Cardiovis 1 mg · 2017-10-05 ·...

ROTOP Pharmaka AG Bautzner Landstraße 400

D-01328 Dresden

phone: +49 (0) 35 1 - 26 31 0 - 210 fax: +49 (0) 35 1 - 26 31 0 - 313

[email protected] www.rotop-pharmaka.de

myocardial perfusion scintigraphy

assessment of global ventricular function

Localisation of hyperfunctioning parathyroid tissue

Scintimammography for the detection of breast cancer

10 mL vials

Labelling activity up to 11 GBq

Labelling volume 1 - 5 ml

Shelf life after labelling: 12 hours

Indicated for

Advantages

comfortable labelling - flexible patient management

Cardiovis 1 mg

PACKAGE LEAFLET: INFORMATION FOR THE USER

Cardiovis 1 mgkit for radiopharmaceutical preparation

Tetrakis (2-methoxy-isobutyl isonitrile) Copper(I)-Tetrafluoroborate

In this leaflet:

1. What Cardiovis is and what it is used for2. Before you use Cardiovis3. How to use Cardiovis4. Possible side effects5. How to store Cardiovis6. Further information

1. WHAT CARDIOVIS IS AND WHAT IT IS USED FOR

Cardiovis is a radiopharmaceutical used for diagnostic purposes tostudy the heart’s function and blood flow (myocardial perfusion) by mak-ing an image of the heart (scintigraphy), for example in the detection ofheart attacks (myocardial infarctions) or when a disease causesreduced 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 muchblood it pumps per beat (total ventricular function, i.e. the function ofthe heart chambers; or by using the first pass method to determinethe stroke volume and/or local wall motion).

- an examination in the detection of breast cancer when mammographyis equivocal

- an examination to localize parathyroid tissue with over-production ofparathyroid hormone (hyperparathyroidism), and in patients withdiseased 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 otherpersons from external radiation or contamination from spill of urine,vomiting etc. Radiation protection precautions in accordance withnational regulations must therefore be taken.

Radiopharmaceuticals may be administered only by appropriately au-thorised staff. Special caution should be exercised while handling, andstaff and patients should not be exposed to unnecessary risk. Theconsent to possess and use radiopharmaceuticals depends on currentnational standards and regulations.

The Cardiovis kit vial content is indicated for the preparation ofTechnetium (99mTc) Sestamibi radiopharmaceutical and may beadministered to a patient only after the procedure of adding theradioactive isotope. To minimise the dose of radiation absorbed by thebladder, it is recommended that you should drink plenty of water after

the injection in order to help frequent voiding.

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

Taking other medicines

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

Using Cardiovis with food and drink

You should not eat or drink for at least four hours before the start of theinvestigation. Your doctor may ask you to eat a light fatty meal or todrink a glass or two of milk after each injection and before imagingstarts.

Pregnancy and breast-feeding

Pregnancy: If it is necessary to administer radiopharmaceuticals towomen of childbearing potential, pregnancy has to be excluded. If awoman skipped one menstrual cycle, she should be recognised aspregnant until the pregnancy has been confirmed or excluded.

Ask your doctor for advice before taking any medicine. It is importantto tell your doctor whether there is a chance you may be pregnant. Theuse of radiopharmaceuticals during pregnancy should be consideredcarefully. Your doctor will only administer this product during pregnancyif a benefit is expected which would outweigh the risks.

Breastfeeding: If you are breastfeeding, please tell your doctor, ashe/she may advise you to stop doing so until the radioactivity has leftyour body. This takes about 24 hours. The expressed milk should bediscarded.

Driving and using machines

The radiopharmaceutical has no effect on ability to drive and usemachines.

Important information about some of the ingredients of Cardiovis

This medicinal product contains less than 1 mmol sodium (23 mg) pervial, i.e. essentially ‘sodium-free’.

3. HOW TO USE CARDIOVIS

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

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

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 twoinjections will be done at least two hours apart and not more than 2000MBq in total (1 day protocol) will be administered. A two day protocolis feasible, also.For breast imaging 740 - 925 MBq are injected as a bolus in the armopposite to the lesion.For parathyroid imaging 200 - 750 MBq are injected as a bolus.

Administration method

Radioactive Technetium (99mTc) Sestamibi preparation is designed forintravenous use only under a close supervision of specializedpersonnel. The safety regulations regarding work in the conditions ofionising radiation exposure should be strictly complied with during thepreparation and administration of a radiopharmaceutical.

Read all of this leaflet carefully before this medicine isadministered.- 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 sideeffects not listed in this leaflet, please tell your doctor.

1. NAME OF THE MEDICINAL PRODUCT


2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains 1 mgTetrakis (2-methoxy-isobutyl isonitrile) Copper(I)-Tetrafluoroborate

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

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

3. PHARMACEUTICAL FORM

Kit for radiopharmaceutical preparationThe product is a white, lyophilised powder

4. CLINICAL PARTICULARS

4.1 Therapeutic indicationsThis medicinal product is for diagnostic use only.After reconstitution with Sodium pertechnetate (99mTc) solution for injection, the solutionof Technetium (99mTc) Sestamibi obtained is indicated:- for myocardial perfusion scintigraphy for the detection and localisation of coronaryartery disease and myocardial infarction

- for the assessment of global ventricular function (gated SPECT for evaluation of leftventricular ejection fraction, volumes and regional wall motion).

- Scintimammography for the detection of breast cancerDetection of breast cancer when mammography is equivocal, inadequate orindeterminate.

- Localisation of hyperfunctioning parathyroid tissue in patients with recurrent orpersistent hyperparathyroidism, and in patients scheduled to undergo surgery of theparathyroid glands.

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

Posology

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

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

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

The doses of radioactivity to be administered to paediatric patients should be modifiedaccording to the recommendations of the Paediatric Task Group of the EANM (1990).The radioactivity dose can be determined from the recommended radioactivity dose foradults on the basis of body mass, using the following multiplying coefficient:

3 kg = 0.10 22 kg = 0.50 42 kg = 0.784 kg = 0.14 24 kg = 0.53 44 kg = 0.806 kg = 0.19 26 kg = 0.56 46 kg = 0.828 kg = 0.23 28 kg = 0.58 48 kg = 0.85

10 kg = 0.27 30 kg = 0.62 50 kg = 0.8812 kg = 0.32 32 kg = 0.65 52 - 54 kg = 0.90

14 kg = 0.36 34 kg = 0.68 56 - 58 kg = 0.9216 kg = 0.40 36 kg = 0.71 60 - 62 kg = 0.9618 kg = 0.44 38 kg = 0.73 64 - 66 kg = 0.9820 kg = 0.46 40 kg = 0.76 68 kg = 0.99

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

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

Method of administration of Cardiovis and scintigraphy examination:For the diagnosis of ischemic heart disease two injections are required (at stress andat rest) in order to differentiate between transiently and persistently reduced myocardialuptake. For the two-day stress/rest protocol 600 - 900 MBq per study injected at restand 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 MBqfor the second injection, but not more than a total dose of 2000 MBq. The one-dayprotocol may be performed in either order (stress/rest or rest/stress) but the twoinjections should be administered at least two hours apart (to allow for physical decayof Technetium (99mTc) from the first injection) and after the stress exercise the patientshould be encouraged to exercise for an additional one minute (if possible).

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

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

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

Imaging should begin approximately after 60 min after injection to allow for hepatobiliaryclearance. Longer delay can be required for resting images and for stress withvasodilatators alone because of the risk of higher subdiaphragmatic 99mTc activity.No evidence exists for significant changes in myocardial tracer concentration orredistribution. Imaging for up to 6 hours post injection is therefore possible. Test maybe done in a one day or two days protocol.

For diagnosis of ischaemic heart disease and myocardial infarction either planar ortomographic imaging can be performed. Both may be performed ECG gated.

For planar imaging the standard three view planar projections (anterior, LAO (left anterioroblique) 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 beacquired for approximately 20-40 seconds.

For assessment of global ventricular function the same standard techniques andprojections 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 countrate scintillation camera. Gated Blood Pool Imaging protocols may be used forassessment of regional wall motion, however, they must only be evaluated visuallyunless these images are evaluated by specific software.

Breast imaging is optimally initiated 5 to 10 minutes post injection with the patient inthe prone position with breast freely pendant. A 10 minute lateral image of the breastsuspected of containing cancer should be obtained with the camera face as close tothe breast as practical.

The patient should then be repositioned so that the contralateral breast is pendant anda lateral image of it should be obtained. An anterior supine image may then be obtainedwith the patient’s arms behind her head.

Parathyroid imaging depends on whether subtraction technique or wash-out techniqueis used. For the subtraction technique either 123I or 99mTc can be used and should beperformed according to literature, guidelines and recommended activities.

If the double phase technique is used, 370 to 740 MBq of Technetium (99mTc) Sestamibiare injected and the first neck and thorax image obtained 10 minutes later. After awash-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 ContraindicationsHypersensitivity to the active substance or to any of the excipients.

4.4 Special warnings and precautions for usePregnancy: see section 4.6Newborns, infants, children and adolescents: see section 4.2Alternative techniques which do not involve ionising radiation should be especiallyconsidered.

Indication of the examinationFor all patients, the radiation exposure must be justifiable by the expected diagnosticinformation achieved with the lowest possible radiation dose.

In patients with reduced kidney function, a very careful indication is required since anincreased radiation exposure is possible in these patients.

Patient preparationThe patient should be well hydrated before the start of the examination and urged tovoid as often as possible during the first hours after the study in order to reduceradiation.

Cardiac Imaging: If possible, patients should fast for at least four hours prior to thestudy. It is recommended that after each injection and prior to imaging patients eat alight fatty meal or drink one or two glasses of milk. This will promote rapid hepatobiliaryclearance of Technetium (99mTc) Sestamibi resulting in less liver activity in the image.

For the stress test the general contraindications and precautions of ergometric andpharmacological assessments have to be taken into consideration.

If a hypersensitivity reaction occurs the administration of the medicinal product mustbe discontinued immediately and if necessary, intravenous treatment initiated.Respective medicinal products and equipment (e.g. endotracheal tube and ventilatorhave to be readily available).

General warningsThis radiopharmaceutical may be received, used and administered only by authorisedpersons in designated clinical settings. Its receipt, storage, use, transfer and disposalare subject to the regulations and/or appropriate licences of the local competent officialorganisation.Radiopharmaceuticals should be prepared by the user in a manner which satisfies bothradiation safety and pharmaceutical quality requirements. Appropriate asepticprecautions should be taken, complying with the requirements of Good ManufacturingPractice 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 undergoingthe preparative procedure.Because of potential tissue damage extravasal injection of this radioactive product hasto be strictly avoided.

Breast imagingNo lesion of < 5mm has been described with the use of standard detectors.

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

4.5 Interaction with other medicinal products and other forms of interactionNo interaction studies have been performed. However, medicinal products which affectmyocardial function and/or blood flow may cause false negative results in the diagnosisof coronary arterial disease. For this reason, concomitant medication should be takeninto consideration when interpreting the results of the scintigraphic examination.

4.6 Pregnancy and lactationWomen of childbearing potentialWhen it is necessary to administer radioactive products to women of childbearingpotential, information has to be sought about pregnancy. Any woman who has misseda period should be assumed to be pregnant until proven otherwise. Where uncertaintyexists it is important that radiation exposure should be the minimum consistent withobtaining the desired clinical information. Alternative techniques which do not involveionising radiation should be considered.

Pregnant womenThe 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 annualbackground radiation) could potentially result in risk to the foetus. It is therefore notrecommended in women known to be pregnant. If it is decided that the procedureshould be undertaken in women known to be pregnant, special attention should begiven to the optimisation of the exposure, taking into account the exposure of theexpectant mother and the unborn child. A dose to foetus exceeding 1 mGy should notbe exceeded. Any reduction in administered activity must not impact on the likelihoodof achieving a diagnostic outcome.

Breast-feeding mothersBefore administering a radioactive medicinal product to a mother who is breast-feedingconsideration should be given as to whether the investigation could be reasonablydelayed until after the mother has ceased breast-feeding and as to whether the mostappropriate choice of radiopharmaceutical has been made, bearing in mind thesecretion of activity in breast milk.If the administration is considered necessary, breast-feeding should be interrupted for24 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 machinesEffects on the ability to drive and use machines have not been described.

4.8 Undesirable effectsThe following table reflects the occurrence of frequencies in this section:

Very common (≥1/10)Common (≥1/100 to <1/10)Uncommon (≥1/1,000 to <1/100)Rare (≥1/10,000 to <1/1,000)Very rare (<1/10,000), not known

(cannot be estimated from the available data)

Cardiac disordersUncommon: 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 andparaesthesia, 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, partlyin 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. Afteradministration of the maximum recommended activity of this product of 2000 MBq, theeffective dose is 18 mSv at rest and 15.8 mSv at stress.

4.9 OverdoseIn the event of administration of a radiation overdose with Technetium (99mTc) Sestamibithe absorbed dose to the patient should be reduced where possible by increasing theelimination of the radionuclide from the body by frequent micturition and defaecation.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic propertiesPharmacotherapeutic group: diagnostic radiopharmaceuticals;

Technetium (99mTc) compoundsATC 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, thefollowing complex forms Technetium (99mTc) Sestamibi:

99mTc (MIBI)6+ Where : MIBI = 2-methoxyisobutylisonitrile.

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

General99mTc-Sestamibi being a lipophilic cationic complex is taken up into cells driven bynegative electron transmembrane potentials and accumulated in the most negativelycharged compartment of the cell, the mitochondria.

This procedure primarily depends on tissue vascularization and according blood flowrelated to the size of target, extracellular concentration of Sestamibi and cellularmetabolic activity, mainly represented by number and activity of mitochondria.

Sestamibi accumulation in principle cannot differentiate between malignant and benigntissue. However, comparisons with cytological/histological findings indicate that it coulddistinguish between lesions of differing mitochondrial metabolism.

Although tumour cells generally are supposed to show elevated intrinsic membranepotentials and increased mitochondria activity, cellular uptake of Sestamibi is deemedto be a predominantly tumor-nonspecific procedure.

In case of Multi Drug Resistance (MDR) efflux of Sestamibi was demonstrated to beincreased in correlation to P-Glycoprotein overexpression and activity. This may haveprognostic value but also may result in false negative results if not recognized.

Cardiac indicationTechnetium (99mTc) Sestamibi binds to the mitochondrial membrane and an intactmitochondrial membrane potential is important for intracellular binding.

The uptake of Technetium (99mTc) Sestamibi in the myocardium is proportional to bloodflow in the physiologic flow range. The rate of passive uptake is determined by themembrane permeability of the drug and the surface area of the vascular beds to whichit is exposed. Since the radiotracer enters the cell via diffusion, it will underestimateblood 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 forTechnetium (99mTc) Sestamibi averaged 0.38 +/- 0.09. Technetium (99mTc) Sestamibi fromthe blood is rapidly distributed into the tissue. Five minutes after injection only about 8percent of the injected dose is still in circulation.

Technetium (99mTc) Sestamibi undergoes minimal redistribution over time. This mayimpact on lesion detection as the differential washout between the normal and ischemicmyocardium may result in a reduction in defect size or severity with time.

Mastology indicationThe cellular concentration of Technetium (99mTc) Sestamibi was demonstrated to beincreased in mammary tumour tissue probably because of the high content ofmitochondria in tumour cells and the high membrane potential of tumour cells.

Several in vitro studies demonstrated that Technetium (99mTc) Sestamibi is a substrateof P-glycoprotein. A direct correlation between the P-glycoprotein expression and theelimination of Technetium (99mTc) Sestamibi from tumours has been established. The

SUMMARY OF PRODUCT CHARACTERISTICS

PL+SmPC-Mibi-UK-eng-02:Layout 1 29.09.2010 16:53 Uhr Seite 1

PACKAGE LEAFLET: INFORMATION FOR THE USER


Tetrakis (2-methoxy-isobutyl isonitrile) Copper(I)-Tetrafluoroborate

In this leaflet:

1. What Cardiovis is and what it is used for2. Before you use Cardiovis3. How to use Cardiovis4. Possible side effects5. How to store Cardiovis6. Further information

1. WHAT CARDIOVIS IS AND WHAT IT IS USED FOR

Cardiovis is a radiopharmaceutical used for diagnostic purposes tostudy the heart’s function and blood flow (myocardial perfusion) by mak-ing an image of the heart (scintigraphy), for example in the detection ofheart attacks (myocardial infarctions) or when a disease causesreduced 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 muchblood it pumps per beat (total ventricular function, i.e. the function ofthe heart chambers; or by using the first pass method to determinethe stroke volume and/or local wall motion).

- an examination in the detection of breast cancer when mammographyis equivocal

- an examination to localize parathyroid tissue with over-production ofparathyroid hormone (hyperparathyroidism), and in patients withdiseased 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 otherpersons from external radiation or contamination from spill of urine,vomiting etc. Radiation protection precautions in accordance withnational regulations must therefore be taken.

Radiopharmaceuticals may be administered only by appropriately au-thorised staff. Special caution should be exercised while handling, andstaff and patients should not be exposed to unnecessary risk. Theconsent to possess and use radiopharmaceuticals depends on currentnational standards and regulations.

The Cardiovis kit vial content is indicated for the preparation ofTechnetium (99mTc) Sestamibi radiopharmaceutical and may beadministered to a patient only after the procedure of adding theradioactive isotope. To minimise the dose of radiation absorbed by thebladder, it is recommended that you should drink plenty of water after

the injection in order to help frequent voiding.

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

Taking other medicines

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

Using Cardiovis with food and drink

You should not eat or drink for at least four hours before the start of theinvestigation. Your doctor may ask you to eat a light fatty meal or todrink a glass or two of milk after each injection and before imagingstarts.

Pregnancy and breast-feeding

Pregnancy: If it is necessary to administer radiopharmaceuticals towomen of childbearing potential, pregnancy has to be excluded. If awoman skipped one menstrual cycle, she should be recognised aspregnant until the pregnancy has been confirmed or excluded.

Ask your doctor for advice before taking any medicine. It is importantto tell your doctor whether there is a chance you may be pregnant. Theuse of radiopharmaceuticals during pregnancy should be consideredcarefully. Your doctor will only administer this product during pregnancyif a benefit is expected which would outweigh the risks.

Breastfeeding: If you are breastfeeding, please tell your doctor, ashe/she may advise you to stop doing so until the radioactivity has leftyour body. This takes about 24 hours. The expressed milk should bediscarded.

Driving and using machines

The radiopharmaceutical has no effect on ability to drive and usemachines.

Important information about some of the ingredients of Cardiovis

This medicinal product contains less than 1 mmol sodium (23 mg) pervial, i.e. essentially ‘sodium-free’.

3. HOW TO USE CARDIOVIS

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

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

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 twoinjections will be done at least two hours apart and not more than 2000MBq in total (1 day protocol) will be administered. A two day protocolis feasible, also.For breast imaging 740 - 925 MBq are injected as a bolus in the armopposite to the lesion.For parathyroid imaging 200 - 750 MBq are injected as a bolus.

Administration method

Radioactive Technetium (99mTc) Sestamibi preparation is designed forintravenous use only under a close supervision of specializedpersonnel. The safety regulations regarding work in the conditions ofionising radiation exposure should be strictly complied with during thepreparation and administration of a radiopharmaceutical.

Read all of this leaflet carefully before this medicine isadministered.- 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 sideeffects not listed in this leaflet, please tell your doctor.

1. NAME OF THE MEDICINAL PRODUCT


2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains 1 mgTetrakis (2-methoxy-isobutyl isonitrile) Copper(I)-Tetrafluoroborate

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

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

3. PHARMACEUTICAL FORM

Kit for radiopharmaceutical preparationThe product is a white, lyophilised powder

4. CLINICAL PARTICULARS

4.1 Therapeutic indicationsThis medicinal product is for diagnostic use only.After reconstitution with Sodium pertechnetate (99mTc) solution for injection, the solutionof Technetium (99mTc) Sestamibi obtained is indicated:- for myocardial perfusion scintigraphy for the detection and localisation of coronaryartery disease and myocardial infarction

- for the assessment of global ventricular function (gated SPECT for evaluation of leftventricular ejection fraction, volumes and regional wall motion).

- Scintimammography for the detection of breast cancerDetection of breast cancer when mammography is equivocal, inadequate orindeterminate.

- Localisation of hyperfunctioning parathyroid tissue in patients with recurrent orpersistent hyperparathyroidism, and in patients scheduled to undergo surgery of theparathyroid glands.

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

Posology

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

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

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

The doses of radioactivity to be administered to paediatric patients should be modifiedaccording to the recommendations of the Paediatric Task Group of the EANM (1990).The radioactivity dose can be determined from the recommended radioactivity dose foradults on the basis of body mass, using the following multiplying coefficient:

3 kg = 0.10 22 kg = 0.50 42 kg = 0.784 kg = 0.14 24 kg = 0.53 44 kg = 0.806 kg = 0.19 26 kg = 0.56 46 kg = 0.828 kg = 0.23 28 kg = 0.58 48 kg = 0.85

10 kg = 0.27 30 kg = 0.62 50 kg = 0.8812 kg = 0.32 32 kg = 0.65 52 - 54 kg = 0.90

14 kg = 0.36 34 kg = 0.68 56 - 58 kg = 0.9216 kg = 0.40 36 kg = 0.71 60 - 62 kg = 0.9618 kg = 0.44 38 kg = 0.73 64 - 66 kg = 0.9820 kg = 0.46 40 kg = 0.76 68 kg = 0.99

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

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

Method of administration of Cardiovis and scintigraphy examination:For the diagnosis of ischemic heart disease two injections are required (at stress andat rest) in order to differentiate between transiently and persistently reduced myocardialuptake. For the two-day stress/rest protocol 600 - 900 MBq per study injected at restand 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 MBqfor the second injection, but not more than a total dose of 2000 MBq. The one-dayprotocol may be performed in either order (stress/rest or rest/stress) but the twoinjections should be administered at least two hours apart (to allow for physical decayof Technetium (99mTc) from the first injection) and after the stress exercise the patientshould be encouraged to exercise for an additional one minute (if possible).

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

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

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

Imaging should begin approximately after 60 min after injection to allow for hepatobiliaryclearance. Longer delay can be required for resting images and for stress withvasodilatators alone because of the risk of higher subdiaphragmatic 99mTc activity.No evidence exists for significant changes in myocardial tracer concentration orredistribution. Imaging for up to 6 hours post injection is therefore possible. Test maybe done in a one day or two days protocol.

For diagnosis of ischaemic heart disease and myocardial infarction either planar ortomographic imaging can be performed. Both may be performed ECG gated.

For planar imaging the standard three view planar projections (anterior, LAO (left anterioroblique) 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 beacquired for approximately 20-40 seconds.

For assessment of global ventricular function the same standard techniques andprojections 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 countrate scintillation camera. Gated Blood Pool Imaging protocols may be used forassessment of regional wall motion, however, they must only be evaluated visuallyunless these images are evaluated by specific software.

Breast imaging is optimally initiated 5 to 10 minutes post injection with the patient inthe prone position with breast freely pendant. A 10 minute lateral image of the breastsuspected of containing cancer should be obtained with the camera face as close tothe breast as practical.

The patient should then be repositioned so that the contralateral breast is pendant anda lateral image of it should be obtained. An anterior supine image may then be obtainedwith the patient’s arms behind her head.

Parathyroid imaging depends on whether subtraction technique or wash-out techniqueis used. For the subtraction technique either 123I or 99mTc can be used and should beperformed according to literature, guidelines and recommended activities.

If the double phase technique is used, 370 to 740 MBq of Technetium (99mTc) Sestamibiare injected and the first neck and thorax image obtained 10 minutes later. After awash-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 ContraindicationsHypersensitivity to the active substance or to any of the excipients.

4.4 Special warnings and precautions for usePregnancy: see section 4.6Newborns, infants, children and adolescents: see section 4.2Alternative techniques which do not involve ionising radiation should be especiallyconsidered.

Indication of the examinationFor all patients, the radiation exposure must be justifiable by the expected diagnosticinformation achieved with the lowest possible radiation dose.

In patients with reduced kidney function, a very careful indication is required since anincreased radiation exposure is possible in these patients.

Patient preparationThe patient should be well hydrated before the start of the examination and urged tovoid as often as possible during the first hours after the study in order to reduceradiation.

Cardiac Imaging: If possible, patients should fast for at least four hours prior to thestudy. It is recommended that after each injection and prior to imaging patients eat alight fatty meal or drink one or two glasses of milk. This will promote rapid hepatobiliaryclearance of Technetium (99mTc) Sestamibi resulting in less liver activity in the image.

For the stress test the general contraindications and precautions of ergometric andpharmacological assessments have to be taken into consideration.

If a hypersensitivity reaction occurs the administration of the medicinal product mustbe discontinued immediately and if necessary, intravenous treatment initiated.Respective medicinal products and equipment (e.g. endotracheal tube and ventilatorhave to be readily available).

General warningsThis radiopharmaceutical may be received, used and administered only by authorisedpersons in designated clinical settings. Its receipt, storage, use, transfer and disposalare subject to the regulations and/or appropriate licences of the local competent officialorganisation.Radiopharmaceuticals should be prepared by the user in a manner which satisfies bothradiation safety and pharmaceutical quality requirements. Appropriate asepticprecautions should be taken, complying with the requirements of Good ManufacturingPractice 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 undergoingthe preparative procedure.Because of potential tissue damage extravasal injection of this radioactive product hasto be strictly avoided.

Breast imagingNo lesion of < 5mm has been described with the use of standard detectors.

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

4.5 Interaction with other medicinal products and other forms of interactionNo interaction studies have been performed. However, medicinal products which affectmyocardial function and/or blood flow may cause false negative results in the diagnosisof coronary arterial disease. For this reason, concomitant medication should be takeninto consideration when interpreting the results of the scintigraphic examination.

4.6 Pregnancy and lactationWomen of childbearing potentialWhen it is necessary to administer radioactive products to women of childbearingpotential, information has to be sought about pregnancy. Any woman who has misseda period should be assumed to be pregnant until proven otherwise. Where uncertaintyexists it is important that radiation exposure should be the minimum consistent withobtaining the desired clinical information. Alternative techniques which do not involveionising radiation should be considered.

Pregnant womenThe 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 annualbackground radiation) could potentially result in risk to the foetus. It is therefore notrecommended in women known to be pregnant. If it is decided that the procedureshould be undertaken in women known to be pregnant, special attention should begiven to the optimisation of the exposure, taking into account the exposure of theexpectant mother and the unborn child. A dose to foetus exceeding 1 mGy should notbe exceeded. Any reduction in administered activity must not impact on the likelihoodof achieving a diagnostic outcome.

Breast-feeding mothersBefore administering a radioactive medicinal product to a mother who is breast-feedingconsideration should be given as to whether the investigation could be reasonablydelayed until after the mother has ceased breast-feeding and as to whether the mostappropriate choice of radiopharmaceutical has been made, bearing in mind thesecretion of activity in breast milk.If the administration is considered necessary, breast-feeding should be interrupted for24 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 machinesEffects on the ability to drive and use machines have not been described.

4.8 Undesirable effectsThe following table reflects the occurrence of frequencies in this section:

Very common (≥1/10)Common (≥1/100 to <1/10)Uncommon (≥1/1,000 to <1/100)Rare (≥1/10,000 to <1/1,000)Very rare (<1/10,000), not known

(cannot be estimated from the available data)

Cardiac disordersUncommon: 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 andparaesthesia, 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, partlyin 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. Afteradministration of the maximum recommended activity of this product of 2000 MBq, theeffective dose is 18 mSv at rest and 15.8 mSv at stress.

4.9 OverdoseIn the event of administration of a radiation overdose with Technetium (99mTc) Sestamibithe absorbed dose to the patient should be reduced where possible by increasing theelimination of the radionuclide from the body by frequent micturition and defaecation.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic propertiesPharmacotherapeutic group: diagnostic radiopharmaceuticals;

Technetium (99mTc) compoundsATC 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, thefollowing complex forms Technetium (99mTc) Sestamibi:

99mTc (MIBI)6+ Where : MIBI = 2-methoxyisobutylisonitrile.

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

General99mTc-Sestamibi being a lipophilic cationic complex is taken up into cells driven bynegative electron transmembrane potentials and accumulated in the most negativelycharged compartment of the cell, the mitochondria.

This procedure primarily depends on tissue vascularization and according blood flowrelated to the size of target, extracellular concentration of Sestamibi and cellularmetabolic activity, mainly represented by number and activity of mitochondria.

Sestamibi accumulation in principle cannot differentiate between malignant and benigntissue. However, comparisons with cytological/histological findings indicate that it coulddistinguish between lesions of differing mitochondrial metabolism.

Although tumour cells generally are supposed to show elevated intrinsic membranepotentials and increased mitochondria activity, cellular uptake of Sestamibi is deemedto be a predominantly tumor-nonspecific procedure.

In case of Multi Drug Resistance (MDR) efflux of Sestamibi was demonstrated to beincreased in correlation to P-Glycoprotein overexpression and activity. This may haveprognostic value but also may result in false negative results if not recognized.

Cardiac indicationTechnetium (99mTc) Sestamibi binds to the mitochondrial membrane and an intactmitochondrial membrane potential is important for intracellular binding.

The uptake of Technetium (99mTc) Sestamibi in the myocardium is proportional to bloodflow in the physiologic flow range. The rate of passive uptake is determined by themembrane permeability of the drug and the surface area of the vascular beds to whichit is exposed. Since the radiotracer enters the cell via diffusion, it will underestimateblood 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 forTechnetium (99mTc) Sestamibi averaged 0.38 +/- 0.09. Technetium (99mTc) Sestamibi fromthe blood is rapidly distributed into the tissue. Five minutes after injection only about 8percent of the injected dose is still in circulation.

Technetium (99mTc) Sestamibi undergoes minimal redistribution over time. This mayimpact on lesion detection as the differential washout between the normal and ischemicmyocardium may result in a reduction in defect size or severity with time.

Mastology indicationThe cellular concentration of Technetium (99mTc) Sestamibi was demonstrated to beincreased in mammary tumour tissue probably because of the high content ofmitochondria in tumour cells and the high membrane potential of tumour cells.

Several in vitro studies demonstrated that Technetium (99mTc) Sestamibi is a substrateof P-glycoprotein. A direct correlation between the P-glycoprotein expression and theelimination of Technetium (99mTc) Sestamibi from tumours has been established. The

SUMMARY OF PRODUCT CHARACTERISTICS

�


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

If more Cardiovis is used than should

In the unlikely event of an overdose, your doctor may recommend thatyou drink plenty of fluids to remove the traces of radioactivity from yourbody.If you have any further questions on the use of this product, ask yourdoctor or pharmacist.

4. POSSIBLE SIDE EFFECTS

Like all medicines, Cardiovis can cause side effects, although noteverybody gets them.

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

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

Rare side effects (observed in 1 to10 patients in 10,000) arehypersensitivity reactions, abnormal heart rhythm, oedema, localreactions at the injection site, stomach pain, vomiting, itching, hives,fever, fainting, seizures, dizziness, flushing, rash, skin numbness ortingling, fatigue, shortness of breath (dyspnoea), hypotension, and jointpains.

Very rare side effects (observed in less than 1 patient in 10,000) havenot been reported.

One single case has been discovered in literature describing theoccurrence of Erythema multiforme, a widespread rash of skin andmucosa.

In case of every patient the exposure to radiation should besubstantiated by benefits resulting from the performed test.Radioactivity which is administered should be adjusted so as the doseof radiation received by a patient is the lowest possible while achievingdesired diagnostic effect at the same time.

The exposure to ionising radiation is connected with the risk ofdevelopment of cancer and genetic effects. According to up-to-datestatistics of diagnostic tests radiation doses connected with the testsare very low and therefore the frequency of undesirable effects is low.

If any of the side effects gets serious, or if you notice any side effectsnot listed in this leaflet, please tell your doctor or pharmacist.

5. HOW TO STORE CARDIOVIS

Keep out of the reach and sight of children.

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

Store in a refrigerator (2°C - 8ºC).

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

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

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

After reconstitution the container and any unused contents should bedisposed of in accordance with local requirements for radioactivematerials.

6. FURTHER INFORMATION

What Cardiovis contains

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

The other ingredients are:tin (II) chloride dihydrateL-cysteine hydrochloride monohydratesodium citrate dihydrateD-mannitol (E421)

What Cardiovis looks like and contents of the pack

Kit for radiopharmaceutical preparation.

White, lyophilised powder.

The kit is delivered in 10 ml glass vials. The vial is covered with achlorobutyl rubber stopper and aluminium cap. Vials are packed incardboard boxes. The kits are offered in boxes containing 3 or 6 vials.Each vial contains a lyophilisate for preparation of the solution forinjections.

Not all pack sizes may be marketed.

Marketing Authorisation Holder

Institute of Atomic Energy POLATOM05-400 Otwock-SwierkPolandTel. +48 22 718 0 754Fax: +48 22 779 7381e-mail: [email protected]

Manufacturers

Institute of Atomic Energy POLATOM05-400 Otwock-SwierkPoland

ROTOP Pharmaka AGBautzner Landstraße 4501454 RadebergGermany

This leaflet was last approved in: August 2010.

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

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

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

Parathyroid indicationIn adenoma of the parathyroid glands blood flow and the number of mitochondria areincreased. 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 tothe tissue, the concentration of Technetium (99mTc) Sestamibi presented to the tissue,and the size of the parathyroid adenoma.

5.2 Pharmacokinetic propertiesThe cationic complex accumulates in the viable myocardial tissue proportional to theregional coronary blood flow.

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

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

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

Half-lifeThe biological myocardial T½ is approximately seven (7) hours at rest and stress. Theeffective T½ (which includes biological and physical half-lives) is approximately three(3) hours.

Myocardial uptakeMyocardial uptake which is coronary flow dependent is 1.5% of the injected dose atstress and 1.2% of the injected dose at rest.

Since the radiotracer enters the cell via diffusion it will underestimate blood flow at highflow 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 leftventricular function along the time.

5.3 Preclinical safety dataIn acute intravenous toxicity studies in mice, rats and dogs, the lowest dose ofTechnetium (99mTc) Sestamibi that resulted in any deaths was 7 mg/kg (expressed asCu (MIBI)4 BF4 content) in female rats. This corresponds to 500 times the maximalhuman dose (MHD) of 0.014 mg/kg for adults (70 kg). LD50 value (calculated byLitchfield-Wilcoxon method) in mice is 19 mg/kg of body weight, which correspondsto 1300 times the maximal human dose (MHD). Neither rats nor dogs exhibitedtreatment related effects at Technetium (99mTc) Sestamibi doses of 0.42 mg/kg (30 timesMHD) and 0.07 mg/kg (5 times MHD) respectively for 28 days. Studies on reproductivetoxicity have not been conducted. Cu (MIBI)4 BF4 showed no genotoxic activity in theAmes, CHO/HPRT and sister chromatid exchange tests. At cytotoxic concentrations,an increase in chromosome aberration was observed in the in vitro human lymphocyteassay. No genotoxic activity was observed in the in vivo mouse micronucleus test at 9mg/kg. Studies to assess the carcinogenic potential of Technetium (99mTc) Sestamibihave not been conducted.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipientstin (II) chloride dihydrateL-cysteine hydrochloride monohydratesodium citrate dihydrateD-mannitol (E421)

6.2 IncompatibilitiesThe Technetium labelling reactions involved depend on maintaining the stannous levelin the reduced state. Hence, Sodium Pertechnetate (99mTc) Injection, containing oxidantsshould not be employed.

6.3 Shelf life1 year

Chemical and physical in-use stability has been demonstrated for 12 hours below25°C.

From a microbiological point of view, unless the method of opening / radiolabelling /dilution precludes the risk of microbiological contamination, the product should beused immediately.

If not used immediately, in-use storage times and conditions are the responsibility of theuser.

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

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

For storage conditions of the reconstituted medicinal product, see section 6.3.

6.5 Nature and contents of containerThe 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.


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

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

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

After reconstitution the container and any unused contents should be disposed of asradioactive waste in accordance with national and international law regardingradioactive materials.

7. MARKETING AUTHORISATION HOLDER


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

September 2010

11. DOSIMETRY (IF APPLICABLE)

Technetium (99mTc) is produced by means of a 99Mo/99mTc-generator and decays with theemission of gamma radiation with a mean energy of 140 keV and a half-life of 6.02hours to technetium (99Tc) which, in view of its long half-life of 2.13 x 105 years can beregarded as quasi stable.

The projected radiation doses to organs and tissues of a patient of average weight (70kg) 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 andaccumulates mainly in muscular tissues (including heart), liver, kidneys and a smalleramount in salivary glands and thyroid. When the substance is injected in conjunctionwith 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 administeredto a patient [mGy/MBq]

(resting test)

Organ Adults 15-year-olds 10-year-olds 5-year-olds 1-year-olds

Adrenal glands 0.0075 0.0099 0.015 0.022 0.038Bladder walls 0.011 0.014 0.019 0.023 0.041Bone surface 0.0082 0.010 0.016 0.021 0.038Brain 0.0052 0.0071 0.011 0.016 0.027Breasts 0.0038 0.0053 0.0071 0.011 0.020Gall bladder 0.039 0.045 0.058 0.010 0.32Alimentary tract:Stomach 0.0065 0.0090 0.015 0.021 0.035Small intestine 0.015 0.018 0.029 0.045 0.080Colon 0.024 0.031 0.050 0.079 0.015ULI 0.027 0.035 0.057 0.089 0.17LLI 0.019 0.025 0.041 0.065 0.12

Heart 0.0063 0.0082 0.012 0.018 0.030Kidneys 0.036 0.043 0.059 0.085 0.15Liver 0.011 0.014 0.021 0.030 0.052Lungs 0.0046 0.0064 0.0097 0.014 0.025

Muscles 0.0029 0.0037 0.0054 0.0076 0.014Oesophagus 0.0041 0.0057 0.0086 0.013 0.023Ovaries 0.0091 0.012 0.018 0.025 0.045Pancreas 0.0077 0.010 0.016 0.024 0.039Bone marrow 0.0055 0.0071 0.011 0.030 0.044Salivary glands 0.014 0.017 0.022 0.015 0.026Skin 0.0031 0.0041 0.0064 0.0098 0.019Spleen 0.0065 0.0086 0.014 0.020 0.034Testicles 0.0038 0.0050 0.0075 0.011 0.021Thymus 0.0041 0.0057 0.0086 0.013 0.023Thyroid 0.0053 0.0079 0.012 0.024 0.045Uterus 0.0078 0.010 0.015 0.022 0.038Other organs 0.0031 0.0039 0.0060 0.0088 0.016

Effective dose 0.0090 0.012 0.018 0.028 0.053[mSv/MBq]


(exercise test)



Heart 0.0072 0.0094 0.010 0.021 0.035Kidneys 0.026 0.032 0.044 0.063 0.11Liver 0.0092 0.012 0.018 0.025 0.044Lungs 0.0044 0.0060 0.0087 0.013 0.023Muscles 0.0032 0.0041 0.0060 0.0090 0.017Oesophagus 0.0040 0.0055 0.0080 0.012 0.023Ovaries 0.0081 0.011 0.015 0.023 0.040Pancreas 0.0069 0.0091 0.014 0.021 0.035Bone marrow 0.0050 0.0064 0.0095 0.013 0.023Salivary glands 0.0092 0.011 0.0015 0.0020 0.0029Skin 0.0029 0.0037 0.0058 0.0090 0.017Spleen 0.0058 0.0076 0.012 0.017 0.030Testicles 0.0037 0.0048 0.0071 0.011 0.020Thymus 0.0040 0.0055 0.0080 0.012 0.023Thyroid 0.0044 0.0064 0.0099 0.019 0.035Uterus 0.0072 0.0093 0.014 0.020 0.035Other organs 0.0033 0.0043 0.0064 0.0098 0.018


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

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 about18 mSv at rest and 15.8 mSv at stress.

12. INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS (IFAPPLICABLE)

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

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

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

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

After completion of the radiolabelling procedure control the contents of the vial to beclear and free from particulate matter and discolouration.

Instructions for Preparation of Technetium (99mTc) Sestamibi

A) Boiling procedure

- Place a vial with lyophilisate in a lead protective container

- With a sterile, lead-shielded syringe (piercing the rubber stopper) introduce1 - 5 ml eluate [Sodium Pertechnetate (99mTc) Injection Ph. Eur. with an activity ofmaximum 11000 MBq (or the eluate volume with the desired radioactivity adjustedwith physiological saline solution) into a vial containing lyophilised Tetrakis (2-methoxy-isobutyl isonitrile) Copper(I)-Tetrafluoroborate.

- Without withdrawing the needle, remove a volume of gas equal to the volume ofintroduced solution with the same syringe in order to compensate for pressure build-up.

- 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 watershould be boiling during the procedure of labelling) and boil for 10 - 12 minutes. Whileboiling do not allow contact between boiling water and the aluminium cap. Keepingthe vial upright in the water bath can be achieved by placing the vial in a standard leadshielding for the vial, which has been mounted in the water bath by means of anErlenmeyer or four finger clamp attached to a laboratory stand. For better heathconduction 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 cooldown to room temperature (about 15 minutes).

- The resulting solution is a ready-to-use solution for injections.

B) Thermal Cycler procedure

- Place a vial with lyophilisate in a lead protective container- With a syringe (piercing the rubber stopper) introduce 1 - 5 ml of eluate with sodiumpertechnetate (99mTc) with an activity of maximum 11000 MBq (or the eluate volumewith desired activity supplemented with physiological saline solution) into a vialcontaining lyophilised Tetrakis (2-methoxy-isobutyl isonitrile) Copper(I)-Tetrafluoroborate.

- Without withdrawing a needle, remove the volume of gas equal to the volume ofintroduced solution with the same syringe in order to compensate for pressure build-up.

- 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 thermo-cycler intended for radiolabelling and run the cycler on auto-program.

- Alternatively, place the vial in a tight fitting brass or copper pig (wall thickness ≥ 3mmfor radioprotection) and place the brass pig on a pre-heated programmable flat platethermal cycler. Program the thermal cycler for a pre-heat cycle to 99°C during 5minutes, followed by a heating cycle of the vial at 99°C during 12 minutes and finallyfollowed 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 ofthe heater used.


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

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 beused.- Apply 2 - 5 µl of Technetium (99mTc) Sestamibi about 1.5 cm from the bottom of a2 cm x 8 cm aluminium oxide chromatographic plate.

- Put the plate in a chromatographic chamber and develop the chromatograms in anabsolute 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 suitableradiation detector or cut the plate as shown below (three pieces) and measure the99mTc 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.

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

Activity in Upper Part% RCR = ----------------------------- x 100

Activity Sum of all Parts

- % 99mTc Sestamibi should be 94%; otherwise the preparation should be discarded.

Note: Do not use material if the radiochemical purity is less than 94%.

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

If more Cardiovis is used than should

In the unlikely event of an overdose, your doctor may recommend thatyou drink plenty of fluids to remove the traces of radioactivity from yourbody.If you have any further questions on the use of this product, ask yourdoctor or pharmacist.

4. POSSIBLE SIDE EFFECTS

Like all medicines, Cardiovis can cause side effects, although noteverybody gets them.

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

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

Rare side effects (observed in 1 to10 patients in 10,000) arehypersensitivity reactions, abnormal heart rhythm, oedema, localreactions at the injection site, stomach pain, vomiting, itching, hives,fever, fainting, seizures, dizziness, flushing, rash, skin numbness ortingling, fatigue, shortness of breath (dyspnoea), hypotension, and jointpains.

Very rare side effects (observed in less than 1 patient in 10,000) havenot been reported.

One single case has been discovered in literature describing theoccurrence of Erythema multiforme, a widespread rash of skin andmucosa.

In case of every patient the exposure to radiation should besubstantiated by benefits resulting from the performed test.Radioactivity which is administered should be adjusted so as the doseof radiation received by a patient is the lowest possible while achievingdesired diagnostic effect at the same time.

The exposure to ionising radiation is connected with the risk ofdevelopment of cancer and genetic effects. According to up-to-datestatistics of diagnostic tests radiation doses connected with the testsare very low and therefore the frequency of undesirable effects is low.

If any of the side effects gets serious, or if you notice any side effectsnot listed in this leaflet, please tell your doctor or pharmacist.

5. HOW TO STORE CARDIOVIS

Keep out of the reach and sight of children.

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

Store in a refrigerator (2°C - 8ºC).

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

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

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

After reconstitution the container and any unused contents should bedisposed of in accordance with local requirements for radioactivematerials.

6. FURTHER INFORMATION

What Cardiovis contains

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

The other ingredients are:tin (II) chloride dihydrateL-cysteine hydrochloride monohydratesodium citrate dihydrateD-mannitol (E421)

What Cardiovis looks like and contents of the pack

Kit for radiopharmaceutical preparation.

White, lyophilised powder.

The kit is delivered in 10 ml glass vials. The vial is covered with achlorobutyl rubber stopper and aluminium cap. Vials are packed incardboard boxes. The kits are offered in boxes containing 3 or 6 vials.Each vial contains a lyophilisate for preparation of the solution forinjections.


Marketing Authorisation Holder

Institute of Atomic Energy POLATOM05-400 Otwock-SwierkPolandTel. +48 22 718 0 754Fax: +48 22 779 7381e-mail: [email protected]

Manufacturers


ROTOP Pharmaka AGBautzner Landstraße 4501454 RadebergGermany

This leaflet was last approved in: August 2010.

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

PL-M

ibi-U

K-e

ng-0

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

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

Parathyroid indicationIn adenoma of the parathyroid glands blood flow and the number of mitochondria areincreased. 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 tothe tissue, the concentration of Technetium (99mTc) Sestamibi presented to the tissue,and the size of the parathyroid adenoma.

5.2 Pharmacokinetic propertiesThe cationic complex accumulates in the viable myocardial tissue proportional to theregional coronary blood flow.

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

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

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

Half-lifeThe biological myocardial T½ is approximately seven (7) hours at rest and stress. Theeffective T½ (which includes biological and physical half-lives) is approximately three(3) hours.

Myocardial uptakeMyocardial uptake which is coronary flow dependent is 1.5% of the injected dose atstress and 1.2% of the injected dose at rest.

Since the radiotracer enters the cell via diffusion it will underestimate blood flow at highflow 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 leftventricular function along the time.

5.3 Preclinical safety dataIn acute intravenous toxicity studies in mice, rats and dogs, the lowest dose ofTechnetium (99mTc) Sestamibi that resulted in any deaths was 7 mg/kg (expressed asCu (MIBI)4 BF4 content) in female rats. This corresponds to 500 times the maximalhuman dose (MHD) of 0.014 mg/kg for adults (70 kg). LD50 value (calculated byLitchfield-Wilcoxon method) in mice is 19 mg/kg of body weight, which correspondsto 1300 times the maximal human dose (MHD). Neither rats nor dogs exhibitedtreatment related effects at Technetium (99mTc) Sestamibi doses of 0.42 mg/kg (30 timesMHD) and 0.07 mg/kg (5 times MHD) respectively for 28 days. Studies on reproductivetoxicity have not been conducted. Cu (MIBI)4 BF4 showed no genotoxic activity in theAmes, CHO/HPRT and sister chromatid exchange tests. At cytotoxic concentrations,an increase in chromosome aberration was observed in the in vitro human lymphocyteassay. No genotoxic activity was observed in the in vivo mouse micronucleus test at 9mg/kg. Studies to assess the carcinogenic potential of Technetium (99mTc) Sestamibihave not been conducted.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipientstin (II) chloride dihydrateL-cysteine hydrochloride monohydratesodium citrate dihydrateD-mannitol (E421)

6.2 IncompatibilitiesThe Technetium labelling reactions involved depend on maintaining the stannous levelin the reduced state. Hence, Sodium Pertechnetate (99mTc) Injection, containing oxidantsshould not be employed.

6.3 Shelf life1 year

Chemical and physical in-use stability has been demonstrated for 12 hours below25°C.

From a microbiological point of view, unless the method of opening / radiolabelling /dilution precludes the risk of microbiological contamination, the product should beused immediately.

If not used immediately, in-use storage times and conditions are the responsibility of theuser.

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

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

For storage conditions of the reconstituted medicinal product, see section 6.3.

6.5 Nature and contents of containerThe 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.


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

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

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

After reconstitution the container and any unused contents should be disposed of asradioactive waste in accordance with national and international law regardingradioactive materials.

7. MARKETING AUTHORISATION HOLDER


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

September 2010

11. DOSIMETRY (IF APPLICABLE)

Technetium (99mTc) is produced by means of a 99Mo/99mTc-generator and decays with theemission of gamma radiation with a mean energy of 140 keV and a half-life of 6.02hours to technetium (99Tc) which, in view of its long half-life of 2.13 x 105 years can beregarded as quasi stable.

The projected radiation doses to organs and tissues of a patient of average weight (70kg) 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 andaccumulates mainly in muscular tissues (including heart), liver, kidneys and a smalleramount in salivary glands and thyroid. When the substance is injected in conjunctionwith 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.


(resting test)



Heart 0.0063 0.0082 0.012 0.018 0.030Kidneys 0.036 0.043 0.059 0.085 0.15Liver 0.011 0.014 0.021 0.030 0.052Lungs 0.0046 0.0064 0.0097 0.014 0.025

Muscles 0.0029 0.0037 0.0054 0.0076 0.014Oesophagus 0.0041 0.0057 0.0086 0.013 0.023Ovaries 0.0091 0.012 0.018 0.025 0.045Pancreas 0.0077 0.010 0.016 0.024 0.039Bone marrow 0.0055 0.0071 0.011 0.030 0.044Salivary glands 0.014 0.017 0.022 0.015 0.026Skin 0.0031 0.0041 0.0064 0.0098 0.019Spleen 0.0065 0.0086 0.014 0.020 0.034Testicles 0.0038 0.0050 0.0075 0.011 0.021Thymus 0.0041 0.0057 0.0086 0.013 0.023Thyroid 0.0053 0.0079 0.012 0.024 0.045Uterus 0.0078 0.010 0.015 0.022 0.038Other organs 0.0031 0.0039 0.0060 0.0088 0.016



(exercise test)



Heart 0.0072 0.0094 0.010 0.021 0.035Kidneys 0.026 0.032 0.044 0.063 0.11Liver 0.0092 0.012 0.018 0.025 0.044Lungs 0.0044 0.0060 0.0087 0.013 0.023Muscles 0.0032 0.0041 0.0060 0.0090 0.017Oesophagus 0.0040 0.0055 0.0080 0.012 0.023Ovaries 0.0081 0.011 0.015 0.023 0.040Pancreas 0.0069 0.0091 0.014 0.021 0.035Bone marrow 0.0050 0.0064 0.0095 0.013 0.023Salivary glands 0.0092 0.011 0.0015 0.0020 0.0029Skin 0.0029 0.0037 0.0058 0.0090 0.017Spleen 0.0058 0.0076 0.012 0.017 0.030Testicles 0.0037 0.0048 0.0071 0.011 0.020Thymus 0.0040 0.0055 0.0080 0.012 0.023Thyroid 0.0044 0.0064 0.0099 0.019 0.035Uterus 0.0072 0.0093 0.014 0.020 0.035Other organs 0.0033 0.0043 0.0064 0.0098 0.018


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

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 about18 mSv at rest and 15.8 mSv at stress.

12. INSTRUCTIONS FOR PREPARATION OF RADIOPHARMACEUTICALS (IFAPPLICABLE)

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

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

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

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

After completion of the radiolabelling procedure control the contents of the vial to beclear and free from particulate matter and discolouration.

Instructions for Preparation of Technetium (99mTc) Sestamibi

A) Boiling procedure

- Place a vial with lyophilisate in a lead protective container

- With a sterile, lead-shielded syringe (piercing the rubber stopper) introduce1 - 5 ml eluate [Sodium Pertechnetate (99mTc) Injection Ph. Eur. with an activity ofmaximum 11000 MBq (or the eluate volume with the desired radioactivity adjustedwith physiological saline solution) into a vial containing lyophilised Tetrakis (2-methoxy-isobutyl isonitrile) Copper(I)-Tetrafluoroborate.

- Without withdrawing the needle, remove a volume of gas equal to the volume ofintroduced solution with the same syringe in order to compensate for pressure build-up.

- 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 watershould be boiling during the procedure of labelling) and boil for 10 - 12 minutes. Whileboiling do not allow contact between boiling water and the aluminium cap. Keepingthe vial upright in the water bath can be achieved by placing the vial in a standard leadshielding for the vial, which has been mounted in the water bath by means of anErlenmeyer or four finger clamp attached to a laboratory stand. For better heathconduction 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 cooldown to room temperature (about 15 minutes).


B) Thermal Cycler procedure

- Place a vial with lyophilisate in a lead protective container- With a syringe (piercing the rubber stopper) introduce 1 - 5 ml of eluate with sodiumpertechnetate (99mTc) with an activity of maximum 11000 MBq (or the eluate volumewith desired activity supplemented with physiological saline solution) into a vialcontaining lyophilised Tetrakis (2-methoxy-isobutyl isonitrile) Copper(I)-Tetrafluoroborate.

- Without withdrawing a needle, remove the volume of gas equal to the volume ofintroduced solution with the same syringe in order to compensate for pressure build-up.

- 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 thermo-cycler intended for radiolabelling and run the cycler on auto-program.

- Alternatively, place the vial in a tight fitting brass or copper pig (wall thickness ≥ 3mmfor radioprotection) and place the brass pig on a pre-heated programmable flat platethermal cycler. Program the thermal cycler for a pre-heat cycle to 99°C during 5minutes, followed by a heating cycle of the vial at 99°C during 12 minutes and finallyfollowed 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 ofthe heater used.


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

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 beused.- Apply 2 - 5 µl of Technetium (99mTc) Sestamibi about 1.5 cm from the bottom of a2 cm x 8 cm aluminium oxide chromatographic plate.

- Put the plate in a chromatographic chamber and develop the chromatograms in anabsolute 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 suitableradiation detector or cut the plate as shown below (three pieces) and measure the99mTc 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.

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

Activity in Upper Part% RCR = ----------------------------- x 100

Activity Sum of all Parts

- % 99mTc Sestamibi should be 94%; otherwise the preparation should be discarded.

Note: Do not use material if the radiochemical purity is less than 94%.

SmPC

-Mib

i-UK

-eng

-02


ROTOP Pharmaka AG Bautzner Landstraße 400

D-01328 Dresden

[email protected] www.rotop-pharmaka.de

myocardial perfusion scintigraphy

assessment of global ventricular function

Localisation of hyperfunctioning parathyroid tissue

Scintimammography for the detection of breast cancer

10 mL vials

Labelling activity up to 11 GBq

Labelling volume 1 - 5 ml

Shelf life after labelling: 12 hours

Indicated for

Advantages

CardioTOP 1 mg

comfortable labelling - flexible patient management p: +49 (0) 35 1 - 26 31 0 - 210

f: +49 (0) 35 1 - 26 31 0 - 313

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