Cardiolite

• Tell all of your health care providers that you take this medicine. This includes your doctors, nurses, pharmacists, and dentists.
• This medicine is radioactive. You will need to follow what the doctor has told you to lessen being exposed to Cardiolite. Talk with the doctor.
• Patients who have or may have heart disease: Rarely, deaths have happened 4 to 24 hours after using this medicine in people with heart disease. Most of the time, these have happened with exercise stress tests.
• Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using Cardiolite while you are pregnant.
• Tell your doctor if you are breast-feeding. You will need to talk about any risks to your baby.

Technetium Tc99m decays by isomeric transition with a physical half-life of 6.02 hours1. Photons that are useful for detection and imaging studies are listed in Table 1.

Table 1. Principal Radiation Emission Data

Radiation	Mean %/ Disintegration	Mean Energy (KeV)
Gamma -2	89.07	140.5

1 Kocher, David, C., Radioactive Decay Data Tables, DOE/TIC-11026, 108(1981).

EXTERNAL RADIATION

The specific gamma ray constant for Tc99m is 5.4 microcoulombs/Kg-MBq-hr (0.78R/mCi-hr) at 1 cm. The first half value layer is 0.017 cm of 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. To facilitate control of the radiation exposure from Megabequerel (millicurie) amounts of this radionuclide, the use of a 0.25 cm thickness of Pb will attenuate the radiation emitted by a factor of 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; Tc99m Half-Life 6.02 Hours

Hours	Fraction Remaining	Hours	Fraction Remaining
*Calibration Time
0*	1.000	8	.398
1	.891	9	.355
2	.794	10	.316
3	.708	11	.282
4	.631	12	.251
5	.562
6	.501
7	.447

General

Technetium Tc99m Sestamibi is a cationic Tc99m complex which has been found to accumulate in viable myocardial tissue in a manner analogous to that of thallous chloride Tl-201. Scintigraphic images obtained in humans after the intravenous administration of the drug have been comparable to those obtained with thallous chloride Tl-201 in normal and abnormal myocardial tissue.

Animal studies have shown that myocardial uptake is not blocked when the sodium pump mechanism is inhibited. Although studies of subcellular fractionation and electron micrographic analysis of heart cell aggregates suggest that Tc99m Sestamibi cellular retention occurs specifically within the mitochondria as a result of electrostatic interactions, the clinical relevance of these findings has not been determined.

The mechanism of Tc99m Sestamibi localization in various types of breast tissue (e.g., benign, inflammatory, malignant, fibrous) has not been established.

Pharmacokinetics

Pulmonary activity is negligible even immediately after injection. Blood clearance studies indicate that the fast clearing component clears with a t1/2 of 4.3 minutes at rest, and clears with a t1/2 of 1.6 minutes under exercise conditions. At five minutes post injection about 8% of the injected dose remains in circulation. There is less than 1% protein binding of Technetium Tc99m Sestamibi in plasma. The myocardial biological half-life is approximately six hours after a rest or exercise injection. The biological half-life for the liver is approximately 30 minutes after a rest or exercise injection. The effective half-life of clearance (which includes both the biological half-life and radionuclide decay) for the heart is approximately 3 hours, and for the liver is approximately 30 minutes, after a rest or exercise injection. The ideal imaging time reflects the best compromise between heart count rate and surrounding organ uptake.

Myocardial uptake which is coronary flow dependent is 1.2% of the injected dose at rest and 1.5% of the injected dose at exercise. Table 4 illustrates the biological clearance as well as effective clearance (which includes biological clearance and radionuclide decay) of Tc99m Sestamibi from the heart and liver.

[Organ concentrations expressed as percentage of injected dose; data based on an average of 5 subjects at rest and 5 subjects during exercise].

Table 4

	Rest					Stress
	Heart		Liver			Heart		Liver
Time	Biological	Effective	Biological	Effective		Biological	Effective	Biological	Effective
5 min.	1.2	1.2	19.6	19.4		1.5	1.5	5.9	5.8
30 min.	1.1	1.0	12.2	11.5		1.4	1.3	4.5	4.2
1 hour	1.0	0.9	5.6	5.0		1.4	1.2	2.4	2.1
2 hours	1.0	0.8	2.2	1.7		1.2	1.0	0.9	0.7
4 hours	0.8	0.5	0.7	0.4		1.0	0.6	0.3	0.2

A study in a dog myocardial ischemia model reported that Technetium Tc99m Sestamibi undergoes myocardial distribution (redistribution), although more slowly and less completely than thallous chloride Tl-201. A study in a dog myocardial infarction model reported that the drug showed no redistribution of any consequence. Definitive human studies to demonstrate possible redistribution have not been reported. In patients with documented myocardial infarction, imaging revealed the infarct up to four hours post dose.

Metabolism

The agent is excreted without any evidence of metabolism.

Elimination

The major pathway for clearance of Tc99m Sestamibi is the hepatobiliary system. Activity from the gall bladder appears in the intestines within one hour of injection. Twenty-seven percent of the injected dose is excreted in the urine, and approximately thirty-three percent of the injected dose is cleared through the feces in 48 hours.

Drug Interactions

Specific drug-drug interactions have not been studied.

Myocardial Imaging: Cardiolite®, Kit for the Preparation of Technetium Tc99m Sestamibi for Injection, is a myocardial perfusion agent that is indicated for detecting coronary artery disease by localizing myocardial ischemia (reversible defects) and infarction (non-reversible defects), in evaluating myocardial function and developing information for use in patient management decisions. Cardiolite® evaluation of myocardial ischemia can be accomplished with rest and cardiovascular stress techniques (e.g., exercise or pharmacologic stress in accordance with the pharmacologic stress agent's labeling).

It is usually not possible to determine the age of a myocardial infarction or to differentiate a recent myocardial infarction from ischemia.

Breast Imaging: MIRALUMA®, Kit for the Preparation of Technetium Tc99m Sestamibi for Injection, is indicated for planar imaging as a second line diagnostic drug after mammography to assist in the evaluation of breast lesions in patients with an abnormal mammogram or a palpable breast mass.

MIRALUMA® is not indicated for breast cancer screening, to confirm the presence or absence of malignancy, and it is not an alternative to biopsy.

In studying patients in whom cardiac disease is known or suspected, care should be taken to assure continuous monitoring and treatment in accordance with safe, accepted clinical procedure. Infrequently, death has occurred 4 to 24 hours after Tc99m Sestamibi use and is usually associated with exercise stress testing (See Precautions).

Pharmacologic induction of cardiovascular stress may be associated with serious adverse events such as myocardial infarction, arrhythmia, hypotension, bronchoconstriction and cerebrovascular events. Caution should be used when pharmacologic stress is selected as an alternative to exercise; it should be used when indicated and in accordance with the pharmacologic stress agent's labeling.

Technetium Tc99m Sestamibi has been rarely associated with acute severe allergic and anaphylactic events of angioedema and generalized urticaria. In some patients the allergic symptoms developed on the second injection during Cardiolite® imaging. Patients who receive Cardiolite® or MIRALUMA® imaging are receiving the same drug. Caution should be exercised and emergency equipment should be available when administering Technetium Tc99m Sestamibi. Also, before administering either Cardiolite® or MIRALUMA®, patients should be asked about the possibility of allergic reactions to either drug.

The radiation doses to organs and tissues of an average patient (70 Kg) per 1110 MBq (30 mCi) of Technetium Tc99m Sestamibi injected intravenously are shown in Table 10.

Table 10. Radiation Absorbed Doses from Tc99m Sestamibi

	Estimated Radiation Absorbed Dose
	REST
	2.0 hour void		4.8 hour void
Organ	rads/ 30 mCi	mGy/ 1110 MBq	rads/ 30 mCi	mGy/ 1110 MBq
Breasts	0.2	2.0	0.2	1.9
Gallbladder Wall	2.0	20.0	2.0	20.0
Small Intestine	3.0	30.0	3.0	30.0
Upper Large Intestine Wall	5.4	55.5	5.4	55.5
Lower Large Intestine Wall	3.9	40.0	4.2	41.1
Stomach Wall	0.6	6.1	0.6	5.8
Heart Wall	0.5	5.1	0.5	4.9
Kidneys	2.0	20.0	2.0	20.0
Liver	0.6	5.8	0.6	5.7
Lungs	0.3	2.8	0.3	2.7
Bone Surfaces	0.7	6.8	0.7	6.4
Thyroid	0.7	7.0	0.7	2.4
Ovaries	1.5	15.5	1.6	15.5
Testes	0.3	3.4	0.4	3.9
Red Marrow	0.5	5.1	0.5	5.0
Urinary Bladder Wall	2.0	20.0	4.2	41.1
Total Body	0.5	4.8	0.5	4.8
	STRESS
	2.0 hour void		4.8 hour void
Organ	rads/ 30 mCi	mGy/ 1110 MBq	rads/ 30 mCi	mGy/ 1110 MBq
Breasts	0.2	2.0	0.2	1.8
Gallbladder Wall	2.8	28.9	2.8	27.8
Small Intestine	2.4	24.4	2.4	24.4
Upper Large Intestine Wall	4.5	44.4	4.5	44.4
Lower Large Intestine Wall	3.3	32.2	3.3	32.2
Stomach Wall	0.6	5.3	0.5	5.2
Heart Wall	0.5	5.6	0.5	5.3
Kidneys	1.7	16.7	1.7	16.7
Liver	0.4	4.2	0.4	4.1
Lungs	0.3	2.6	0.2	2.4
Bone Surfaces	0.6	6.2	0.6	6.0
Thyroid	0.3	2.7	0.2	2.4
Ovaries	1.2	12.2	1.3	13.3
Testes	0.3	3.1	0.3	3.4
Red Marrow	0.5	4.6	0.5	4.4
Urinary Bladder Wall	1.5	15.5	3.0	30.0
Total Body	0.4	4.2	0.4	4.2

Radiation dosimetry calculations performed by Radiation Internal Dose Information Center, Oak Ridge Institute for Science and Education, PO Box 117, Oak Ridge, TN 37831-0117, (865) 576-3448.

The patient dose should be measured by a suitable radioactivity calibration system immediately prior to patient administration. Radiochemical purity should be checked prior to patient administration.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Store at 15-25°C before and after reconstitution.

Preparation of the Technetium Tc99m Sestamibi from the Kit for the Preparation of Technetium Tc99m Sestamibi is done by the following aseptic procedure:

General Procedure:

1. Prior to adding the Sodium Pertechnetate Tc99m Injection to the vial, inspect the vial carefully for the presence of damage, particularly cracks, and do not use the vial if found. Tear off a radiation symbol and attach it to the neck of the vial.
2. Waterproof gloves should be worn during the preparation procedure. Remove the plastic disc from the vial and swab the top of the vial closure with alcohol to sanitize the surface.

Boiling Water Bath Procedure:

c. Place the vial in a suitable radiation shield with a fitted radiation cap. d. With a sterile shielded syringe, aseptically obtain additive-free, sterile, non-pyrogenic Sodium Pertechnetate Tc99m Injection [925-5550 MBq, (25-150 mCi)] in approximately 1 to 3 mL. e. Aseptically add the Sodium Pertechnetate Tc99m Injection to the vial in the lead shield. Without withdrawing the needle, remove an equal volume of headspace to maintain atmospheric pressure within the vial. f. Shake vigorously, about 5 to 10 quick upward-downward motions. g. Remove the vial from the lead shield and place upright in an appropriately shielded and contained boiling water bath, such that the vial is suspended above the bottom of the bath, and boil for 10 minutes. Timing for 10 minutes is begun as soon as the water begins to boil again. Do not allow the boiling water to come in contact with the aluminum crimp. h. Remove the vial from the water bath, place in the lead shield and allow to cool for fifteen minutes.

Recon-o-Stat (thermal cycler) Procedure:

c. Place the vial in the thermal cycler radiation shield. d. With a sterile shielded syringe, aseptically obtain additive-free, sterile, non-pyrogenic Sodium Pertechnetate Tc99m Injection [925-5550 MBq, (25-150 mCi)] in approximately 1 to 3 mL. e. Aseptically add the Sodium Pertechnetate Tc99m Injection to the vial in the lead shield. Without withdrawing the needle, remove an equal volume of headspace to maintain atmospheric pressure within the vial. f. Shake vigorously, about 5 to 10 quick upward-downward motions. g. Place shield on sample block. While slightly pressing downward, give the shield a quarter turn to make certain there is a firm fit between the shield and the sample block. h. Press the proceed button to initiate the program (the thermal cycler automatically heats & cools the vial and contents). Please see the Recon-o-Stat Instruction Manual for further details.

General Procedure (cont.):

i. Using proper shielding, the vial contents should be visually inspected. Use only if the solution is clear and free of particulate matter and discoloration. j. Assay the reaction vial using a suitable radioactivity calibration system. Record the Technetium Tc99m concentration, total volume, assay time and date, expiration time and lot number on the vial shield label and affix the label to the shield. k. Store the reaction vial containing the Technetium Tc99m Sestamibi at 15° to 25°C until use; at such time the product should be aseptically withdrawn. Technetium Tc99m Sestamibi should be used within six hours of preparation. The vial contains no preservative.

Note: Adherence to the above product reconstitution instructions is recommended.

The potential for cracking and significant contamination exists whenever vials containing radioactive material are heated.

Product should be used within 6 hours after preparation.

Final product with radiochemical purity of at least 90% was used in the clinical trials that established safety and effectiveness. The radiochemical purity was determined by the following method.

1. Obtain a Baker-Flex Aluminum Oxide coated, plastic TLC plate, #1 B-F, pre-cut to 2.5 cm x 7.5 cm.
2. Dry the plate or plates at 100°C for 1 hour and store in a desiccator. Remove pre-dried plate from the desiccator just prior to use.
3. Apply 1 drop of ethanol* using a 1 mL syringe with a 22-26 gauge needle, 1.5 cm from the bottom of the plate. THE SPOT SHOULD NOT BE ALLOWED TO DRY.
4. Add 2 drops of Technetium Tc99m Sestamibi solution, side by side on top of the ethanol* spot. Return the plate to a desiccator and allow the sample spot to dry (typically 15 minutes).
5. The TLC tank is prepared by pouring ethanol* to a depth of 3-4 mm. Cover the tank and let it equilibrate for ~10 minutes.
6. Develop the plate in the covered TLC tank in ethanol* for a distance of 5 cm from the point of application.
7. Cut the TLC plate 4 cm from the bottom and measure the Tc99m activity in each piece by appropriate radiation detector.
8. Calculate the % Tc99m Sestamibi as:
     % Tc99m Sestamibi =    µCi Top Piece    X 100
                                            µCi Both Pieces

* The ethanol used in this procedure should be 95% or greater. Absolute ethanol (99%) should remain at ≥ 95% ethanol content for one week after opening if stored tightly capped, in a cool dry place.