CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY:. During the initial 24 hours following intravenous injection of Technetium Tc 99m Medronate, about 50% of each dose is retained in the skeleton, and about 50% is excreted in the urine. Upon intravenous injection, Technetium Tc 99m Medronate exhibits specific affinity for areas of altered osteogenesis. In humans, blood levels fall to to 10% of the injected dose by two hours post-injection and to to 5% by three hours.Uptake of Technetium Tc 99m Medronate Injection in bone appears to be related to osteogenic activity and to skeletal blood perfusion. The deposition in the skeleton is bilaterally symmetrical, with increased accumulation in the axial structure as compared to the appendicular skeleton. There is increased activity in the distal aspect on long bones as compared to the diaphyses.

DESCRIPTION SECTION.

Description. Kit for the Preparation of Technetium Tc 99m Medronate is multidose reaction vial which contains the sterile, non-pyrogenic, non-radioactive ingredients necessary to produce Technetium Tc 99m Medronate Injection for diagnostic use by Intravenous injection.Each 10mL multidose vial contains:oMedronic acid: 20 mgoAscorbic acid: mgoStannous fluoride, SnF2: 0.13 mg (minimum)oTotal tin (maximum, as stannous fluoride, SnF2): 0.38 mgThe pH is adjusted to 6.5 (6.3 to 6.7) with sodium hydroxide and/or hydrochloric acid prior to lyophilization. No bacteriostatic preservative is present in the vial. The contents of the vial are lyophilized and sealed under nitrogen at the time of manufacture. The structural formula is:When solution of sterile, non-pyrogenic, oxidant-free Sodium Pertechnetate Tc 99m Injection is added to the vial, the diagnostic agent, Technetium Tc 99m Medronate is formed for administration by intravenous injection. The pH of the reconstituted product is 5.4 to 6.8. The precise structure of Technetium Tc 99m Medronate Injection is not known at this time.. oMedronic acid: 20 mg. oAscorbic acid: mg. oStannous fluoride, SnF2: 0.13 mg (minimum). oTotal tin (maximum, as stannous fluoride, SnF2): 0.38 mg. PHYSICAL CHARACTERISTICS: Technetium Tc 99m decays by isomeric transition with physical half-life of 6.02 hours1. The principal photon that is useful for detection and imaging studies is listed in Table 1.TABLE Principal Radiation Emission DataRadiationMean per DisintegrationMean Energy (keV)Gamma-289.07140.51Kocher, DC: Radioactive Decay Data Tables, DOE/TIC-11026, 108, 1981.. EXTERNAL RADIATION:. The specific gamma ray constant for Tc 99m is 0.78 R/millicurie-hr at cm. The first half-value layer is 0.017 cm of lead (Pb). range of values for the relative attenuation of the radiation emitted by this radionuclide that results from interposition of the various thicknesses of Pb is shown in Table 2. To facilitate control of the radiation exposure from millicurie amounts of this radionuclide, the use of 0.25 cm thickness of Pb will attenuate the radiation emitted by factor of about 1,000.TABLE Radiation Attenuation by Lead ShieldingShield Thickness (Pb) cmCoefficient of Attenuation 0.0170.50.0810-1 0.1610-2 0.2510-3 0.3310-4 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 Physical Decay Chart: Tc 99m, Half-Life 6.02 HoursHoursFraction RemainingHoursFraction Remaining01.00070.44710.89180.39820.79490.35530.708100.31640.631110.28250.562120.25160.501 Calibration Time. Structural Formula.

DOSAGE & ADMINISTRATION SECTION.

DOSAGES AND ADMINISTRATION:. Shielding should be utilized when preparing Technetium Tc 99m Medronate Injection.After preparation with oxidant-free Sodium Pertechnetate Tc 99m Injection, the suggested dose range of Technetium Tc 99m Medronate Injection in the average ADULT patient (70 kg.) is:o370-740 megabecquerels: (10-20 millicuries) given intravenously. oImaging is optimal at to hours post Injection.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 suitable radioactivity calibration system immediately prior to administration.. o370-740 megabecquerels: (10-20 millicuries) given intravenously. oImaging is optimal at to hours post Injection.. Radiation Dosimetry. 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 maximum of 740 megabecquerels (20 millicuries) of Technetium Tc 99m Medronate Injection are shown in Table 4.TABLE Estimated Absorbed Radiation Dose2 Technetium Tc 99m Medronate Organ(MGy/740 MBq)(Rads 20 mCi) Total Body 1.30.13 Bone Total 7.00.70 Red Marrow 5.60.56 Kidneys 8.00.80 Liver 0.60.06 Bladder Wall hour void262.604.8 hour void62 6.20 Ovaries hour void 2.4 0.244.8 hour void 3.40.34 Testes hour void 1.60.164.8 hour void 2.20.222Method of calculation: S Absorbed Dose Per Unit Cumulated Activity for Selected Radionuclides and Organs, MIRD Pamphlet No 11 (1975).

GENERAL PRECAUTIONS SECTION.

EXTERNAL RADIATION:. The specific gamma ray constant for Tc 99m is 0.78 R/millicurie-hr at cm. The first half-value layer is 0.017 cm of lead (Pb). range of values for the relative attenuation of the radiation emitted by this radionuclide that results from interposition of the various thicknesses of Pb is shown in Table 2. To facilitate control of the radiation exposure from millicurie amounts of this radionuclide, the use of 0.25 cm thickness of Pb will attenuate the radiation emitted by factor of about 1,000.TABLE Radiation Attenuation by Lead ShieldingShield Thickness (Pb) cmCoefficient of Attenuation 0.0170.50.0810-1 0.1610-2 0.2510-3 0.3310-4 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 Physical Decay Chart: Tc 99m, Half-Life 6.02 HoursHoursFraction RemainingHoursFraction Remaining01.00070.44710.89180.39820.79490.35530.708100.31640.631110.28250.562120.25160.501 Calibration Time.

HOW SUPPLIED SECTION.

HOW SUPPLIED:. Kit for the Preparation of Technetium Tc 99m Medronate Injection is supplied in kits of five (5) or thirty (30) sterile, non-pyrogenic vials. Each 10 mL multidose vial contains 20 mg medronic acid, mg ascorbic acid, 0.13 mg minimum stannous fluoride (SnF2) and 0.38 mg maximum total tin, as stannous fluoride, SnF2 in lyophilized form. The pH is adjusted with sodium hydroxide and/or hydrochloric acid prior to lyophilization. The vial does not contain preservative. The contents of the vial are lyophilized and sealed under nitrogen at the time of manufacture. The pH of the reconstituted product is 5.4 to 6.8.. Kit Contents. Included in each five (5) vial kit is one (1) package insert and ten (10) radiation labels. Included in each thirty (30) vial kit is one (1) package insert and sixty (60) radiation labels.. Storage. Store the product as supplied at 20-25C (68-77F) [See USP]. After reconstitution store at 20-25C (68-77F) [See USP] (see DOSAGE AND ADMINISTRATION).

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE LABEL PRINCIPAL DISPLAY PANEL 5 VIAL CONTAINER. NDC 045567-0040-1Sun Pharmaceutical Industries, Inc.Kit for the Preparation of Technetium Tc99m Medronate for InjectionRx OnlySTERILEDIAGNOSTICMULTIDOSENON-PYROGENICEach 10mL multidose reaction vial contains: 20 mg medronic acid; mg ascorbic acid; 0.13mg (minimum) stannous fluoride; 0.38 mg total tin (maximum, as stannous fluoride) in lyophilized form. The pH is adjusted to 6.5 (6.3 6.7) with NaOH and/or HCI prior to lyophilization. Sealed under nitrogen. The recommended adult dose is 370 740 megabecquerels (10-20 millicuries). Refer to the package insert for directions for use.CONTAINS NO BACTERIOSTATIC PRESERVATIVE. FOR INTRAVENOUS USE ONLY AFTER LABELING WITH OXIDANT-FREE TECHNETIUM Tc99m. After labeling with Technetium Tc99m, store at 20-25C (68-77F), see USP. Use within hours after reconstitution.10 mLManufactured By:Sun Pharmaceutical Industries, Inc.Billerica, MA 01821PL-000008Rev 0.2Mar 2020. Vial Container Label.

PRECAUTIONS SECTION.

PRECAUTIONS:. General. Contents of the vial are intended only for use in the preparation of Technetium Tc 99m Medronate Injection and are NOT to be administered directly to the patient.Technetium Tc 99m Medronate 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 patient and clinical personnel consistent with proper patient management.To minimize radiation dose to the bladder, the patients should be encouraged to drink fluids and to void immediately before the examination and as often thereafter as possible for the next to hours.Technetium Tc 99m Medronate Injection should be formulated within six (6) hours prior to clinical use. Optimal imaging results are obtained to hours after administration.The finding of an abnormal concentration of radioactivity implies the existence of underlying pathology, but further study is required to distinguish benign from malignant lesions.The image quality may be adversely affected by obesity, old age, or impaired renal function.The components of the kit are sterile and non-pyrogenic. It is essential to follow directions carefully and to adhere to strict aseptic procedures during preparation. Technetium Tc 99m labeling reactions involved depend on maintaining the stannous ion in the reduced state. Hence, Sodium Pertechnetate Tc 99m Injection containing oxidants should not be used.The preparation contains no bacteriostatic preservative. Technetium Tc 99m Medronate Injection should be stored at 20-25oC (68-77oF) and discarded hours after reconstitution. The solution should not be used if the contents are cloudy. 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 Medronate for 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 pertechnetate solution and the withdrawal of doses for patient administration. Shielding should be utilized when preparing Technetium Tc 99m Medronate Injection.No special handling is required for the non-radioactive drug product.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.. Carcinogenesis, Mutagenesis, Impairment of Fertility. No long-term animal studies have been performed to evaluate carcinogenic potential or whether Technetium Tc 99m Medronate Injection affects fertility in males or females. Mutagenesis studies have not been conducted.. Pregnancy. Animal reproduction and teratogenicity studies have not been conducted on Technetium Tc 99m Medronate Injection. It is also not known whether Technetium Tc 99m Medronate Injection can cause fetal harm when administered to pregnant woman or can affect reproductive capacity. Technetium Tc 99m Medronate Injection should be given to pregnant woman only if clearly needed.Ideally, examinations using radiopharmaceuticals, especially those elective in nature, on woman of childbearing capability, should be performed during the first few (approximately 10) days following the onset of menses.. Nursing mothers. Technetium Tc 99m Medronate Injection is excreted in human milk during lactation; therefore, formula feeding should be substituted for breast feeding.. Pediatric Use. Safety and effectiveness in pediatric subjects have not been established.