DESCRIPTION:

The Ultra-TechneKow(r) DTE Generator is prepared with fission-produced molybdenum Mo 99 adsorbed onto alumina in a lead shielded column. This generator provides a closed system for the production of sterile metastable technetium Tc 99m, which is produced by the decay of molybdenum Mo 99. Sterile, non-pyrogenic isotonic solutions of Sodium Pertechnetate Tc 99m can be obtained conveniently by periodic aseptic elution of the generator. These solutions should be clear, colorless, and free from any particulate matter. The carrier-free solution may be used as is, or diluted to the proper concentration. Over the life of the generator, an elution will contain an amount of technetium Tc 99m in direct proportion to the quantity of Mo 99 decay since the previous elution of the generator. The exact quantity of Tc 99m in the eluate is determined by column elution efficiency, quantity of Mo 99 on the column, and the elapsed time between elutions. Each eluate of the generator should not contain more than the USP limit of 0.15 kilobecquerel molybdenum Mo 99 per megabecquerel technetium Tc 99m (0.15 microcurie Mo 99 per millicurie Tc 99m) per administered dose at the time of administration and an aluminum ion concentration of not more than 10 micrograms per milliliter of the generator eluate, both of which must be determined by the user before administration. Since the eluate does not contain an antimicrobial agent, it should not be used after 12 hours from the time of generator elution.

Physical Characteristics:

Technetium Tc 99m decays by isomeric transition with a physical half- life of 6.02 hours.1 The principal photon that is useful for detection and imaging studies is listed in Table 1. Table 1. Principal Radiation Emission Data

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 lead (Pb). 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 2. For example, the use of 0.25 cm thickness of Pb will attenuate the radiation emitted by a factor of about 1000. Kocher, David C., "Radioactive Decay Data Tables", DOE/TIC-11026, 108 (1981). Table 2. Radiation Attenuation by Lead Shielding

Molybdenum Mo 99 decays to technetium Tc 99m with a molybdenum Mo 99 half- life of 2.75 days. The physical decay characteristics of molybdenum Mo 99 are such that only 88.6% of the decaying molybdenum Mo 99 atoms form technetium Tc 99m. Generator elutions may be made at any time, but the amount of technetium Tc 99m available will depend on the interval measured from the last elution. Approximately 47% of the maximum available technetium Tc 99m is reached after 6 hours and 95% after 23 hours. To correct for physical decay of technetium Tc 99m, the fractions that remain at selected intervals of time are shown in Table 3. Table 3. Physical Decay Chart; Technetium Tc 99m, Half Life 6.02 Hours

*Calibration time.

Clinical Pharmacology:

The pertechnetate ion distributes in the body similarly to the iodide ion but is not organified when trapped in the thyroid gland. Pertechnetate tends to accumulate in intracranial lesions with excessive neovascularity or an altered blood-brain barrier. It also concentrates in the thyroid gland, salivary glands, stomach and choroid plexus. After intravenous administration it remains in the circulatory system for sufficient time to permit blood pool, organ perfusion, and major vessel studies. It gradually equilibrates with the extracellular space. A fraction is promptly excreted via the kidneys. Following the administration of Sodium Pertechnetate Tc 99m as an eye drop, the drug mixes with tears within the conjunctival space. Within seconds to minutes it leaves the conjunctival space and escapes into the inferior meatus of the nose through the nasolacrimal drainage system. During this process the pertechnetate ion passes through the canaliculi, the lacrimal sac and the nasolacrimal duct. In the event of any anatomical or functional blockage of the drainage system there will be a backflow resulting in tearing (epiphora). Thus the pertechnetate escapes the conjunctival space in the tears. While the major part of the pertechnetate escapes within a few minutes of normal drainage and tearing, it has been documented that there is some degree of transconjunctival absorption with turnover of 1.5% per minute in normal individuals, 2.1 % per minute in patients without any sac and 2.7% per minute in patients with inflammed conjunctiva due to chronic dacryocystitis. Individual values may vary but these rates are probably representative and indicate that the maximum possible pertechnetate absorbed will remain below one thousandth of that used in other routine diagnostic procedures.

CONTRAINDICATIONS:

None known.

WARNINGS:

Radiation risks associated with the use of Sodium Pertechnetate Tc 99m are greater in pediatric patients than in adults and, in general, the younger the patient the greater the risk owing to greater absorbed radiation doses and longer life expectancy. These greater risks should be taken firmly into account in all benefit risk assessments involving pediatric patients. Only use generator eluant specified for use with the Ultra-TechneKow(r) DTE Generator. Do not use any other generator eluant or saline from any other source.

PRECAUTIONS:

As in the use of any radioactive material, care should be taken to minimize radiation exposure to the patient consistent with proper patient management and to insure minimum radiation exposure to occupational workers. Radiopharmaceuticals should be used only by physicians who are qualified by training and experience in the safe use and handling of radionuclides and whose experience and training have been approved by the appropriate government agency authorized to license the use of radionuclides. After the termination of the nasolacrimal imaging procedure, blowing the nose and washing the eyes with sterile distilled water or an isotonic sodium chloride solution will further minimize the radiation dose. Since the eluate does not contain an antimicrobial agent, it should not be used after 12 hours from time of generator elution.

Carcinogenesis, Mutagenesis, Impairment of Fertility:

No long-term animal studies have been performed to evaluate carcinogenic or mutagenic potential or whether Sodium Pertechnetate Tc 99m may affect fertility in males or females.

Pregnancy Category C:

Animal reproductive studies have not been conducted with Sodium Pertechnetate Tc 99m. It is also not known whether Sodium Pertechnetate Tc 99m can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Sodium Pertechnetate Tc 99m should be given to pregnant women only if the expected benefits to be gained clearly outweigh the potential hazards. Ideally, examinations using radiopharmaceutical drug products - especially those elective in nature - of women of childbearing capability should be performed during the first ten days following the onset of menses.

Nursing Mothers:

Technetium Tc 99m is excreted in human milk during lactation, therefore, formula- feedings should be substituted for breast- feedings.

Pediatric Use:

See Indications and Usage and Dosage and Administration sections. Also see the description of additional risk under Warnings.

DOSAGE AND ADMINISTRATION:

Sodium Pertechnetate Tc 99m is usually administered by intravenous injection, but can be given orally. When imaging the nasolacrimal drainage system, instill the Sodium Pertechnetate Tc 99m by the use of a device such as a micropipette or similar method which will ensure the accuracy of the dose. For imaging the urinary bladder and ureters (direct isotopic cystography), the Sodium Pertechnetate Tc 99m is administered by direct instillation aseptically into the bladder via a urethral catheter, following which the catheter is flushed with approximately 200 mL of sterile saline directly into the bladder. The dosage employed varies with each diagnostic procedure. If the oral route is elected, the patient sho uld fast for at least six (6) hours before and two (2) hours after administration. The suggested dose ranges employed for various diagnostic indications in the average ADULT PATIENT (70 kg) are as follows: Vesico- ureteral imaging: 18.5 to 37 MBq (0.5 to 1 mCi) Brain imaging: 370 to 740 MBq (10 to 20 mCi) Thyroid gland imaging: 37 to 370 MBq (1 to 10 mCi) Salivary gland imaging: 37 to 185 MBq (1 to 5 mCi) Placenta localization: 37 to 111 MBq (1 to 3 mCi) Blood pool imaging: 370 to 1110 MBq (10 to 30 mCi) Nasolacrimal drainage system: Maximum dose of 3.7 MBq (100uCi) The recommended dosages in PEDIATRIC PATIENTS are: Vesico- ureteral imaging: 18.5 to 37 MBq (0.5 to 1 mCi) Brain imaging: 5.18 to 10.36 MBq (140 to 280 uCi) per kg body weight Thyroid gland imaging: 2.22 to 2.96 MBq (60 to 80 uCi) per kg body weight Blood pool imaging: 5.18 to 10.36 MBq (140 to 280 uCi) per kg body weight Minimum dose of 111 to 185 MBq (3 to 5 mCi) should be employed if radionuclide angiography is performed as part of the brain imaging or blood pool imaging procedures. NOTE: Up to 1 gram of pharmaceutical grade potassium perchlorate in a suitable base or capsule may be given orally prior to administration of Sodium Pertechnetate Tc 99m for brain imaging, placenta localization and blood pool imaging. When Sodium Pertechnetate Tc 99m is used in pediatric patients for brain or blood pool imaging, administration of potassium perchlorate is especially important to minimize the absorbed radiation dose to the thyroid gland. The patient dose should be measured by a suitable radioactivity calibration system immediately prior to administration. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solut ion and container permit. The solution to be administered as the patient dose should be clear, colorless, and contain no particulate matter.

Radiation Dosimetry:

The estimated absorbed radiation doses2 to an average ADULT patient (70 kg) from an intravenous injection of a maximum dose of 1110 megabecquerels (30 millicuries) of Sodium Pertechnetate Tc 99m distributed uniformly in the total body of subjects not pretreated with blocking agents, such as pharmaceutical grade potassium perchlorate, are shown in Table 4. For placental localization studies, when a maximum dose of 111 megabecquerels (3 millicuries) is used, it is assumed to be uniformly equilibrated between maternal and fetal tissues. Modified from: Summary of Current Radiation Dose Estimates to Normal Humans from Tc 99m as Sodium Pertechnetate. MIRD Dose Estimate Report No. 8. J. Nucl. Med., 17 (1): 74-7, 1976. The estimated absorbed radiation doses to an ADULT patient from the nasolacrimal imaging procedure using a maximum dose of 3.7 megabecquerels (100 microcuries) of Sodium Pertechnetate Tc 99m are shown in Table 5. Table 4. Absorbed Radiation Doses From Intravenous Injection (ADULTS)

*Assuming no blockage of draining system. MIRD Dose Estimate Report No. 8, J Nucl. Med., 17: 74-77,1976 In PEDIATRIC patients, the maximum radiatio n doses when a dose of 185 megabecquerels (5 millicuries) Sodium Pertechnetate Tc 99m is administered to a neonate (3.5 kg) for brain or blood pool imaging with radionuclide angiography are shown in Table 6. In pediatric patients, an average 30 minute exposure to 37 megabecquerels (1 millicurie) of Sodium Pertechnetate Tc 99m following instillation for direct cystography, results in an estimated absorbed radiation dose of approximately 300 micrograys (30 millirads) to the bladder wall and 40 to 50 micrograys (4 to 5 millirads) to the gonads.3 Table 6. Absorbed Radiation Doses From Intravenous Injection (PEDIATRIC)

HOW SUPPLIED:

The Ultra-TechneKow DTE (Technetium Tc 99m) Generators contain the following amount of molybdenum Mo 99 at the date and time of calibration stated on the label. Catalog No.

Conway, J.J., et al., Direct and indirect radionuclide cystography. J. Urol. 113:689-693, May 1975. Each generator is supplied with the following components for the elution of the generator 7 - Evacuated Collecting Vials, 10 mL, Sterile, Non-pyrogenic or 5 - Evacuated Collecting Vials, 20 mL, Sterile, Non-Pyrogenic 7 - 70% (v/v) Isopropyl Alcohol Wipes 7 - Pressure-sensitive "Caution - Radioactive Material" collecting vial labels 7 - Pressure-sensitive radioassay data labels for lead elution shield 1 - Generator Eluant Vial, 135 mL, Sterile, Non-Pyrogenic 1 - TechneStatTM Vial, 5mL, containing 0.5 mL of 1.5 mg/mL methylparaben and 0.2 mg/mL propylparaben 1- Package Insert The sterile, non-pyrogenic solution used to elute the generator column contains 0.9% sodium chloride. The eluant does not contain an antimicrobial agent. EVACUATED COLLECTING VIALS. Collecting vials are available on request in 10 and 20 milliliter sizes.

Storage:

Store generator and Sodium Pertechnetate Tc 99m solution at controlled room temperature 20- 25degC (68-77degF).

Expiration Date:

The generator should not be used after the expiration date stated on the label. The expiration time of the Sodium Pertechnetate Tc 99m solution is not later than 12 hours after time of elution. If the eluate is used to reconstitute a kit, the radiolabeled kit should not be used after 12 hours from the time of generator elution or after the expiration time stated on the labeling for the prepared drug, whichever is earlier.

Directions for Use of the Technetium Tc 99m Generator:

NOTE 1: Immediately upon delivery, the generator should be placed within a minimum of one - inch of lead shielding in such a manner so as to minimize radiation exposure to attending personnel. NOTE 2: Wear waterproof gloves during the elution procedure and during subsequent reconstitution of kits with the eluate. NOTE 3: Use a shielded syringe to withdraw patient dose or to transfer Sodium Pertechnetate Tc 99m into mixing vials during kit reconstitution. NOTE 4: The needles in the generator are sterile beneath their covers, and the generator has been cleaned underneath the top cover. Additional disinfection of these areas with agents containing alcohol may unfavorably influence the Tc 99m yield. Eluting the generator every 24 hours will provide optimal amounts of Sodium Pertechnetate Tc 99m. However, the generator may be eluted whenever sufficient amounts of technetium Tc 99m have accumulated within the column.

For Example:

Time After Approximate Yield

First Elution (hrs.) (% of First Elution)

1 10

2 19 3 27 4 35 5 41 6 47

Preparation:

1. Rotate the top cover 30deg counterclockwise and lift up to remove.

2. Lift generator by its handle and position inside the auxiliary shield, aligning the notch in the elution station with leaded glass window in the auxiliary shield.

3. Remove the flip-top cap of the eluant vial, disinfect the stopper, remove and store the

needle cover over the eluant needles, invert the eluant vial and push down into place on the eluant needles. Remove the flip-top cap of the TechneStat vial and place it into the TechneStat vial shield. Remove and store the needle cover from the elution station, replace the lid of the auxiliary shield and insert the shielded TechneStat vial into the elution station.

Elution:

1. Remove the flip-top cap of the appropriate evacuated vial, disinfect the stopper, and put the vial into the elution shield aligning the volume scale on the evacuated vial with the leaded glass window.

2. Replace the shielded TechneStat vial with the shielded evacuated vial, aligning the two leaded glass windows. Piercing the septum of the evacuated vial with the elution needle will begin the elution process.

3. Wait until the evacuated vial has completely filled itself (a few minutes). Never interrupt the elution by lifting the via l shielding! NOTE: Do not use generator eluate if its

appearance is discolored. Replace the shielded vial with the shielded TechneStat via l. Determine the technetium Tc 99m concentration and molybdenum Mo 99 content for dispensing purposes. NOTE: Molybdenum Mo 99 breakthrough Limit - The acceptable limit is 0.15 kilobecquerel molybdenum Mo 99 per megabecquerel technetium Tc 99m (0.15 microcurie Mo 99 per millicurie Tc 99m) at the time of administration. Determine the aluminum ion concentration of the eluate. NOTE: Aluminum Ion breakthrough Limit - The acceptable limit is not more than 10 micrograms per milliliter of eluate.

Subsequent Elutions:

Repeat steps 1 through 6 of the Elution procedure above.

Vacuum Loss:

If the vacuum in the collecting vial is lost, do not attempt to re-evacuate the vial, but discard and use a new collecting vial.

EXPIRED GENERATOR DISPOSAL:

1. Following the life of the generator, remove and dispose of the used TechneStat vial and the

eluant vial. Cover the inlet and outlet needles with the stored needle covers. Close the generator system with its top cover by rotating with downward pressure. The intact generator assembly should be either returned to Mallinckrodt Inc. or disposed of in accordance with applicable regulations. This generator is approved for use by persons licensed by the U.S. Nuclear Regulatory Commission to use by-product material identified in Section 35.200 or under equivalent licenses of Agreement States. Revised 6/2001 Mallinckrodt Inc. St. Louis, MO 63134 MALLINCKRODT 880-887