TECHNETIUM TC-99M PYROPHOSPHATE: 46 Adverse Event Reports & Safety Profile

DESCRIPTION Kit for the Preparation of Technetium Tc 99m Pyrophosphate Injection is a multidose reaction vial which contains the sterile, non-pyrogenic, non-radioactive ingredients necessary to produce Technetium Tc 99m Pyrophosphate Injection for diagnostic use by intravenous injection.

Each

10 mL vial contains 12.0 mg of sodium pyrophosphate, 2.8 mg minimum stannous tin as stannous chloride dihydrate and 4.9 mg maximum total tin as stannous chloride dihydrate; pH is adjusted to 5.3-5.7 with hydrochloric acid prior to lyophilization. No bacteriostatic preservative is present. Sealed under nitrogen. The chemical names are: (1) Diphosphoric acid, Ditin (2 + ) salt; (2) Ditin (2 + ) pyrophosphate (4 - ). The structural formula is: When a solution of sterile, non-pyrogenic, oxidant-free isotonic Sodium Pertechnetate Tc 99m Injection U.S.P. is added to the vial, Technetium Tc 99m Pyrophosphate Injection is formed for intravenous injection. When a solution of sterile, non-pyrogenic, isotonic saline is added to the vial, it forms a blood pool imaging agent when Sodium Pertechnetate Tc 99m Injection is injected intravenously 30 minutes after the intravenous administration of the non-radioactive reconstituted Kit for the Preparation of Technetium Tc 99m Pyrophosphate Injection. The precise structure of Technetium Tc 99m Pyrophosphate Injection is not known at this time.

Structural Formula 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 Radiation Mean Percent Per Disintegration Mean Energy (keV) Gamma-2 89.07 140.5 ¹Kocher DC: Radioactive decay data tables. DOE/TIC-11026: 108, 1981 External Radiation The specific gamma ray constant for Tc 99m is 0.78 R/hr-millicurie 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 a 0.25 cm thickness of Pb will attenuate the radiation emitted by a factor of about 1,000. TABLE 2: Radiation Attenuation by Lead Shielding Shield Thickness (Pb) cm Coefficient of Attenuation 0.017 0.5 0.08 10 -1 0.16 10 -2 0.25 10 -3 0.33 10 -4 To correct for physical decay of this radionuclide, the fractions that remain at selected intervals after the time of calibration are shown in Table 3. TABLE 3: Physical Decay Chart: Tc 99m, half-life 6.02 hours Hours Fraction Remaining Hours Fraction Remaining 0* 1.000 7 0.447 1 0.891 8 0.398 2 0.794 9 0.355 3 0.708 10 0.316 4 0.631 11 0.282 5 0.562 12 0.251 6 0.501 * Calibration time

INDICATIONS AND USAGE Technetium Tc 99m Pyrophosphate Injection is a bone imaging agent used to demonstrate areas of altered osteogenesis, and a cardiac imaging agent used as an adjunct in the diagnosis of acute myocardial infarction. Kit for the Preparation of Technetium Tc 99m Pyrophosphate Injection is a blood pool imaging agent which may be used for gated blood pool imaging and for the detection of sites of gastrointestinal bleeding. When reconstituted with sterile non-pyrogenic isotonic saline and administered intravenously 30 minutes prior to the intravenous administration of Sodium Pertechnetate Tc 99m Injection, approximately 76% of the injected radioactivity remains in the blood pool.

DOSAGE AND ADMINISTRATION After preparation with oxidant-free Sodium Pertechnetate Tc 99m Injection, the suggested dose range of Technetium Tc 99m Pyrophosphate Injection in the average ADULT patient (70 kg) is: Bone Imaging - 185-555 megabecquerels (5-15 mCi)

Cardiac

Imaging - 370-555 megabecquerels (10-15 mCi) The suggested dose range of the non-radioactive reconstituted Kit for the Preparation of Technetium Tc 99m Pyrophosphate Injection in the average ADULT patient (70 kg) is: Blood Imaging - Administer not less than one-third nor more than the total contents of one vial [555 - 740 megabecquerels (15-20mCi) of Pertechnetate Tc 99m Injection]. Bone and Cardiac Imaging Technetium Tc 99m Pyrophosphate Injection is injected intravenously over a 10 to 20 second period. For optimal results, bone imaging should be done 1 to 6 hours following administration. Cardiac imaging should be done 30 to 90 minutes following administration. The acute myocardial infarct can be visualized from 24 hours to 6 days following onset of symptoms, with maximum localization at 48 to 72 hours. Cardiac imaging should be done with a gamma scintillation camera. It is recommended that images be made of the anterior, left anterior oblique and left lateral projections.

Blood Pool Imaging

Kit for the Preparation of Technetium Tc 99m Pyrophosphate Injection may be reconstituted with sterile, non-pyrogenic isotonic saline containing no preservatives. Administer not less than one-third nor more than the total contents of one vial 30 minutes prior to the intravenous administration of 555 to 740 megabecquerels (15-20 mCi)

Sodium Pertechnetate Tc

99m Injection. The non-radioactive reconstituted Kit for the Preparation of Technetium Tc 99m Pyrophosphate Injection should be injected by direct venipuncture. Heparinized catheter systems should be avoided. Cardiac imaging should be done 10 to 30 minutes following the administration of Sodium Pertechnetate Tc 99m Injection utilizing a scintillation camera interfaced to an electrocardiographic gating device. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. The patient dose should be measured by a suitable radioactivity calibration system immediately prior to administration.

Radiation Dosimetry

Bone and Cardiac Imaging The effective half-life was assumed to be the physical half-life for all calculated values. The estimated radiation absorbed doses to an average ADULT patient (70 kg) from an intravenous injection of a maximum of 555 megabecquerels (15 mCi) of Technetium Tc 99m Pyrophosphate Injection are shown in Table 4. TABLE 4: Estimated Absorbed Radiation Doses Bone and Cardiac Imaging* Technetium Tc 99m Pyrophosphate Injection Target Organ mGy/555 MBq rads/15 mCi Total Body 1.8

0.18 Kidneys 3.6

0.36 Red Marrow 3.5

0.35 Bone Surfaces 21.1

2.11 Bladder Wall 13.3

1.33 Testes 1.4

0.14 Ovaries 2.1

0.21 Effective Dose Equivalent 3.3 mSv 0.33 rem *Based on the model in MIRD Dose Estimate Report No. 13 (J Nucl Med 30:1117-1122, 1989). Estimate calculated using phantoms of Cristy & Eckerman (Report ORNL/TM-8381/V1 & V7). Bone and marrow model of Eckerman (Aspects of dosimetry of radionuclides within the skeleton with particular emphasis on the active marrow.

In Fourth International Radiopharmaceutical Dosimetry

Symposium; A.T. Schlafke-Stelson and E.E. Watson eds. CONF-851113, Oak Ridge Associated Universities, Oak Ridge, TN 37831, 1986. pp 514-534.) used. The effective dose equivalent is a quantity which may be suitable for comparing risks of different procedures in nuclear medicine, radiology, and other applications involving ionizing radiation, but should not be construed to give information about risks to individual patients and should not be applied to situations involving radiation therapy.

Blood Pool Imaging

The estimated absorbed radiation doses to an average adult patient (70 kg) from an intravenous injection of 740 megabecquerels (20 mCi) of Sodium Pertechnetate Tc 99m Injection, 30 minutes after the intravenous administration of the non-radioactive reconstituted Kit for the Preparation of Technetium Tc 99m Pyrophosphate Injection are shown in Table 5. TABLE 5: Estimated Absorbed Radiation Doses Blood Pool Imaging a Sodium Pertechnetate Tc 99m 30 min.

Post

Injection with Pyrophosphate Target Organ mGy/740 MBq rads/20 mCi Total Body 3.2

0.32 Spleen 3.6

0.36 Bladder Wall b 24.0

2.40 Testes 2.4

0.24 Ovaries 4.6

0.46 Blood 10.4

1.04 Red Marrow 4.4 0.44 a Assume 75% of the Sodium Pertechnetate Tc 99m labels red blood cells and the other 25% remains as pertechnetate. Method of calculation: MIRD Dose Estimate Report No. 8, J Nucl Med . 17: 74-77, 1976. b If 25% excreted with 1 hour T b

CONTRAINDICATIONS None known.

ADVERSE REACTIONS Some hypersensitivity reactions have been associated with pyrophosphate use.

WARNINGS As an adjunct in the diagnosis of confirmed myocardial infarction (ECG and serum enzymes positive), the incidence of false negative images has been found to be 6 percent. False negative images can also occur if made prior to 24 hours in the evolutionary phase of the infarct or after 6 days in the resolution phase. In a limited study involving 22 patients in whom the ECG was positive and serum enzymes questionable or negative, but in whom the final diagnosis of acute myocardial infarction was made, the incidence of false negative images was 23 percent. The incidence of false positive images has been found to be 7 to 9 percent. False positive images have also been reported following coronary by-pass graft surgery, in unstable angina pectoris, old myocardial infarcts and in cardiac contusions. Preliminary reports indicate impairment of brain scans using Sodium Pertechnetate Tc99m Injection which have been preceded by a bone scan using an agent containing stannous ions. The impairment may result in false positive or false negative brain scans. It is recommended, where feasible, that brain scans precede bone imaging procedures. Alternately, a brain imaging agent such as Technetium Tc 99m Pentetate Injection may be employed. The biodistribution of technetium Tc 99m pyrophosphate may be altered in the presence of high levels of certain cations (iron, calcium, and aluminum). This may result in reduced uptake of radionuclide in the skeleton and increased extraosseal uptake, which may potentially degrade imaging quality. High levels of these cations may be caused by concomitant medications or medical conditions (e.g., iron overload, hypercalcemia, etc.). Most cases were observed after iron infusion. (See PRECAUTIONS, Drug Interactions .)

PRECAUTIONS General The lyophilized contents of the Kit for the Preparation of Technetium Tc 99m Pyrophosphate Injection reaction vial are to be administered to the patient only as an intravenous solution (see Procedures for Reconstitution).

Any Sodium Pertechnetate Tc

99m solution which contains an oxidizing agent is not suitable for use with Kit for the Preparation of Technetium Tc 99m Pyrophosphate Injection. When reconstituted with Sodium Pertechnetate Tc 99m, Technetium Tc 99m Pyrophosphate Injection must be used within 6 hours. Kit for the Preparation of Technetium Tc 99m Pyrophosphate Injection may also be reconstituted with sterile, non-pyrogenic isotonic saline containing no preservatives and injected intravenously prior to the administration of Sodium Pertechnetate Tc 99m Injection. Kit for the Preparation of Technetium Tc 99m Pyrophosphate Injection contains no preservatives. Vials are sealed under nitrogen: air or oxygen is harmful to the contents of the vials and the vials should not be vented. The components of the Kit for the Preparation of Technetium Tc 99m Pyrophosphate Injection are supplied sterile and non-pyrogenic. Aseptic procedures normally employed in making additions and withdrawals for sterile, non-pyrogenic containers should be used during addition of the Sodium Pertechnetate Tc 99m Injection and the withdrawal of doses for patient administration. Shielding should be utilized when preparing Technetium Tc 99m Pyrophosphate Injection.

Technetium Tc

99m Pyrophosphate Injection as well as other radioactive drugs must be handled with care, and appropriate safety measures should be used to minimize radiation exposure to the patients and clinical personnel consistent with proper patient management. The solution should not be used if cloudy, discolored, or found to contain particulate matter. 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. No special handling is required for the non-radioactive drug product.

Bone Imaging

Both prior to and following Technetium Tc 99m Pyrophosphate Injection administration, if not contraindicated for the patient’s cardiac condition, patients should be encouraged to drink fluids. Patients should void as often as possible after the Technetium Tc 99m Pyrophosphate Injection to minimize background interference and unnecessary radiation exposure from accumulation in the bladder.

Cardiac Imaging

Patient’s cardiac condition should be stable before beginning the cardiac imaging procedure. Interference from chest wall lesions such as breast tumors and healing rib fractures can be minimized by employing the three recommended projections. (See DOSAGE AND ADMINISTRATION ). False-positive and false-negative myocardial scans may occur; therefore, the diagnosis of acute myocardial infarction depends on the overall assessment of laboratory and clinical findings.

Blood Pool Imaging

The non-radioactive reconstituted agent should be injected by direct venipuncture. Heparinized catheter systems should be avoided, as interference with red blood cell tagging will result. Cardiac pool imaging should be initiated 15 to 30 minutes after the administration of Sodium Pertechnetate Tc 99m Injection. The imaging of gastrointestinal bleeding is dependent on such factors as the region of imaging, rate and volume of the bleed, efficacy of the labeling of the red blood cells and timeliness of imaging. Due to these factors, images should be taken sequentially over a period of time until a positive image is obtained or clinical conditions warrant the discontinuance of the procedure. The period of time for collecting the images may range up to 36 hours.

Technetium Tc

99m Pyrophosphate Injection and the non-radioactive reconstituted Kit for the Preparation of Technetium Tc 99m Pyrophosphate Injection should be formulated within six (6) hours prior to clinical use.

Drug Interactions

The biodistribution of technetium Tc 99m pyrophosphate may be altered in the presence of high levels of certain cations (iron, calcium, and aluminum). This may result in reduced uptake of radionuclide in the skeleton and increased extraosseal uptake, which may potentially degrade imaging quality. In patients with high levels of these cations caused by concomitant medications, particularly patients receiving iron infusions, consider performing an imaging study with technetium Tc 99m pyrophosphate injection once the cation levels have normalized (e.g., after 3 to 5 half-lives of the cation). (See WARNINGS .) Carcinogenesis, Mutagenesis, Impairment of Fertility No long-term animal studies have been performed to evaluate carcinogenic potential or whether Technetium Tc 99m Pyrophosphate Injection affects fertility in males or females. Mutagenesis studies have not been conducted.

Pregnancy

Animal reproduction and teratogenicity studies have not been conducted with Technetium Tc 99m Pyrophosphate Injection. It is also not known whether Technetium Tc 99 Pyrophosphate Injection can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity.

Technetium Tc

99m Pyrophosphate Injection should be given to a pregnant woman only if clearly needed. Ideally, examinations using radiopharmaceuticals, especially those elective in nature, to a woman of childbearing capability should be performed during the first few (approximately 10) days following the onset of menses. Nursing mothers Technetium Tc 99m Pyrophosphate Injection is excreted in human milk during lactation, therefore, formula feeding should be substituted for breast feeding. Pediatric use Safety and effectiveness in pediatric patients have not been established. Geriatric use Clinical studies of the Kit for the Preparation of Technetium Tc 99m Pyrophosphate Injection 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. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.