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CARDIOVIS 1 MG KIT FOR RADIOPHARMACEUTICAL PREPARATION

Active substance(s): TETRAKIS COPPER TETRAFLUOROBORATE

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PL+SmPC-Mibi-UK-eng-02:Layout 1

29.09.2010

16:53 Uhr

Seite 1

the injection in order to help frequent voiding.

Cardiovis 1 mg
kit for radiopharmaceutical preparation
Tetrakis (2-methoxy-isobutyl isonitrile) Copper(I)-Tetrafluoroborate

Read all of this leaflet carefully before this medicine is
administered.
- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your doctor.
- If any of the side effects gets serious, or if you notice any side
effects not listed in this leaflet, please tell your doctor.
In this leaflet:
1. What Cardiovis is and what it is used for
2. Before you use Cardiovis
3. How to use Cardiovis
4. Possible side effects
5. How to store Cardiovis
6. Further information
1. WHAT CARDIOVIS IS AND WHAT IT IS USED FOR
Cardiovis is a radiopharmaceutical used for diagnostic purposes to
study the heart’s function and blood flow (myocardial perfusion) by making an image of the heart (scintigraphy), for example in the detection of
heart attacks (myocardial infarctions) or when a disease causes
reduced blood supply to (a part of) the heart muscle (ischaemia).
Scintigraphy with Technetium (99mTc) Sestamibi is used as:
- an examination in ischaemic heart disease
- an examination in the detection and localisation of infarction areas
- an examination of how well the heart is pumping and/or how much
blood it pumps per beat (total ventricular function, i.e. the function of
the heart chambers; or by using the first pass method to determine
the stroke volume and/or local wall motion).
- an examination in the detection of breast cancer when mammography
is equivocal
- an examination to localize parathyroid tissue with over-production of
parathyroid hormone (hyperparathyroidism), and in patients with
diseased parathyroid glands prior to an operation
2. BEFORE YOU USE CARDIOVIS
When Cardiovis must not be used
Cardiovis must not be used in patients who are allergic (hypersensitive)
to the active substance or to any of the other ingredients.
Take special care with Cardiovis
The administration of radiopharmaceuticals creates risks for other
persons from external radiation or contamination from spill of urine,
vomiting etc. Radiation protection precautions in accordance with
national regulations must therefore be taken.
Radiopharmaceuticals may be administered only by appropriately authorised staff. Special caution should be exercised while handling, and
staff and patients should not be exposed to unnecessary risk. The
consent to possess and use radiopharmaceuticals depends on current
national standards and regulations.
The Cardiovis kit vial content is indicated for the preparation of
Technetium (99mTc) Sestamibi radiopharmaceutical and may be
administered to a patient only after the procedure of adding the
radioactive isotope. To minimise the dose of radiation absorbed by the
bladder, it is recommended that you should drink plenty of water after

It is not usual for this product to be used in patients under 18 years
because it has not been fully investigated in this age group.

SUMMARY OF PRODUCT CHARACTERISTICS

Taking other medicines does not influence the effects of this medicine.
This product is for diagnostic use only.

56 - 58 kg = 0.92
60 - 62 kg = 0.96
64 - 66 kg = 0.98
68 kg
= 0.99

Patients with renal impairment:
In case of kidney failure, exposure to ionising radiation can be increased. This must be
taken into account when calculating the activity to be administered.

1. NAME OF THE MEDICINAL PRODUCT
Cardiovis 1 mg
kit for radiopharmaceutical preparation

Using Cardiovis with food and drink
You should not eat or drink for at least four hours before the start of the
investigation. Your doctor may ask you to eat a light fatty meal or to
drink a glass or two of milk after each injection and before imaging
starts.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each vial contains 1 mg
Tetrakis (2-methoxy-isobutyl isonitrile) Copper(I)-Tetrafluoroborate

Pregnancy and breast-feeding

To be reconstituted with sodium pertechnetate (99mTc) solution for injection.
The radioisotope is not part of the kit.

Pregnancy: If it is necessary to administer radiopharmaceuticals to
women of childbearing potential, pregnancy has to be excluded. If a
woman skipped one menstrual cycle, she should be recognised as
pregnant until the pregnancy has been confirmed or excluded.

Excipients:
Sodium 0.009 mmol (0.2 mg) per vial.
For a full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM

Ask your doctor for advice before taking any medicine. It is important
to tell your doctor whether there is a chance you may be pregnant. The
use of radiopharmaceuticals during pregnancy should be considered
carefully. Your doctor will only administer this product during pregnancy
if a benefit is expected which would outweigh the risks.

Kit for radiopharmaceutical preparation
The product is a white, lyophilised powder
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
This medicinal product is for diagnostic use only.
After reconstitution with Sodium pertechnetate (99mTc) solution for injection, the solution
of Technetium (99mTc) Sestamibi obtained is indicated:
- for myocardial perfusion scintigraphy for the detection and localisation of coronary
artery disease and myocardial infarction
- for the assessment of global ventricular function (gated SPECT for evaluation of left
ventricular ejection fraction, volumes and regional wall motion).
- Scintimammography for the detection of breast cancer
Detection of breast cancer when mammography is equivocal, inadequate or
indeterminate.
- Localisation of hyperfunctioning parathyroid tissue in patients with recurrent or
persistent hyperparathyroidism, and in patients scheduled to undergo surgery of the
parathyroid glands.

Breastfeeding: If you are breastfeeding, please tell your doctor, as
he/she may advise you to stop doing so until the radioactivity has left
your body. This takes about 24 hours. The expressed milk should be
discarded.
Driving and using machines
The radiopharmaceutical has no effect on ability to drive and use
machines.
Important information about some of the ingredients of Cardiovis

4.2 Posology and method of administration
For intravenous use after reconstitution with sodium pertechnetate (99mTc) solution for
injection (not included in this kit).
For instructions for preparation and control of the radiochemical purity of the
radiopharmaceutical, see section 12.
For patient preparation see section 4.4.

This medicinal product contains less than 1 mmol sodium (23 mg) per
vial, i.e. essentially ‘sodium-free’.
3. HOW TO USE CARDIOVIS

Posology

Cardiovis must be reconstituted with a sodium pertechnetate (99mTc)
solution before it can be administered. Your doctor will decide what
quantity should be used.

Adults, including patients aged 65 and over:
The suggested dose range for intravenous administration to a patient of average weight
(70 kg) is:
Diagnosis of reduced coronary perfusion and myocardial infarction:
400 – 900 MBq

Depending on the investigation to be performed, the recommended
dosage will range between 200 and 2000 MBq (Mega Bequerel, the
unit used to express radioactivity).
The finished solution for injection will be injected for you in a vein before
the scan is taken. The scanning may take place within 5 to 10 minutes
or up to 6 hours after injection, depending on the investigation.

Assessment of global ventricular function:
600 – 800 MBq injected as a bolus.
For breast imaging:
740 - 925 MBq injected as a bolus in the arm opposite to the lesion
For parathyroid imaging:
200 - 750 MBq injected as a bolus

In the case of a heart investigation, two injections may be necessary,
one at rest and one at stress (e.g. during a physical exercise). The two
injections will be done at least two hours apart and not more than 2000
MBq in total (1 day protocol) will be administered. A two day protocol
is feasible, also.
For breast imaging 740 - 925 MBq are injected as a bolus in the arm
opposite to the lesion.
For parathyroid imaging 200 - 750 MBq are injected as a bolus.

The doses of radioactivity to be administered to paediatric patients should be modified
according to the recommendations of the Paediatric Task Group of the EANM (1990).
The radioactivity dose can be determined from the recommended radioactivity dose for
adults on the basis of body mass, using the following multiplying coefficient:
3 kg = 0.10
4 kg = 0.14
6 kg = 0.19
8 kg = 0.23
10 kg = 0.27
12 kg = 0.32

22 kg = 0.50
24 kg = 0.53
26 kg = 0.56
28 kg = 0.58
30 kg = 0.62
32 kg = 0.65

42 kg
= 0.78
44 kg
= 0.80
46 kg
= 0.82
48 kg
= 0.85
50 kg
= 0.88
52 - 54 kg = 0.90

Cardiac Imaging: If possible, patients should fast for at least four hours prior to the
study. It is recommended that after each injection and prior to imaging patients eat a
light fatty meal or drink one or two glasses of milk. This will promote rapid hepatobiliary
clearance of Technetium (99mTc) Sestamibi resulting in less liver activity in the image.
For the stress test the general contraindications and precautions of ergometric and
pharmacological assessments have to be taken into consideration.
If a hypersensitivity reaction occurs the administration of the medicinal product must
be discontinued immediately and if necessary, intravenous treatment initiated.
Respective medicinal products and equipment (e.g. endotracheal tube and ventilator
have to be readily available).

For diagnosis of myocardial infarction one injection at rest is usually sufficient.

General warnings
This radiopharmaceutical may be received, used and administered only by authorised
persons in designated clinical settings. Its receipt, storage, use, transfer and disposal
are subject to the regulations and/or appropriate licences of the local competent official
organisation.
Radiopharmaceuticals should be prepared by the user in a manner which satisfies both
radiation safety and pharmaceutical quality requirements. Appropriate aseptic
precautions should be taken, complying with the requirements of Good Manufacturing
Practice for pharmaceuticals.
Contents of the vial are intended only for use in the preparation of Technetium (99mTc)
Sestamibi and are not to be administered directly to the patient without first undergoing
the preparative procedure.
Because of potential tissue damage extravasal injection of this radioactive product has
to be strictly avoided.

The dose used should in every case be as low as possible to obtain the required
diagnostic information.

Breast imaging
No lesion of < 5mm has been described with the use of standard detectors.

The injection of activities greater than local DRLs (Diagnostic Reference Levels) should
be justified.

Warnings related to excipients
This medicinal product contains less than 1 mmol sodium (23 mg) per vial, i.e.
essentially ‘sodium-free’.

Method of administration of Cardiovis and scintigraphy examination:
For the diagnosis of ischemic heart disease two injections are required (at stress and
at rest) in order to differentiate between transiently and persistently reduced myocardial
uptake. For the two-day stress/rest protocol 600 - 900 MBq per study injected at rest
and during exercise on two different days, but not more than a total dose of 1800 MBq.
For the one-day protocol 400 - 500 MBq for the first injection and 1200 - 1500 MBq
for the second injection, but not more than a total dose of 2000 MBq. The one-day
protocol may be performed in either order (stress/rest or rest/stress) but the two
injections should be administered at least two hours apart (to allow for physical decay
of Technetium (99mTc) from the first injection) and after the stress exercise the patient
should be encouraged to exercise for an additional one minute (if possible).

Imaging should begin approximately after 60 min after injection to allow for hepatobiliary
clearance. Longer delay can be required for resting images and for stress with
vasodilatators alone because of the risk of higher subdiaphragmatic 99mTc activity.
No evidence exists for significant changes in myocardial tracer concentration or
redistribution. Imaging for up to 6 hours post injection is therefore possible. Test may
be done in a one day or two days protocol.
For diagnosis of ischaemic heart disease and myocardial infarction either planar or
tomographic imaging can be performed. Both may be performed ECG gated.
For planar imaging the standard three view planar projections (anterior, LAO (left anterior
oblique) 45°, LAO 70° or LL (left lateral)) should be used (e.g. 5-10 minutes each).
For tomographic imaging depending on injected dose each projection should be
acquired for approximately 20-40 seconds.
For assessment of global ventricular function the same standard techniques and
projections can be used, as established for Technetium (99mTc) first pass ejection studies;
data should be acquired in list or fast frame mode in a computer using a high count
rate scintillation camera. Gated Blood Pool Imaging protocols may be used for
assessment of regional wall motion, however, they must only be evaluated visually
unless these images are evaluated by specific software.
Breast imaging is optimally initiated 5 to 10 minutes post injection with the patient in
the prone position with breast freely pendant. A 10 minute lateral image of the breast
suspected of containing cancer should be obtained with the camera face as close to
the breast as practical.
The patient should then be repositioned so that the contralateral breast is pendant and
a lateral image of it should be obtained. An anterior supine image may then be obtained
with the patient’s arms behind her head.
Parathyroid imaging depends on whether subtraction technique or wash-out technique
is used. For the subtraction technique either 123I or 99mTc can be used and should be
performed according to literature, guidelines and recommended activities.
If the double phase technique is used, 370 to 740 MBq of Technetium (99mTc) Sestamibi
are injected and the first neck and thorax image obtained 10 minutes later. After a
wash-out period of 1 to 2 hours, neck and thorax imaging is again performed.
The planar images may be complemented by early and delayed SPECT or SPECT/CT.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients.

Paediatric patients:
Newborns, infants, children and adolescents:
The use in children and adolescents has to be considered carefully, based upon
clinical needs and assessing the risk/benefit ratio in this patient group. Safety
and efficacy in children and adolescents below the age of 18 have not been fully
established.

Administration method
Radioactive Technetium (99mTc) Sestamibi preparation is designed for
intravenous use only under a close supervision of specialized
personnel. The safety regulations regarding work in the conditions of
ionising radiation exposure should be strictly complied with during the
preparation and administration of a radiopharmaceutical.

34 kg = 0.68
36 kg = 0.71
38 kg = 0.73
40 kg = 0.76

Patients with hepatic impairment:
Dose selection for patients with a decreased hepatic function should in general be
cautious and usually start at the low end of the dosing range.

Taking other medicines



PACKAGE LEAFLET: INFORMATION FOR THE USER

14 kg = 0.36
16 kg = 0.40
18 kg = 0.44
20 kg = 0.46

4.4 Special warnings and precautions for use
Pregnancy: see section 4.6
Newborns, infants, children and adolescents: see section 4.2
Alternative techniques which do not involve ionising radiation should be especially
considered.
Indication of the examination
For all patients, the radiation exposure must be justifiable by the expected diagnostic
information achieved with the lowest possible radiation dose.
In patients with reduced kidney function, a very careful indication is required since an
increased radiation exposure is possible in these patients.
Patient preparation
The patient should be well hydrated before the start of the examination and urged to
void as often as possible during the first hours after the study in order to reduce
radiation.

4.5 Interaction with other medicinal products and other forms of interaction
No interaction studies have been performed. However, medicinal products which affect
myocardial function and/or blood flow may cause false negative results in the diagnosis
of coronary arterial disease. For this reason, concomitant medication should be taken
into consideration when interpreting the results of the scintigraphic examination.
4.6 Pregnancy and lactation
Women of childbearing potential
When it is necessary to administer radioactive products to women of childbearing
potential, information has to be sought about pregnancy. Any woman who has missed
a period should be assumed to be pregnant until proven otherwise. Where uncertainty
exists it is important that radiation exposure should be the minimum consistent with
obtaining the desired clinical information. Alternative techniques which do not involve
ionising radiation should be considered.
Pregnant women
The anticipated dose to the uterus from a 740 MBq rest injection would be 5.8 mGy.
A radiation dose above 0.5 mGy (approximately equivalent to that exposure from annual
background radiation) could potentially result in risk to the foetus. It is therefore not
recommended in women known to be pregnant. If it is decided that the procedure
should be undertaken in women known to be pregnant, special attention should be
given to the optimisation of the exposure, taking into account the exposure of the
expectant mother and the unborn child. A dose to foetus exceeding 1 mGy should not
be exceeded. Any reduction in administered activity must not impact on the likelihood
of achieving a diagnostic outcome.
Breast-feeding mothers
Before administering a radioactive medicinal product to a mother who is breast-feeding
consideration should be given as to whether the investigation could be reasonably
delayed until after the mother has ceased breast-feeding and as to whether the most
appropriate choice of radiopharmaceutical has been made, bearing in mind the
secretion of activity in breast milk.
If the administration is considered necessary, breast-feeding should be interrupted for
24 hours and the expressed feeds discarded.
Close contact with infants should be restricted during this period.
4.7 Effects on ability to drive and use machines
Effects on the ability to drive and use machines have not been described.
4.8 Undesirable effects
The following table reflects the occurrence of frequencies in this section:
Very common
Common
Uncommon
Rare
Very rare

(≥1/10)
(≥1/100 to <1/10)
(≥1/1,000 to <1/100)
(≥1/10,000 to <1/1,000)
(<1/10,000), not known
(cannot be estimated from the available data)

Cardiac disorders
Uncommon: Chest pain/angina pectoris, abnormal ECG.
Rare: Arrhythmia.
Nervous system disorders:
Uncommon: Headache.
Rare: Seizures (shortly after administration), syncope.
Gastrointestinal disorders:
Uncommon: Nausea.

Rare: Abdominal pain.
Skin and subcutaneous tissue disorders:
Rare: Allergic skin and mucosa reactions with exanthema (pruritus, urticaria, oedema),
vasodilatation, local reactions at the injection site, non-itching rash, hypoaesthesia and
paraesthesia, flushing.
Very rare: Other hypersensitivity reactions have been described in predisposed patients.
Not known (cannot be estimated from the available data): Erythema multiforme.
General disorders and administration site conditions:
Common: Immediately after injection, a metallic or bitter taste may be noticed, partly
in combination with dry mouth and an alteration in the sense of smell.
Rare: Fever, fatigue, dizziness, transient arthritic-like pain, dyspepsia.
Immune system disorders:
Rare: Severe hypersensitivity reactions such as dyspnoea, hypotension, bradycardia,
asthenia and vomiting (usually within two hours of administration), angioedema.
Other disorders:
Exposure to ionising radiation can lead to cancer or development of hereditary defects.
Most examinations involving nuclear medicine involve levels of radiation (effective dose)
less than 20 mSv. These effects can be expected with a low probability. After
administration of the maximum recommended activity of this product of 2000 MBq, the
effective dose is 18 mSv at rest and 15.8 mSv at stress.
4.9 Overdose
In the event of administration of a radiation overdose with Technetium (99mTc) Sestamibi
the absorbed dose to the patient should be reduced where possible by increasing the
elimination of the radionuclide from the body by frequent micturition and defaecation.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group:
diagnostic radiopharmaceuticals;
Technetium (99mTc) compounds
ATC code: V 09G A01
Pharmacodynamic effects are not expected after administration of Technetium (99mTc)
Sestamibi.
After reconstitution with Sodium Pertechnetate (99mTc) Injection, Ph. Eur. solution, the
following complex forms Technetium (99mTc) Sestamibi:
Tc (MIBI)6+

99m

Where : MIBI = 2-methoxyisobutylisonitrile.

Technetium ( Tc) Sestamibi has no pharmacodynamic effects detectable clinically,
when administrated in usual activities and by the usual way.
99m

General
99m
Tc-Sestamibi being a lipophilic cationic complex is taken up into cells driven by
negative electron transmembrane potentials and accumulated in the most negatively
charged compartment of the cell, the mitochondria.
This procedure primarily depends on tissue vascularization and according blood flow
related to the size of target, extracellular concentration of Sestamibi and cellular
metabolic activity, mainly represented by number and activity of mitochondria.
Sestamibi accumulation in principle cannot differentiate between malignant and benign
tissue. However, comparisons with cytological/histological findings indicate that it could
distinguish between lesions of differing mitochondrial metabolism.
Although tumour cells generally are supposed to show elevated intrinsic membrane
potentials and increased mitochondria activity, cellular uptake of Sestamibi is deemed
to be a predominantly tumor-nonspecific procedure.
In case of Multi Drug Resistance (MDR) efflux of Sestamibi was demonstrated to be
increased in correlation to P-Glycoprotein overexpression and activity. This may have
prognostic value but also may result in false negative results if not recognized.
Cardiac indication
Technetium (99mTc) Sestamibi binds to the mitochondrial membrane and an intact
mitochondrial membrane potential is important for intracellular binding.
The uptake of Technetium (99mTc) Sestamibi in the myocardium is proportional to blood
flow in the physiologic flow range. The rate of passive uptake is determined by the
membrane permeability of the drug and the surface area of the vascular beds to which
it is exposed. Since the radiotracer enters the cell via diffusion, it will underestimate
blood flow at high flow rates (>2.0 ml/g/min).
When coronary flow varied from 0.52 to 3.19 ml/g/min, myocardial extraction for
Technetium (99mTc) Sestamibi averaged 0.38 +/- 0.09. Technetium (99mTc) Sestamibi from
the blood is rapidly distributed into the tissue. Five minutes after injection only about 8
percent of the injected dose is still in circulation.
Technetium (99mTc) Sestamibi undergoes minimal redistribution over time. This may
impact on lesion detection as the differential washout between the normal and ischemic
myocardium may result in a reduction in defect size or severity with time.
Mastology indication
The cellular concentration of Technetium (99mTc) Sestamibi was demonstrated to be
increased in mammary tumour tissue probably because of the high content of
mitochondria in tumour cells and the high membrane potential of tumour cells.
Several in vitro studies demonstrated that Technetium (99mTc) Sestamibi is a substrate
of P-glycoprotein. A direct correlation between the P-glycoprotein expression and the
elimination of Technetium (99mTc) Sestamibi from tumours has been established. The

Seite 2

6.4 Special precautions for storage
Store in a refrigerator (2°C - 8ºC).

Furthermore uptake in mammarian tissue seems to be dependent on female
reproduction cycle.

The contents of the vial are not radioactive. However, after labelling with Sodium
Pertechnetate (99mTc) Injection the contents are radioactive and the currently valid
protection and safety regulations must be complied with.

Parathyroid indication
In adenoma of the parathyroid glands blood flow and the number of mitochondria are
increased. This fact may explain the elevated uptake and trapping of Technetium (99mTc)
Sestamibi in parathyroid adenoma.
Localization of Technetium (99mTc) Sestamibi appears to be dependent on blood flow to
the tissue, the concentration of Technetium (99mTc) Sestamibi presented to the tissue,
and the size of the parathyroid adenoma.
5.2 Pharmacokinetic properties
The cationic complex accumulates in the viable myocardial tissue proportional to the
regional coronary blood flow.

For storage conditions of the reconstituted medicinal product, see section 6.3.
6.5 Nature and contents of container
The container is a 10 ml nominal capacity, multi-dose borosilicate glass vial (Type I Ph.
Eur.) sealed with a synthetic chlorobutyl rubber stopper and an aluminium crimp cap.
Vials are packed in cardboard boxes and pack sizes of 3 or 6 vials are available.
Not all pack sizes may be marketed.

Technetium (99mTc) Sestamibi from the blood is rapidly distributed into the tissue: 5
minutes after injection only about 8% of the injected dose is still in circulation.

6.6 Special precautions for disposal and other handling of the product
Before administration dilution of the labelled product with sodium chloride solution (0.9
%, physiological saline) is possible.

Animal experiments have shown that uptake is not dependent on the functional
capability of the sodium-potassium pump.

Any unused product or waste material should be disposed of in accordance with local
requirements.

Elimination
The major metabolic pathway for clearance of Technetium (99mTc) Sestamibi is the
hepatobiliary system. Activity from the gallbladder appears in the intestine within one
hour of injection. About twenty-seven percent of the injected dose is cleared through
renal elimination after 24 hours and approximately thirty-three percent of the injected
dose is cleared through the faeces in 48 hours. At five minutes post injection about 8%
of the injected dose remains in circulation.

The contents of the kit before preparation are not radioactive. However, after Sodium
Pertechnetate (99mTc) Injection is added, adequate shielding of the final preparation must
be maintained.

Half-life
The biological myocardial T½ is approximately seven (7) hours at rest and stress. The
effective T½ (which includes biological and physical half-lives) is approximately three
(3) hours.
Myocardial uptake
Myocardial uptake which is coronary flow dependent is 1.5% of the injected dose at
stress and 1.2% of the injected dose at rest.
Since the radiotracer enters the cell via diffusion it will underestimate blood flow at high
flow rates (>2.0 ml/g/min). When coronary flow varied from 0.52 to 3.10 ml/g/min,
myocardial extraction for 99mTc MIBI averaged 0.38 +/- 0.09.
Myocardial perfusion gated-SPECT may be used to monitor changes (or stability) of left
ventricular function along the time.
5.3 Preclinical safety data
In acute intravenous toxicity studies in mice, rats and dogs, the lowest dose of
Technetium (99mTc) Sestamibi that resulted in any deaths was 7 mg/kg (expressed as
Cu (MIBI)4 BF4 content) in female rats. This corresponds to 500 times the maximal
human dose (MHD) of 0.014 mg/kg for adults (70 kg). LD50 value (calculated by
Litchfield-Wilcoxon method) in mice is 19 mg/kg of body weight, which corresponds
to 1300 times the maximal human dose (MHD). Neither rats nor dogs exhibited
treatment related effects at Technetium (99mTc) Sestamibi doses of 0.42 mg/kg (30 times
MHD) and 0.07 mg/kg (5 times MHD) respectively for 28 days. Studies on reproductive
toxicity have not been conducted. Cu (MIBI)4 BF4 showed no genotoxic activity in the
Ames, CHO/HPRT and sister chromatid exchange tests. At cytotoxic concentrations,
an increase in chromosome aberration was observed in the in vitro human lymphocyte
assay. No genotoxic activity was observed in the in vivo mouse micronucleus test at 9
mg/kg. Studies to assess the carcinogenic potential of Technetium (99mTc) Sestamibi
have not been conducted.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
tin (II) chloride dihydrate
L-cysteine hydrochloride monohydrate
sodium citrate dihydrate
D-mannitol (E421)
6.2 Incompatibilities
The Technetium labelling reactions involved depend on maintaining the stannous level
in the reduced state. Hence, Sodium Pertechnetate (99mTc) Injection, containing oxidants
should not be employed.
6.3 Shelf life
1 year
Chemical and physical in-use stability has been demonstrated for 12 hours below
25°C.
From a microbiological point of view, unless the method of opening / radiolabelling /
dilution precludes the risk of microbiological contamination, the product should be
used immediately.
If not used immediately, in-use storage times and conditions are the responsibility of the
user.

Muscles
Oesophagus
Ovaries
Pancreas
Bone marrow
Salivary glands
Skin
Spleen
Testicles
Thymus
Thyroid
Uterus
Other organs

0.0029
0.0041
0.0091
0.0077
0.0055
0.014
0.0031
0.0065
0.0038
0.0041
0.0053
0.0078
0.0031

0.0037
0.0057
0.012
0.010
0.0071
0.017
0.0041
0.0086
0.0050
0.0057
0.0079
0.010
0.0039

0.0054
0.0086
0.018
0.016
0.011
0.022
0.0064
0.014
0.0075
0.0086
0.012
0.015
0.0060

0.0076
0.013
0.025
0.024
0.030
0.015
0.0098
0.020
0.011
0.013
0.024
0.022
0.0088

0.014
0.023
0.045
0.039
0.044
0.026
0.019
0.034
0.021
0.023
0.045
0.038
0.016

Effective dose
[mSv/MBq]

0.0090

0.012

0.018

0.028

0.053

Dose absorbed per one activity unit administered
to a patient [mGy/MBq]

Adults

15/05/2012

Adrenal glands
Bladder walls
Bone surface
Brain
Breasts
Gall bladder
Alimentary tract:
Stomach
Small intestine
Colon
ULI
LLI
Heart
Kidneys
Liver
Lungs
Muscles
Oesophagus
Ovaries
Pancreas
Bone marrow
Salivary glands
Skin
Spleen
Testicles
Thymus
Thyroid
Uterus
Other organs

11. DOSIMETRY (IF APPLICABLE)

Effective dose
[mSv/MBq]

After reconstitution the container and any unused contents should be disposed of as
radioactive waste in accordance with national and international law regarding
radioactive materials.
7. MARKETING AUTHORISATION HOLDER

National Centre for Nuclear Research
Andrzej Soltan 7
05-400 Otwock, Poland
8. MARKETING AUTHORISATION NUMBER(S)
PL 34397/0001
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
15/01/2009
10. DATE OF REVISION OF THE TEXT

Technetium (99mTc) is produced by means of a 99Mo/99mTc-generator and decays with the
emission of gamma radiation with a mean energy of 140 keV and a half-life of 6.02
hours to technetium (99Tc) which, in view of its long half-life of 2.13 x 105 years can be
regarded as quasi stable.
The projected radiation doses to organs and tissues of a patient of average weight (70
kg) after intravenous injection of Technetium (99mTc) Sestamibi are given below:
The data are from ICRP 80 and are calculated according to the following assumptions:
After intravenous injection the substance is rapidly cleared from the blood and
accumulates mainly in muscular tissues (including heart), liver, kidneys and a smaller
amount in salivary glands and thyroid. When the substance is injected in conjunction
with a stress test, there is a considerable increase of the uptake in organs and tissues.
The substance is excreted by the liver and the kidneys in proportions 75% and 25%,
respectively.
Dose absorbed per one activity unit administered
to a patient [mGy/MBq]
(resting test)
Organ

Adults

15-year-olds

10-year-olds

5-year-olds

1-year-olds

Adrenal glands
Bladder walls
Bone surface
Brain
Breasts
Gall bladder
Alimentary tract:
Stomach
Small intestine
Colon
ULI
LLI
Heart
Kidneys
Liver
Lungs

0.0075
0.011
0.0082
0.0052
0.0038
0.039

0.0099
0.014
0.010
0.0071
0.0053
0.045

0.015
0.019
0.016
0.011
0.0071
0.058

0.022
0.023
0.021
0.016
0.011
0.010

0.038
0.041
0.038
0.027
0.020
0.32

0.0065
0.015
0.024
0.027
0.019
0.0063
0.036
0.011
0.0046

0.0090
0.018
0.031
0.035
0.025
0.0082
0.043
0.014
0.0064

0.015
0.029
0.050
0.057
0.041
0.012
0.059
0.021
0.0097

0.021
0.045
0.079
0.089
0.065
0.018
0.085
0.030
0.014

0.035
0.080
0.015
0.17
0.12
0.030
0.15
0.052
0.025

If more Cardiovis is used than should
In the unlikely event of an overdose, your doctor may recommend that
you drink plenty of fluids to remove the traces of radioactivity from your
body.
If you have any further questions on the use of this product, ask your
doctor or pharmacist.

15-year-olds

10-year-olds

5-year-olds

1-year-olds

0.0066
0.0098
0.0078
0.0044
0.0034
0.033

0.0087
0.013
0.0097
0.0060
0.0047
0.038

0.013
0.017
0.014
0.0093
0.0062
0.049

0.019
0.021
0.020
0.014
0.0097
0.086

0.033
0.038
0.036
0.023
0.018
0.26

0.0059
0.012
0.019
0.022
0.016
0.0072
0.026
0.0092
0.0044
0.0032
0.0040
0.0081
0.0069
0.0050
0.0092
0.0029
0.0058
0.0037
0.0040
0.0044
0.0072
0.0033

0.0081
0.015
0.025
0.028
0.021
0.0094
0.032
0.012
0.0060
0.0041
0.0055
0.011
0.0091
0.0064
0.011
0.0037
0.0076
0.0048
0.0055
0.0064
0.0093
0.0043

0.013
0.024
0.041
0.046
0.034
0.010
0.044
0.018
0.0087
0.0060
0.0080
0.015
0.014
0.0095
0.0015
0.0058
0.012
0.0071
0.0080
0.0099
0.014
0.0064

0.019
0.037
0.064
0.072
0.053
0.021
0.063
0.025
0.013
0.0090
0.012
0.023
0.021
0.013
0.0020
0.0090
0.017
0.011
0.012
0.019
0.020
0.0098

0.032
0.066
0.12
0.13
0.099
0.035
0.11
0.044
0.023
0.017
0.023
0.040
0.035
0.023
0.0029
0.017
0.030
0.020
0.023
0.035
0.035
0.018

0.0079

0.010

0.016

0.023

0.045

The effective dose per unit of administered activity has been calculated according to a
voiding frequency of 3.5 hours in adults.

After completion of the radiolabelling procedure control the contents of the vial to be
clear and free from particulate matter and discolouration.
Instructions for Preparation of Technetium ( Tc) Sestamibi
99m

A) Boiling procedure
- Place a vial with lyophilisate in a lead protective container

Like all medicines, Cardiovis can cause side effects, although not
everybody gets them.

The active substance is: Tetrakis (2-methoxy-isobutyl isonitrile) Copper(I)-Tetrafluoroborate. One vial contains 1.0 mg Tetrakis (2-methoxyisobutyl isonitrile) Copper(I)-Tetrafluoroborate.

Rare side effects (observed in 1 to10 patients in 10,000) are
hypersensitivity reactions, abnormal heart rhythm, oedema, local
reactions at the injection site, stomach pain, vomiting, itching, hives,
fever, fainting, seizures, dizziness, flushing, rash, skin numbness or
tingling, fatigue, shortness of breath (dyspnoea), hypotension, and joint
pains.
Very rare side effects (observed in less than 1 patient in 10,000) have
not been reported.

Methods for quality control of Technetium (99mTc) Sestamibi:

One single case has been discovered in literature describing the
occurrence of Erythema multiforme, a widespread rash of skin and
mucosa.

In addition to the recommended method described below the method from the Ph. Eur.
monograph No. 1926 [99mTc] Technetium Sestamibi Solution for Injection can also be
used.
- Apply 2 - 5 µl of Technetium (99mTc) Sestamibi about 1.5 cm from the bottom of a
2 cm x 8 cm aluminium oxide chromatographic plate.
- Put the plate in a chromatographic chamber and develop the chromatograms in an
absolute ethanol until the solvent front moves about 6 cm from the origin.
- Remove the plate and allow it to air-dry.
- Determine the radioactivity distribution by scanning the chromatogram with a suitable
radiation detector or cut the plate as shown below (three pieces) and measure the
99m
Tc activity in each piece with an appropriate radiation detector.
- Under these conditions:
Radiocolloid remains at the origin (Rf = 0.0 - 0.1)
Free pertechnetate 99mTcO4- , migrates with the solvent (Rf = 0.4 - 0.7).
The labelled complex, Technetium (99mTc) Sestamibi, migrates with the solvent.

In case of every patient the exposure to radiation should be
substantiated by benefits resulting from the performed test.
Radioactivity which is administered should be adjusted so as the dose
of radiation received by a patient is the lowest possible while achieving
desired diagnostic effect at the same time.
The exposure to ionising radiation is connected with the risk of
development of cancer and genetic effects. According to up-to-date
statistics of diagnostic tests radiation doses connected with the tests
are very low and therefore the frequency of undesirable effects is low.

The vial is reconstituted with a maximum of 11 GBq of sterile, oxidant-free solution of
Sodium Pertechnetate (99mTc) injection in 1 - 5 ml. The radiochemical purity of the
solution from the reconstituted vial must be checked prior to patient administration
with the recommended method as described below.
The radiolabelling procedure must be performed aseptically by qualified and
experienced personnel.

During preparation of the radiolabelled product the hands of the operator should be
protected with watertight gloves. Remove the plastic cap from the vial and disinfect the
surface of the rubber stopper with alcohol.

What Cardiovis contains

Uncommon side effects (observed in 1 to10 patients in 1,000) are
headache, chest pain, abnormal ECG and feeling sick.

12. INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS (IF
APPLICABLE)

Prior to adding Sodium Pertechnetate (99mTc) to the vial a label with date, time, strength
of the radioactivity to be added and showing a radioactivity symbol should be attached
to the neck of the vial.

After reconstitution the container and any unused contents should be
disposed of in accordance with local requirements for radioactive
materials.

4. POSSIBLE SIDE EFFECTS

A common side effect (observed in 1 to10 patients in 100) is a metallic
or bitter taste, alteration of smell, and dry mouth immediately after
injection.

- Place a vial with lyophilisate in a lead protective container
- With a syringe (piercing the rubber stopper) introduce 1 - 5 ml of eluate with sodium
pertechnetate (99mTc) with an activity of maximum 11000 MBq (or the eluate volume
with desired activity supplemented with physiological saline solution) into a vial
containing lyophilised Tetrakis (2-methoxy-isobutyl isonitrile) Copper(I)Tetrafluoroborate.
- Without withdrawing a needle, remove the volume of gas equal to the volume of
introduced solution with the same syringe in order to compensate for pressure buildup.
- Shake the vial until the contents are fully dissolved (about 1 minute).
- Take the vial out of the lead container, place it in the block (with a tight fit) of a thermocycler intended for radiolabelling and run the cycler on auto-program.
- Alternatively, place the vial in a tight fitting brass or copper pig (wall thickness ≥ 3mm
for radioprotection) and place the brass pig on a pre-heated programmable flat plate
thermal cycler. Program the thermal cycler for a pre-heat cycle to 99°C during 5
minutes, followed by a heating cycle of the vial at 99°C during 12 minutes and finally
followed by a cooling cycle to 25 - 30°C until constant temperature (approx. 10 min).
Duration of times mentioned may differ according to the heating/cooling capacity of
the heater used.
- The resulting solution is a ready-to-use solution for injections.

The effective dose resulting from the administration of a (maximal recommended)
activity of 2000 MBq Technetium (99mTc) Sestamibi for an adult weighing 70 kg is about
18 mSv at rest and 15.8 mSv at stress.

As with any pharmaceutical product, if at any time in the preparation of this product the
integrity of this vial is compromised it should not be used. Therefore, prior to the
radiolabelling procedure carefully inspect the vial for the presence of damage, in
particular cracks. Do not use a damaged vial as it may break during heating.

The contents of the vial are not radioactive. However, after labelling
with Sodium Pertechnetate (99mTc) Injection the contents are radioactive
and the currently valid protection and safety regulations must be
complied with.

6. FURTHER INFORMATION

B) Thermal Cycler procedure

(exercise test)
Organ

Safety and efficacy in children and adolescents below the age of 18
have not been fully established.

- With a sterile, lead-shielded syringe (piercing the rubber stopper) introduce
1 - 5 ml eluate [Sodium Pertechnetate (99mTc) Injection Ph. Eur. with an activity of
maximum 11000 MBq (or the eluate volume with the desired radioactivity adjusted
with physiological saline solution) into a vial containing lyophilised Tetrakis (2-methoxyisobutyl isonitrile) Copper(I)-Tetrafluoroborate.
- Without withdrawing the needle, remove a volume of gas equal to the volume of
introduced solution with the same syringe in order to compensate for pressure buildup.
- Shake the vial until the contents are fully dissolved (about 1 minute).
- Take the vial out of the lead container, place in a hot boiling water bath (the water
should be boiling during the procedure of labelling) and boil for 10 - 12 minutes. While
boiling do not allow contact between boiling water and the aluminium cap. Keeping
the vial upright in the water bath can be achieved by placing the vial in a standard lead
shielding for the vial, which has been mounted in the water bath by means of an
Erlenmeyer or four finger clamp attached to a laboratory stand. For better heath
conduction a few ml of water may be added to the lead shielding.
- Take the vial out of the boiling water bath, put into a lead container and leave to cool
down to room temperature (about 15 minutes).
- The resulting solution is a ready-to-use solution for injections.

- % 99mTc Sestamibi should be 94%; otherwise the preparation should be discarded.
Note: Do not use material if the radiochemical purity is less than 94%.

Kit for radiopharmaceutical preparation.
White, lyophilised powder.
The kit is delivered in 10 ml glass vials. The vial is covered with a
chlorobutyl rubber stopper and aluminium cap. Vials are packed in
cardboard boxes. The kits are offered in boxes containing 3 or 6 vials.
Each vial contains a lyophilisate for preparation of the solution for
injections.
Not all pack sizes may be marketed.
Marketing Authorisation Holder
National Centre for Nuclear Research
Andrzej Soltan 7
05-400 Otwock, Poland

Tel. +48 22 718 07 00
Fax: +48 22 718 03 50
e-mail: polatom@polatom.pl
Manufacturers
National Centre for Nuclear Research
Andrzej Soltan 7
05-400 Otwock, Poland

5. HOW TO STORE CARDIOVIS

ROTOP Pharmaka GmbH
Bautzner Landstraße 400
D-01328 Dresden
Germany

Do not use Cardiovis after the expiry date which is stated on the label
and carton after EXP.

This leaflet was last approved in: March 2015.

Store in a refrigerator (2°C - 8ºC).

The SmPC is attached to this PL as a tear-off section.

Chemical and physical in-use stability has been demonstrated for 12
hours below 25°C.
From a microbiological point of view, unless the method of opening /
radiolabelling / dilution precludes the risk of microbiological contamination, the product should be used immediately.
If not used immediately, in-use storage times and conditions are the
responsibility of the user.

Activity in Upper Part
% RCR = ----------------------------- x 100
Activity Sum of all Parts

What Cardiovis looks like and contents of the pack

If any of the side effects gets serious, or if you notice any side effects
not listed in this leaflet, please tell your doctor or pharmacist.

Keep out of the reach and sight of children.

- Calculate the % Radiochemical purity as:
% 99mTc Sestamibi = activity of the upper part (Rf = 0.8 - 1.0) divided by the sum of
the activity in all parts and multiplied by 100:

The other ingredients are:
tin (II) chloride dihydrate
L-cysteine hydrochloride monohydrate
sodium citrate dihydrate
D-mannitol (E421)

The vial should not be used if its integrity is compromised at any time
in the preparation of this product. The vial should also not be used
when the contents has changed colour (it should contain a white
powder) or when it is contaminated with adhering dirt particles. The
unused vial can be disposed of as ordinary waste.

19530

cellular over-expression of P-glycoprotein could result in false negative images of
tumours, especially of tumours larger than 1 cm.

PL-Mibi-UK-eng-04

16:53 Uhr



29.09.2010

SmPC-Mibi-UK-eng-04

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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