Technetium Tc-99m Exametazime and Cobaltous Chloride

Ceretec is a radioactive diagnostic agent, indicated in adults and pediatric patients age 2 to 17 for: Leukocyte Labeled Scintigraphy – As an adjunct in the localization of intraabdominal infection and inflammatory bowel disease. ( 1.1 ) Cerebral Scintigraphy – As an adjunct in the detection of altered regional cerebral perfusion in stroke. ( 1.2 )

1.1 Leukocyte Labeled Scintigraphy Ceretec, when reconstituted with technetium Tc 99m exametazime (without cobalt stabilizer solution), is indicated in adults and pediatric patients age 2 to 17 for leukocyte labeled scintigraphy as an adjunct in the localization of intraabdominal infection and inflammatory bowel disease.

1.2 Cerebral Scintigraphy Ceretec, when reconstituted with technetium Tc 99m exametazime (with or without cobalt stabilizer solution), is indicated in adults and pediatric patients age 2 to 17 for cerebral scintigraphy as an adjunct in the detection of altered regional cerebral perfusion in stroke.

The Ceretec Kit is supplied as a five-unit package. Each unit contains: One (10 mL, multiple-dose) vial of Ceretec: A lyophilized mixture of 0.5 mg exametazime, sealed under nitrogen atmosphere with a rubber closure. One vial cobalt stabilizer solution: 200 mcg cobaltous chloride 6-hydrate stabilizer solution in 2 mL of Water for Injection. Each Ceretec kit consists of 5 units. ( 3 ) Each unit contains: One vial of Ceretec: A lyophilized mixture of 0.5 mg exametazime and 4.5 mg sodium chloride. One vial of cobalt stabilizer solution: 200 mcg cobalt chloride 6-hydrate stabilizer solution in 2 mL of Water for Injection.

None None. ( 4 )

Hypersensitivity reactions: Have cardiopulmonary resuscitation equipment and personnel available and monitor all patients for hypersensitivity reactions ( 5.1 )

5.1 Hypersensitivity Reactions Hypersensitivity reactions have been reported following the administration of Tc 99m exametazime injection and Tc 99m exametazime labeled leukocytes including serious signs and symptoms of anaphylaxis following administration [see Adverse Reactions (6) ] . Always have cardiopulmonary resuscitation equipment and personnel available and monitor all patients for hypersensitivity reactions.

5.2 Risk for Image Interpretation Errors The interpretation of images for leukocyte labeled imaging can be affected by the presence of other pathophysiological processes such as: tumor, infarction, trauma, and inflammatory conditions.

5.3 Radiation Exposure Risk Technetium Tc 99m contributes to a patient's overall long-term cumulative radiation exposure, which is associated with an increased risk of cancer. Ensure safe handling and preparation procedures to protect patients and health care workers from unintentional radiation exposure. Encourage patients to drink fluids and instruct patients to void when the examination is completed and as often thereafter as frequently as possible after administration [see Dosage and Administration (2.1 , 2.3) ] . Radiation risks associated with the use of Tc 99m exametazime injection and Tc 99m exametazime labeled leukocytes are greater in pediatric patients than in adults due to greater radiosensitivity and longer life expectancy.

The following serious 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 Ceretec were identified in clinical studies or postmarketing reports. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiovascular disorders: Reversible increase in blood pressure, flushing Gastrointestinal disorders: Nausea, vomiting General disorders and administration site conditions: Malaise, fatigue, fever Immune system disorders: Hypersensitivity reactions: anaphylactic reactions including shock, facial edema, rash, pruritus or erythema Nervous system disorders: Headache, dizziness, paresthesia Most common adverse reactions include a reversible increase in blood pressure . ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact GE Healthcare at 1-800-654-0118 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

Pregnancy – Advise the pregnant woman of the potential risk to the fetus based on the radiation dose from the Technetium Tc 99m exametazime injection and the gestational timing of exposure. ( 8.1 ) Lactation – Temporarily discontinue breastfeeding. A lactating woman should pump and discard breastmilk for 12 to 24 hours after Technetium Tc 99m Exametazime labeled leukocyte administration. ( 8.2 )

8.1 Pregnancy Risk Summary Limited available data with technetium Tc 99m exametazime use in pregnant women are insufficient to inform any drug associated risks 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 a 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 a 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 is 2-4% and 15-20%, respectively. Data Human Data Limited published literature describes Tc 99m exametazime crossing the placental barrier and visualization of radioactivity in the fetal liver. No adverse fetal effects or radiation-related risks have been identified for diagnostic procedures involving less than 50 mGy, which represents less than 10 mGy fetal doses.

8.2 Lactation Risk Summary There are limited data available in the scientific literature on the presence of technetium Tc 99m exametazime in human milk. There are no data available regarding the effects of technetium Tc 99m exametazime on the breastfed infant or on milk production. Exposure of technetium Tc 99m exametazime to a 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 mother's clinical need for Ceretec and any potential adverse effects on the breastfed child from Ceretec or from the underlying maternal condition. Clinical Considerations To decrease radiation exposure to the breastfed infant, advise a lactating woman to pump and discard breast milk after the administration of technetium Tc 99m exametazime injection or 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 Ceretec is indicated for use in pediatric patients from 2 to 17 years of age for leukocyte labelled scintigraphy and brain scintigraphy. The use of Ceretec for leukocyte labelled scintigraphy and brain scintigraphy is supported by extrapolation from clinical effectiveness in adults. The safety and dosing recommendations are based on clinical experience. Safety and effectiveness in pediatric patients less than 2 years of age have not been established.

8.5 Geriatric Use Clinical studies of Ceretec 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 This drug is known to be substantially excreted by the kidney, and radiation exposure may be greater in patients with impaired renal function. A reduction in administered Tc 99m can be considered provided an adequate number of leukocytes are administered.

General When technetium Tc 99m pertechnetate is added to exametazime in the presence of stannous reductant, a lipophilic technetium Tc 99m complex is formed. This lipophilic complex is the active moiety and is able to cross the blood-brain barrier as well as penetrate cell membranes to label leukocytes. It converts to a polar hydrophilic species at approximately 12% per hour. The polar hydrophilic species is unable to cross the blood-brain barrier or cell membranes. Mechanism for Labeling Leukocytes When incubated with leukocytes, which have been isolated from whole blood, the technetium Tc 99m exametazime complex, being lipid-soluble, penetrates the cell membrane of the leukocytes by passive diffusion. The lipophilic complex is then converted to a polar hydrophilic species, in a process possibly involving intracellular glutathione, thus trapping the technetium Tc 99m label within the cells. Mechanism for Brain Uptake The agent localizes in the brain as a function of regional cerebral perfusion. Technetium Tc 99m exametazime is primarily extracted and trapped by cerebral gray matter and the basal ganglia during the first pass through the brain. It has been proposed that the retention in the brain of technetium Tc 99m exametazime results from in vivo conversion of the primary complex to a less lipophilic complex, which is unable to cross the blood-brain barrier.