WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Hypersensitivity Reactions: Hypersensitivity reactions, including serious signs and symptoms of anaphylaxis, following administration of Tc 99m labeled leukocytes prepared using Tc 99m exametazime have been reported. Always have cardiopulmonary resuscitation equipment and personnel available and monitor all patients for hypersensitivity reactions. (5.1). Hypersensitivity Reactions: Hypersensitivity reactions, including serious signs and symptoms of anaphylaxis, following administration of Tc 99m labeled leukocytes prepared using Tc 99m exametazime have been reported. Always have cardiopulmonary resuscitation equipment and personnel available and monitor all patients for hypersensitivity reactions. (5.1). 5.1 Hypersensitivity Reactions. Hypersensitivity reactions, including serious signs and symptoms of anaphylaxis, following administration of Tc 99m labeled leukocytes prepared using Tc 99m exametazime have been reported. Always have cardiopulmonary resuscitation equipment and personnel available and monitor all patients for hypersensitivity reactions.. 5.2 Risk for Image Interpretation Error. The interpretation of images can be affected by the presence of other pathophysiological processes within and outside of the abdominal cavity such as: tumor, infarction, trauma, and other inflammatory conditions.. 5.3 Radiation Exposure Risk. Technetium Tc 99m contributes to patients overall long-term cumulative radiation exposure. Long-term cumulative radiation exposure is associated with an increased risk of cancer. Ensure safe handling and preparation reconstitution procedures to protect patients and health care workers from unintentional radiation exposure. Encourage patients to drink fluids and void as frequently as possible after administration [see Dosage and Administration (2.1, 2.2)].

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. DistributionDuring the first hour following the injection, radioactivity is seen in the lungs, liver, gall bladder, spleen, blood pool, bone marrow, kidneys, and bladder. Over the first 1-6 hours, the Tc 99m is visualized in the bowel. At 24 hours post-injection substantial colonic activity is seen. The normal areas visualized in earlier scans are still visible.Elimination Excretion Tc 99m excretion occurs via urine and feces.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Administration Instructions:Advise patients to hydrate after administration of technetium Tc 99m exametazime labeled leukocytes and to void frequently to minimize radiation dose [see Dosage and Administration (2.2)].PregnancyAdvise pregnant women of the risk of fetal exposure to radiation doses if they undergo radionuclide procedure [see Use in Specific Populations (8.1)].LactationAdvise lactating women that exposure of the infant to technetium Tc 99m through breast milk can be minimized if breastfeeding is interrupted when technetium Tc99m exametazime labeled leukocytes are administered. Advise lactating woman to pump and discard breast milk for 12 to 24 hours based on injected dose [see Use in Specific Populations (8.2)].Manufactured for:Jubilant DraxImage Inc., Kirkland, Quebec, Canada, H9H 4J4.Art rev.: 1.0. Advise patients to hydrate after administration of technetium Tc 99m exametazime labeled leukocytes and to void frequently to minimize radiation dose [see Dosage and Administration (2.2)].. Advise pregnant women of the risk of fetal exposure to radiation doses if they undergo radionuclide procedure [see Use in Specific Populations (8.1)].. Advise lactating women that exposure of the infant to technetium Tc 99m through breast milk can be minimized if breastfeeding is interrupted when technetium Tc99m exametazime labeled leukocytes are administered. Advise lactating woman to pump and discard breast milk for 12 to 24 hours based on injected dose [see Use in Specific Populations (8.2)].

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere are limited data available in the scientific literature on the presence of technetium Tc 99m exametazime in human milk. There no data available on the effects of technetium Tc 99m exametazime on the breastfed infant or the effects on milk production. Exposure of technetium Tc 99m exametazine to breast fed infant can be minimized by temporary discontinuation of breastfeeding [see Clinical Considerations]. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for technetium Tc 99m exametazime, any potential adverse effects on the breastfed child from technetium Tc 99m exametazime or from the underlying maternal condition.Clinical ConsiderationsTo decrease radiation exposure to the breastfed infant, advise lactating woman to pump and discard breast milk after the administration of technetium Tc 99m exametazime-labeled leukocytes for 12 to 24 hours, where the duration corresponds to the typical range of administered activity, 259 MBq to 925 MBq (7 mCi to 25 mCi).

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. When technetium Tc 99m pertechnetate is added to exametazime in the presence of stannous reductant, lipophilic technetium Tc 99m complex is formed. This lipophilic complex is the active moiety. The lipophilic technetium Tc 99m exametazime complex is taken up and retained in leukocytes.

OVERDOSAGE SECTION.

10 OVERDOSAGE. In the event of the administration of radiation overdose, hydration and frequent micturition should be encouraged in order to minimize the absorbed dose to patient.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

Carton Label. Rx onlyFor Reconstitution and Radiolabelling Instructions:See package insert.Important: For intravenous use as directed. Use appropriate radiation shielding. Use only for radiolabeling of leukocytes after reconstitution with technetium Tc 99m.Storage Conditions: Store the kit at 15C-25C (59F-77F) up to the expiry date. After reconsitution with technetium Tc 99m, store at 20C-25C (68F-77F) and use for labeling leukocytes within 30 minutes.NDC 65174-200-05 single dose vialsDrax Exametazime Kit for the Preparation of Technetium Tc 99m Exametazime for Leukocyte Labeling 0.5 mg/vialManufactured for Jubilant DraxImage Inc. Kirkland, Quebec H9H 4J4 CanadaContents: single-dose vials each containing sterile and non-pyrogenic lyophilized mixture of:0.5 mg exametazime7.6 mcg stannous chloride dihydrate (minimum stannous tin 0.6 mcg; maximum total stannous and stannic tin 4mcg per vial)4.5 mg sodium chloride10 Radiation Labels/Radiolabeled Leukocyte Labels/Lead Pot Labels Labeling Efficiency/Radiochemical Purity Testing Worksheets Leukocyte Labeling Schematic Package InsertMade in CanadaVial LabelDrax Exametazime Kit for the Preparation of Technetium Tc 99m Exametazime for Leukocyte Labeling 0.5 mg/vialNDC 65174-200-01Rx OnlySingle-dose vialDiagnostic agent for intravenous use after reconstitution with Technetium Tc 99m and radiolabeling of leukocytes. For composition, reconstitution and radiolabeling instructions see package insert. Before reconstitution, store at 15C-25C (59F-77F) up to expirty date. After reconstitution store at 20C-25C (68F-77F) and use for labeling leukocytes within 30 minutes.Manufactured for Jubilant DraxImage Inc. Kirkland, Quebec, Canada H9H 4J4Contains 0.5 mg of exametazime per vial, 7.6 mcg stannous chloride dihydrate (minimum stannous tin 0.6 mcg; maximum total stannous and stannic tin mcg per vial), and 4.5 mg sodium chloride.Radiation LabelDrax Exametazime Kit for the Preparation of Technetium Tc 99m Exametazime for Leukocyte Labeling Rx OnlyFOR INTRAVENOUS USEFor preparation instructions see package insert. Contains no antimicrobial preservative.Before reconstitution, store at 15C-25C (59F-77F) up to expiry date. After reconstitution store at 20C-25C (68F-77F) and use for labeling leukocytes within 30 minutes.Radiolabeled Leukocyte Lead Pot LabelDrax Exametazime Kit for the Preparation of Technetium Tc 99m Exametazime for Leukocyte Labeling Rx OnlyFOR INTRAVENOUS USERadiolabled LeukocytesFor preparation instructions see package insert.Labeling SchematicDrax Exametazime (Kit for the Preparation of Technetium Tc 99m Exametazime for Leukocyte Labeling)Leukocyte Preparation: see Package Insert for detailed instructions.60 mL syringe Anticoagulant (see insert)Needle: 19- or 20-gauge Withdraw 40mL bloodGently Mix min.Clamp and tilt syringe 10-20Sedimentation: 60 minutesTransfer LRP in WBC tubeCap tube; centrifugeTransfer LPP to another tubeAdd mL of NaCl to WBC; Swirl gentlyMultiple washings; see insertCentrifuge. Keep 0.5-1.0 mL supernate, discard restAdd 1.5 mL of NaCl to WBC; Swirl gentlyReconstitute Exametazime with 30mCi99mTcO4 in mL NaCl 0.9%Add 99mTc to Exametazime to WBC; swirl gentlyIncubate WBCs and swirl tube every min.Add mL LPP to WBC tubeCap WBC tube, swirl gently; centrifuge 400gDecant supernatant into wash tubeMeasure radioactivity record on worksheetAdd to 10 mL of LPP to WBCWhile in suspension, withdraw cells in syringe, cap and assay activityVerify the identity of the leukocyte recipient.Inject 99mTc WBC with 19-gauge as soon as possibleJubilant DraxImage Inc. 16751 TransCanada HwyKirkland, QC Canada H9H 4J41-888-633-5343LPP: Leukocyte Poor Plasma, LRP: Leukocyte Rich PlasmaRCP Efficiency Worksheets. 0.5 mg exametazime. 7.6 mcg stannous chloride dihydrate (minimum stannous tin 0.6 mcg; maximum total stannous and stannic tin 4mcg per vial). 4.5 mg sodium chloride. 60 mL syringe Anticoagulant (see insert). Needle: 19- or 20-gauge Withdraw 40mL blood. Gently Mix min.. Clamp and tilt syringe 10-20. Sedimentation: 60 minutes. Transfer LRP in WBC tube. Cap tube; centrifuge. Transfer LPP to another tube. Add mL of NaCl to WBC; Swirl gently. Multiple washings; see insert. Centrifuge. Keep 0.5-1.0 mL supernate, discard rest. Add 1.5 mL of NaCl to WBC; Swirl gently. Reconstitute Exametazime with 30mCi99mTcO4 in mL NaCl 0.9%. Add 99mTc to Exametazime to WBC; swirl gently. Incubate WBCs and swirl tube every min.. Add mL LPP to WBC tubeCap WBC tube, swirl gently; centrifuge 400g. Decant supernatant into wash tube. Measure radioactivity record on worksheet. Add to 10 mL of LPP to WBC. While in suspension, withdraw cells in syringe, cap and assay activity. Verify the identity of the leukocyte recipient.. Inject 99mTc WBC with 19-gauge as soon as possible. carton label. vial label. vial label 2. radiation label. lead pot label. labeling schematic 1. labeling schematic 2. worksheet page 1. worksheet page 2.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. Safety and efficacy in pediatric patients have not been assessed.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. The relationship between technetium Tc 99m exametazime labeled WBC concentrations and successful imaging was not explored in clinical trials. GI activity is typically not seen through the initial four (4) hours post-injection. By four (4) hours, the hepatobiliary excretion of the Tc 99m exametazime allows tracer (Tc 99m) accumulation in the hepatobiliary system and, hence bowel activity.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryLimited available data with technetium Tc 99m exametazime use in pregnant women are insufficient to inform drug associated risk for major birth defects and miscarriage. Technetium Tc 99m exametazime is transferred across the placenta [see Data]. Animal reproduction studies with technetium Tc 99m exametazime have not been conducted. However, all radiopharmaceuticals have the potential to cause fetal harm depending on the fetal stage of development and the magnitude of the radiation dose. If considering technetium Tc 99m exametazime administration to pregnant woman, inform the patient about the potential for adverse pregnancy outcomes based on the radiation dose from technetium Tc 99m exametazime and the gestational timing of exposure.The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have 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 are 2-4% and 15-20%, respectively.DataHuman DataLimited published literature describes Tc-99m exametazime crossing the placental barrier and accumulating in the fetal liver. No adverse fetal effects or radiation-related risks have been identified for diagnostic procedures involving less than 50mGy, which represents less than 10mGy fetal doses.

SPL UNCLASSIFIED SECTION.

2.1 Radiation Safety Drug Handling. Technetium Tc 99m exametazime is radioactive solution and should be handled with appropriate safety measures to minimize radiation exposure. During handling use waterproof gloves and effective shielding, including syringe shields [see Warnings and Precautions (5.3)].

STORAGE AND HANDLING SECTION.

16.2 Storage and Handling. Store Drax Exametazime kit at 15C 25C (59F 77F).Drax Exametazime is for distribution to and use by persons licensed authorized by the U.S. Nuclear Regulatory Commission or the relevant regulatory authority of an Agreement State. Store and dispose of technetium Tc 99m exametazime in compliance with the appropriate regulations of the government agency authorized to license the use of this radionuclide.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Temporarily discontinue breastfeeding. lactating woman should pump and discard breastmilk for 12 to 24 hours after Technetium Tc 99m Exametazime labeled leukocyte administration. (8.2)Renal impairment: Increased radiation exposure in patients with impaired renal function. reduction in administered Tc 99m can be considered provided adequate numbers of labeled WBCs are administered (8.6). Lactation: Temporarily discontinue breastfeeding. lactating woman should pump and discard breastmilk for 12 to 24 hours after Technetium Tc 99m Exametazime labeled leukocyte administration. (8.2). Renal impairment: Increased radiation exposure in patients with impaired renal function. reduction in administered Tc 99m can be considered provided adequate numbers of labeled WBCs are administered (8.6). 8.1 Pregnancy. Risk SummaryLimited available data with technetium Tc 99m exametazime use in pregnant women are insufficient to inform drug associated risk for major birth defects and miscarriage. Technetium Tc 99m exametazime is transferred across the placenta [see Data]. Animal reproduction studies with technetium Tc 99m exametazime have not been conducted. However, all radiopharmaceuticals have the potential to cause fetal harm depending on the fetal stage of development and the magnitude of the radiation dose. If considering technetium Tc 99m exametazime administration to pregnant woman, inform the patient about the potential for adverse pregnancy outcomes based on the radiation dose from technetium Tc 99m exametazime and the gestational timing of exposure.The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have 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 are 2-4% and 15-20%, respectively.DataHuman DataLimited published literature describes Tc-99m exametazime crossing the placental barrier and accumulating in the fetal liver. No adverse fetal effects or radiation-related risks have been identified for diagnostic procedures involving less than 50mGy, which represents less than 10mGy fetal doses.. 8.2 Lactation. Risk SummaryThere are limited data available in the scientific literature on the presence of technetium Tc 99m exametazime in human milk. There no data available on the effects of technetium Tc 99m exametazime on the breastfed infant or the effects on milk production. Exposure of technetium Tc 99m exametazine to breast fed infant can be minimized by temporary discontinuation of breastfeeding [see Clinical Considerations]. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for technetium Tc 99m exametazime, any potential adverse effects on the breastfed child from technetium Tc 99m exametazime or from the underlying maternal condition.Clinical ConsiderationsTo decrease radiation exposure to the breastfed infant, advise lactating woman to pump and discard breast milk after the administration of technetium Tc 99m exametazime-labeled leukocytes for 12 to 24 hours, where the duration corresponds to the typical range of administered activity, 259 MBq to 925 MBq (7 mCi to 25 mCi).. 8.4 Pediatric Use. Safety and efficacy in pediatric patients have not been assessed.. 8.5 Geriatric Use. Clinical studies of Tc 99m exametazime 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.. 8.6 Renal Impairment. Technetium Tc 99m exametazime is substantially excreted by the kidneys, so excretion is decreased delayed and therefore radiation exposure is greater in patients with impaired renal function. reduction in administered Tc 99m can be considered provided an adequate number of labeled WBCs are administered.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following adverse reactions are described elsewhere in the labeling;Hypersensitivity reactions [see Warnings and Precautions (5.1)].The following adverse reactions associated with the use of technetium Tc 99m exametazime have been identified in clinical trials or post-marketing reports. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Cardiovascular: transient blood pressure increaseSkin and subcutaneous tissue disorders: rash, generalized erythema, urticaria, angioedema, pruritus.General disorders and administration site conditions: facial edema, fever, asthenic conditions (e.g., malaise, fatigue).Nervous system disorders: headache, dizziness, paraesthesia.Vascular disorders: flushing.Gastrointestinal disorders: nausea, vomiting.. Hypersensitivity reactions [see Warnings and Precautions (5.1)].. Cardiovascular: transient blood pressure increase. Skin and subcutaneous tissue disorders: rash, generalized erythema, urticaria, angioedema, pruritus.. General disorders and administration site conditions: facial edema, fever, asthenic conditions (e.g., malaise, fatigue).. Nervous system disorders: headache, dizziness, paraesthesia.. Vascular disorders: flushing.. Gastrointestinal disorders: nausea, vomiting.. Most common adverse reactions include transient increase in blood pressure, rash, generalized erythema, facial edema and fever. (6)To report SUSPECTED ADVERSE REACTIONS, contact Jubilant DraxImage Inc. at 1-888-633-5343 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. When technetium Tc 99m pertechnetate is added to exametazime in the presence of stannous reductant, lipophilic technetium Tc 99m complex is formed. This lipophilic complex is the active moiety. The lipophilic technetium Tc 99m exametazime complex is taken up and retained in leukocytes.. 12.2 Pharmacodynamics. The relationship between technetium Tc 99m exametazime labeled WBC concentrations and successful imaging was not explored in clinical trials. GI activity is typically not seen through the initial four (4) hours post-injection. By four (4) hours, the hepatobiliary excretion of the Tc 99m exametazime allows tracer (Tc 99m) accumulation in the hepatobiliary system and, hence bowel activity.. 12.3 Pharmacokinetics. DistributionDuring the first hour following the injection, radioactivity is seen in the lungs, liver, gall bladder, spleen, blood pool, bone marrow, kidneys, and bladder. Over the first 1-6 hours, the Tc 99m is visualized in the bowel. At 24 hours post-injection substantial colonic activity is seen. The normal areas visualized in earlier scans are still visible.Elimination Excretion Tc 99m excretion occurs via urine and feces.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. Two clinical trials of technetium Tc 99m exametazime were performed in total of 88 patients who had suspected intra-abdominal infection or inflammation. Subjects received both Tc 99m labeled leukocytes and radiolabeled comparator. Images were obtained at and 30 minutes and at 2, and 24 hours. In two other clinical trials, total of 127 patients with suspected abdominal inflammation or infection received Tc 99m labeled leukocytes. Imaging was at 24 hours in one study and at 1, and 24 hours in the other. In all four studies images were blindly evaluated and the findings were confirmed by surgery, biopsy or other clinical data.Based on the above studies, between to hours Tc 99m labeled leukocytes had 95-100% sensitivity and 62-85% specificity. In all studies the false positive and false negatives relate to the bowel background, the location of the site of infection/inflammation and whether or not it is contiguous with the bowel. Images obtained at 24 hours can be unreliable because of high bowel background.The interpretation of the images could also be affected by the presence of tumors, infarction and peritonitis [See Warning and Precautions (5.2)]. Liver abscess may be missed in planar imaging because of the bowel background.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. None.. None. (4).

DESCRIPTION SECTION.

11 DESCRIPTION. 11.1 Chemical Characteristics. Drax Exametazime (kit for the preparation of technetium Tc 99m exametazime for leukocyte labeling) prepares radioactive diagnostic agent. Each single-dose vial contains sterile, non-pyrogenic, lyophilized mixture of 0.5 mg exametazime, 7.6 mcg stannous chloride dihydrate (minimum stannous tin 0.6 mcg; maximum total stannous and stannic tin mcg per vial) and 4.5 mg sodium chloride, sealed under nitrogen atmosphere with rubber closure. The product contains no antimicrobial preservative.The chemical formula of exametazime is C13H28N4O2, with the following structural formula:Prior to publication of the USAN, exametazime [also known as (RR,SS)-4.8-diaza-3,6,6,9-tetramethylundecane-2, 10-dione bisoxime] was known as hexamethylpropylene amine oxime (HM-PAO). The name HM-PAO appears in many publications.When Tc 99m pertechnetate in Sodium Chloride Injection, USP (0.9%) is added to Drax Exametazime vial, Tc 99m complex of exametazime is formed.. chemical formula. 11.2 Physical Characteristics. Tc 99m decays by isomeric transition with physical half-life of hours. Photons that are useful for imaging studies are listed in Table 2.Table Principal Radiation Emission Data Tc 99m RadiationMean %/Disintegration Mean Energy (keV) Gamma 288.5140.5. 11.3 External Radiation. The air-kerma-rate (exposure-rate) constant for technetium Tc 99m is 5.23 m2.pGy.(MBq)-1.s-1 [0.795 cm2.R.(mCi)-1.h-1]. The first half-value thickness of lead (Pb) for Tc 99m is 0.25 mm. 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 3. For example, the use of 3 mm thickness of Pb will decrease the external radiation exposure by factor of approximately 1,000.Table Radiation Attenuation by Lead Shielding Shield Thickness (Pb) mmCoefficient of Attenuation 0.25 0.5 10-1 10-2 10-3 10-4 10-5 To correct for physical decay of this radionuclide, the fractions that remain at selected intervals relative to the time of calibration are shown in Table 4.Table Physical Decay Chart Tc 99m half-life hours Hours Fraction Remaining HoursFraction Remaining 0Calibration time (time of preparation) 1.00 0.45 0.89 0.4 0.79 0.35 0.71 10 0.32 0.63 11 0.28 0.56 12 0.25 0.50 24 0.063.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Use careful handling with appropriate safety measures to minimize radiation exposure to both patients and healthcare professionals. (2.1)For an adult patient, recommended dose is 259 925 megabecquerels (MBq) [7-25 millicuries (mCi)]. (2.3). Use careful handling with appropriate safety measures to minimize radiation exposure to both patients and healthcare professionals. (2.1). For an adult patient, recommended dose is 259 925 megabecquerels (MBq) [7-25 millicuries (mCi)]. (2.3). 2.1 Radiation Safety Drug Handling. Technetium Tc 99m exametazime is radioactive solution and should be handled with appropriate safety measures to minimize radiation exposure. During handling use waterproof gloves and effective shielding, including syringe shields [see Warnings and Precautions (5.3)].. 2.2 Important Administration Instructions. Use strict aseptic procedures throughout preparation and handling.Visually inspect the reconstituted technetium Tc 99m exametazime solution for particulate matter and discoloration prior to radiolabeling of white blood cells. Do not use the reconstituted solution if there is evidence of particulate matter or discoloration.Follow the directions of drug preparation carefully to ensure efficient leukocytes labeling [see Dosage and Administration (2.5 2.6)].Measure patient dose with suitable radioactivity calibration system immediately prior to administration.Instruct patients to hydrate, after administration of technetium Tc 99m exametazime labeled white blood cells and void frequently to minimize radiation dose to the kidneys and bladder [see Warnings and Precautions (5.3)].. Use strict aseptic procedures throughout preparation and handling.. Visually inspect the reconstituted technetium Tc 99m exametazime solution for particulate matter and discoloration prior to radiolabeling of white blood cells. Do not use the reconstituted solution if there is evidence of particulate matter or discoloration.. Follow the directions of drug preparation carefully to ensure efficient leukocytes labeling [see Dosage and Administration (2.5 2.6)].. Measure patient dose with suitable radioactivity calibration system immediately prior to administration.. Instruct patients to hydrate, after administration of technetium Tc 99m exametazime labeled white blood cells and void frequently to minimize radiation dose to the kidneys and bladder [see Warnings and Precautions (5.3)].. 2.3 Recommended Dosage and Administration. For an adult patient the recommended intravenous injection dose range for technetium Tc 99m exametazime labeled leukocytes is 259 925 Megabecquerels (MBq) [7-25 millicuries (mCi)].. 2.4 Image Acquisition and Inerpretation. AcquisitionInstruct patients to empty their bladder prior to imaging.Obtain serial pelvic and abdominal images beginning at 0.5 1 hour post-injection and continue up to hours.InterpretationAccumulation of radioactivity in bowel seen in early images [less than hours] with increasing intensity and/or no evidence of changing location secondary to GI motility likely represents inflammatory bowel disease or infection. Radioactivity from hepatic excretion detected in the bowel hours post-injection and changing in GI location on serial/subsequent images is indicative of normal GI transit [see Clinical Pharmacology (12.2)] Instruct patients to empty their bladder prior to imaging.. Obtain serial pelvic and abdominal images beginning at 0.5 1 hour post-injection and continue up to hours.. Accumulation of radioactivity in bowel seen in early images [less than hours] with increasing intensity and/or no evidence of changing location secondary to GI motility likely represents inflammatory bowel disease or infection. Radioactivity from hepatic excretion detected in the bowel hours post-injection and changing in GI location on serial/subsequent images is indicative of normal GI transit [see Clinical Pharmacology (12.2)] 2.5 Preparation of Autologous Leukocytes. IMPORTANT Label all syringes and tubes used in this labeling procedure with the patients name and unique identification number.Leukocyte Harvest and Separation1. Draw mL of Heparin and mL of 6% Hydroxyethyl starch into 60 mL plastic syringe.2. Withdraw approximately 40 mL whole blood from the patient into the syringe using 19-gauge Butterfly needle infusion set. Close the syringe with sterile hub.3. Gently mix the contents for minutes.4. Clamp the syringe barrel to the ring stand in an upright (hub side up) position and tilt the syringe approximately 10-20 degrees from its position perpendicular to the bench.5. Allow the syringe to stand minimum of 60 minutes until the red blood cells sediment and the supernatant looks clear.6. Using an infusion set, transfer the leukocyte-rich plasma (LRP), the supernatant, from the previous step, into sterile, conical centrifuge tube marked WBC (white blood cell) and assure that only minimum amount of red cells enter the centrifuge tube.7. Immediately centrifuge the capped WBC tube at 400-450 for minutes. The plasma will separate out into liquid [leukocyte poor plasma (LPP)] and solid (WBC button). The WBC button often contains small number of red blood cells and may appear red.8. Transfer the leukocyte poor plasma (LPP) into another sterile centrifuge tube marked as Plasma tube, without disturbing the WBC button. Save the LPP in the Plasma tube for later use (Steps 16 and 19).Red Blood Cell Lysis and Washing9. Add mL Sodium Chloride (Na Cl) Injection, USP (0.9%) to the WBC button and suspend.10. Add the following to the WBC suspension in succession and swirl the centrifuge tube (WBC tube) for 5-30 seconds after each addition. (Attention to timing is important as exposing leukocytes to hypotonic solution for prolonged period will damage leukocytes and result in poor leukocyte labeling results): a) mL sterile water; b) mL of 5% Na Cl; and c) 10 mL of 0.9% Na Cl.11. Cap the WBC tube and centrifuge at 400 for 5-7 minutes. Draw off the supernatant into the Waste tube.12. Add 1.5 mL of 0.9% Na Cl and re-suspend the WBC button by gentle shaking.13. Reconstitute technetium Tc 99m exametazime with generator eluate [see Dosage and Administration (2.7)]. Measure the radioactivity and record as text (1) on the Technetium Tc 99m Exametazime Labeling Efficiency Worksheet. Use for radiolabeling WBC within 30 minutes.. 2.6 Labeling of Autologous Leukocytes with Technetium Tc 99m Exametazime. 14. Carefully add the reconstituted technetium Tc 99m exametazime to the WBC tube containing the WBC button isolated in Step 12.15. Incubate the WBCs at room temperature for 15 minutes. Swirl during the incubation every minutes.16. Add mL of LPP (from Step 8) to the WBC tube. Cap the WBC tube and centrifuge at 400 for minutes.17. Carefully remove the supernatant and place into the tube labeled Wash. Keep the labeled white cells in the WBC tube.18. Measure the radioactivity of the Wash tube and record as text (2) on the Technetium Tc 99m Exametazime Labeling Efficiency Worksheet.19. Add 5-10 mL of LPP (from Step 8) to the Tc 99m labeled leukocyte preparation (WBC tube). Gently swirl to mix.20. Draw up the labeled cells into non-heparinized syringe with large bore needle (no smaller than 19-gauge) and cap it with sterile hub. Measure the radioactivity of the cells and record as text (3) on the Technetium Tc 99m Exametazime Labeling Efficiency Worksheet. 21. Verify the identity of the leukocyte recipient. 22. Labeled cells are now ready for administration. Administer as soon as possible and preferably within 1-2 hours after labeling.23. Calculate the labeling efficiency from the Labeling Efficiency Worksheet: Radioactivity of the cells [text (3)] Radioactivity of the cells [text (3)] activity in the supernatant [text (2)]Labeling efficiency >50% is anticipated.. 2.7 Preparation of Technetium Tc 99m Exametazime. The technetium Tc 99m labeling reaction involved in preparing the agent depends on maintaining the stannous ion in the reduced state. Any oxidant present in the sodium pertechnetate Tc 99m may adversely affect the radiolabeling efficiency.Elute the Tc 99m generator according to the manufacturers instructions. Use only eluate from Tc 99m generator which was eluted within the previous 24 hours.Prepare the technetium Tc99m exametazime with eluate that is not more than hours old. Add 370 MBq up to 2000 MBq (10 mCi up to 54 mCi) sodium pertechnetate Tc 99m to Drax Exametazime vial.Before reconstitution, add up to mL preservative-free, non-bacteriostatic Sodium Chloride Injection USP (0.9%) to the generator eluate to achieve radioactive concentration no greater than 74-370 MBq/mL (2-10 mCi/mL).Measure the radioactivity and record as text (1) on the Technetium Tc 99m Exametazime Labeling Efficiency Worksheet.Use sample for Quality Control [see Dosage and Administration (2.8)].Maintain reconstituted product at 20C 25C (68F 77F).Use for WBC labeling within 30 minutes.Discard any unused material according to local radiation safety procedures.. Elute the Tc 99m generator according to the manufacturers instructions. Use only eluate from Tc 99m generator which was eluted within the previous 24 hours.Prepare the technetium Tc99m exametazime with eluate that is not more than hours old. Use only eluate from Tc 99m generator which was eluted within the previous 24 hours.. Prepare the technetium Tc99m exametazime with eluate that is not more than hours old.. Add 370 MBq up to 2000 MBq (10 mCi up to 54 mCi) sodium pertechnetate Tc 99m to Drax Exametazime vial.. Before reconstitution, add up to mL preservative-free, non-bacteriostatic Sodium Chloride Injection USP (0.9%) to the generator eluate to achieve radioactive concentration no greater than 74-370 MBq/mL (2-10 mCi/mL).. Measure the radioactivity and record as text (1) on the Technetium Tc 99m Exametazime Labeling Efficiency Worksheet.. Use sample for Quality Control [see Dosage and Administration (2.8)].. Maintain reconstituted product at 20C 25C (68F 77F).. Use for WBC labeling within 30 minutes.. Discard any unused material according to local radiation safety procedures.. 2.8 Radiochemical Purity Testing Quality control of Tc 99m Exametazime. Obtain the Following Materials: SG ITLC strips cm 0.7 cm Whatman Grade 31ET chromatographic paper strip cm 0.7 cm MEK (methyl ethyl ketone [butanone]) (99.9 % HPLC Grade) 0.9% aqueous sodium chloride (non-bacteriostatic) 50% aqueous acetonitrile (99.9 % HPLC Grade) Glass test tubes (12 75 mm) with covers mL syringes with 25-gauge needles. Collimated radiation detector.Perform radiochemical purity testing of technetium Tc 99m exametazime before leukocyte labeling and within minutes of reconstitution.This entire radiochemical purity testing procedure takes approximately 15 minutes.A combination of chromatographic systems is necessary for the complete definition of the radiochemical composition of the injection.System 1: methyl ethyl ketone (MEK) SG ITLC stripSystem 2: 0.9% non-bacteriostatic sodium chloride solution SG ITLC stripSystem 3: 50% acetonitrile solution Whatman 31ET paper strip Three potential radiochemical impurities may be present in the prepared injection of the lipophilic Tc 99m exametazime complex:secondary Tc 99m exametazime complex free Tc 99m pertechnetatereduced-hydrolyzed Tc 99m Method1. Prepare three chromatographic systems using 12 mm 75 mm chromatographic tubes with the following solvents (identify the solvent in each tube):System 1- 0.3 mL of fresh methyl ethyl ketone (MEK),System - 0.9% non-bacteriostatic sodium chloride solution,System - 50% acetonitrile solution, prepared with non-bacteriostatic water2. Apply uL of freshly prepared Tc 99m exametazime solution (within minutes of reconstitution) about cm from the bottom of three strips: two 6cm 0.7cm instant thin-layer chromatographic strips and one cm 0.7cm strip of chromatographic paper. Do not allow to dry. 3. Place one SG ITLC strip into the MEK tube (System 1), the second SG ITLC strip into the saline tube (System 2) and the Whatman 31ET paper strip into the 50% acetonitrile tube (System 3). Make sure strips are not adhering to the sides of the tube.4. Allow the chromatograms to develop until the solvent front has moved to the top of the strips. Remove the strips from the tubes, and allow the solvents to evaporate.5. Determine the radioactive distribution by scanning the strip sections, using suitable collimated radiation detector.Chromatogram Interpretation6. Using the Radiochemical Purity Worksheet, record the following counts:System (SG ITLC: MEK [butanone]) Migrate at Rf 0.8-1 Lipophilic Tc 99m exametazime complex and Tc 99m pertechnetate Origin Secondary Tc 99m exametazime complex and reduced-hydrolyzed Tc 99m.System (SG ITLC: 0.9% sodium chloride)Migrate at Rf 0.8-1 Tc 99m pertechnetate Origin Lipophilic Tc 99m exametazime complex, secondary Tc 99m exametazime complex and reduced- hydrolyzed Tc 99mSystem (Whatman 31ET: 50% aqueous acetonitrile)Migrate at Rf 0.8-1 Lipophilic Tc 99m exametazime complex, secondary Tc 99m exametazime complex and Tc 99m pertechnetate Origin Reduced-hydrolyzed Tc 99m7. Determine and record on the Radiochemical Purity Worksheet: at the origin of saline strip (D) at the origin of MEK strip (B) at the solvent front of saline strip (C) [% Tc 99m pertechnetate] at the origin of Whatman 31ET paper strip (F) [% reduced-hydrolyzed Tc 99m]8. Calculate the radiochemical purity: lipophilic exametazime complex % at the origin of saline strip (D) % at the origin of MEK strip (B)9. Do not use if radiochemical purity of Lipophilic Tc 99m Exametazime is less than 80%. Perform radiochemical purity testing of technetium Tc 99m exametazime before leukocyte labeling and within minutes of reconstitution.. This entire radiochemical purity testing procedure takes approximately 15 minutes.. combination of chromatographic systems is necessary for the complete definition of the radiochemical composition of the injection.System 1: methyl ethyl ketone (MEK) SG ITLC stripSystem 2: 0.9% non-bacteriostatic sodium chloride solution SG ITLC stripSystem 3: 50% acetonitrile solution Whatman 31ET paper strip System 1: methyl ethyl ketone (MEK) SG ITLC strip. System 2: 0.9% non-bacteriostatic sodium chloride solution SG ITLC strip. System 3: 50% acetonitrile solution Whatman 31ET paper strip. Three potential radiochemical impurities may be present in the prepared injection of the lipophilic Tc 99m exametazime complex:secondary Tc 99m exametazime complex free Tc 99m pertechnetatereduced-hydrolyzed Tc 99m secondary Tc 99m exametazime complex. free Tc 99m pertechnetate. reduced-hydrolyzed Tc 99m. 2.9 Radiation Dosimetry. Based on human data, the radiation absorbed doses in an adult patient from an intravenous injection of Tc 99m labeled leukocytes have been estimated and are provided in Table 1.Table Tc 99m Exametazime Labeled Leukocytes OrganAbsorbed dose per unit activity administered Absorbed dose per unit activity administered (microGy/MBq) (mrad/mCi) Spleen 88 327 Red marrow 15 54 Liver 13 48 Bone surfaces 8.4 31 Urinary bladder 8.2 30 Lungs 7.4 27 Stomach 6.7 25 Upper large intestine 5.5 20 Colon 4.5 17 Lower large intestine 3.3 12 Small intestine 2.5 9.3 Ovaries 1.6 Thyroid 1.3 4.8 Breast 0.9 3.3 Testes 0.8 Kidneys 0.3 1.1 Remaining organs 2.2 8.1 Effective dose per administered activity 7.5 microSv/MBq 28 mrem/mCi.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Drax Exametazime is kit containing five (5) single-dose vials. Each 10 mL, clear glass vial contains non-radioactive lyophilized mixture of: 0.5 mg exametazime, 7.6 mcg stannous chloride dihydrate (minimum stannous tin 0.6 mcg; maximum total stannous and stannic tin mcg per vial) and 4.5 mg sodium chloride, sealed under nitrogen atmosphere with rubber closure.When reconstituted with the technetium Tc 99m eluate, each vial will contain clear, colorless, and foreign particles-free solution of 370 MBq up to 2000 MBq (10 mCi up to 54 mCi) [74 370 MBq mL (2 10 mCi mL)]. The radioactive solution produced will be used for leukocyte labeling before intravenous administration to the patient.. Five (5) single-dose vials, each vial contains: 370 MBq up to 2000 MBq (10 mCi up to 54 mCi) [74 370 MBq mL (2 10 mCi mL)] at time of preparation (reconstitution). (3).

GERIATRIC USE SECTION.

8.5 Geriatric Use. Clinical studies of Tc 99m exametazime 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.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. 16.1 How Supplied. Drax Exametazime kit (NDC 65174-200-05) comprises:5 Single-dose vials (0.5 mg/vial). Each vial contains non-radioactive sterile, non-pyrogenic lyophilized mixture of: 0.5 mg of exametazime, 7.6 mcg stannous chloride dihydrate, and 4.5 mg sodium chloride (NDC 65174-200-01);10 Radiation Labels/Radiolabeled Leukocytes Labels/Lead Pot Labels ;5 Labeling Efficiency/Radiochemical Purity Testing Worksheets;1 Leukocyte Labeling Schematic;1 Package Insert.Sodium Pertechnetate Tc 99m is not part of Drax Exametazime kit. Before reconstitution and radiolabeling with Tc 99m, the contents of the kit are not radioactive.. Single-dose vials (0.5 mg/vial). Each vial contains non-radioactive sterile, non-pyrogenic lyophilized mixture of: 0.5 mg of exametazime, 7.6 mcg stannous chloride dihydrate, and 4.5 mg sodium chloride (NDC 65174-200-01);. 10 Radiation Labels/Radiolabeled Leukocytes Labels/Lead Pot Labels ;. Labeling Efficiency/Radiochemical Purity Testing Worksheets;. Leukocyte Labeling Schematic;. Package Insert.. 16.2 Storage and Handling. Store Drax Exametazime kit at 15C 25C (59F 77F).Drax Exametazime is for distribution to and use by persons licensed authorized by the U.S. Nuclear Regulatory Commission or the relevant regulatory authority of an Agreement State. Store and dispose of technetium Tc 99m exametazime in compliance with the appropriate regulations of the government agency authorized to license the use of this radionuclide.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Drax Exametazime is indicated for leukocyte (white blood cell) labeled scintigraphy as an adjunct in the localization of intra-abdominal infection and inflammatory bowel disease.. Drax Exametazime is radioactive diagnostic agent indicated for leukocyte (white blood cell) labeled scintigraphy as an adjunct in the localization of intra-abdominal infection and inflammatory bowel disease. (1).