumin aggregated have not been fully characterized.

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).

13.1       Carcinogenesis, Mutagenesis, Impairment of Fertility

No long-term animal studies have been performed to evaluate carcinogenic or mutagenic potential or whether technetium Tc 99m albumin aggregated affects fertility in males or females.