TECHNETIUM TC-99M PERTECHNETATE: 248 Adverse Event Reports & Safety Profile

DESCRIPTION: Sodium Pertechnetate Tc 99m Injection, as eluted according to the elution instructions with Lantheus Medical Imaging, Inc. TECHNELITE ® , Technetium Tc 99m Generator, is in 0.9% Sodium Chloride Injection, USP as a sterile, non-pyrogenic, diagnostic radiopharmaceutical suitable for intravenous injection and direct instillation. The pH is 4.5-7.5. The eluate should be clear, colorless, and free from visible foreign material. Each eluate of the TECHNELITE ® , Technetium Tc 99m Generator should not contain more than 0.0056MBq (0.15 microcuries) of Molybdenum Mo99 per 37MBq (1 millicurie) of Technetium Tc 99m per administered dose at the time of administration, and not more than 10 micrograms of aluminum per milliliter of the Technetium Tc 99m 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 later than one (1) working day after the elution (12 hours).

Lantheus Medical

Imaging, Inc. TECHNELITE ® , Technetium Tc 99m Generator consists of a column containing uranium fission produced Molybdenum Mo99 adsorbed on alumina. The terminally sterilized and sealed column is enclosed in a lead shield; the shield and other components are sealed in a cylindrical plastic container with an attached handle. Built into the top surface are two recessed wells marked SALINE CHARGE and COLLECT. Needles protruding from these two wells accommodate supplied sterile eluant charge vials and sterile eluate collection vials. The eluting solvent consists of 0.9% Sodium Chloride Injection, USP, prepacked into septum-sealed vials, to make the solution isotonic. The eluate collection vial is evacuated, sterile and non-pyrogenic. A sterile 0.22 micrometer bacteriological filter is incorporated between the column outlet and the collection vials. During and subsequent to elution, the eluate collection vial should be kept in a radiation shield.

The

Generator is shipped with a silicone needle seal over the charge needle and a vented needle cover over the collect needle. A sterile collect needle seal is supplied for the customer to aseptically reseal the collect needle after each elution.

Physical Characteristics Technetium Tc

99m decays by isomeric transition with a physical half-life of 6.02 hours. 1 Photons that are useful for imaging studies are listed in Table 1.

Table

1.

Principal Radiation Emission

Data - Technetium Tc 99m Radiation Mean %/Disintegration Mean Energy (keV) Gamma-2 89.07

140.5 External Radiation The specific gamma ray constant for Technetium Tc 99m is 5.4 microcoulombs/Kg-MBq-hr (0.795 R/mCi-hr) at 1cm. The first half-value thickness is 0.023cm of lead (Pb). To facilitate control of radiation exposure from millicurie amounts of Technetium Tc 99m, for example, the use of a 0.27 cm thick standard radiation elution lead shield will attenuate the radiation emitted by a factor of about 1000. A range of values for the relative attenuation of the radiation emitted by this radionuclide that results from interposition of various thicknesses of lead is shown in Table 2. NOTE : Because the generator is well contained and essentially dry, there is little likelihood of contamination due to damage in transit.

Table

2.

Radiation

Attenuation of Technetium Tc 99m by Lead Shielding Shield Thickness lead (Pb) cm Coefficient of Attenuation 0.023 0.5 0.09 10 -1 0.18 10 -2 0.27 10 -3 0.33 10 -4 Molybdenum Mo99 decays to Technetium Tc 99m with a Molybdenum Mo99 half-life of 66 hours. This means that only 78% of the activity remains after 24 hours; 60% remains after 48 hours, etc. (see Table 3). All units have a minimum of 38 mm, 1.5 inches (~ 6 half-value layers) of lead surrounding the activity. (See Table 3.)

Table

3. Molybdenum Mo99 Decay Chart Half-Life

66.0 Hours Days Percent Remaining Days Percent Remaining 0 100 10 8 1 78 11 6 2 60 12 5 3 47 13 4 4 37 14 3 5 28 15 2 6 22 20 0.6 7 17 25 0.2 8 13 30 0.05 9 10 The physical decay characteristics of Molybdenum Mo99 are such that approximately 88% of the decaying Molybdenum Mo99 atoms form Technetium Tc 99m. Since the Molybdenum Mo99 is constantly decaying to fresh Technetium Tc 99m, it is possible to elute the generator at any time. However, the total amount of Technetium Tc 99m available will depend on the time interval from the previous elution, the quantity of Molydenum Mo99 remaining and the efficiency of the elution.

Approximately

47% of maximum Technetium Tc 99m is reached after 6 hours and 95% after 23 hours. The elution vial shield has a wall thickness of 7.9 mm, 0.31 inches, and reduces transmitted Technetium Tc 99m radiation essentially to zero. To correct for physical decay of Tc 99m, the fractions that remain at selected intervals of time are shown in Table 4.

Table

4.

Physical Decay

Chart: Technetium Tc 99m Half-Life 6 Hours *Calibration Time Hours Percent Remaining Hours Percent Remaining 0* 100.0 9 35 1 89 10 32 2 79 11 28 3 71 12 25 4 63 14 20 5 56 16 16 6 50 18 13 7 45 24 6 8 40

INDICATIONS AND USAGE The Ultra-Technekow™ V4 generator is a source of sodium pertechnetate Tc 99m for use in the preparation of FDA-approved diagnostic radiopharmaceuticals, as described in the labeling of these diagnostic radiopharmaceutical kits.

Sodium Pertechnetate Tc

99m is used IN ADULTS as an agent for: Thyroid Imaging Salivary Gland Imaging Urinary Bladder Imaging (direct isotopic cystography) for detection of vesico-ureteral reflux Nasolacrimal Drainage System Imaging (dacryoscintigraphy)

Sodium Pertechnetate Tc

99m is used IN PEDIATRIC PATIENTS as an agent for: Thyroid Imaging Urinary Bladder Imaging (direct isotopic cystography) for the detection of vesico-ureteral reflux

DOSAGE AND ADMINISTRATION: Sodium Pertechnetate Tc 99m Injection is usually administered by intravascular injection. For imaging the urinary bladder and ureters (direct isotopic cystography), the Sodium Pertechnetate Tc 99m Injection is administered by direct instillation aseptically into the bladder via a urethral catheter, following which the catheter is flushed with approximately 200 mL of 0.9% Sodium Chloride Injection, USP directly into the bladder. The dosage employed varies with each diagnostic procedure. When imaging the nasolacrimal drainage system, instill the Sodium Pertechnetate Tc 99m Injection by the use of a device such as a micropipette or similar method which will ensure the accuracy of the dose. The suggested dose range employed for various diagnostic indications in the average ADULT PATIENT (70kg) is: Vesico-ureteral Imaging 18.5 to 37MBq (0.5 to 1mCi)

Thyroid Gland Imaging

37 to 370MBq (1 to 10mCi)

Salivary Gland Imaging

37 to 185MBq (1 to 5mCi)

Nasolacrimal Drainage System Maximum

3.7MBq (100µCi) The recommended dosage range in PEDIATRIC PATIENTS is: Vesico-ureteral Imaging 18.5 to 37MBq (0.5 to 1mCi)

Thyroid Gland Imaging

2.22 to 2.96MBq (60 to 80µCi)/kg body weight The patient dose should be measured by a suitable radioactivity calibration system immediately prior to administration of the dose. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. The solution to be administered as the patient dose should be clear and contain no particulate matter. Do not use an eluate of the TECHNELITE ® , Technetium Tc 99m Generator later than one (1) working day after elution (12 hours).

Radiation Dosimetry

The estimated absorbed radiation doses to an average ADULT and Pediatric patient from an intravenous injection of a maximum dose of 1110MBq (30 millicuries) of Sodium Pertechnetate Tc 99m Injection distributed uniformly in the total body are shown in Tables 5 and 6.

Table

5.

Adult Absorbed Radiation

Doses (mGy) from Intravenous Injection Organ Absorbed Radiation Dose (mGy) for a 1110 MBq (30mCi) dose To obtain radiation absorbed dose in rads (30 mCi dose) from the above table, divide individual organ values by a factor of 10 (does not apply for effective dose). Adrenals

4.1 Urinary Bladder Wall 20 Bone Surfaces

6.2 Brain

2.2 Breasts 2 Gallbladder Wall

8.3 Stomach Wall 29 Small Intestine 18 ULI Wall 63 LLI Wall 23 Heart Wall

3.5 Kidneys 6 Liver

4.7 Lungs

2.9 Muscle

3.6 Ovaries 11 Pancreas

6.3 Red Marrow

4.1 Skin 2 Spleen

4.8 Testes

3.1 Thymus

2.7 Thyroid 24 Uterus 9 Remaining Tissues

3.9 Effective Dose (mSv) 14 Table 6.

Pediatric Absorbed Radiation

Doses (mGy) from Intravenous Injection Age 15 years 10 years 5 years 1 year To obtain radiation absorbed dose in rads (30 mCi dose) from the above table, divide individual organ values by a factor of 10 (does not apply for effective dose). Administered activity in MBq (mCi) 1110 (30) 740 (20) 555 (15) 370 (10)

Organ Adrenals

5.3 5.4 6.2

7.1 Urinary Bladder Wall 26 22 18 22 Bone Surfaces 7.6 7.5 8.1 10 Brain 2.8 3.1 3.7

4.5 Breasts 2.6 2.6 3.2

4.1 Gallbladder Wall 11 12 13 13 Stomach Wall 38 36 43 59 Small Intestine 22 23 26 30 ULI Wall 81 89 110 140 LLI Wall 31 33 40 48 Heart Wall 4.5 4.6 5.2

6.4 Kidneys 7.2 6.9 7.8

8.5 Liver 6 6.7 8

9.1 Lungs 3.8 3.8 4.4

5.3 Muscle 4.5 4.5 5 6 Ovaries 14 13 14 17 Pancreas 8.1 8.2 8.9 10 Red Marrow 5.1 5 5.2 6 Skin 2.5 2.6 3.2

3.8 Spleen 6 6 6.7

7.8 Testes 4.1 4.3 4.9 6 Thymus 3.6 3.5 4.2

5.3 Thyroid 40 41 67 81 Uterus 11 11 12 14 Remaining Tissues 4.8 4.8 5.4

6.4 Effective Dose (mSv) 19 19 23 29 The estimated absorbed radiation doses to an average ADULT from the instillation of Sodium Pertechnetate Tc 99m Injection for imaging the nasolacrimal drainage system are shown in Table 7.

Table

7.

Absorbed Radiation

Dose from Dacryoscintigraphy Using Sodium Pertechnetate Tc 99m Absorbed Dose Target Organ mGy/ 3.7MBq (rad/ 100µCi) * Assuming no blockage of drainage system Eye Lens: If lacrimal fluid turnover is 16%/min If lacrimal fluid turnover is 100%/min If drainage system is blocked Total Body* Ovaries* Testes* Thyroid* 0.140 0.022 4.020 0.011 0.030 0.009 0.130 0.014 0.002 0.402 0.001 0.003 0.001

0.013 In pediatric patients, an average 30 minute exposure to 37MBq (1 millicurie) of Sodium Pertechnetate Tc 99m Injection following instillation for direct cystography, results in an estimated absorbed radiation dose shown in Table 8.

Table

8.

Pediatric Absorbed Radiation

Dose from Cystography Age Bladder wall dose, mGy (rad) Gonadal dose, mGy (rad) 1 year 3.6 (0.36) 0.15 (0.015) 5 years 2.0 (0.2) 0.095 (0.0095) 10 years 1.3 (0.13) 0.066 (0.0066) 15 years 0.92 (0.092) 0.046 (0.0046)

CONTRAINDICATIONS: None known.

ADVERSE REACTIONS: Allergic reactions including anaphylaxis have been reported infrequently following the administration of Sodium Pertechnetate Tc 99m Injection.

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. Long-term cumulative radiation exposure may be associated with an increased risk of cancer. Only use generator eluant specified for use with the Ultra-Technekow ™ V4 Generator. Do not use any other generator eluant or saline from any other source.

PRECAUTIONS: General 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 ensure minimum radiation exposure to occupational workers. Since the eluate does not contain an antimicrobial agent, it should not be used after 12 hours from the time of TECHNELITE ® , Technetium Tc 99m Generator elution. 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. Radiopharmaceuticals should be used only by physicians who are qualified by training and experience in the safe handling of radionuclides and whose experience and training have been approved by the appropriate government agency authorized to license the use of radionuclides. Carcinogenesis, Mutagenesis, Impairment of Fertility No animal studies have been performed to evaluate carcinogenic potential or whether Sodium Pertechnetate Tc 99m affects fertility in males or females.

Pregnancy

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 reproduction capacity.

Sodium Pertechnetate Tc

99m Injection should be given to a pregnant woman only if clearly needed. Ideally examinations using radiopharmaceuticals, especially those elective in nature, of a woman of childbearing capability should be performed during the first few (approximately 10) days following the onset of menses.

Nursing Mothers Sodium Pertechnetate Tc

99m is excreted in human milk during lactation; therefore formula feedings should be substituted for breast feeding. This radiopharmaceutical preparation should not be administered to pregnant or lactating women unless expected benefits to be gained outweigh the potential risks.

Pediatric Use

See INDICATIONS and DOSAGE AND ADMINISTRATION sections. Also see the description of additional risks under WARNINGS.

Geriatric Use

Clinical studies of TechneLite ® did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.